C12.Rheumatology: musculoskeletal and connective

tissue diseases

There are over 200 rheumatological disorders, producing about 25% of the average GP’s workload. Some disorders are primary joint problems, but muscles, tendons and ligaments may also be affected. Systemic diseases may present as a joint problem and trigger a rheumatological referral. Our progressively ageing population, with prolonged joint stresses and poor working practices may cause persistent problems, increasing the workload.

Many patients imagine that ‘rheumatism’ leads inexorably to chronic disability. This does not reflect current practice, but derives from times when life and work were much harder than now and good medical care was generally unavailable. Most patients are now treated effectively by their GP or paramedical staff and counselling can relieve inappropriate anxiety, but the drugs used can have serious side-effects.

Rheumatic fever is covered in Chapter 8.

Introduction

This chapter describes the principal rheumato-

logical conditions to aid an understanding of

their treatment and to assist recognition of those

non-joint  signs,  e.g.  facial  or  other  rashes,

conjunctivitis, bowel problems, etc., which may

indicate significant underlying disease and the

need for prompt referral. The term ‘rheumatism’

is used loosely by laypeople to describe any form

of pain or dysfunction associated with the joints

or muscles. This covers a wide range of condi-

tions (Table 12.1). None of the many attempts at

classification is wholly satisfactory, because the

aetiology of most of the diseases is obscure. Joint

disease (arthropathy)  and  joint  inflammation

(arthritis)  frequently  accompany  a  variety  of

diseases whose principal effects are elsewhere

than on the joints, e.g. diabetes mellitus, psori-

asis and UC, so careful diagnosis is essential.

Only the principal disease states in this group are

discussed below. Table 12.1 also gives the disease

abbreviations used most frequently throughout

this chapter.

In this chapter, the terms ‘rheumatoid’ and

‘arthritis’ are used only for inflammatory joint

conditions: ‘rheumatic’ and ‘rheumatism’ apply

non-specifically to all types of pain or abnor-

mality involving the joints, muscles, tendons and

associated  structures,  e.g.  in  SLE (p. 798)  or

rheumatic fever (p. 564).

Specialization in this field is especially impor-

tant because of the large variety of diseases and

drug  toxicities.  NSAIDs  are  widely  used  and

cause the largest proportion of adverse reaction

reports of any drug group (see p. 775). Some of

the other drugs used may also cause severe side-

effects. Unless the condition is acute and severe,

most patients are self-medicating when they seek

advice, increasing the risk of drug interactions.

Anatomy and physiological principles of the musculoskeletal system

Two types of joint are affected by rheumatic

disease, synovial  and fibrocartilaginous. The

former allows a wide range of free movement

and so includes all the hinge joints of the limbs.

The latter allows only limited movement and

include primarily those joints of the vertebral

column   and   the   hip   girdle,   including   the

sacroiliac joints and the pubic symphysis (the

anterior joint between the two pubic bones).

Disease of fibrocartilaginous joints is primarily degenerative and traumatic, whereas problems in synovial joints tend to be inflammatory.

Synovial joints

This is the type of joint found in the legs, arms,

hands and feet. From the generalized diagram

given in Figure 12.1 it can be seen that the ends

of the two opposing bones are covered with a

firmly  attached  layer  of  hyaline (articular)

cartilage. This is about 6 mm thick in young

adults but only 1-3 mm thick in the elderly. The

cartilage is radiolucent and avascular, giving the

appearance of a joint space on X-ray (Figure

12.2(a); see also Figure 12.6(a)), though the two

layers of cartilage are normally in close contact.

The   bearing   surfaces   of   the   cartilage   are

lubricated  and  supplied  with  nutrients  by  a

small  volume  (÷2 mL  in  a  knee  joint)  of  a

viscous,  colourless  synovial  fluid  containing

a hyaluronate-protein complex, albumin and

some white cells, electrolytes, etc. The whole is

surrounded and stabilized by a tough, fibrous

capsule that may be thickened in places and by

ligaments, which further strengthen the joint.

However, joint stability depends largely on the

strengths   of   the   attached   and   surrounding

muscles, and one of the objects of physiotherapy

is to strengthen the muscles and so reinforce the

joints. Some joints have additional structures,

e.g. the tough, fibrous cartilage of the menisci in

the knee joint (Figure 12.2(a)) that helps to

absorb stresses and further improve stability, and

bursae (see below).

The   synovial   fluid   is   produced   by   the

surrounding synovial membrane that contains

the cells that secrete the fluid, and phagocytic

cells. This membrane is not flat and featureless:

it has numerous folds, which allow for wide-

ranging  joint  movement,  and  fat  pads  and

inner projections together fill much of the joint

cavity. These internal projections ensure good

distribution of the synovial fluid and provide

some cushioning against mechanical shock to the joint. The synovial fluid does not normally clot but, if there is inflammation, fibrinogen

enters the fluid, which is then able to clot like normal inflammatory exudates (see Chapter 2). The  increased  volume  and  pressure  of  fluid within the joint (due to inflammation) and any clotting, limit joint movement.

Joint   pain   derives   primarily   from   the

stretching and inflammation of the fibrous struc-

tures (capsule and ligaments) and the periosteum,

the thin layer of tissue that covers all bones in the

body: sensation in the synovial tissues is poor.

Inflammation  often  results  in  joint  deformity because there is a variable amount of inflamma-tory exudate, causing swelling, and the limb is held unconsciously in a position that provides the maximum joint volume, to accommodate the increased volume of synovial fluid and so reduce the  pressure  and  pain.  Chronic  inflammation may lead to permanent joint damage.

Fibrocartilaginous joints           

column is illustrated in Figure 12.3. The verte-

brae are covered with a thin layer of hyaline

cartilage, similarly to synovial joints, but there is

no capsule and associated synovium or synovial

fluid. However, there is a very small amount of

extracellular fluid that gives some lubrication.

The vertebrae are separated by intervertebral

discs, which consist of a strong fibrous capsule

filled with a proteoglycan gel that provides an

effective shock absorber.

Synovial sheaths and bursae

These  occur  where  closely  opposed  structures

move  relative  to  each  other,  and  especially

where skin or tendons need to move freely over

bony  surfaces.  Bursae  are  enclosed  clefts  of

synovial membrane that are supported by dense

connective  tissue,  the  synovium  sometimes

being continuous with that of an adjacent joint.

The  central  potential  space  is  normally  filled

with  a  capillary  film  of  synovial  fluid  that

permits  free  movement  to  occur  between  the

two  layers  of  bursal  synovium.  Thus  the prepatellar bursa lies between the skin and the

lower half of the patella (kneecap). It provides

The arrangement of the joints in the vertebral     free, smooth movement when the knee is flexed and prevents damage to the skin and the tibial

head by the tendons. Similarly, the olecranon

bursa  prevents  friction  between  the  skin  and

the point of the elbow. Inflammation of these

bursae (bursitis)  causes  the  accumulation  of

synovial fluid, with swelling, tenderness, pain

and restriction of movement and the conditions

of ‘housemaid’s  knee’, ‘students’  elbow’  or

‘miner’s elbow’.

Synovial sheaths occur around tendons that

pass under ligaments or through fibrous tunnels,

e.g. the carpal tunnel (see Figure 12.11) in the

wrist. The sheath consists of a closed, double-

walled synovial cylinder enclosing a capillary

film of interwall synovial fluid. The inner wall is

attached loosely to the tendon, and the outer

wall to the bones, ligaments or other adjacent

structures. This arrangement again permits free

movement of the tendon through surrounding

tissues, similarly to the bursae, and inflamma-

tion of the sheaths (tendonitis) causes similar

problems to bursitis.

‘Ganglia’  are  synovial  herniations  (bulges) from a tendon sheath or joint and should not be confused with nerve ganglia.

Joint nutrition, maintenance and repair

The synovial membrane is supplied with blood and  nutrients  from  the  underlying  vascular connective tissue. Nutrients for the chondro-

cytes, which are responsible for synthesizing all of the components of the joint cartilage, diffuse from the blood supply of the synovium through the synovial fluid. The latter also returns waste products from the avascular cartilage covering the bone back to the circulation.

There is normally a slow continuous turnover of  joint  cartilage,  which  contains  largely  a unique type of collagen (type II) plus highly

hydrophilic proteoglycans. The latter bind the structurally important type IX and XI collagens, which are present in only small amounts but are crucial for cartilage stability.

When collagen is compressed, the structural

water, held by hydrogen bonding, is released from

the proteoglycans and is regained when the force

is   removed.   This   mechanism   temporarily

increases the synovial fluid volume and makes it

less viscous, thus cushioning stresses and facili-

tating movement. In adults the chondrocytes do

not normally replicate, but repeated trauma reac-

tivates  their  division.  The  resultant  increased

metabolism  accelerates  the  dismantling  and

regeneration of damaged cartilage, but the effect is

not a true replacement but a remodelling, which

may result in an imbalance between cartilage

degradation and synthesis, and so inappropriate

replacement.

In osteoarthritis (a degenerative joint disease;

p. 754), the composition and size of the proteo-

glycan  molecules  is  altered,  and  the  type  II collagen  fibrils  are  replaced  with  the  more common, less suitable type I collagen that is

characteristic of skin and tendons. Changes also occur in the underlying bone.

The immune system and rheumatic diseases

Genetic aspects

There  are  clear  associations  between  human

leucocyte locus A (HLA) genes and rheumatic

diseases,  especially  inflammatory  ones.  It  will

be recalled that the HLA system consists of a

series of closely linked genetic loci located on

the  short  arm  of  chromosome  6,  and  forms

part  of  the  major  histocompatibility  complex

(MHC; see Chapter 2). Certain of the HLA anti-

gens  occur  more  frequently  in  patients  with

some rheumatic diseases than in general popu-

lations of the same ethnic origin (Table 12.2).

For example, HLA-DR4 tends to be associated

with   severe   RA   and   the   presence   of   a

nucleotide sequence in the allele coding for a

detectable  pentapeptide  in  the  HLA-DRb1-1

gene that, in association with the presence of

rheumatoid   factor,   indicates   a          13        times

increased risk of development of bone erosions

(see below).

However,   although   associations   between

rheumatic diseases and HLA antigens are valu-

able pointers to pathogenesis, few of these are of

diagnostic  value  and  they  do  not  currently

influence management. The genetic status of an

individual   merely   indicates   an   increased

likelihood of suffering a rheumatic disease: the

development of symptoms requires exposure to

a  currently  unknown  environmental  trigger.

Further, tissue typing is a complex and expensive

process and does not help in prognosis, except in

certain limited situations. The principal reason

for pursuing these genetic relationships is the

hope that better understanding of the funda-

mental mechanisms involved may lead to more

effective,  less  toxic  treatments  and  to  better diagnostic   and   prognostic   tests.   This   has  Ankylosing spondylitis

occurred already to some extent, leading to the

The association of ankylosing spondylitis (AS, p.

very  successful  introduction  of  anti-cytokine antibodies in treatment.

Osteoarthritis

A mutation in the COL2A1 gene causes the

production of a variant form of type II collagen

and is associated with the occurrence of prema-

ture  osteoarthritis (OA).  Further,  the  risk  of

needing a hip replacement for OA in siblings of

a patient who has had the operation is three

times that in the general population. Aggrecan,

a protein-chondroitin-keratan sulphate macro-

molecule,  is  important  in  load  dispersal  in

joints, and genetically determined variants are

associated with hand OA in elderly men.

These and other similar considerations have led to the estimate that about two-thirds of OA has a genetic basis.

Rheumatoid arthritis

The concordance rate for monozygotic (iden-

tical) twins, i.e. the risk of one contracting RA if

the other has the disease, has been estimated as

12-30%. This is four to five times the risk in

dizygotic (non-identical) twins. The general risk

to other siblings is about eight times that in the

general population.

Overall, about  40% of RA is linked to the

possession of specific HLA antigens, especially DR4 and Dw4. This clearly points to RA being an autoimmune  disease,  or  at  least  having  an autoimmune component. The presence of HLA-

DR4 is associated with the severity of RA and, in decreasing order of disease severity, its preva-

lence is 90% in Felty’s syndrome (p. 767), 70% in patients referred to rheumatologists, and 40% in general practice patients with RA.

Other HLA-DR antigens are implicated in the

occurrence of RA in particular geographical and

ethnic groups, e.g. DR1 in most of Southern

Europe, DR10 in Spaniards, Indians and Jews,

and DR14 in some North American Indians.

Interestingly, the likelihood of the occurrence of  some  side-effects  to  gold  or  penicillamine (p. 772) is also genetically linked, e.g. nephrotic syndrome with HLA-DR3.

788)  with  HLA-B27  is  the  strongest  for  any

rheumatic  disease  and  carries  a 200 times

increased risk. HLA-B60 carries only a threefold

risk.  Thus,  the  concordance  rate  for  HLA-

B27-positive monozygotic twins, one of whom

has AS, is 75%. In a general group of dizygotic

twins this risk falls to only 12%. Taking all genes

into account, the chance of inheriting AS is about

90%, so inheritance far outweighs environmental

factors as a risk factor for the condition.

The association is confirmed if we compare the

prevalences of HLA-B27 and AS in different popu-

lation groups: in some native North Americans

these are 50% and 8%, respectively; in Northern

Europeans these levels fall to 8% and 0.3%; and in

indigenous Australians to ÷0.5% and zero.

Environmental factors and other genes are also important for the disease to occur. It seems likely that the HLA-B27 gene requires additional genes, plus an environmental determinant, to cause

rheumatic symptoms: no disease results if an

additional gene is absent, even in the presence of the environmental trigger.

Tissue typing may be useful in prognosis in certain limited situations. Young patients with inconclusive symptoms and signs who are HLA-

B27 positive need to be watched for the onset of significant disease, some of them being more

likely   to   develop   AS   than   typical   juvenile chronic arthritis. Also, young male patients with low back pain who are HLA-B27 negative and do not have IBD (see Chapter 3) or psoriasis (see Chapter 13) are unlikely to have AS.

Cytokines

Many  of  these  small  protein  autacoids  are involved in inflammation (see Chapter 2) and have  been  implicated  in  rheumatic  diseases, though their precise roles are uncertain. They may be autocrines, acting on the cell that secretes

them, paracrines, acting on neighbouring cells, or they may have endocrine properties and act on remote tissues, e.g. erythropoietin.

Tumour necrosis factor alpha (TNF-a) is a

potent   pro-inflammatory   agent,   released   by macrophages, that induces interleukin-1 (IL-1)

production by T cells. IL-1 in turn promotes the

hepatic production of acute-phase proteins (see

Chapter 2), in association with IL-6, and is found

in  the  synovial  fluid  associated  with  several

types of arthritis. IL-1 has been implicated in

stimulating the release of lysosomal enzymes,

producing joint erosions in RA, and collagen

degradation in OA. Excessive production of IL-1

may be responsible for maintaining a chronic

inflammatory reaction in damaged joints.

The major treatment development for RA in

recent years is the introduction of anti-TNFa

monoclonal antibodies, i.e. adalimumab, etaner-

cept and infliximab (see below). These are used to

treat RA that has not responded adequately to

conventional disease-modifying agents. There is

also   one   anti-IL-1   agent (anakinra)   that   is

currently used primarily in clinical trials.

Interleukin-2 (IL-2) is crucial in promoting

antigen elimination, and a deficiency of it has

been demonstrated in RA and SLE (p. 798). This

deficiency may also contribute to the mainte-

nance of joint inflammation, owing to a failure

to clear antigens completely. Interferons (IFNs)

are produced by several types of cell, and IFN-

gamma may also be involved in joint pathology.

A deficiency of T helper cell production of

erythropoietic interleukins (IL-3 and IL-5) may be implicated in causing the anaemia often seen in RA (p. 751). Finally, trials of IL-1 inhibitors, IFN-gamma and IL-2 for treating a variety of

arthritides are in progress.

Examination, investigation and assessment

History and examination

Many  diseases  can  give  rise  secondarily  to

muscular or joint pain (Table 12.3), and patient

misconceptions   may   lead   them   to   give

misleading descriptions of pain that they ascribe

to joint disease. It is therefore important to

regard the patient as a whole and to decide

whether there is actually an arthropathy or other related problem that falls within the speciality of rheumatology. The relevant details of the history and examination are given in Table 12.4.

Investigation

Although a wide range of investigations might be carried out, only those that are commonly

performed are dealt with briefly below. They are discussed in this section only in general terms, the specific indications being dealt with under the various disease headings.

Haematology

Acute-phase proteins

These are a family of about 30 proteins produced

by the liver in response to cytokines released

from macrophages and other cells at the site of

inflammation (see Chapter 2). Some of these can

be used as indicators of acute rheumatic disease

activity,  e.g.  CRP,  SAA, (pp. 751,  807)  serum

ferritin  and  fibrinogen.  The  fibrinogen  is  not

measured   directly,   its   concentration   being reflected in the ESR. The increased blood protein

causes an increase in blood and plasma viscosity,

but this effect is outweighed by red cell clumping.

Erythrocyte sedimentation rate (ESR)  is a

non-specific  indicator  of  inflammation  any-

where in the body. However, because the test is

easily performed at the bedside, it is widely used

as a rapid and simple screening test. The sedi-

mentation  rate  increases  owing  to  increased

levels of fibrinogen and Igs that increase RBC

clumping, thus increasing sedimentation, and so

apparently causing a mild anaemia. Very low ESR

values may be due to serious underlying disease,

e.g. multisystem disorders (pp. 798-807), certain

infections,    or    malignancy.    Unfortunately,

changes in RBC size or morphology that occur in

some severe anaemias (see Chapter 11) can also

affect the ESR.

C-reactive  protein  (CRP)  is  another  non-

specific  indicator  of  inflammation,  which  is

normally   present   in   low   concentration   in

plasma. The protein, so-called originally because

it reacts with Streptococcus pneumoniae  type C

polysaccharide, is synthesized in the liver and its

concentration rises within 6 h of fever, inflam-

mation, tissue damage or necrosis. This is a

much more rapid response than the ESR, and

CRP is the marker of choice in the diagnosis of

inflammatory diseases. However, it is less useful

than ESR and plasma viscosity for monitoring

the progress of chronic inflammatory states.

Serum   amyloid-A   protein  (SAA)  is   the

precursor of one type of amyloid, the fibrous

protein that is characteristic of amyloidosis (p.

807) and is present in some patients with RA.

SAA levels, similarly to CRP, are modestly raised

in SLE, but may be high in RA and Still’s disease,

and RA is the most common cause of secondary

amyloidosis.

Anaemia

Many  chronic  inflammatory  diseases  cause  a

mild, normocytic anaemia, related to reduced

erythropoiesis (see Chapter 11). This may reflect

the level of inflammatory disease activity, as also

do ESR and CRP, and reduced levels of IL-3 and

IL-5. Hb levels lower than about 10 g/dL in males

and 9 g/dL   in   females   may   indicate   other

possible causes (for example, iatrogenic gastro-

intestinal blood loss due to drugs used to treat

rheumatic disease, e.g. NSAIDs, which irritate

the  GIT  and  also  inhibit  the  production  of

gastroprotective PGs).

Leucocytes

Leucocytosis (raised white cell count) may result

from infection, severe exacerbations of RA, or

treatment with corticosteroids. The condition

may also be an indication of serious systemic

inflammatory   disease,   notably   polyarteritis

nodosa (PAN; p. 807). Neutropenia (see Chapter

11) may indicate the presence of SLE (p. 798), or

Felty’s  syndrome (p. 767)  in  a  patient  with

RA, but may also reflect drug-induced myelo-

suppression (bone  marrow  depression),  e.g.

due to sodium aurothiomalate, penicillamine and

immunosuppressive drugs.

Platelets

The platelet count may be raised (thrombocy-

tosis) in active inflammatory diseases or after an acute bleeding episode. The converse, thrombo-

cytopenia, may indicate Felty’s syndrome or

iatrogenic   bone   marrow   toxicity.   In   both neutropenia and thrombocytopenia, immediate drug withdrawal is essential because fatal bone marrow depression may follow.

Biochemistry

Serum phosphatases.   Raised serum alkaline

phosphatase (ALP) may be used to detect those

patients whose bone pain is due to metabolic

bone  disease,  e.g.  Paget’s  disease  and  osteo-

malacia. High levels of serum acid phosphatase

(ACP) in older men indicate the possibility of

backache being due to metastatic deposits from

prostatic carcinoma.

Creatine   kinase           (CK).   This   is   a   useful

screening test in patients who may have muscle

damage in polymyositis or dermatomyositis. It

is also a feature of heart muscle damage in MI

and sometimes in myositis caused by statins (see

Chapter 4).

Serology

Rheumatoid factors (RFs).   These are autoanti-

bodies  against  the  Fc  fragment  of  IgG (see

Chapter 2).   The   tests   routinely   employed

primarily detect IgMs, though some RFs are IgGs.

Normally,  the  IgG  molecule  is  folded  and

protected, but reaction with antigens exposes

reaction  sites  so  that  flocculation  can  occur.

Patients whose serum contains significant levels

of RFs are described as ‘seropositive’, and the RF

titre roughly reflects disease activity. Some labo-

ratories use the differential agglutinating test,

which gives a titratable measure of RFs in the

serum, but the test has poor specificity. RFs are

present in the serum of only about 75% of RA

patients and are also found in those with SLE,

some chronic infections and in some of the

elderly-well.

A recent advance is based on the detection

of antibodies to cyclic citrullinated peptide

(CCP), which has been shown to perform better

than the test for RFs. Anti-CCP assays are about

85% sensitive for RA and can detect about a third

of patients who are RF-negative, but have RA.

Complement.   Raised  levels  of  complement

components  (see  Chapter 2)  occur  in  many

of  the  significantly  inflammatory  rheumatic

diseases. Low levels of complement components,

especially C3 and C4, reflect disease activity in

SLE,  because  they  indicate  immune  complex

formation: decreasing levels imply deterioration

in the patient’s condition.

Fluorescent antinuclear antibody test (ANA or ANF).   This is used as a rapid preliminary, non-

specific  screening  test  for  diseases  in  which autoantibodies to cell nuclei occur, e.g. in SLE and mixed connective tissue disease.

DNA  binding  test.   This  radioimmunoassay

detects   antibodies   against   native      (normal),

double-stranded DNA. The level of DNA binding

indicates disease activity in SLE, though the test

is rather insensitive. It is usually used only in

patients who are strongly positive in the ANA

test.

Extractable   antigens.   A   wide   range   of      Imaging

autoantibodies  against  soluble  nuclear  and

and assessment 753

cytoplasmic  antigens  detected  by  counter-

immunoelectrophoresis are used to contribute to diagnosis in a variety of systemic connective

tissue  disorders,  e.g.  SLE,  Sjögren’s  syndrome and systemic sclerosis.

Anti-streptolysin  ‘O’  titre  (ASO).   Levels  of

this antibody indicate recent streptococcal infec-

tion and may be used to confirm a diagnosis of

rheumatic fever.

Tissue typing.   Detection of the presence of

the  histocompatibility  antigen  HLA-B27  may occasionally help in the diagnosis or exclusion of seronegative arthropathies (p. 789).

Synovial fluid

This is normally present as a small volume of a clear, pale yellow, viscous fluid. It may be

examined for the following:

•  Protein (high in inflammatory arthritis).

•  Leucocytes (see  Chapter 11;  high  in  RA,

neutrophil counts are high in septic arthritis). •  Microorganisms (septic arthritis).

•  Crystals of urate (gout) and pyrophosphate

            (pseudogout).

Urinalysis

This may give clues to the origin of symptoms,

e.g.:

•  Glycosuria:   frozen   shoulder   and   tendon

            contractures   are   associated   with   diabetes

(Chapter 9).

•  Microscopic  haematuria:  Reiter’s  syndrome

            (p. 809), or metastatic bone pain caused by

urinary-tract carcinoma.

•  Proteinuria: multiple myeloma as a cause of

            back pain.

•  Sterile pyuria: TB causing bone and joint pain.

            Mycobacterium tuberculosis will not grow in the

medium used for the normal bacteriological examination of urine (see Chapter 8).

Radiology

X-rays are invaluable in revealing joint damage

(Figure 12.2(b); see also Figure 12.6(b)) and for

monitoring the progress of joint disease. Radiog-

raphy is also useful in distinguishing between

OA and RA, and as an aid in the diagnosis of AS

and pseudogout. Occasionally, it may be neces-

sary to use more specialized techniques, e.g. CT,

MRI, arthrography (with radio-opaque contrast

media injected into the joint) or arthroscopy (see

below), and radionuclide bone scanning, when

X-ray findings are negative or equivocal. CT

and MRI scans can provide greater information

on changes that are difficult to visualize using

normal   techniques,   e.g.   intervertebral   disc

prolapse (Figure 12.3 and p. 812).

Arthroscopy

An endoscope (a thinner version of that shown

in Chapter 3, Figure 3.5) can be inserted into

a joint to examine it, and this is a relatively

safe  and  simple  procedure.  Arthroscopy  is

particularly  valuable  in  the  knee,  where  it

permits complete examination of the cartilage,

synovium and ligaments. Biopsies can be taken,

synovial fluid aspirated and loose fragments or

torn sections of cartilage can be removed with

minimal trauma.

In   scintiscanning,   technetium-99m-labelled disodium   etidronate  and   similar   agents   are occasionally used to detect bone lesions.

Ultrasound scanning

This is rapidly becoming a first-line procedure

for detecting musculoskeletal problems and can

be used to guide injection into joints, etc. and

to  measure  bone  density  in  the  feet.  High-

resolution  ultrasonography  is  more  sensitive

than radiography for detecting synovitis and

bone erosions. It can also visualize periarticular

structures.

Tissue biopsy

Biopsy is only occasionally helpful, as a confir-

matory test, in some diseases associated with

rheumatic  symptoms,  e.g.  giant  cell  arteritis

(temporal arteritis, p. 805), SLE (kidney, p. 798), and some myopathies.

Functional capacity

The principal components of a detailed assess-

ment of functional capacity are listed in Table

12.5. However, a simpler approach is used for most clinical purposes:

•  Grade 1: completely independent.

•  Grade 2: needs aids and appliances, but is still

independent.

•  Grade 3: needs help with daily tasks, e.g.

            bathing, dressing, cooking.

•  Grade  4:  needs  considerable  and  constant

help; confined to a wheelchair or to bed.

The Stanford Health Assessment Questionnaire

(Disability Index) is widely used in patients with

RA and the WOMAC index in those with OA (see References and further reading.

Principal arthritic diseases

Osteoarthritis

Description and epidemiology

Osteoarthritis

Osteoarthritis (OA, osteoarthrosis) is the most common cause of arthritis, the most common disease of synovial joints, and is a major cause of disability, but it does not have a simple definition. OA is characterized by:

•  Changes in the structure of joint cartilage,

            sometimes with calcification, and cartilage

loss.

•  Loss of joint  ‘space’ on X-ray, which also

shows  osteophytes,  i.e.  bony  outgrowths

from the margins of the affected bones, and hardening (sclerosis) of the bone adjacent to an affected joint. Note that the apparent joint ‘space’  is  normally  occupied  by  opposing layers of cartilage.

•  The larger joints are the most affected, i.e.

            hip, knee and ankle, but the wrist, finger, foot

            and spinal joints may also be involved.

•  Inflammation is a minor primary feature and

            may be secondary to irritation of the soft

tissues surrounding affected joints, e.g. by

osteophytes. A variable degree of secondary inflammation is very common, but does not cause increases in the ESR and CRP.

These features contrast with those of RA (see below).

As in all mechanical bearings, wear tends to

occur in joints after a long period of use, and

some  degree  of  cartilage  damage  is  almost

universal in the elderly. This may affect the

synovial  joints (osteoarthrosis)  or  the  fibro-

cartilaginous  joints  of  the  vertebral  column

(spondylosis). The term osteoarthritis implies

inflammation,  which  is  secondary  to  joint

damage, unlike RA (see below) in which inflam-

mation  is  the  primary  condition.  Thus  the

neutral  term  osteoarthrosis  is  better  termi-

nology, but osteoarthritis is almost universally

used.

OA is often called ‘degenerative joint disease’,

but this is inaccurate because symptoms are

probably due to an imbalance between damage

and repair. Inappropriate repair  (remodelling)

secondary  to  joint  damage  also  occurs.  This

remodelling process should be contrasted with

the situation in RA (see below), where the under-

lying pathogenetic mechanism is a maladaptive

immune response.

OA  and  soft  tissue  rheumatism  (p.  809)

together are responsible for most of the primary

care  rheumatological  workload.  They  are  the

cause for most prescriptions for NSAIDs, but this

is likely to change (pp. 759, 772). Although OA

occurs worldwide and most Caucasians over 60

show radiological evidence of OA, hip involve-

ment  is  less  common  in  Black  Africans  and

Chinese.

Classification

Osteoarthritis is classifiable into two groups:

•  Primary (idiopathic) is of unknown origin,

            and may be localized to a single joint or

involve three or more groups of joints.

•  Secondary to other conditions. These are:

-  Excessive joint stress, e.g. overloading in

            obesity and manual labour.

-  Consequent  on  trauma,  overuse,  joint

            misalignment, joint surgery, etc., or bone

disease, e.g. Paget’s disease.

-  Congenital or developmental.

-  Inherited:       e.g.       metabolic          disease,

acromegaly, Gaucher’s disease.

-  Neuropathic, e.g. Charcot’s arthropathy.

Pathology and aetiology

Primary osteoarthritis

This comprises a cluster of conditions affecting the cartilage and bone of mostly the hip, spine, hand and knee synovial joints. Important risk

factors for primary OA are:

•  Age. Although OA is a very frequent condi-

            tion in the elderly, being present in         70% of

75-year-olds, it is not universal and so cannot be  considered  as  a  normal  feature  of  the ageing process.

•  Wear   and   tear.   The   subchondral   bone

            (immediately   underlying   the   cartilage)   is

Osteoarthritis    755

known to undergo microfractures in normal

use, and repeated fracture and healing results

in bone changes that reduce its ability to

absorb shocks and increase the fracture risk.

Further, muscle weakening with lack of exer-

cise, due to joint pain, and advancing age

results in loss of adequate joint support, thus

allowing abnormal joint movement which

causes further cartilage damage. The cartilage

is softened and there is separation of the

collagen fibrils.

Although wear and tear does not, by itself, neces-

sarily cause OA, lengthy involvement in weight-

bearing work or sports increases the risk of knee

and back OA, and continual occupational lifting

of heavy loads increases the incidence of hip OA

five times.

Joint surgery, e.g. menisectomy (removal of the semilunar cartilage in the knee) predisposes to OA of the treated joint.

Local biochemical factors in individual joints may contribute and acute exacerbations may be due  to  calcium   pyrophosphate   deposition

disease (p. 798).

The composition and size of the proteoglycan

molecules of the joint cartilage is altered and the

rate of repair no longer keeps pace with that of

degradation. Further, the type II collagen fibrils

are replaced with the more common, less suit-

able type I collagen that is characteristic of skin

and tendons. There is synovitis with production

of IL-1 and TNFa, which recruit the metallopro-

teinases  that  cause  collagen  breakdown.  IL-1

inhibits  the  production  of  new  collagen  II.

Changes also occur in the underlying bone, with

new bone formation occurring at the margins of

the articular cartilage, to form the osteophytes

(Figure 12.2(b)), and in the subchondral bone,

which  is  denser,  but  weaker,  than  normal.

Mutant genes (see below), producing abnormal

collagen, may also be involved.

The   persuasive   argument   that   increased

weight or obesity imposes additional stresses and

wear on joints fails to explain why the ankle

joint is usually spared. However, in middle-aged

women, every 5-kg increase in weight increases

the risk of OA of the knee by 30%. Knee OA

causes considerable morbidity and disability in

10% of those affected over 50 years of age.

There is a genetic predisposition - it is esti-

mated that about 50% of OA is the result of

inherited factors. In primary generalized OA

(PGOA) there is widespread early joint involve-

ment. It is sex-linked, being three times more

common  in  women,  and  tends  to  run  in

families, as does the development of Heberden’s

nodes, i.e. bony enlargement of the distal inter-

phalangeal joints (DIP; terminal finger joints;

Figure 12.4).  Less  common  are  the  similar

Bouchard’s nodes at the proximal interpha-

langeal joints (PIP joints). Symptoms tend to

start at about the time of the menopause and

there is a low-grade inflammatory component.

Involvement of the first metacarpophalangeal

joint (MCP; thumb) causes swelling and gives

the hand a squarish appearance. The nodes are

the readily visible results of osteophytes. The

spine also tends to be affected (spondylosis),

especially in the neck (cervical) region. PGOA is

unusual in Black populations, but is particularly

common in people of British descent, with about

30% of white North American and Northern

European   adults   having   some   osteoarthritic

features. PGOA is not related to climatic or envi-

ronmental factors, and there is no association with HLA antigens. Any genetic effect is likely to be polygenic.

Secondary osteoarthritis

Accelerated   wear   due   to   joint   damage   or malfunction,  e.g.  obesity  and  sports  injury, may lead to impaired or inappropriate repair

mechanisms, e.g. osteophyte formation causing Heberden’s nodes (see above). A listing of some common causes is given in Table 12.6.

The condition may develop insidiously over up to 50 years, and may be due to the produc-

tion of an abnormal collagen structure that is

less able to withstand the applied stresses.

Immunodeficient  patients  (e.g.  those  with

AIDS and hypogammaglobulinaemia) are partic-

ularly  susceptible  to  the  complication  of  an

episode of septic arthritis (joint infection), which

leads to OA.

Clinical features

The frequently used and weight-bearing joints

(hands, hip, knee, spine; Figure 12.2(b)) are prin-

cipally  affected  and  contribute  to  disability.

Unlike RA, there is no systemic (extra-articular)

involvement (p. 766) in OA. The predominant

features are:

•           Pain. Onset is gradual, occurring initially after

exercise, i.e. exacerbated by use, but later also at

night and at rest, with tenderness on pressure.

•           Stiffness. This may be severe after a period of

rest, but is transient, and although patients

often complain of stiffness on rising (‘morning stiffness’), this usually lasts less than 15 min. This should be contrasted with the situation in RA in which morning stiffness may be

severe and prolonged.

•           Loss of function. This is extremely variable

and may occur early, even though the pain is

slight. Conversely, even gross joint changes may   not   be   accompanied   by   significant functional impairment, though there may be some limitation of movement.

•           Joint  swellings.  These  are  usually  hard

(Heberden’s and Bouchard’s nodes; see above),

due to osteophytes (sidewards outgrowths at

the bone ends, Figure 12.2(b)), or they may be

softer and partly due to inflammation. This

differs from RA, in which the swellings are

‘boggy’ and tender. Inflammation and tender-

ness may occur in the early stages and during

the acute exacerbations, and last a few weeks.

These  conditions  occur  without  apparent

cause, notably if joints are over-used.

The joints most commonly involved are:

•  DIP joints, normally spared in RA. •  PIP joints, less common.

•  The feet, especially the first metatarsopha-

            langeal (MTP) joint (large toe), which takes

the heaviest loading.

•  The knees (Figure 12.2(b)), hips, cervical and

            lumbar spine.

Osteoarthritis    757

The joints most commonly spared, unless the

damage  results  from  repetitive  occupational

trauma (e.g. road drill operators and motorcycle

dispatch riders), are the shoulder, elbows, wrists,

MCP joints (usually affected in RA) and ankle.

The  course  of  OA  is  highly  variable,  and 25-30% of patients with established features may show no clinical or radiographic deterioration over long periods.

Investigation

X-radiography is an important aid in differential

diagnosis  and  assessment  of  OA.  Table 12.7

contrasts the principal radiographic features in OA

and RA, which are illustrated in Figures 12.2(b)

and 12.6(b). There is a correlation between radio-

graphic features and the reporting of pain, though

not with pain severity. Ultrasonography is used

increasingly.

All  other  tests  are  usually  normal  in  OA,

though there may occasionally be an increase in

ESR during an acute inflammatory exacerbation.

Management

Aims

Because OA is not reversible, except by surgical interventions  such  as  joint  replacement,  the aims of management are to:

•  relieve pain;

•  maintain mobility and function; •  prevent further joint damage;

improve  the  patient’s  mental  health  and

            quality of life.

The modes used in management include patient education and counselling, physiotherapy and occupational  therapy,  the  correction  of  any exacerbating factors, drugs, and surgery.

Patient education and counselling

Many  patients  fear  that  their  condition  will develop into crippling arthritis, so it is important to reassure them and stress that disease progres-

sion is very gradual and that function is usually well maintained. Even if severe deterioration of major joints occurs, e.g. in the hips, knees or

hands, surgery is very effective.

Because the problem is an imbalance between

the wear and repair of joints, patients should

understand that it is essential for them to follow

proper physiotherapist guidance on exercises,

which are designed to maintain muscle strength

without  undue  joint  stress,  e.g.  swimming.

Unwise exercise causes further damage to joints

that are already compromised. However, rest is

not advisable except during an acute exacerba-

tion because it may lead to loss of muscle power

and   to   excessive   stiffness:   patients   need

controlled exercise. Attaining an ideal weight

reduces joint stress in overweight patients.

Research has demonstrated that mental health improves  with  effective  treatment  and  thus reflects disease activity.

Physical therapies

Physiotherapy (PT) and occupational therapy

(OT) have an important role to play in main-

taining muscle strength, and so increasing joint

stability, in giving the patient additional confi-

dence to manage independently, and in main-

taining mobility and independence as far as

possible. The modes used include the following.

Exercises  to  maintain  and  restore  muscle

power and function are effective, especially after

surgery. The power of the quadriceps muscles in

the thigh must be sufficient to preserve general

mobility, balance and the ability to rise from

chairs, etc. Muscle power should be improved

before a patient undergoes elective surgery as

this greatly aids recovery: any period of bed rest

causes a rapid loss of muscle mass and power.

Isometric exercises, in which muscles are exer-

cised against fixed resistance with minimal joint

movement   and   change   in   muscle   length,

improve  muscle  power  without  joint  wear.

Swimming and hydrotherapy (exercising in a

warm  pool  against  water  resistance)  are  also

excellent forms of exercise, because the weight of

the  body  is  supported  by  the  water,  thus

reducing joint stress.

Occupational assessment and training, i.e.

advice on alternative methods of carrying out tasks at home and at work, or retraining by occu-

pational  therapists  to  minimize  joint  trauma includes the following:

•  Provision of aids and appliances, and modifi-

            cations of the home to improve mobility and

ease  tasks,  e.g.  splints,  easy-turning  taps, specially adapted implements and, in excep-

tional  circumstances,  widening  doors  and providing ramps for wheelchair access.

•  Local heat, diathermy, ultrasound, etc. are

widely  used,  but  provide  only  temporary

relief.

•  Physiotherapists, osteopaths and chiroprac-

            tors can help by mobilizing and realigning

joints and relieving associated muscle spasm.

Correction of exacerbating factors

The effects of OA may be exacerbated by a

variety of conditions, some of which are poten-

tially  correctable,  at  least  in  part.  Corrective measures include:

•  Weight reduction.

•  Treatment of any concurrent disease.

•  Surgical or other orthopaedic correction of

anatomical    abnormalities        that       place

abnormal   stresses   on   other   joints.   For

example, unequal leg length causes wear both

to the leg joints and to those of the pelvis and

vertebral column.

•  Maintenance of physical activity and general

            fitness.

•  Wearing  of  correct  footwear  and  use  of

            appropriate walking aids.

•  Encouraging a positive outlook.

Pharmacotherapy

Medicines have in the past had only a limited role in the treatment of OA patients, the aims

being symptomatic relief , i.e. reduction of pain and  discomfort;  inflammatory  exacerbations; depression and anxiety.

However, good control of all of these is now possible and should give an acceptable quality of life. Although complete abolition of pain may not be possible without undue side-effects, some residual pain is a useful reminder to patients that they should exercise cautiously.

Analgesics and non-steroidal anti-inflammatory drugs

Opinions differ as to which of these groups is

most   appropriate.   Simple   analgesics            (see

Chapter 7) are widely used, but there is consid-

erable variation in their tolerance and efficacy

between patients. Most patients are maintained

on   a   single   product  (paracetamol    (aceta-

minophen), occasionally codeine, dihydrocodeine

or tramadol, depending on pain severity, taken

regularly.  Combinations  of  paracetamol  with

codeine  or  dihydrocodeine (co-codamol  and  co-

dydramol, respectively, in the UK) are widely used

but may not be more effective than paracetamol

alone and can cause opioid dependence and

severe constipation.

The  paracetamol-dextropropoxyphene  combina-

tion (co-proxamol in the UK) will be withdrawn

completely, because it is no more effective than

paracetamol  alone  and  is  the  most  common

suicide agent there (see Chapter 7). Normal anal-

gesic doses (600-900 mg) of aspirin are effective

but are rarely used because of gastric toxicity.

NSAIDs  are discussed more fully under the

treatment of RA (pp. 772-8), but some points are

relevant  here.  Although  NSAIDs  are  popular,

there have been reports that some, e.g. ibuprofen

and naproxen, may accelerate cartilage damage or

prevent its repair. However, although the clinical

significance of this is unclear it may be more

appropriate  to  use  a  drug  that  is  alleged  to

promote   cartilage   repair,   e.g.   aceclofenac.

However, NSAIDs, especially the COX-2 selective

agents, which have significant adverse cardio-

vascular effects, are usually not justified unless

there is a significant inflammatory component.

Osteoarthritis    759

Elderly patients, the group most likely to be

affected  by  OA,  are  particularly  sensitive  to

NSAID toxicity (pp. 774-8). Naproxen probably

has  the  best  balance  between  efficacy  and

toxicity.

It is reasonable to use NSAIDs only for the

occasional painful exacerbation, e.g. when OA is

accompanied  by  joint  deposition  of  apatite

(p. 798). Several NSAIDs seem to be unsuitable in

OA on grounds of toxicity (e.g. indometacin and

ketoprofen), because treatment is usually lifelong.

Tolmetin,  which  is  not  licensed  in  the  UK,

belongs in this group.

Meloxicam, the first ‘second-generation’ NSAID

to be marketed as a relatively selective cyclo-

oxygenase 2   inhibitor (see  Figure 12.9),  is

licensed for the short-term treatment of exacer-

bations   of   OA,   and   existing   NSAIDs,   e.g.

diclofenac,  etodolac,  nabumetone,  naproxen  and

piroxicam, are also partially COX-2-selective and

are licensed similarly. These agents do cause less

gastrointestinal distress than other non-selective

NSAIDs and may be suitable in the older group

of patients involved.

Some  of  the  ‘third-generation’  NSAIDs,  the

highly  selective  COX-2  inhibitors,  may  cause

severe cardiovascular problems and rofecoxib has

been withdrawn in the UK. NICE advice is that,

until further research data are obtained, the COX-

2 inhibitors are appropriate for patients at high risk  of  gastrointestinal  complications,  such  as gastric or duodenal ulcer (see Chapter 3), perfora-

tion  and  bleeding.  The  patients  principally affected include:

•  those over the age of 65;

•  patients   who   have   taken   non-selective

            NSAIDs and have peptic ulceration or epigas-

tric  pain,  with  bleeding  or  are  regular  or chronic  users  of  antacids  or  antisecretory drugs (see Chapter 3) or have ceased treat-

ment due to gastrointestinal side-effects;

•  people who are regular smokers or alcohol

consumers;

•  those  who  have  any  concurrent  chronic

            disease and take associated medications.

COX-2 selective NSAIDs are contra-indicated in patients with IHD or cerebrovascular disease.

Until  definitive  information  is  available,

patients taking NSAIDs require careful monitoring for  adverse  gastrointestinal  and  cardiac  signs.

Those prescribed older NSAIDs or highly selective

COX-2 inhibitors should be told to report imme-

diately any new epigastric or chest pain, breath-

lessness or exercise limitation. Presumably the

prescriber will do this and pharmacists should

reinforce the advice. However, the need for this

type of medication clearly requires review, espe-

cially in older patients and those with adverse

cardiovascular and cerebrovascular risk profiles.

Despite this evidence, the absolute risk of a

serious cardiovascular event is small and a deci-

sion should be taken with the active involve-

ment of patients as to whether they are prepared

to accept the risk in view of the benefit they

receive  from  an  NSAID.  None  of  this  has  a

bearing on the occasional short-term NSAID use,

e.g.  for  gout (see  below),  sports  injury  and

headaches. Further, some patients obtain relief

from topical NSAID treatment, to which the

above considerations presumably do not apply,

because of the very low systemic absorption of

drug.

Other drugs

Slow-acting antirheumatic drugs (SAARDs; see

Table 12.13 and p. 770) and systemic cortico-

steroids have no place in the treatment of OA.

However,   a   severely   affected   joint   that   is

inflamed, or in which there is a fluid effusion,

may respond well to an intra-articular cortico-

steroid injection, though this is controversial,

and  the  benefit  is  usually  only  temporary.

Because there is the possibility of long-term joint

damage  with  repeated  injections,  owing  to

suppression of protein (cartilage) synthesis, this

should be done only occasionally.

Intra-articular injections of sodium hyaluronate, given  weekly  on  three  to  five  occasions,  is reported to be more beneficial than a steroid

injection, and hyaluronic acid derivatives are

now available to supplement that in synovial

fluid. These products are mentioned in the BNF but do not have a formal entry.

There   have   been   several   reports   of   the

beneficial   effect   of   glucosamine   sulphate,

750-1500 mg twice daily, taken over at least

3-6 months. One international group found that

this   abolished   cartilage   loss   from   synovial

weight-bearing  joints,  e.g.  the  knee,  over  a

period of 3 years and have proposed that this

agent should be regarded as a disease-modifying

agent for OA. Treatment will have to be life-long

because otherwise cartilage loss will resume at a

similar rate to previously when the medication is

stopped. The question of whether glucosamine

sulphate should be taken prophylactically by all

elderly   people   has   not   been   addressed   in

research, but is clearly a point of interest. About

one-third of patients withdrew from the trial,

mostly because of side-effects (20%) or lack of

efficacy (3%), but this is similar to withdrawal in

the placebo group. The beneficial effect may take

6 months or more to be noticeable, so persever-

ance is required. Glucosamine is not licensed as a medicine in the UK and is not prescribable

through the NHS.

Levels of the pain transmitter substance P (see

Chapter 7) are raised in OA and this causes

increased synovial levels of PGs and collagenase.

Reduction of the substance P level is therefore

desirable and this can be done using topical

capsaicin cream. This product is thus a logical

second-line agent after a simple analgesic, or as

an adjunct to systemic treatment. However, it is

very irritant and must not be used on inflamed

or broken skin, and the hands should be washed

thoroughly after application, to avoid eye and

facial contamination.

Antidepressants are used to alleviate the depres-

sion  associated  with  chronic  pain  and  may

improve the analgesic response (see Chapter 7).

Women   receiving   hormone   replacement

therapy (HRT)  have  been  shown  to  be  less

likely  to  develop  OA,  especially  of  the  knee,

and HRT can also be euphoriant. The benefit

on the knee, which is lost if HRT is stopped,

may  be  related  to  the  prevention  of  osteo-

porosis  and  so  to  the  maintenance  of  bone

density  adjacent  to  joints.  However,  many

women have stopped taking HRT, or refused to

start it, because of the perceived cancer risk. A

bisphosphonate is a suitable alternative to HRT

if  osteoporosis  has  been  documented  by  dual

energy X-ray absorptiometry.

Surgery

Severe, uncontrolled pain or serious loss of func-

tion may necessitate surgery. Arthroplasty (joint replacement) is especially successful for the hip,

the  pain  relief  being  excellent  and  mobility

usually being returned close to normal, provided

that the operation is carried out before joint

damage is too severe and collateral damage, e.g.

to the joints of the vertebral column, has not

occurred. Knee and finger joint replacement are

slightly less successful and that of other joints

still less so, though techniques and results are

improving continually.

Arthroscopic debridement.   Joint lavage with physiological   saline   benefits   some   patients, possibly by removing debris or inflammatory mediators from the joint space.

Other operations to fix joints permanently

(arthrodesis) or to remove osteophytes (e.g. for

bunions) may be undertaken occasionally for

particular patients. In those for whom arthro-

plasty is inappropriate, osteotomy, i.e. cutting

the bone or removing a section of bone near a

joint, with or without re-alignment, may be

successful for pain relief in disease of the knee or

hip joints. The reasons for this are poorly under-

stood, but correction of misalignment of the

limbs  clearly  relieves  stresses  on  associated

joints. Also, diversion of metabolic activity to

the surgically produced wound away from the

adjacent joint, and may reduce further inflam-

mation and cartilage damage there.

Rheumatoid arthritis

Introduction

Unlike  OA,  which  is  a  local,  generally  non-

inflammatory disease, rheumatoid arthritis (RA) is usually a chronic, progressive, inflammatory, systemic disease that primarily affects synovial joints (see above).

The most common extra-articular features are

anaemia, soft tissue nodules (p. 767), vasculitis,

sicca syndrome (p. 802) and fibrosing alveolitis.

Epidemiology and aetiology

In  the  UK,  about  1%  of  the  population  is

affected, with a 1:2 male:female premenopausal

Rheumatoid arthritis      761

sex ratio, although among the elderly the inci-

dence is equal in both sexes: this points to a

hormonal influence. Although RA often remits

in  pregnancy (75%  of  patients),  use  of  the

combined contraceptive pill does not reduce the

overall risk of developing RA, but may delay its

onset. It has also been suggested that changes in

sex   hormone   levels   may   modulate   T   cell

responses  by  suppressing  IL-2  production,  a

promoter of T cell proliferation and cytolytic

killer cells.

The incidence of RA seems to be decreasing. In

the   UK,   the   prevalence   in   women   aged

45-64 years halved over a recent 30-year period

and the incidence in Pima (North American)

Indians fell by about 60% over 17 years, to about

0.5% annually. Although the global prevalence is

about 1%, with only minor racial and geograph-

ical variations, RA is almost unknown in rural

Africa. The peak period of onset of RA is between

35 and 55 years of age, though it can start at

almost any age.

The concordance in monozygotic twins gives a

heritability of 50-60%, partly due to the genes

encoding  HLA-DRB1  class  II  molecules (see

Chapter 2). Also, HLA-DRB1 in first-degree rela-

tives gives a six times increased risk. HLA-DR4

and DR1 are also involved, but these genes prob-

ably determine disease severity and persistence

rather than causation. Patients with an allele of

the HLA-DRB1 gene who are seropositive for RFs

(see below) have a 13 times increased risk of

having bone erosions after 1 year.

The  trigger  factors  and  the  basis  of  the

prolonged, intense inflammatory process of RA

are largely unknown: despite extensive research

and   our   much   greater   understanding   of

immunopathology,   current   explanations   are

speculative. The concept of RA as an autoim-

mune disease is popular, and there are large

numbers of mature memory T cells (CD45RO) in

rheumatoid joints, derived from CD4     (TH) cells

(see Chapter 2). These promote Ig production by

B cells, and there is no negative feedback, hence

the production of rheumatoid factors (RFs, a

class of autoantibodies; see above).

The presence of CD45RO cells implies prior

exposure to antigen. However, the experimental

use of anti-CD4 Igs does not affect the course of

the disease. Further, although infection with HIV

specifically targets CD4            T cells, HIV/AIDS does

not seem to affect the incidence or course of RA.

However, some HIV-positive patients do have a

polyarthritis, which is believed to be a reactive

arthritis (p. 809).

It has been suggested that there is a persistent

antigenic stimulation by Epstein-Barr virus, the

cause of glandular fever. Retroviruses have also

been suspected in experimental animal models,

but no virus has been implicated to date. Bacterial

causes, e.g. Proteus mirabilis, are also disputed, but

infection followed by incomplete clearance of

microbial  nucleic  acid  is  a  possible  persistent

stimulus. There is a high incidence of HLA-DR1,

DR4 and Dw4 genes in RA patients. DR4 carriers

have a high reactivity to M. tuberculosis and, inter-

estingly, T cells cloned from the synovial fluid of

RA patients seem to react with tubercular anti-

gens. There may also be an association between

DR4 and T cell receptor genes.

The  temporary  ablation  of  B  cells  induces

remission, suggesting the important role of RFs

in maintaining inflammation. Also, the benefit

derived   from   the   use   of   antiproliferative

immunosuppressants  and  anti-cytokine  anti-

bodies (see below) emphasizes the central impor-

tance   of   immunological   processes   in   RA

pathogenesis.

It is possible that RA was introduced into

Europe in the 18th century by contact with

Native   Americans,   implying   an   infectious

aetiology.

A low socioeconomic status is predictive of a

poor outcome, but this is a common finding in

many diseases and is probably associated with an

adverse lifestyle, e.g. a diet high in saturated fats

and  with  low  fish  consumption,  and  under-

utilization of medical resources. Further, it is

known that smoking confers an increased risk,

and is greater in population sectors with a low

socioeconomic status.

Course

The onset of classical RA is normally insidious,

polyarticular (i.e. several joints are affected) and

symmetrical (i.e.  the  same  joints  are  usually

affected on both sides of the body at any one

time). The small joints (PIP, MCP, MTP, wrists)

are  affected  first,  although  a  monoarticular

onset, usually in the knee or the wrist, occurs in

some 20% of patients (Table 12.8). Fatigue and

malaise may precede joint symptoms by several

months.

In about 20% of patients there is an abrupt

onset  with  marked  systemic  symptoms.  This acute form is alleged to have a better prognosis, but  the  eventual  outcome  is  probably  not

affected. Following recovery, it may be many years before another attack occurs.

Even less common is a palindromic onset,

with acute episodes affecting one joint for up to

48 h, followed by remissions and exacerbations

affecting other joints at intervals of days to

months. About 50% of patients who experience

this type of onset will suffer typical chronic RA

after a very variable period, sometimes lasting

several years.

Disease activity has been reported to wax and

wane  unpredictably  and  spontaneously,  so

patients who experience a remission while taking

or  using  some  product  will  naturally,  though

often mistakenly, attribute their improvement to

that  use.  However,  spontaneous  remission  is

unlikely in those who have synovitis and high

levels of inflammatory markers at 12 weeks after

initial diagnosis. This is the basis of the move to

early  diagnosis  and  early  aggressive  treatment

(see below).

Natural variation in disease activity is one of the

principal problems in the evaluation of new anti-

rheumatoid drugs: large numbers of patients have

to be used in very well-designed trials over long

periods in order to obtain statistically meaningful

results.

Patients with severe disease have significant

morbidity and mortality. Of those referred to

hospital consultants only about 50% are likely to

be working after 10 years of active disease and

women have a 5-year reduced life expectancy

and  men  7 years,  or  were  severely  disabled.

However, these data are over 12 years old and

the situation has since improved. Moreover, RA

is not necessarily relentlessly progressive (see

below).

Poor prognostic factors include:

•  Inadequately controlled polyarthritis with a

            high ESR/CRP and high levels of RFs.

•  Structural joint damage leading to disability.

•  Genetic susceptibility, indicated by the pres-

ence of HLA-DR4, and/or a family history of

RA.

•  Low socioeconomic status and educational

            attainment and heavy manual labour.

RA is rare in men under 30 years, and reaches a peak at about age 65. In women, the incidence rises progressively from about age 25 to a broad peak at 45-75 years.

Pathology

Inflammation of the synovial membrane is the

cardinal initial feature (Figure 12.5) and RA has

been  grouped  with  other  immune-mediated

inflammatory diseases (IMIDs; see Chapter 2)

that share a common inflammatory pathway.

The  cells  lining  the  synovium  multiply,  the

surface becomes thickened and covered with

villi, and fibrin is deposited from the inflamma-

tory exudate. In severe cases the synovium may

be 1 cm thick, normally being less than 1 mm.

The  deeper  layers  become  infiltrated  with

lymphocytes   and   plasma   cells,   the   latter

producing RFs. Most patients become seroposi-

tive within a year of symptom onset and may

show high RF titres, and most joint damage

occurs   in   the   early   stage   after   diagnosis.

However,  there  are  few  neutrophils  in  the

synovium, though they are the commonest cells in   the   synovial   fluid.   Phagocytosis   of   the immune complexes formed in the fluid results in an increase in oxidative metabolism, liberating damaging free radicals and lysosomal enzymes that attack joint tissues.

As the inflammation proceeds, the synovial

margin  develops  outgrowths  of  metabolically

active pannus that invades and dissolves under-

lying cartilage and bone to produce the charac-

teristic erosions (Figures 12.5 and 12.6(b)). With

severe disease progression, the supporting liga-

ments and tendons are weakened and the joint

will sublux, i.e. become partially or completely

dislocated (Figure 12.6(b)), and eventually the

associated   limbs   are   deformed   and   non-

functional. Finally, the joint may become anky-

losed, i.e. fibrosed and calcified and thus stiff

and non-functional, but pain-free. This progres-

sion of changes is illustrated in Figure 12.5.

Tendons and tendon sheaths undergo changes

similar to the synovial changes.

The mechanisms responsible for these changes

are  unknown,  but  activation  of  T  cells  by

macrophages and unidentified antigens cause

cytokine release. Cytokines are also produced by

synovial fibroblasts. Thus TNFa and IL-1, IL-2,

IL-4 and IL-8 are important in the initiation and

maintenance of inflammation and cartilage and

bone  damage  and  synovitis,  so  the  use  of cytokine inhibitors in treatment is logical (see below). It has also been suggested that deposi-

tion of iron in the synovial tissues, which does occur,  promotes  free  radical  damage.  Hence chelating agents are being investigated to treat some patients with severe RA.

Clinical features

Articular features

These  are  outlined  in  Table  12.8.  The  most characteristic form of onset involves:

•  Symmetrical   small   joint   polyarthritis

            commencing in the MCP and PIP joints of

the hands (Figure  12.6(b)), the wrists and

the corresponding joints in the feet. Affected joints are very hot, swollen, red and tender, and are often shiny.

•  Morning stiffness. Initially, morning stiffness

            lasts      15 min and may persist for        1 h before

maximal  relief.  With  disease  progression,

morning    stiffness    increases,    becoming

prolonged and disabling, and it may eventu-

ally take a patient some 2 h to dress. Almost

any  joint  may  be  affected,  especially  the

wrists and the upper cervical spine. Wrist and

PIP   involvement (Figure 12.6(b))   always

suggests a diagnosis of RA, because these are

usually spared in OA.

Despite this catalogue of potential disability, it

is important to appreciate that the majority of

patients  have  only  mild  to  moderate  disease

and are treated adequately by GPs: 25% recover

partially, but few remit completely. A minority,

perhaps 10%, is referred to hospital consultants

and about 50% of these, i.e. only some 5% of

the total, suffer serious disability. Most GPs will

have   one   or   more   significantly   disabled

patients.

More advanced disease may produce character-

istic hand deformities, resulting in a progressive loss of function that manifests as:

•  Subluxation of the MCP joints, so that the proximal phalangeal heads slip partly under the metacarpal heads.

•  Ulnar deviation  (Figure 12.7(a)), in which

            the hand is tilted laterally away from the

thumb.

•  Boutonnière and swan neck deformities of

            the fingers (Figure 12.7(b)) due to damage to

joint ligaments.

Changes in the upper cervical spine may cause

serious instability, because ligament damage may

allow  subluxation  of  one  or  more  vertebrae,

producing  kinking  and  compression  of  the

spinal cord (Figure 12.8), resulting in reduced

neck mobility and occipital, neck, shoulder and

arm pain, or sensory loss. In particular, subluxa-

tion of the atlas on the axis may allow the dens

to compress the upper cervical spine, and trau-

matic  injury  in  this  area,  e.g.  caused  by  a

whiplash effect in a motor accident, may even

cause  death,  though  this  is  fortunately  rare.

Similarly, manipulation of the cervical spine in

RA  may  result  in  permanent  disability,  even

tetraparesis (partial or total paralysis of all four

limbs), so physiotherapy or other manipulation

of this area is usually totally contra-indicated in

RA  unless  investigation  demonstrates  normal

anatomy there.

Periarticular features

These  changes  are  those  associated  with  the

joints, but not arising from within the joint. Pain

and stiffness within a joint may result in wasting

of   the   associated   muscles.   Because   tendon

sheaths   resemble   synovium,   tenosynovitis

(p. 811) may occur with pain and diminished

joint movement. Tendons may be extensively

damaged and may even rupture. Swelling of the

tendon sheaths within the restricted confines of

the carpal tunnel often causes carpal tunnel

syndrome         (p.        809).   Raynaud’s   syndrome

(p. 804) and carpal tunnel syndrome may appear

before the joint symptoms.

Bursitis (p. 811) is also common, especially in the feet, with resultant bunion formation.

In the knees, high intra-articular pressure may cause the synovium to balloon out into the

popliteal fossa to form a Baker’s cyst. If this

ruptures, due to increased pressure occurring in the joint during knee flexion, synovial fluid is forced into the calf muscle, causing severe pain, mimicking a DVT (see Chapter 11).

Extra-articular features

These are sometimes described as complications

of RA (see below), but because RA is a systemic

disease, signs and symptoms, often inflamma-

tory, may occur almost anywhere in the body

(Table 12.9).

Haematological  abnormalities  are  common. Anaemia is the most frequent of these, and is an almost   invariable   accompaniment   to   active disease. Iron-deficiency anaemia is common in patients being treated with NSAIDs, due to upper gastrointestinal bleeding, and this may be super-

imposed  on  the  normochromic,  normocytic type  associated  with  many  chronic  diseases, caused by bone marrow hypoplasia (see Chapter 11).  Splenomegaly  is  common,  occurring  in some 5% of patients (Table 12.10).

Most of the other types of blood abnormality that occur are associated with drug therapy and include   leucopenia,   thrombocytopenia   and, infrequently, aplastic anaemia.

Involvement   of   the   lymphoid   system   is

common   and   lymphadenopathy (enlarged,

rubbery, non-tender ‘glands’) occurs in some

30%  of  patients,  usually  in  association  with

active disease.

Felty’s   syndrome  is   an   uncommon,   late

feature of seropositive RA. It occurs in 1% of

patients with severe RA, and is characterized by

splenomegaly and neutropenia, though wide-

spread  haematological  and  other  signs  may

occur (Table 12.10).  The  syndrome  runs  an

unpredictable course, with severe neutropenia

predisposing to serious infections. In rare cases,

systemic  corticosteroids  and  splenectomy  are

required.

Rheumatoid nodules are painless, often SC,

granulomas (see Chapter 2), 0.5-3 cm in diam-

eter. They usually occur near the elbow but may

occur in bursae, tendons or tendon sheaths at

any pressure site. They may also occur internally,

e.g. in the lungs or heart or, fortunately rarely,

in the eye. If the nodules occur in the lungs,

then bronchoscopy with biopsy is indicated to

distinguish them from bronchial carcinoma or

tubercles (see  Chapters 2 and  5).  If  bronch-

oscopy is not readily available, the nodules are

usually removed surgically, to provide a certain

diagnosis  and  protect  the  patient  from  the

possibility  of  bronchial  carcinoma,  as  far  as

possible.  Although  nodules  usually  occur  in

seropositive RA and are virtually diagnostic, they

are also found in a few patients with SLE (see p.

798 and Chapter 13).

RA  is  associated  with  a  reduced  lifespan, largely due to an increased incidence of infec-

tion, progressive systemic disease and amyloid-

osis. Nodules may form in the myocardium,

usually associated with high titres of RFs.

Investigation and diagnosis

Classic criteria

A diagnosis of definite RA requires at least four of

the following criteria, developed by the American

College of Rheumatology (ACR) and revised in

1988. The following are expressed more briefly

than the ACR criteria. To satisfy criteria 1 to 4,

symptoms or signs must be present continuously

for at least 6 weeks.

1. Morning stiffness for 1 h.

2. Arthritis of three or more joints and soft tissue

            swelling.

3. Arthritis of hand joints (wrist, MCP or PIP

            joints).

4. Symmetrical arthritis.

5. Rheumatoid nodules.

6. Serum RF (positive in ÷5% of normal control

            subjects).

7. Radiographic changes. Hand X-ray changes

            typical   of   RA   must   include   erosions   or

unequivocal bony decalcification.

Strict  formal  application  of  these  criteria  is

helpful in doubtful cases, but most doctors would

make a provisional diagnosis on less rigid ones.

Investigation

Typical results of some common investigations in patients with RA are given in Table 12.11. The general picture is that of a chronic inflammatory disease, primarily affecting the joints, with an immunological component.

The anaemia is typical of that which accompa-

nies many chronic diseases (see Chapter 11), and

serum iron studies may be unhelpful in diag-

nosis. In particular, serum ferritin is an acute-

phase reactant (see Chapter 2), and levels may be

elevated in RA. Confirmation of the nature and

extent of anaemia may therefore require bone

marrow examination. Another common cause of

anaemia in RA is drug-induced gastrointestinal bleeding (p. 775), and this may complicate the interpretation of haematological data.

The WBC count is usually normal, but leucocy-

tosis and thombocytosis may be associated with

severe  exacerbations.  Conversely,  neutropenia

and  thombocytopenia  may  occur  in  Felty’s

syndrome, and may also be caused by iatrogenic

myelosuppression, predisposing to infections and

a bleeding tendency.

Plasma viscosity is usually increased, due to

increased levels of acute phase proteins, notably

fibrinogen,   complement,   gamma   globulins

and  RFs.

Diagnosis

Although full-blown RA is unmistakable, many

patients show only certain features and, because

there is no pathognomonic test, the diagnosis

is sometimes revealed with certainty only after

some time. The occurrence of early morning stiff-

ness, symmetrical painful polyarthritis, high RF

titre and joint erosions, i.e. ACR criteria 1, 2, 4, 6

and 7, is usually conclusive. The occurrence of

certain features may make a diagnosis particularly

difficult, namely:

•  Mono-articular involvement.

•  Lack of erosions after several years of disease. •  Seronegativity.

•  High antinuclear antibody titre (p. 799).

•  Involvement   of   the   lumbar   spine,   skin,

kidneys or CNS.

The significance of these is discussed later in this chapter.

Functional assessment

Regular functional assessment (see Table 12.5) is essential in charting the progress of the disease and the effectiveness of treatment.

Complications

Complications of RA fall into four groups (see Table 12.9).

Inflammatory

Eye involvement is common:

•  Sjögren’s syndrome (p. 801) may affect about

            20% of patients, 85% of them female and

mostly seropositive. The syndrome causes dry eyes and a dry mouth, resulting from lympho-

cytic infiltration of the lachrymal and salivary glands. Other exocrine glands, e.g. in the

digestive tract and the sweat glands, may also be affected. This syndrome may also occur in association  with  related  diseases,  e.g.  SLE, systemic sclerosis and polymyositis.

•  Episcleritis,  causing  a  localized  or  diffuse

            hyperaemia of the sclera (white of the eye) is

less common.

•  Severe scleritis, which involves the deeper

            layers of the sclera, is uncommon but more

serious.

Arteritis  (vasculitis)  may cause widespread

obstructive vascular lesions and is an indication

of severe disease. Together with the formation of

myocardial  nodules  it  is  also  the  principal

cardiovascular problem. Arteritis usually presents

as nail fold (periungual) infarcts, i.e. small

areas of black or brown dead tissue around the

nail margins. The involvement of larger vessels

may   result   in   leg   ulceration   or   peripheral

neuropathies.

Respiratory   complications  reflect   diffuse inflammation and include fibrosing alveolitis

and, especially in men, pleurisy  and pleural

effusions (‘rheumatoid lung’).

Infective

Septic arthritis, due to joint infection by Staphy-

lococcus   aureus (in   adults   and   children)   or

Haemophilus influenzae (mostly in children), is a

rare but important complication. The latter is

now  unusual,  since  the  introduction  of  Hib

vaccine. Debilitated and immunosuppressed or

immunodeficient patients, e.g. those with AIDS

and hypogammaglobulinaemia, are particularly

susceptible.

Rheumatoid arthritis      769

Secondary to abnormal metabolism

Mild anaemia occurs in about 80% of cases.

More severe anaemia is usually iatrogenic and may require treatment (see Chapter 11).

Osteoporosis  may  lead  to  bone  fractures. Amyloidosis (p. 807), the widespread deposition in tissues of abnormal amyloid protein, may

occasionally  cause  clinical  problems,  notably nephrotic syndrome (see Chapter 14).

Iatrogenic

Adverse   reactions   to   medication   are   very common and are discussed below in the section on pharmacotherapy.

Management

Objectives and strategy

The aims are to:

•  relieve pain and discomfort and ameliorate

            symptoms;

•  arrest  or  limit  disease  progression  and,  if

            possible, reverse pathological changes;

•  maintain mobility and function, and promote

the best possible quality of life.

These  are  achieved  by  a  holistic  approach,

considering  the  patient’s  functional,  medical,

social and economic problems. The modes used

are:

•  Patient education and counselling.

•  Physical: physiotherapy, osteopathy, occupa-

tional therapy, appliances, etc.

•  Social: domestic assistance, modification of

            the home environment, financial support.

•  Pharmacotherapy:     analgesics,        anti-

inflammatory   agents    (i.e.   NSAIDs,   anti-

cytokine           drugs    and     corticosteroids),

slow-acting       (‘disease-modifying’)    anti-

rheumatic drugs (i.e. immunoregulators and antiproliferative immunosuppressants).

•  Appropriate  management  of  anaemia  and

other complications. Psychiatric support (see Chapter 6).

•  Surgery: synovectomy, arthroplasty and other

            joint surgery.

Patient education and counselling

Because of the wide range of symptoms and their

severity, and because patients almost inevitably

fear that they will be completely crippled, it is

important for them to comprehend as fully as

possible the nature of the disease and the various

procedures that may be used for management.

An  optimistic,  but  realistic,  approach  by  all

medical and paramedical staff is helpful, because

only a small proportion of patients have serious

disability and effective new treatments are being

introduced.

Patient education underpins all subsequent

management. Useful information is given in the

patient leaflets provided by the NHS and the

UK’s  Arthritis  and  Rheumatism  Council,  but

these can only supplement authoritative verbal

information.  Such  patient  education  needs  to

be an ongoing process because of the need to

respond to the development of new symptoms

and because there is a large amount of informa-

tion to assimilate, which is impossible to convey

in one or two sessions.

Depression   may   be   sufficiently   severe   to require psychiatric intervention.

Physical methods

Rest  may  be  valuable  in  an  acute  episode. Complete  bedrest  is  occasionally  used  for  a minority of patients but if not properly super-

vised, with adequate physiotherapy, this may

lead  to  permanent  disability  owing  to  joint disuse and muscle wasting.

Physiotherapy is very valuable, and includes

the use of splints or support bandaging to rest

particular joints or to correct deformity. A care-

fully planned series of exercises, e.g. swimming

and isometric exercises, is important in main-

taining  muscle  power  without  over-stressing

damaged joints. Other widely used methods, e.g.

the application of heat wax baths, cold, short

wave therapy, etc., may provide some short-term relief of pain and stiffness.

Occupational    therapy    is    an    essential component of management.

Monitoring

The   ACR   has   recommended   the   following criteria for defining improvement. There should be demonstrable improvement in:

•  The number of swollen and tender joints.

•  At least three of the following measures of

disease activity:

-  Patient assessment.

-  Physician assessment.

-  Pain score.

-  Disability score.

-  Serum levels of acute-phase reactants, e.g.

            CRP, ESR, plasma viscosity.

An appropriate goal for treatment is a better than 50% improvement in these criteria.

Pharmacotherapy: introduction

The drug treatment of RA is summarized in Table

12.12. Early drug management for mild disease is

similar to that used in OA (p. 759), although anti-

inflammatory drugs (mostly NSAIDs) are used,

with  an  increased  risk  of  adverse  reactions.

Inadequate relief or control, more severe symp-

toms or a definite diagnosis of seropositive RA

leads  to  the  use  of  slow-acting  antirheumatic

drugs (SAARDs),  also  described  as ‘disease

modifying  anti-rheumatic  drugs (DMARDS)’.

However, the extent to which any of this group of

drugs significantly modifies disease progression

in the long term is arguable. The term SAARD

defines the principal characteristic of this group,

that they take about 4-6 months’ treatment to

achieve their maximum therapeutic effect.

Although  the  inflammation  responds  to

current treatments, the destructive process due to

pannus (p. 763) is less amenable. However, TNFa blockade (see below) does reduce the irreversible joint erosions that cause much disability.

Anti-inflammatory drugs include:

•  NSAIDs.

•  Corticosteroids.

•  High-dose aspirin  and salicylates are rarely

            used nowadays, except in some Third World

countries where drug cost is an overriding

consideration.

In   comparison,   the   SAARDs  (Table  12.13)

include:

•  Immunomodulators,   i.e.   immunosuppres-

            sants;   e.g.   methotrexate,   ciclosporin   and

leflunomide.

•  Cytokine inhibitors, e.g. inhibitors of:

-  TNFa,   i.e.   adalimumab,   etanercept  and

            infliximab

-  IL 1, i.e. anakinra.

•  Sulfasalazine (SSZ).

•  Gold     compounds,     penicillamine  and

antimalarials.

Pharmacotherapy: anti-inflammatory drugs and analgesics

Non-steroidal anti-inflammatory drugs

NSAIDs  have  been  the  drugs  of  first  choice for the treatment of mild RA for many years

because   they   possess   both   analgesic   and anti-inflammatory  properties,  and  many  are available (Table  12.14).  They  are  also  used  as

an adjunct to SAARDs if symptomatic support is required until benefit is obtained.

Patient response to NSAIDs and tolerance of

them is very variable, so it may be necessary to try

several products to determine which has the best

combination  of  efficacy  and  tolerability.  The

basis for this inter-patient variability is unclear,

but it is likely to be more related to disease activity

than  to  drug  pharmacokinetics  or  anti-PG

activity. These drugs have a rapid onset of action

but  the  full  analgesic  and  anti-inflammatory

effect may not be apparent for a week or so,

largely dependent on dose frequency and the

consequent time to reach steady state. If adequate

relief is not obtained within 2-3 weeks at full

dosage, a change to another product is indicated.

However, relief of pain and early morning stiff-

ness is often incomplete at tolerable doses.

Mode of action

The activity of NSAIDs is ascribed to their inhi-

bition of cyclo-oxygenase (COX) activity and

thus of PG synthesis. COX exists in two isoforms

that may be expressed constitutively, i.e. they are

always produced, in only a limited range of

tissues. COX-1 is constitutive in the stomach,

kidneys, intestines and platelets, while COX-2 is

inducible by inflammation in joints, the brain,

kidney, vascular endothelium and reproductive

tract.

Rheumatoid arthritis      773

Activation of COX-1 leads to the formation of

autacoids, e.g. protective prostacyclins, in the

gastric mucosa and vascular endothelium, PGE2

in the kidney and thromboxane (TXA2) in the

platelets. COX-2 is involved in fever, the central

modulation of pain and the initiation of uterine

contractions and fetal expulsion in childbirth,

but its physiological roles are not fully defined.

Although COX-2 may play a role in ulcer

healing in animals and occurs around human

gastric ulcers, the clinical significance of this is

unknown.   COX-2   is   mostly   inducible   by

cytokines and other pro-inflammatory stimuli

that cause an inflammatory response localized to

the site of production, e.g. in joints (Figure 12.9).

COX-2 differs from COX-1 only by the substitu-

tion of isoleucine by valine in the active site. This

produces a larger NSAID binding site, which is the

rationale  for  the  development  of  the  COX-2

inhibitors.

Aspirin and most of the older NSAIDs inhibit

both COX isozymes but the relative effects differ

considerably  between  drugs,  and  most  of  the

older NSAIDs are relatively selective for COX-1

inhibition.  This  may  be  clinically  significant

because selective inhibition of leukotriene (LT)

production by COX-2 induction should therefore

spare distant, uninflamed sites, e.g. the stomach.

Because COX-1 is not inhibited by the selective

COX-2 agents, its normal actions in the stomach

and  kidney  will  still  produce  the  eicosanoids

necessary for normal gastrointestinal and renal functions,  so  COX-2 inhibition  spares  the

harmful effects on these organs caused by the non-selective agents.

Differing  relative  potencies  and  selectivities

against COX-1/COX-2 are alleged to account for

the  differences  between  NSAIDs.  It  has  been

suggested that inhibition of COX-1 causes most of

the side-effects of NSAIDs, while that of COX-2 is

principally responsible for the anti-inflammatory

action.

It is still unclear whether these alleged benefits

of selective COX-2 inhibitors (coxibs) are trans-

lated fully into clinical superiority. Etodolac, now

known to be a coxib, has been in use for many

years and its side-effect profile does not seem to

be markedly different from that of non-selective

NSAIDs.

The large RCT (VIGOR) with rofecoxib, the first

coxib  to  be  licensed  as  such,  confirmed  its

gastrointestinal safety relative to naproxen (rela-

tive risk (RR) 0.4). However, there was a relative

fivefold increase in the risk of MI (see Chapter 4).

The subsequent APPROVe trial, in which partici-

pants were allowed to take daily aspirin, found

an RR of 1.92 for MI or cerebrovascular events

(stroke) with rofecoxib, and an increased risk of

heart failure. This increased cardiovascular risk

has  been  confirmed  by  case-control  studies.

Consequently, rofecoxib has been withdrawn by

the manufacturer.

Other coxibs (celecoxib, valdecoxib  and pare-

coxib) have also produced an increased cardio-

vascular  risk.  Valdecoxib  has  been  withdrawn

because of severe skin problems and parecoxib is

licensed only for the short-term relief of acute

post-operative  pain.  Cardiovascular  problems

with   etoricoxib  are   similar   to   those   with

diclofenac,  although  etoricoxib  does  not  differ

from placebo in causing headache, nausea and

diarrhoea.

It has been suggested that the basis for these

observations   is   that   the   selective   COX-2

inhibitors significantly reduce levels of prostacy-

clin (PGI2), an inhibitor of platelet aggregation,

and do not affect thromboxane (TXA2, a potent

vasoconstrictor) formation by COX-1. There is therefore  an  increased  tendency  for  vascular obstruction.

Although   the   incidence   of   serious   upper

gastrointestinal damage does appear to be less

with selective COX-2 inhibitors, a 2006 system-

atic analysis concluded that these drugs and

high-dose non-selective COX inhibitors other

than naproxen are associated with about a 45%

increased risk of adverse cardiovascular events

(MI, stroke or vascular death; see Chapter 4).

This  does  not  appear  to  apply  to  high-dose

naproxen.

The UK’s CSM and the European Medicines Evaluation Agency (EMEA) therefore recommend that  COX-2  inhibitors  are  contra-indicated  in patients who have:

•  IHD.

•  Cerebrovascular disease.

•  Moderate to severe heart failure (NYHA II-IV;

            see Chapter 4)

•  Significant   risk   factors   for   cardiovascular

            events,   i.e.   diabetes   mellitus,   hyperlipi-

daemia, hypertension and smoking, or for

peripheral artery disease.

If a patient taking a coxib has a significant

cardiovascular risk profile, or develops such a risk,  they  should  be  switched  to  alternative medication.

Coxibs should only be used in preference to

non-selective  NSAIDs  when  specifically  indi-

cated, i.e. in those who are at particular risk of

gastroduodenal   ulcer,   with   perforation   or

bleeding (see Chapter 3), and after a careful

assessment  of  a  patient’s  cardiovascular  and

overall risks.

Although Commission on Human Medicines

(CHM)  recommends  that  the  lowest  effective

dose of any NSAID should be prescribed for the

shortest possible time, this is hardly meaningful

for many of those needing NSAIDs, because the

principal conditions for which they are used e.g.

osteoarthritis, RA and ankylosing spondylitis are

of long duration. For most of the current coxibs

that have been introduced, the cardiovascular

risks outweigh their beneficial gastroprotective

and anti-inflammatory effects.

However,  this  presumably  does  not  affect

short-term coxib use for treating or preventing

Rheumatoid arthritis      775

dental, post-operative and other pain, though

prescribers may prefer well-tried simple anal-

gesics in the light of current information.

The new selective COX-2 inhibitor lumiracoxib was licensed in 2003 but was withheld pending review of its adverse effects. It was marketed in 2005 for the treatment of osteoarthritis. The

large TARGET trial showed it to have a gastro-

protective   effect   compared   to   non-selective NSAIDs in patients with OA.

Further,   a   meta-analysis   of   lumiracoxib

osteoarthritis trials showed that, for a combined

end-point of MI, ischaemic and haemorrhage

stroke  and  cardiovascular  death  there  was  a

slightly lower incidence of adverse cardiovas-

cular events than with non-naproxen NSAIDs,

but about a 40% increased risk compared with

naproxen. Despite all this, as this text was about

to go to press it was announced that the MHRA

has suspended approval for lumiraroxib because

an unacceptable number of patients taking stan-

dard doses for a short period have exprienced

severe liver damage.

Interestingly, the results of this scrutiny of

lumiracoxib safety, provoked by the findings with

other coxibs, indicates that naproxen has rather

different characteristics from other non-selective

NSAIDs and has a relatively low incidence of

adverse cardiovascular events, including small

reductions in both diastolic and systolic blood

pressure.  However,  the  concomitant  use  of

aspirin probably counteracts these benefits.

Side-effects

NSAIDs are responsible for the largest number of

‘yellow card’ reports to the CSM of any drug

group,  reflecting  both  their  numerous  side-

effects and interactions (Table 12.15) and their

frequency of use. Most adverse drug reactions

(ADRs) are minor, but the principal adverse reac-

tion, gastric ulceration, may lead to significant

bleeding and severe anaemia, even perforation.

Taking NSAIDs increases the risk of these reac-

tions in RA patients about three times, with a

sixfold increase in the risk of perforation of the

gut. Patients do not become tolerant to this effect

and the incidence of hospital admission due to

gastrointestinal haemorrhage is increasing.

Factors   that   increase   the   risk   of   serious gastrointestinal  side-effects  by  at  least 50% include the following:

•  Age  65 years.

•  History   of   gastrointestinal   problems,   e.g.

            recent upper abdominal pain, active peptic

ulcer and regular or recurrent use of antacids or antisecretory drugs.

•  Previous NSAID intolerance or cessation of

            treatment due to gastrointestinal disturbance.

•  Cigarette smoking.

•  Alcohol consumption

•  Any concurrent chronic disease and associated

            medications.

NSAIDs  may  also  cause  deterioration  in  renal

function,  with  fluid  retention  and  oedema.

This  is  particularly  important  in  the  elderly

and  in  patients  in  whom  renal  function  is

already compromised, e.g. creatinine clearance

÷30 mL/min.  All  NSAIDs  tend  to  cause  fluid

retention, resulting in acute cardiac decompen-

sation  in  patients  with  heart  failure  and

limited cardiac reserve. There is one Australian

report suggesting that 29% of the hypertension

cases  found  among  the  elderly  Australian

population are due to NSAIDs.

Other  side-effects  are  rashes,  notably  with diclofenac, fenbufen and sulindac.

All NSAIDs cause premature closure of the ductus   arteriosus   if   used   regularly   during pregnancy,  delay  childbirth  and  increase  the duration of labour.

Minimizing gastrointestinal side-effects

The gastric side-effects of NSAIDs are due to a combination  of  local  irritation  and  systemic mechanisms, but antisecretory agents (e.g. H2-RAs and PPIs) help to protect against NSAID-induced gastric ulceration.

Also   misoprostol,   a   ‘cytoprotective’   PGE1

analogue, is marketed for co-administration with

NSAIDs to minimize gastric damage, and fixed

combinations with diclofenac and naproxen are

available. Misoprostol may be slightly more effec-

tive  than  the  H2-RAs  in  preventing  gastric

ulcers, but both types of drug are equivalent in

protecting         against  duodenal    ulceration. However, misoprostol may cause severe diarrhoea and   other   gastrointestinal,   central   nervous and   gynaecological   side-effects,   which   may necessitate withdrawal.

These agents are intended to overcome the

damaging  gastrointestinal  effects  of  NSAIDs,

while permitting the anti-inflammatory benefits

to continue. Although the coxibs may make it

possible to minimize the use of antisecretory and

other  gastroprotective  drugs  in  a  particular

patient, it is likely that prescribers will now

avoid coxib use.

It has been alleged that NSAIDs increase carti-

lage damage in the long term. They are known

Rheumatoid arthritis      777

to suppress bone formation, and have been used to  prevent  undesirable  ossification  following total hip replacement. The clinical significance of this in treating RA is unclear.

There is a continuous turnover of articular

cartilage throughout life, and the glycosamino-

glycan (GAG) matrix turns over considerably

more rapidly than the fibrillar collagen. This

remodelling has been reflected in the regression

of joint pathology in some arthritic patients.

Changes  in  chondrocyte  activity  affect  this

process and may be the pathological basis of OA

and   some   other   arthritides.   Local   cytokine

release, notably IL-1, may interfere with natural

repair mechanisms and we know that human

cartilage is more sensitive than animal tissue:

this emphasizes the need for caution when inter-

preting the results of experiments with animal

models  of  rheumatic  diseases.  Further,  it  is

known that some NSAIDs modulate IL-1 activity,

e.g. indometacin increases it seven times.

One short-term in vitro  study with human

osteoarthritic and normal cartilage has shown

that NSAIDs probably fall into three groups on

the basis of their effects on GAG synthesis: i.e.

stimulatory (e.g.  aceclofenac);  no  effect (e.g.

aspirin, diclofenac, tiaprofenic acid) and inhibitory

(e.g. ibuprofen, indometacin, naproxen). This result

with indometacin may reflect its known effect on

IL-1 levels.

The effects of aspirin and diclofenac appear to

depend on individual cartilage metabolism. Keto-

profen   and   piroxicam   may   stimulate   GAG

synthesis in young cartilage but not in adults.

Although   these   laboratory   results   were

obtained at NSAID concentrations similar to the

plasma levels achieved with normal dosing, it is

notoriously difficult to extrapolate from short-

term in vitro  studies to the clinical situation.

These findings provide some rational basis for

NSAID selection, at least in OA, and may be

unimportant if, for example, indometacin is used

for the short-term treatment of acute gout (see

below). However, they may be significant if long-

term  use  is  contemplated  in  patients  with

demonstrable cartilage damage. The effects are

quite distinct from the analgesic properties of

this drug group.

It must be concluded that, despite the advan-

tages  and  wide  use  of  NSAIDs,  there  is  an

obvious need to develop safer alternatives to the present generation of these agents.

Selection

NSAIDs are often classified by their chemical

structures (see Table 12.14), but this is generally

unhelpful in choosing a product for a patient

except to select a chemically unrelated drug if an

ADR, e.g. hypersensitivity, dictates a change of

medication. The main differences between the

approximately 20 available NSAIDs are their in

vitro potency and the incidence of side-effects.

However, the potency differences do not trans-

late   into   increased   clinical   effectiveness   at

recommended dosages and there is nothing to

choose between any of the current NSAIDs in

this  respect.  Thus  the  principal  criterion  for

choice  is  patient  acceptability,  i.e.  minimal

side-effects:

•  Ibuprofen  has a relatively low incidence of

            side-effects and so is a common first choice

for patients with mild symptoms, but it has

            relatively weak anti-inflammatory properties.

•  Naproxen is more potent, has a reasonable effec-

tiveness/toxicity balance and is conveniently taken twice daily: it is probably the first-line drug for those with moderate symptoms.

•  Modified-release   forms   of   diclofenac  and

ketoprofen are widely used alternatives.

•  Nabumetone has been shown to produce less

endoscopically  proven  gastric  lesions  than many other NSAIDs.

Although the coxibs are no longer regarded as a

first-line choice, meloxicam  is licensed for the

treatment   of   pain   and   inflammation   in

rheumatic diseases generally, though the BNF

does  not  currently  list  a  lower  incidence  or

smaller range of side-effects. It may cause serious

skin and gastrointestinal reactions. Tiaprofenic

acid may cause severe bladder irritation.

Unfortunately, effectiveness and toxicity seem to be associated with the current range of non-

selective NSAIDs, of which naproxen seems to be preferable (see above and Table 12.15).

Because the products will be taken for long

periods, compliance is aided by the use of drugs or

products with convenient dosing patterns, i.e.

once or twice daily. However, the differences in the

pharmacokinetic properties of the drugs has been blurred by the introduction of modified-release versions of those with a short half-life.

A procedure used by some rheumatologists is

to give a patient a 14- or 21-day supply of each

of three products, to be taken consecutively, and

allow the patient to choose the most acceptable.

If none of the first group chosen is acceptable, a

further selection can be tried. Some 50% of

patients are likely to respond to the first agent

tried, and a further 30% to the second. Approxi-

mately 5% fail to derive satisfactory benefit from

any of this group of drugs.

However,    NSAIDs    are    probably    over-

prescribed. They are the principal cause of drug-

related problems in the elderly and are often

used when there is no evidence of inflammation and a simple analgesic would suffice.

Restrictions on specific NSAIDs

Azapropazone

The UK CSM has restricted its use to RA, AS and acute gout only when other NSAIDs have been tried and failed. It is contra-indicated in patients with a history of peptic ulcer. The maximum

daily  dose  has  been  reduced  to 600  mg  for those with RA and AS aged over 60y, and those with impaired renal function.

Piroxicam

The Committee on Human Medicinal Products (CHMP) has advised that:

•  Piroxicam should be initiated only by physi-

            cians experienced in treating inflammatory

and degenerative rheumatic disease.

•  Piroxicam should not be used as a first-line

            treatment.

•  In adults, use of piroxicam should be limited

            only to the symptomatic relief of OA, RA and

AS.

•  Piroxicam  dose  should  not  exceed  20  mg

daily.

•  Piroxicam should no longer be used for the

            treatment of acute painful and inflammatory

conditions.

•  Treatment   should   be   reviewed  2   weeks

after  initiating  piroxicam,  and  periodically thereafter.

•  Concomitant   administration   of   a   gastro-

            protective agent should be considered.

Note Topical preparations containing piroxicam are not affected by these restrictions.

Piroxicam is not recommended for the treat-

ment of acute musculoskeletal disorders in chil-

dren (author’s comment).

Corticosteroids

These are the most potent anti-inflammatory

agents available and are also immunosuppres-

sive. They produce a dramatic response. Some

studies have suggested the prevalence of use of

corticosteroids in RA to be as high as 80%,

accounting for about 25% of all steroid usage.

Although it used to be generally believed that

corticosteroids have little effect on the under-

lying disease process, they may limit the extent

of joint damage if used in early RA (see below),

and during severe inflammatory episodes.

Mode of action

Corticosteroids down-regulate the production of

LTs, PGs, complement components, interferons,

other cytokines and histamine. However, they

are not myelosuppressive because they act on

mature immune cells to prevent B cell and T cell

clone proliferation. In contrast, the antiprolifer-

ative  immunomodulators (see  below)  act  on

immune cell precursors in the bone marrow, and

incidentally on all other haemopoietic cells.

Side-effects

Even patients given relatively low doses, e.g.

5 mg prednisolone daily, over long periods may show significant side-effects, and these are more frequent at higher doses, as usual. The effects seen include:

•  Fluid retention and hypertension.

•  Weight gain (additional to fluid retention). •  Loss   of   bone   density (osteoporosis)   and

increased risk of fracture.

•  Increased  susceptibility  to  infections,  e.g.

            shingles, chickenpox may be fatal.

•  Reduced glucose tolerance.

•  Cataract formation and glaucoma. •  Impaired wound healing.

•  Loss of SC tissue.

Rheumatoid arthritis      779

•  Proximal myopathy. •  Steroid psychosis.

•  Cushing’s syndrome.

•  Suppression  of  the  hypothalamic-pituitary-

            adrenal axis.

Interactions

Corticosteroids reduce blood levels of salicylates.

Thus, the introduction of steroids in a patient

taking aspirin as an analgesic is illogical. Further,

if a patient is taking an effective dose of aspirin

plus a steroid, withdrawal of the steroid may

precipitate aspirin toxicity. However, use of this

combination has a high risk of gastrotoxicity

and is undesirable.

They have many other interactions that are

not relevant to antirheumatic drugs, and the

reader is directed to the BNF and standard texts for information on these.

Uses

Because of these well-known side-effects, the

corticosteroids have a strictly limited role in the

treatment  of  RA.  They  are  invaluable  when

serious   complications   occur,   e.g.   intolerable

pain, uncontrolled loss of function, and espe-

cially   vasculitis (p. 805).   High   doses,   i.e.

60-100 mg of prednisolone daily PO, or an equiv-

alent IV or IM injection of methylprednisolone,

may be used in the short term for severe uncon-

trolled   rheumatoid   disease   or   for   serious

systemic  complications,  e.g.  vasculitis.  Pulsed

high doses, e.g. up to 1 g of IV methylprednisolone

on three consecutive days, are sometimes used to

avoid the corticosteroid dependence that occurs

with gradual progressive or prolonged regimens.

Corticosteroids also have a place in the prompt,

short-term relief of severe exacerbations, and

possibly as an adjunct to early SAARD treatment,

to give rapid relief and to prevent early joint

damage, until the SAARD effects are manifest.

However, this application is usually met with

NSAIDs. A few RA patients who are intolerant of

other treatments derive adequate benefit from

low-dose oral prednisolone, i.e. 5.0-7.5 mg/day.

It has been shown that the early introduction

of 7.5 mg/day  of  prednisolone  following  diag-

nosis, in addition to other treatments, retards

joint erosion over a 2- to 4-year period. With-

drawal of the steroid in the third year may result

in  the  initiation  of  joint  damage  in  some

patients and its resumption in those with joint

damage at the start of corticosteroid use. This

anti-erosive dose should be reduced gradually to

zero after 2-4 years, in order to avoid long-term

ADRs.

In very elderly patients, corticosteroids may

be  used  for  the  maintenance  of  already

limited  mobility  and  function,  when  their

advantages,  including  an  increased  sense  of

well-being,   may   outweigh   their   long-term

disadvantages.

Local    corticosteroid   treatment.   Water-

insoluble corticosteroids, e.g. triamcinolone hexa-

cetonide  or  methylprednisolone  acetate,  may  be

injected into a particular joint, with aspiration of

excess synovial fluid, to control a local flare-up

there. Provided the injection is placed correctly

in the joint, and leakage does not occur, periar-

ticular SC atrophy should not be a problem.

Intra-articular injections provide periods of relief

that vary from a few days to months, but such

injections should not be used more than three

times annually, in order to avoid further joint

damage. If greater frequency is indicated, an

alternative treatment should be sought. Corti-

costeroid joint injections must always be carried

out with scrupulous aseptic technique to avoid

the possibility of infection. Joints must not be

injected if infection is suspected, as the steroid is

likely to exacerbate the problem.

Tendons  and  bursae  may  also  be  injected. However, it is essential to inject the tendon

sheath  and  not  the  tendon  itself,  otherwise tendon rupture is likely. Because the Achilles tendon (in the heel) does not have a proper

sheath it should not be injected. Corticosteroid eye drops are essential for the control of serious eye complications (Table 12.9).

Analgesics

Simple  and  compound  analgesics,  e.g.  para-

cetamol            (acetaminophen)   and   codeine-   and dihydrocodeine-based products (see Chapter 7) are used at any stage as ‘top up’ therapy if additional pain   control   is   required.   However,   because inflammation is central to RA, analgesics are

inappropriate as monotherapy.

Pharmacotherapy: slow-acting

anti-rheumatic drugs (SAARDs)

Introduction

Patients with mild disease are treated satisfacto-

rily with NSAIDs. Those with moderate to severe

disease, or if there is a progression from mild to

moderate symptoms or signs, need a SAARD (see

Table 12.13). If a SAARD is effective and tolerated

in a particular patient, any of these second-line

agents will improve both the joint problems and

any extra-articular symptoms and will abolish

the need for corticosteroids, or spare the steroid

dose. Patients usually require an NSAID in the

early stages, if they are not already taking one, to

provide symptom relief until the SAARD is fully

effective. If there is no objective evidence of

benefit with a SAARD after 6 months, it should

be discontinued and an alternative sought.

Irreversible joint damage and impairment of

function tend to occur early in the course of the

disease, especially in the 2 years following diag-

nosis, so SAARDs should be used immediately a

firm diagnosis of RA has been made, i.e. much

earlier   than   previously   recommended   and

certainly  within  the  first 2 years,  to  achieve

maximal benefit. Careful monitoring for both

effectiveness and toxicity is essential, especially

in the early stages of treatment. It may be impor-

tant to try to identify those patients in the subset

who are likely to suffer more aggressive disease.

Some patients may benefit from combination

SAARD   therapy,   especially   if   they   have

responded  partially  to  monotherapy,  but  the

response  is  very  variable.  One  small  North

American  study  found  that  methotrexate-SSZ-

hydroxychloroquine triple therapy gave at least a

50%  improvement  in  symptoms  over  single

agents, with no evidence of excessive toxicity.

In  a  Dutch  trial,  an  intensive  regimen  with

methotrexate-SSZ-prednisolone  gave   significant

improvement over SSZ alone, but this benefit

disappeared  when  the  prednisolone  was  with-

drawn. Patients who respond well but incom-

pletely to methotrexate  may benefit from the

addition of ciclosporin.

The modes of action of most of these agents in

RA are uncertain, but they are all mildly or

significantly   cytotoxic   and   should   suppress

lymphocyte activity and so the inflammatory

response (see Chapter 2).

Antiproliferative immunomodulators

These  are  arguably  the  most  effective  of  the

second-line  agents,  but  they  have  a  relatively

high incidence of ADRs (see also Chapters 10 and

14) and there are hazards associated with long-

term  immunosuppression.  They  are  therefore

used only for patients with proven, moderate or

severe  or  progressive  disease  that  is  not

adequately controlled by NSAIDs, or who cannot

tolerate other products. This is especially impor-

tant with RA because, although distressing, it is

rarely fatal and requires prolonged treatment.

Use is usually restricted to specialized units with adequate monitoring facilities, particularly for undesirable myelosuppression while causing desirable   damage   to   immune   stem   cells, producing   immunosuppression.   In   contrast, corticosteroids act on mature immune cells and so do not cause myelosuppression.

All   antiproliferative  (cytotoxic)   drugs   are

teratogenic and may have side-effects on sper-

matogenesis. They are therefore avoided, used

with great care, or may be absolutely contra-

indicated,   in   women   of   child-bearing   age

and those who are breastfeeding. Exceptionally,

they may be considered for the control of a

severe exacerbation in a woman who is already

pregnant: this is a matter for discussion and

cooperation    between    rheumatologist    and

gynaecologist, and possibly a specialist in cyto-

toxic chemotherapy (see Chapter 10 for a more

detailed discussion).

Methotrexate

Methotrexate   is   a   dihydrofolate   reductase

inhibitor,   and   so   blocks   folate   synthesis.

Methotrexate  is  licensed  for  the  treatment  of

moderate to severe active RA that is unrespon-

sive  to ‘conventional’  therapy.  It  is  relatively

well  tolerated  at  the  lower  doses (5-25 mg

weekly)  used  in  rheumatology.  It  is  currently

the first choice of many rheumatologists and is

increasing in popularity because it has a simple

once-weekly  dosage  regimen:  severe  adverse

reactions  have  resulted  from  daily  dosing,  so

Rheumatoid arthritis      781

pharmacists  need  to  take  special  care  when

dispensing  methotrexate.  However,  its  drop-out

rate after 1-2 years is only about 40-50% of that

found   with   other   SAARDs.   Nevertheless,

methotrexate  must  be  used  with  great  care  if

there is any evidence of renal or hepatic impair-

ment  (it  may  cause  liver  cirrhosis)  or  of  the

pulmonary complications of RA. Renal impair-

ment  may  lead  to  the  accumulation  of  toxic

levels. The UK’s CSM advises a full blood count,

and also that renal and liver function tests be

made  initially  and  weekly  until  patients  are

stabilized, and then at 2- to 3-month intervals

thereafter. Patients should promptly report any

occurrence  of  sore  throat  or  fever,  and  any

other signs of infection.

Methotrexate is unsuitable for the treatment of

RA in pregnant women (it has been used as an

abortifacient),  and  contraceptive  precautions

must be taken both during and for 6-12 months

after therapy. Methotrexate also damages sperma-

tozoa, and there should not be any attempt

made at conception by men within 6 months of

its use.

Azathioprine

This  agent  is  a  prodrug,  being  metabolized slowly to 6-mercaptopurine, a purine antagonist. Like methotrexate, azathioprine is widely used, but it has a slower onset of action.

In addition to their use in treating RA, these two drugs are used to treat severe, progressive psoriatic arthropathy (see Chapter 13). In this setting, azathioprine seems to be the more effec-

tive for the arthritic symptoms, and methotrexate for the skin lesions.

Cyclophosphamide

This nitrogen mustard is an effective DNA alkyl-

ating agent, with a rapid onset of action, though it causes a very high incidence of side-effects (90% of patients). Chlorambucil  is chemically related to cyclophosphamide, but tends to produce fewer short-term side-effects.

Azathioprine, cyclophosphamide, and sometimes

chlorambucil, are usually used as reserve agents.

Other immunomodulators

One promising development is the use of low-

dose  ciclosporin (see  Chapter 14),  which  can

improve all clinical parameters in severe RA.

Ciclosporin inhibits T cell activation and cytokine

production, and so is immunosuppressive, but is

not myelosuppressive. Because long-term treat-

ment is required, careful determinations of drug

blood levels and serum creatinine are essential to

avoid nephrotoxicity. This does not appear to be

as significant a problem with the low-dose regi-

mens that have been used in RA as in those used

for immunosuppression in organ transplanta-

tion. However, ciclosporin is usually reserved for

non-responders  or  those  intolerant  of  other

drugs. Two formulations with very different oral

bioavailabilities are available, so extra care is

needed in prescribing and dispensing.

Leflunomide is a reversible inhibitor of dihydro-

orotate dehydrogenase, an enzyme believed to

be   involved   in   the   autoimmune   processes

leading to RA. It appears to reduce the symptoms

and signs of RA significantly and retards joint

damage. However, it may cause severe hepato-

toxicity, so patients’ liver function should be

monitored   regularly,   especially   in   the   first

6 months of use. It has a very long half-life,

partly due to its active metabolite. Because it

has serious effects on germ-line cells, its long

persistence means that fertile women must take

strict contraceptive precautions before starting,

during, and for at least 2 years after stopping

treatment.

   Men   are   also   affected,   but   the

restriction period after their treatment is reduced

to at least 3 months. Plasma level monitoring

is   required   throughout.   The   long   half-life

also  means  that  any  serious  ADRs  will  also

be   prolonged.   A   washout   procedure   using

colestyramine or activated charcoal for 11 days is

available (see the manufacturer’s literature) to

limit  side-effects  and  to  reduce  the  waiting

period before attempting conception.

Sulfasalazine (SSZ)

This was introduced for the treatment of inflam-

matory bowl disease (IBD; see Chapter 3). In RA,

SSZ is as effective as penicillamine, and slightly

less so than gold, but has significant advantages

over both of these. It has a faster onset of action than the other agents and is less toxic, and so

has emerged as a first-line drug, like methotrexate, if NSAIDs are ineffective or are not tolerated, or if symptoms are moderate to severe.

Adverse  effects  (see  Table  12.13)  are  more

likely to occur in older patients, those who have

previously used other disease-modifying agents

and in slow acetylators. The most serious ADRs

are  due  to  myelosuppression,  e.g.  occasional

leucopenia, neutropenia and thrombocytopenia,

rarely agranulocytosis and aplastic anaemia, and

hypersensitivity   reactions,   e.g.   anaphylaxis,

Stevens-Johnson   syndrome   and   exfoliative

dermatitis. Thus full blood counts, including

differential white cell and platelet counts, should

be performed before starting treatment and at

monthly intervals for the first 3 months. Liver

function tests should be carried out at the same

time. The UK’s CSM recommends that patients

taking  SSZ  should  be  advised  to  report  any

unexplained bleeding, bruising, purpura, sore

throat, fever or malaise. Those with glucose-6-

phosphate   dehydrogenase   deficiency   may

develop haemolytic anaemia.

The UK product licence in RA is only for the

enteric-coated tablets, because trials were carried

out  with  that  dosage  form.  It  was  felt  that

patients who had been taking NSAIDs for some

time  might  be  more  susceptible  to  gastro-

intestinal disturbance, though this has not been

established, and the benefits of enteric coating

have been challenged for patients with IBD.

Though these points require confirmation, it is

reasonable   to   proceed   more   cautiously   in

patients who have experienced gastrointestinal

problems or have been taking other SAARDs and

to increase the dose at 14-day intervals, rather

than the recommended 7, up to the normal

maximum  of  2-3 g  daily.  However,  as  many

patients may withdraw from SSZ treatment as

from gold and penicillamine, mostly in the first

few months.

Patients should be warned that the urine may be coloured orange-yellow and that extended-wear contact lenses may be stained.

The activity of SSZ in RA, and its side-effects,

appears to be related primarily to the sulfapyri-

dine moiety and not to the salicylate compo-

nent, which provides the benefit in IBD. This

finding has prompted a re-investigation of the possibility of a bacterial aetiology for RA. As antimicrobials, the sulphonamides are competi-

tive antagonists of p-aminobenzoic acid, thus

inhibiting folate synthesis. Because human cells are unable to synthesize folate, this cannot be the basis of its anti-inflammatory action. Thus its mode of action is unknown.

Other SAARDs

Like most other SAARDs, these agents (gold, peni-

cillamine and antimalarials) have a slow onset of

action (unlike the NSAIDs), and it make take

4-6 months for their effectiveness to be fully

apparent.

Modes  of  action  in  RA.   These  are  mostly

unknown and several different mechanisms are

likely. Gold salts may inhibit the activation and

maturation of phagocytic and T cells, but their

anti-inflammatory activity in conditions other

than RA is minimal. The only certain activity of

penicillamine is as a chelating agent for heavy

metals, but this is not the basis for its action in

RA, in which it causes a marked reduction in the

levels of RFs (IgMs), by unknown mechanisms.

Antimalarials are known to have mild cytotoxic

activity.

Clinical activity.   Up to 70% of patients may

show improvement in both symptoms and the

objective indicators of disease activity, e.g. ESR,

CRP, RFs and anaemia, though the extent of such

improvement is very variable. Older SAARDs are

usually reserved for patients who are unrespon-

sive to methotrexate, SSZ or ciclosporin, or who are

intolerant of these. Because SAARDs are not cura-

tive, drug administration is necessary for as long

as  active  disease  persists  and  side-effects  are

tolerated.

Toxicity.   SAARDs are significantly more toxic

than NSAIDs, and so are used only in moderate

to severe and progressive disease. They require

careful monitoring with full haematological and

other tests as appropriate (see Table 12.13). It is

thus essential that patients are counselled care-

fully to ensure they appreciate fully the possible

advantages and disadvantages of treatment with

Rheumatoid arthritis      783

these drugs, and that they are prepared to co-

operate in the regular monitoring procedures

required.

Gold salts

These are available as both oral and IM formula-

tions. The most common side-effect with the

oral form is diarrhoea, but the range of toxicities

of the oral and IM agents is otherwise similar,

though the injectables are more troublesome.

Sodium aurothiomalate (gold sodium thioma-

late) is the only injectable gold salt available in

the UK and is equivalent to others that are avail-

able elsewhere, e.g. aurothioglucose. It is given by

deep IM injection, followed by gentle massage at

the injection site. Therapy is initiated with one

or more small test doses to minimize the possi-

bility of a major idiosyncratic adverse reaction.

Aurothiomalate is continued with weekly doses

until clinical improvement is apparent, usually

at 2-4 months, about 300-500 mg cumulative

dose, or there are significant side-effects (e.g.

rashes, blood dyscrasias, renal or hepatic toxi-

city). If a favourable response is seen, mainte-

nance is continued with a lower 2- to 4-weekly

dose, as long as the drug is tolerated, for up to

5 years   after   complete   remission.   If   relapse

occurs, treatment is stepped up to the initial

dose level until control is regained. Complete

relapse must be avoided, if possible, because

second courses of gold  are usually ineffective.

Treatment is stopped if no benefit occurs when a

total dose of 1 g is reached, usually after about

6 months.

Because of its toxicity, careful monitoring is mandatory, especially with sodium aurothiomalate (see Table 12.13).

Auranofin is the orally active agent. The initial

twice-daily dose is increased by 50%, to three

daily doses, after 6 months if the response is

inadequate. The bioavailability is about 25%, but

when  steady-state  serum  concentrations  are

reached after about 10 weeks, less than 1% of the

ingested dose is retained in the body. However,

serum levels do not correlate with activity or

side-effects.  Patients  can  be  transferred  from

parenteral  gold  to  auranofin  directly,  without

overlap   or   washout.   However,   auranofin  is

relatively little used.

Penicillamine

This oral agent is slightly less active than gold

and  has  a  similar  spectrum  of  side-effects,

though it is somewhat better tolerated. The daily

dose is increased every 4-8 weeks until clinical

improvement occurs, and the maintenance dose

is  then  held  at  that  level.  Administration  is

usually stopped if it has not produced benefit

after 1 year or if unacceptable side-effects or

toxicity occur.

Side-effects  may  occur  in  up  to  50%  of

patients, but often respond to dose reduction or

to temporary withdrawal of the drug (see Table

12.13). Minor side-effects, e.g. taste disturbance and nausea, usually clear with continued use.

Antimalarial drugs

Chloroquine and hydroxychloroquine are relatively

weak  antirheumatic  agents  that  are  used  in

rheumatology at about five times the dose used

for malaria prophylaxis. Although they are often

taken  as  antimalarials  for  prolonged  periods

without problems occurring, the combination of

the increased dose, possible greater susceptibility

of rheumatoid patients and the fact that anti-

rheumatic   treatment   is   likely   to   be   very

prolonged, greatly enhances the possibility of

significant side-effects (see BNF, Section 10.1.3),

notably rashes, myopathy and retinopathy.

Although retinopathy is rare in patients with

normal renal and hepatic function, fear of blind-

ness has limited the use of these drugs. Chloro-

quine, which is significantly the more toxic to

the retina, is used to treat RA only if treatment

with all other drugs has failed. The BNF advises

that retinal toxicity is very unlikely with doses of

hydroxychloroquine sulphate up to 4 mg/kg daily,

calculated on the basis of lean body weight in

obese patients. However, the maximum dose is

6.5 mg/kg   daily,   not   exceeding   a   total   of

400 mg/day.  Early  retinopathy  appears  to  be

reversible:  this  places  a  premium  on  patient

counselling to ensure that they appreciate the

importance of stopping treatment immediately

they are aware of any visual impairment, and of

prompt  ophthalmological  referral.  The  Royal

College of Ophthalmologists gives the following

advice, updated 2004:

•  Baseline assessment should include:

-  Establishment of normal renal and hepatic

            function.

-  Enquiry   for   visual   impairment   not

            corrected by glasses.

-  A recording of near visual acuity  (with

glasses if used) by a reading test.

-  A check by an optician if there is any visual

            impairment.

•           If  no  abnormality  is  detected,  commence

treatment  with  hydroxychloroquine  sulphate.

The  annual  evaluation  should  comprise  a simple enquiry about vision and repetition of the reading test.

•           Patients should:

-  Be referred to an ophthalmologist if any

            visual   impairment   or   eye   disease   is

detected at baseline assessment.

-  Stop treatment and consult the prescriber

            immediately if any change in visual acuity

or blurred vision develops.

-  If  long-term  treatment  is  required,  an

            ophthalmologist  should  be  involved  in

regular monitoring.

These drugs have rather complex pharmacoki-

netics,  with  a  wide  variation  in  elimination

half-life between patients. The route of excre-

tion  is  mainly  renal.  The  drugs  are  widely

distributed in the body and are very strongly

bound in the melanin-containing tissues of the

skin  and  the  eye.  They  are  very  persistent;

indeed,  chloroquine  has  been  reported  to  be

detectable in the retina 16 years after stopping

treatment!

There are anecdotal reports of benefit from

normal antimalarial doses, which are smaller

than those used in RA, when patients with RA travel to malarious areas and some patients with mild disease may benefit from such doses, with their preferable safety profile.

An advantage of these drugs is that they can be continued   in   pregnancy,   but   breastfeeding should be avoided if it is essential to continue with this treatment.

Mepacrine is a former antimalarial agent that has been superseded by more effective drugs. However, it is occasionally used to treat RA unre-

sponsive to other agents, discoid lupus erythe-

matosus (p. 800) and the protozoal infection

giardiasis (see Chapter 8).

Cytokine inhibitors

Currently three inhibitors of TNFa, a potent pro-

inflammatory  agent,  are  available.  These  are

adalimumab, etanercept and infliximab. Anakinra

inhibits interleukin-1 (IL-1) activity (Table 12.16).

Use

Adalimumab and etanercept are licensed for use in

severe active and progressive RA in patients who

have not been treated with methotrexate  and

have  failed  to  respond  adequately  to  other

SAARDs.  It  is  normally  used  together  with

methotrexate, but if the latter is inappropriate it

may be used alone.

Anakinra is licensed for use in combination

with  methotrexate  in  patients  who  have  not

responded to methotrexate alone. However, NICE

guidance is that it should not be used for the

routine management of RA, but only in patients

participating in a controlled long-term clinical

Rheumatoid arthritis      785

trial. Further, it is not recommended by the

Scottish Intercollegiate Guidelines Network.

There are special British Society for Rheuma-

tology and NICE guidelines for the use of these

agents and a special Biologics Registry has been

established by the British Paediatric Rheuma-

tology Group.

TNFa inhibitors

All of these agents are potent immunosuppres-

sives   and   may   trigger   latent   infections   by

Mycobacterium  tuberculosis  and  varicella-zoster

virus (VSV, see Chapter 8). Patients should there-

fore be checked for infections, especially latent

or active TB, before treatment commences. Any

active infection is a contra-indication until effec-

tive antimicrobial treatment has been instituted

and the disease is controlled. Further, patients

should be monitored for infections during and

after  treatment  and  should  be  instructed  to

report  any  signs  of  infection,  e.g.  persistent

cough, weight loss or fever for TB. If VSV infec-

tion is likely, varicella-zoster Ig is appropriate. If there are severe side-effects with these agents (Table 12.16) or no response within 3 months, treatment should be discontinued.

Other drugs and treatments

Many other approaches, mostly immunomodu-

latory, have been used in an attempt to control RA,   but   all   of   these   procedures   remain experimental.

The bisphosphonate disodium pamidronate has

been shown to be effective in AS (see below), and

may   prevent   joint   erosions   in   psoriatic

arthropathy (see above and Chapter 13), if used

early enough. Other bisphosphonates may act

similarly.

Thalidomide  (unlicensed  drug)  has  marked

anti-inflammatory    and    immunomodulatory

properties, suppressing superoxide and hydroxyl

free radical formation. It has shown good results

in RA within a few weeks, and remission may last

for years in some patients, though others may

relapse 2 months after stopping the drug. Some

patients may remain symptom-free with low-

dose maintenance treatment. The most common

side-effects are drowsiness, constipation and leg

oedema, with no evidence of neuropathy. The

well-known teratogenicity of thalidomide restricts

its use to males and postmenopausal females. It

is available through the named patient proce-

dure, and its application in RA should only be

undertaken under the supervision of a specialist

experienced in its use.

Intra-articular  injection  of  osmium  tetroxide

(osmic acid, preceded by a local anaesthetic plus

methylprednisolone) has been used for synovial

ablation, as an alternative to surgical synovec-

tomy. About 70% of patients with severe refrac-

tory joint problems may benefit, but pain may

recur. Complete regeneration of both synovial

membranes and nerve endings occurs after a

variable period.

Epoetin,  or  darbepoetin  (longer-acting),  may

correct the resistant anaemia of active disease.

Any  iron,  vitamin  B12 or  folate  deficiency

requires correction before commencing epoietin

treatment.

   In   addition   to   haematological

improvement these agents also reduce the ESR and  improve  well-being.  Use  in  RA  is  an unlicensed indication.

As in asthma (see Chapter 5), LT antagonists

are under investigation for use in the arthritides.

Tenidap  appears  to  have  multiple  actions:  it

inhibits COX and 5-lipoxygenase and also IL-1

formation and action. Injection of IL-1 receptor

antagonist protein (IRAP, IL-1ra) has improved

symptom scores in patients with active severe

RA, with minimal side-effects, though it is likely

to be immunogenic. A liposomal formulation of

the latter has been proposed for injection into

joints, but no products have yet been marketed.

Evidence   is   accumulating   that   synovial macrophages   and   fibroblasts   may   be   more important than T cells, and this is an active

research area.

One limitation of the biological agents is that

they are themselves immunogenic, so they need

to  produce  long-lasting  results  with  a  single

short course of treatment: repeat courses are

unlikely to succeed. However, because immuno-

genicity   is   highly   specific,   treatment   with

another   biological   agent   may   be   possible.

Further, although many of them are human, or

humanized,  recombinant  products  they  still

have numerous side-effects. For example, adali-

mumab, etanercept and infliximab can cause blood

pressure  abnormalities,  gastrointestinal  distur-

bances,  skin  rashes,  respiratory  and  central

nervous problems. Epoetin may produce severe

hypertension,  thromboembolism,  RBC  aplasia

and skin reactions. These agents should be used

only by specialists experienced in their use.

Levamisole,  an  immunostimulant  ascaricide used  against  roundworm  infections,  is  avail-

able on a named patient basis, and dapsone,

which has both immunosuppressive and pro-

inflammatory properties, have also been used. Both are unlicensed indications.

Yttrium-90  radiocolloid  has  been  injected

into  inflamed  joints  as  a  local  cytotoxic  and

immunosuppressive agent, with variable success.

Tetracycline antibiotics, e.g. minocycline, have

been used on the hypothesis that RA is caused

by  mycoplasma  infections,  or  is  associated

with  them.  Although  some  success  has  been

achieved  it  is  unclear  whether  this  is  due  to

their   antimicrobial   or   immunomodulatory properties or to inhibition of phospholipase A2 and collagenases.

It has also been suggested, but unproven, that

selenium  supplementation  is  beneficial.  Sele-

nium  is  an  essential  trace  element  and  a

component  of  glutathione  reductase,  but  the

recommended  daily  allowance  should  not  be

exceeded because it is very toxic in overdose. This

is  difficult  to  manage  because  the  selenium

content of drinking water varies widely with the

locality, so the local water supply utility should be

consulted. Selenium supplements are available

only via ‘health food’ suppliers.

Fish oil supplements, e.g. Maxepa, may help some patients with RA, but not OA.

Surgery

Orthopaedic  surgery  has  a  great  deal  to  offer in  the  management  of  local  problems  when medical management has failed to give adequate control. However, it is important for surgery to be  performed  before  joint  damage  is  so  far advanced that good function cannot be restored. The most successful procedures are:

•  Arthroplasty.

-  Total hip replacement (success rate    95%).

–  Total knee replacement (success rate            90%).

•  Removal  of  metatarsal  heads,  for  eroded,

subluxed MTP joints.

•  Elbow synovectomy and removal of the radial

            head.

Other procedures include hand and wrist surgery,

especially for tendon release, and fusion of the

cervical  spine  if  instability  causes  spinal  cord

compression. Arthroplasty of the PIP joints has

successfully restored hand function. Operations

on other joints are less common. Arthrodesis and

osteotomy (p. 761) are used occasionally.

Juvenile idiopathic chronic arthritis

Definition and epidemiology

Juvenile idiopathic chronic arthritis (JIA) is the

neutral, catch-all classification of conditions that

used to be called juvenile chronic arthritis, juve-

Rheumatoid arthritis      787

nile RA and Still’s disease. In only about 5% of

patients does the condition resemble adult RA.

In the remainder it is clinically and pathologi-

cally distinct from RA, although there are certain

similarities.

It may be defined as persistent joint swelling

starting  before  the  age  of 16,  other  diseases

being  excluded.  However,  some  rheumatolo-

gists define it more tightly as synovitis occur-

ring in at least 1-4 joints persisting for at least

6 weeks, or a lesser number of joints confirmed by  biopsy.  Additional  joints  may  become

involved after some months. The condition is variable  in  presentation  and  its  true  nature may become apparent only some time after the first appearance of symptoms.

The UK incidence is about 1 in 10 000, with a prevalence of 1 in 1000, making it one of the

commonest chronic childhood diseases, and JIA is a major cause of childhood disability.

Aetiology and clinical features

The condition often presents as swelling of a

large joint, e.g. knee, ankle or wrist joint, in that order of frequency. Arthritis of a single small joint  is  unusual,  but  the  fingers,  toes,  hip, shoulder, spine and jaw may become involved, usually assymmetrically (see RA, p. 764). Knee involvement may sometimes be associated with a Baker’s cyst (see p. 766).

Fever, lethargy, weakness and discomfort often

occur, but significant pain is unusual, though

young children often cannot give a good history.

Diagnosis, management and prognosis

Diagnosis  may  be  difficult  unless  the  clini-

cian  is  familiar  with  normal  musculoskeletal development  in  children.

The five or so disease states encompassed by

JIA  are  currently  classified  according  to  the

pattern of clinical presentation, but the bound-

aries between the various groups are difficult to

define.   These   groups   are   classified   by   the

European League Against Rheumatism as given

below.

•           Systemic onset:

-           20% of patients.

–  Usually starts in early childhood, but onset

            is possible up to the age of 17.

-  Often infection-associated.

-  High fever, systemic symptoms and rash

            that often remit after a few weeks.

-  May   be   oligoarticular   or   widespread.

Children   with   polyarthritis   have   poor prognosis.

•           Persistent oligoarticular:

-  One to four joints involved.

-           50% of patients, mainly girls under 5 years,

F:M      5:1.

–  Associated with HLA-B27 in older boys, but

            this may be an early indication of AS (p.

789). Other HLA-DR associations suggest

the possibility of UC (see Chapter 3). Anti-

nuclear antibodies (ANA) are present in

about 75% of this group, but may also

suggest the possibility of SLE (p. 798). Most

develop one of the seronegative spondylo-

arthritides (see below) and possibly IBD

(see Chapter 3).

-  Probable increased risk for anterior uveitis

            (20% of patients in this group). Early diag-

nosis and treatment are essential to avoid sight problems or blindness.

•           Extended oligoarticular, i.e. starts as oligoar-

ticular and progresses to further joint involve-

ment   with   anterior   uveitis.   Prognosis   is

poorer than in the persistent oligoarticular

group.

•           Polyarticular  (RF   negative).  25-30%   of

patients,  usually  girls  under  5 years,  with

symmetrical  arthritis  of  upper  and  lower limbs.  Eye  and  growth  problems  may  be significant.

•           Polyarticular (RF positive). Presents in older

children and resembles adult RA, but erosions

occur rapidly (see above).

•           Psoriatic  juvenile  onset  arthritis.  Similar

arthritic pattern to the extended oligoartic-

ular group, which may precede psoriasis by many years (see Chapter 13).

•           Enthesis-related arthritis. This is probably a

precursor to adult AS (see below). It mostly

affects boys over 8 years, and initially affects

the feet and knees. The characteristic pelvic

and spinal symptoms of AS may appear later.

The   diagnosis   and   management   of   JIA   is

normally carried out in specialist centres, with

the involvement of a multidisciplinary team.

Diagnosis is made solely on clinical grounds and

may initially be difficult because of the variety of

systemic diseases that can cause joint symptoms

(see Table 12.3). However extensive investiga-

tion, although not required for diagnosis, may

be needed to exclude these possibilities, espe-

cially septic arthritis. Marked systemic symp-

toms, e.g. fever, weight loss, bone and night

pain, may indicate an alternative diagnosis. A

single inflamed joint requires joint aspiration to

exclude the possibility of infection or crystal

deposition disease (p. 791).

Generally, the outlook is better than in adult RA of comparable joint involvement, and about 75% of patients have no significant residual

disability. Occasionally, amyloid disease (p. 807) and eye involvement may be severe.

The principal aim of management is to ensure that there is a minimum of physical, educational and social disability while the symptoms are

present   and   when   the   disease   eventually becomes inactive.

Pharmacotherapy

This resembles that in adult RA, with appropriate

allowance for the fact that children are particu-

larly vulnerable to blood dyscrasias and develop-

mental abnormalities. Aspirin must not be used

in children and adolescents under 16 years old

because of the risk of Reye’s syndrome until an

unequivocal   non-febrile   diagnosis   has   been

made. Paracetamol (acetaminophen) is preferred.

NSAIDs (usually diclofenac, ibuprofen, naproxen or

piroxicam) are the usual basis of treatment.

Corticosteroids,   methotrexate   and   hydroxy-

chloroquine  are used as a last resort in severe

systemic disease, but corticosteroids may be used

to manage symptoms until methotrexate  gives

relief. The anti-TNF agent etanercept (p. 785) is

the only anticytokine that is licensed for use

in JIA.

Seronegative spondarthritides

This group of inflammatory diseases has two

features in common. As the name implies, they affect  the  spine  and  rheumatoid  factors  are absent. Other common features are:

•  Sacroiliitis, causing buttock pain.

•  Enthesitis, i.e. inflammation of the points of

            insertion of tendons or ligaments into the

bones (Figure 12.1).

•  Associations with:

-  Psoriasiform skin lesions (see Chapter 13).

-  IBD (see Chapter 3).

-  Eye inflammation, i.e. conjunctivitis and

            iritis.

-  Reactive arthritis (see below). They include:

•  Ankylosing spondylitis.

•  Reiter’s syndrome (p. 809).

•  Psoriatic arthritis (see Chapter 13).

•  Enteropathic  arthritis,  associated  with  IBD

(see Chapter 3).

Ankylosing spondylitis

Definition and epidemiology

Ankylosing  spondylitis  (AS)  is  a  seronegative,

chronic spondyloarthritis, i.e. it is an inflamma-

tory disease, primarily involving the spine, even-

tually leading to fusion of the vertebrae. Young

adult males are the most likely to have significant

symptoms.

The  disease  affects  about  15/10 000  of  UK

Caucasian populations with a male:female ratio

for incidence of about 4:1 for moderate to severe

disease, though mild disease is more common in

women, the overall M:F ratio being about 2:1. AS

is less common in East Asians and Blacks, with a

prevalence about half that in Caucasians. Onset

is  mostly  in  the 20-40-year  age  group,  the

principal  age  of  onset  being  20-25 years,  but

the  inflammatory  symptoms  may  remit  in

older patients. However, residual joint damage

persists.  Some 10%  of  first-degree  relatives

also have AS, and there is a familial association

with the other diseases mentioned above (see

Table 12.2).

Aetiology

This is unknown, but HLA-B27 occurs in more

than 95% of Caucasian patients with uncompli-

cated AS showing no other symptoms, whereas

its prevalence in the general population is about

6%. HLA-B27 occurs infrequently in Black races

and Japanese, who rarely suffer from AS, and the

frequency of this gene in patients suffering from

both AS and psoriasis or IBD is reduced to 60%.

If HLA-B2 occurs in Blacks it confers an increased

risk. There are more than 10 variants of the HLA-

B27 gene, some of which clearly confer a predis-

position to develop these diseases, though others

seem to be protective. However, AS appears to

be  a  multigenic  condition,  with  other  MHC

associations.

There is an environmental component, prob-

ably an unidentified infective agent. HLA-B27

has an important role in antigen presentation to

T cells. One small trial has indeed shown the

presence of cytotoxic (CD8 ) T cells that recog-

nize   arthritogenic   bacteria (e.g.   Salmonella,

Yersinia)  and  possibly  also  auto-antigens  in

arthritic  joints,  and  kill  infected  cell  lines.

A   suggestion   that   Klebsiella   pneumoniae  is

implicated has been disputed.

Pathology

The hallmark of AS is bilateral inflammation of

the  non-synovial  sacroiliac  joints  at  the  base

of the spine. The inflamed areas are infiltrated

with  mature  lymphocytes,  including  plasma

cells. The synovitis that occurs at other joints is

similar to that in RA, but enthesopathy (inflam-

mation of the points of attachment of tendons to bone) is a prominent feature. The interverte-

bral ligaments are especially affected. There is a high tendency for ankylosis and calcification, usually a variable ascending spinal ankylosis, and  the  whole  spine  may  become  rigid  in patients with advanced disease.

Clinical features, diagnosis and complications

Onset is usually insidious, initially with episodic

low back pain and stiffness, especially in the

morning. Much of this arises from pelvic joint

inflammation,  especially  the  sacroiliac  joints,

causing moderate to severe pain and stiffness in

the buttocks and lower back. The pain may alter-

nate between the two sides. Systemic malaise,

tiredness, anorexia and weight loss also occur,

but are less severe than in RA. Some 20% of

patients, usually the younger ones, present with

peripheral joint problems.

Diagnosis is based primarily on the clinical

features and X-rays.

Plantar  fasciitis,  i.e.  inflammation  of  the

enthesis of the plantar fascia, the long, tough

ligament that supports the arch of the foot and

connects the calcaneum (heel bone) and the

metatarsal bases. It is subjected to considerable

stress, because it has to stretch with each take-off

from the ball of the foot when walking, running

or jumping. It is commonly associated with a

plantar spur, an outgrowth from the forward

edge of calcaneum, due to excessive traction on

the  enthesis.  Plantar  fasciitis  is  common  in

runners whose shoes do not have adequate cush-

ioning, in people with flat feet who are standing

for most of the day and in AS.

Spinal   rigidity  compromises   posture   and

movement,  and  respiration  becomes  wholly

diaphragmatic  if  the  rib  articulations  in  the

thoracic  spine  are  severely  affected.  Serious

spinal fractures can occur in patients with rigid

spines.

Iritis (anterior uveitis) may occur in 25% of patients, the severity being unrelated to that of the arthropathy.

Management

The aims of management are the relief of pain, with   anti-inflammatory   analgesics,   and   the minimization  of  stiffness  and  deformity,  by physiotherapy.

Early diagnosis and forceful education about

the value of a regular programme of morning

exercises, to prevent the formation of calcified

bridges  between  vertebrae,  are  the  basis  of

successful   management.   Plantar   fasciitis   is

treated by relieving pressure on the enthesis with

a suitable pad and ensuring suitable footwear.

Rest and a local injection of corticosteroid may

also help.

However, without good pain management it may  be  impossible  to  maintain  an  effective exercise regimen.

NSAIDs are the mainstay of symptomatic treat-

ment and are very effective if used in full dosage.

Aceclofenac and meloxicam are licensed for the

treatment of AS and are probably the drugs of

first choice. Indometacin, one of the most potent,

is often used, though any NSAID that is tolerated

will usually be satisfactory. A COX-2 inhibitor

that has relatively low cardiovascular toxicity,

e.g. lumiracoxib (see above), may be preferable if

a patient is at risk of gastrotoxicity and it proves

effective.

Once improvement has occurred, the dose is

stepped down to the minimum necessary to give

reasonable control of symptoms, and this level

should be maintained as a permanent prophy-

lactic   dose,   regardless   of   apparent   disease

activity, provided that side-effects are not too

obtrusive.

A long-acting NSAID (see above), or a modified-

release formulation, taken at night may reduce the morning stiffness.

A   bisphosphonate,    e.g.    standard-dose

monthly  IV  disodium  pamidronate,  has  been

shown to be effective in patients who do not

respond  to  NSAIDs.  The  bisphosphonates  are

used widely to treat osteoporosis because they

inhibit  bone  resorption  and  so  reduce  bone

turnover. This approach is logical to prevent the

development of osteophytes and the abnormal

bone growth that leads to spinal ankylosis. Any

of  the  other  bisphosphonates,  e.g.  alendronic

acid or risedronate sodium, should act similarly, but are not yet proven to be effective. However, this is likely, and they would obviate the need for repeated IV infusions. This advance in phar-

macotherapy  is  very  welcome,  though  the

benefit demonstrated so far is modest. These are unlicensed indications.

Cytokine (TNFa) inhibitors, e.g. adalimumab,

etanercept and infliximab, have been shown to give

significant improvement (see above; also in psori-

atic arthropathy), but etanercept and infliximab are

the only ones licensed for use in AS. They are

approved for adult patients with severe symp-

toms that have not responded to conventional

agents. Cost, and the necessity for repeated SC

injections (etanercept) or IV infusions (infliximab)

are significant problems. The development of

antibodies limits their utility (see above). They

should be discontinued if there is no response

within 6 weeks of the initial injection or infusion.

SAARDs, e.g. gold and penicillamine (see above),

are not generally useful. SSZ or methotrexate may

help   to   control   any   associated   peripheral

arthropathy,  but  have  little  effect  on  spinal

inflammation.

Common features and pathology           791

Local  corticosteroid  injections  may  also  be helpful   for   peripheral   joint   problems   or enthesopathies.

Active physiotherapy, with a planned morning

exercise programme, is invaluable for the mini-

mization of spinal rigidity, the maintenance of

function and to prevent spinal deformity. Swim-

ming is especially recommended because the

increased body buoyancy permits exercise but

minimizes joint stress. Rest and immobility, e.g.

splinting, increase the risk of deformity.

Surgery  (arthroplasty,   especially   total   hip replacement) may be necessary for severe hip involvement, and to manage the vertebral frac-

tures that occur in a rigid and osteoporotic spine. Other spinal procedures are hazardous.

A single course of spinal radiotherapy is used

occasionally, and is anti-inflammatory within

the  radiation  target  area.  Repeat  courses  are

contra-indicated because they produce a high

incidence of leukaemia and soft tissue tumours.

The prognosis is relatively good: at least 80% of patients are able to maintain employment and there is a normal lifespan.

Crystal deposition arthropathies

Common features and pathology

and promote the release from neutrophils of a

The diseases in this group share the feature of

deposition  of  crystals  of  metabolites  in  the

joints, with consequent inflammation and joint

damage. Their principal characteristics are given

in Table 12.17.

It is not known what factors promote the

deposition of crystals in the synovial fluid. Once

there,  the  positively-charged  crystals  become

coated with negatively-charged proteins, espe-

cially IgG and phospholipids, thus enhancing

phagocytosis by macrophages. This results in

the  liberation  of  lysosomal  and  cytoplasmic

enzymes, which attack the synovial membrane,

specific pro-inflammatory glycoprotein. Injec-

tion of this glycoprotein into joints produces

symptoms that are indistinguishable from those of gout. Chemotactic factors are also released and   promote   leucocyte   recruitment,   thus multiplying the effect.

Similar effects can be produced by a variety of crystals or other substances introduced into the joint space, e.g. cholesterol and corticosteroid suspensions injected to relieve joint inflamma-

tion. Exacerbations of osteoarthritis may be due to microcrystals of hydroxyapatite released from the bone, causing a similar effect

Gout is an arthropathy resulting from the depo-

sition of crystals of monosodium urate in the

joints and surrounding tissues.

Aetiology and epidemiology

Gout is the result of hyperuricaemia, though it

is  difficult  to  define  the  latter  satisfactorily

because there is a continuous normal distribu-

tion of serum urate levels. The solubility of uric

acid in serum is about 0.38 mmol/L (6.3 mg/dL).

The 95% population limits are 0.18-0.42 mmol/L

(3.0-7.0 mg/dL) for men and 0.13-0.34 mmol/L

(2.2-5.7 mg/dL) for women. Consequently, the

serum is supersaturated with urate in about 3%

of UK men and gout is overwhelmingly a male

problem (90-95% of cases). Fortunately, only a

minority of men with high serum urate levels

show clinical symptoms, but it is not clear why

this is so. Further, some patients with gout have

relatively  low  urate  levels.  However,  clinical

symptoms are overwhelmingly associated with

hyperuricaemia.

A simplified outline of uric acid metabolism is

given in Figure 12.10, which shows that hyper-

uricaemia  may  result  either  from  excessive

production of uric acid or from reduced renal

elimination, the latter being the most common

cause.  In  primary  gout  there  are  numerous

factors operating on a background of genetic

predisposition  to  produce  clinical  symptoms.

The causes of secondary hyperuricaemia and

gout are given in Table 12.18. Treatment with

thiazide diuretics often causes some degree of

hyperuricaemia, but fortunately does not often

cause an attack of gout. However, diuretics are a

relatively  common  cause  of  gout  in  elderly

women.

The prevalence of gout varies widely, being about 0.3% in the UK and about 2% in France. In Maoris, who have a strong genetic predisposition, it is about 10%.

Pathology

If hyperuricaemia results in the crystallization of

monosodium  urate  in  synovial  fluid,  small,

needle-shaped crystals can also be seen within

the leucocytes, causing the release of lysosomal

enzymes.

If untreated, gout leads initially to the deposi-

tion of urate crystals on the surface of the carti-

lage,  with  subsequent  cartilage  damage  and

finally to the deposition of masses of urate crys-

tals within and around the joints, producing

extensive joint destruction. Nodular accretions

of monosodium urate (tophi) may occur. A char-

acteristic  site  for  these  is  the  cartilaginous

margin (helix) of the pinna of the ear, but they

occur also on tendons and in bursae associated

with the affected joints. Tophi are granuloma-

tous structures, containing the urate crystals in

a  protein-lipid-polysaccharide  matrix,  which

eventually become calcified. In long-standing

chronic gout, joint erosions occur that contain

calcified  deposits.  Urate  deposition  tends  to

occur in peripheral joints where the temperature

is   lower   than   the   core   body   temperature,

resulting in reduced urate solubility: cartilage is

avascular, and so has no warming blood supply, and the affected joints are normally cool in

unaffected individuals.

The precipitation of monosodium urate from

urine within the kidney, or of uric acid under

acid conditions, may result in the formation of

renal stones, possibly causing urinary-tract infec-

tion  and  obstruction  and  renal  failure (see

Chapter 14).

Clinical features

Acute gout

In some 75% of cases a first attack affects the big

toe,  and  this  form  is  called  podagra.  Other

common  sites  are  the  ankles,  knees,  elbows,

wrists   and   fingers.   An   attack   often   starts

overnight or a few hours after an acutely stressful

episode,  e.g.  MI  or  major  surgery.  The  joint

becomes exquisitely painful and inflamed and

the overlying skin may flake over the next few hours: this sign plus the symptoms is almost

conclusive. The attack subsides spontaneously over a few days or weeks, though most sufferers seek treatment. There may be no recurrence, or a second attack may follow after a variable period ranging from days to years.

Attacks tend to be more severe in younger

patients, aged under 30 years.

Chronic gout

This is uncommon, except in patients who are

non-compliant with medication, or those with a

metabolic  abnormality.  Acute  episodes  occur

with  increasing  frequency,  leading  to  tophus

formation and permanent joint damage. Renal

impairment  increases  with  time  and  this  is

aggravated in about one-third of patients by

associated  hypertension,  though  the  latter  is

probably  a  reflection  of  the  kidney  damage, rather than a cause.

Diagnosis

This  is  based  on  the  symptoms  and  signs

outlined above, and the finding of a high serum

urate level. However, the association of the latter

with joint pain does not necessarily imply a

diagnosis of gout: because 90% of people with

hyperuricaemia do not have gout; there may be

a  coincidental  association  of  hyperuricaemia

with a different arthritic problem. However, gout

is  very  unlikely  if  the  serum  urate  level  is

÷3 mmol/L (5 mg/dL).

The  principal  diagnostic  confusion  occurs

with  septic  arthritis.  The  diagnosis  can  be

confirmed  unequivocally  only  by  the  micro-

scopic demonstration of urate crystals in the

synovial fluid of the affected joint, but this is

necessary only in doubtful cases and it may be

difficult to obtain a sample. Aspiration of small

joints is impossibly painful during an attack.

Three-quarters  of  patients  with  gout  have features of the metabolic syndrome (formerly called ‘syndrome X’; see Chapter 9), i.e.:

•  Glucose intolerance.

•  Hyperinsulinaemia and insulin resistance.

•  Central obesity (waist circumference 94 cm

(37 in) in men,  80 cm (32 in) in women. •  Hypertriglyceridaemia.

•  Low HDL level.

•  Hypercortisolaemia.

•  High small dense, LDL cholesterol levels.

This is linked to the ‘western’ lifestyle, with a

high saturated fat diet and inadequate physical

activity, though genetic factors are thought to be

responsible for about 70% of the variance in fat

distribution.

The implication is that patients should aim for

a  healthy  lifestyle,  regular  physical  activity

(walking  rapidly  for  at  least 30 min  daily),

healthy weight (BMI 21-22 kg/m2) and waist

circumference ÷94 cm   in   men, ÷80 cm   in

women.

Those with a familial history of gout should therefore be educated at an early age to comply with these principles.

Management

Aim

The aims of management of gout are:

•  The prompt relief of pain in an acute attack

            and its rapid termination.

•  To eliminate secondary causes, if possible.

•  The prevention of recurrence and complica-

tions (e.g. renal stones and renal failure, joint damage and the formation of tophi) in chronic sufferers by correction of hyperuricaemia.

General measures

Acute attacks

The approach is to:

•  Rest the affected joint (splinting may help in

            the severe acute stage).

•  Maintain a high fluid intake to reduce hyper-                                                            

            uricaemia  and  prevent  renal  urate  stone

formation.

Chronic gout

The approach is to:

•  Maintain a high fluid intake, to prevent urate

            crystallization in the kidney.

•  Lose weight if obese, to reduce tissue mass

            and  so  urate  production  and  to  reduce

loading on joints (see above). •  Provide dietary advice:

-  Avoid alcohol, which reduces urate solu-

            bility in the serum, and especially beer,

which is high in purines.

-  Reduce   carbohydrate   intake,   which   is

            protein-sparing and so promotes protein

build-up in the tissues.

-  Avoid  foods  rich  in  purines,  e.g.  offal,

            shellfish, spinach.

•  Endoscopic shock wave lithotripsy etc. (see

            Chapter 14) for urate kidney stones.

However, even a strict low-purine diet has only a small effect, reducing the serum urate level by about 10-15%.

Gout     795

Pharmacotherapy

Acute attacks

Immediate initiation of treatment is important,

and NSAIDs are given as early as possible, unless

these are contra-indicated (see below). High-dose

indometacin  is  often  the  drug  of  choice,  e.g.

75 mg immediately, 50 mg 6- to 8-hourly on the

first and second days, 25 mg four times daily on

the third day, then slowly tapering to zero over

10-14 days. Symptoms usually remit completely

after 5-7 days. In the elderly, or if indometacin is

contra-indicated or is not well tolerated, a choice

may   be   made   from   naproxen,   acelofenac,

diclofenol, etoricoxib, ketoprofen  and sulindac  at

clinically  comparable  dosage,  depending  on

acceptability to the patient. Azapropazone may be

needed if other agents are ineffective.

Etoricoxib is the only COX-2 inhibitor licensed

for the management of acute gout and is given

only once daily. Because of the relatively short

period of treatment, the risk of cardiovascular

problems is much reduced. Because it is more

liable than other NSAIDs to cause hypertension,

or   exacerbate   it,   etoricoxib  should   not   be

prescribed to patients with uncontrolled blood

pressure. If etoricoxib is nevertheless considered

advisable, because of its relatively low incidence

of upper gastrointestinal side-effects, full blood

pressure monitoring should be carried out.

Occasionally, moderately potent opioids (see Chapter 7) may need to be added to control

intolerable pain.

If NSAIDs are not tolerated, or if there is renal

impairment (which may accompany gout), a

history  of  peptic  ulceration,  hypertension  or

heart failure, or if the patient is taking warfarin,

the action of which is potentiated by NSAIDs,

then colchicine is indicated. This is very effective:

it suppresses macrophage recruitment and multi-

plication and specifically inhibits production of

the  pro-inflammatory  glycoprotein.  The  pain

normally starts to remit in 12-24 h and may be

completely  controlled  in 2-3 days.  However,

colchicine is more toxic than NSAIDs and tends to

cause diarrhoea and vomiting: these side-effects

are often used as an index of adequate dosage.

Colchicine has been used at the outset as an aid to

diagnosis, but a prompt response to it is not

specific. Pseudogout, which is less common (see

below), tendon calcification and other condi-

tions with symptoms similar to gout, which may cause diagnostic difficulty, also respond.

In resistant cases, systemic injections of corti-

cotrophin  or   a   corticosteroid   may   be   used. Steroids may also be injected into an affected large joint (unlicensed indication) in the course of aspiration for diagnostic purposes, but this

may be impossibly painful.

Cytokine inhibitors (see p. 785) have not yet

been shown to be effective, and cost would be a

problem,  but  this  may  be  acceptable  in  the

short term for a very severe attack. Aspirin and

salicylates  have  no  place  in  the  treatment  of

gout because they reduce urate excretion and

antagonise the action of uricosuric agents.

Paradoxically, allopurinol or a uricosuric agent

(see below) must not be started during an acute

attack  because  they  will  often  worsen  and

prolong   symptoms,   probably   by   mobilizing

urate from deposits. It is known that sudden

changes in serum urate levels tend to precipitate

attacks. Allopurinol also interferes with uric acid

excretion.  If  an  acute  attack  occurs  during

existing urate-lowering treatment, the treatment

should  be  maintained,  and  the  acute  attack

treated normally.

Interval control

This  is  management  of  the  patient  in  the

intervals between attacks. It includes:

•  Control  of  precipitating  and  aggravating

            factors, e.g. diet, alcohol intake, obesity and

drugs,  especially  thiazide  diuretics:  these must  be  dealt  with  regardless  of  possible pharmacotherapy.

•  Evaluation of the need for pharmacotherapy,

            e.g. management of hyperuricaemia, other

antigout drugs.

An  isolated  attack  is  not  an  indication  for

prophylactic pharmacotherapy unless the serum

urate level is consistently very high (it is usually

high,     0.60 mmol/L [ 10 mg/dL]) in an acute

attack), there is evidence of urate nephropathy

or there are tophi. The disadvantages of long-

term prophylaxis need to be weighed carefully

before lifelong treatment is initiated.

Infrequent   attacks   are   best   managed   by

general measures and high-dose NSAIDs, as in an

acute attack, because otherwise therapy needs to

be lifelong. Continuous low-dose colchicine  is

used occasionally, though it is contra-indicated

in pregnancy (it is an antimitotic agent) and if a

mother is breastfeeding. Colchicine must be used

cautiously in the elderly and if there is any suspi-

cion  or  evidence  of  gastrointestinal,  cardiac,

hepatic or renal impairment.

Management of hyperuricaemia

If there are specific indications, i.e. more than two attacks in a year, tophi, joint or renal damage, or if the patient insists on treatment, lifelong

prophylactic pharmacotherapy is considered at least 3 weeks after an initial attack has subsided; earlier treatment may prolong the attack. Urate-

lowering drugs are used, two methods being avail-

able: either by reducing urate production or by increasing renal urate excretion.

The   target   serum   urate   level   is   about

0.25 mmol/L (4.2 mg/dL), maintained over long

periods to achieve regression of tophi. Because

rapid reduction of serum urate levels tends to

provoke attacks of gout, prophylactic colchicine

or NSAID cover should be given for the first

3-6 months of both treatment modes, continued

if necessary until urate levels are normalized.

Reducing   urate   production.   Allopurinol  is

currently the drug of choice for this purpose. It

is a xanthine oxidase inhibitor (Figure 12.10)

that also inhibits purine biosynthesis. Treatment

should be initiated at a low dose, increasing

gradually until urate levels are normalized. An

adequate  fluid  intake (2-3 L/day)  should  be

maintained to minimize the possibility of kidney

stone formation. Because allopurinol is excreted

renally the dose has to be reduced if renal func-

tion is impaired. The dose required is based on

the  creatinine  clearance.  In  severe  hyperuri-

caemia and normal renal function the daily dose

may be as high 700-900 mg, but in severe renal

failure (see Chapter 14) this may have to be

reduced to 100 mg three times per week.

Allopurinol  also   reduces   the   formation   of calcium oxalate renal stones.

A new non-purine xanthine oxidase inhibitor,

febuxostat, is in a late stage of development.

Although apparently well tolerated in the short

term, it remains to be seen whether it will prove

sufficiently non-toxic to be taken over many

years: treatment of hyperuricaemia is normally

life-long.

Secondary  hyperuricaemia.   Allopurinol  may also be used to prevent the acute hyperuricaemia caused by the rapid breakdown of abnormally high numbers of leucocytes when cytotoxic treat-

ment is instituted for treating leukaemias and

lymphomas (see Chapter 10).

The  recombinant  urate  oxidase,  rasburicase,

oxidises uric acid to allantoin, which is water

soluble and so is excreted readily via the kidney,

is used similarly. It acts rapidly, e.g. in a phase III

study the plasma concentration fell by 86% in

4h, and steady state is achieved in 2-3 days.

Treatment  with  these  agents  should  be

commenced before cytotoxic treatment or radio-

therapy  is  initiated,  if  possible,  because  both

treatments may cause rapid tissue and leucocyte

breakdown, leading to increased urate produc-

tion.

Side-effects  and  interactions.   Allopurinol  is

usually well tolerated, the most common side-

effects being rashes, sometimes with fever. The

dosage should be reduced in renal or hepatic

impairment.   In   the   former   case   an   active

metabolite,  oxypurinol,  may  accumulate  and

precipitate the potentially life-threatening allo-

purinol  hypersensitivity  syndrome.  Thus  if

rashes occur, treatment must be stopped imme-

diately, because they may herald a potentially

severe  reaction.  Treatment  may  be  restarted

cautiously following a mild skin reaction, but

recurrence is an absolute contra-indication to

further use, as is an initially severe reaction.

Gastrointestinal discomfort may be reduced by

taking allopurinol after meals. Because the metab-

olism of xanthine is suppressed, high concentra-

tions of the latter may be excreted and may

crystallize in the urinary tract, hence the need

for a high fluid intake, especially in the early

stages of treatment.

The activity of the cytotoxic purine analogues

azathioprine and mercaptopurine is potentiated by

the use of allopurinol, which also inhibits their

metabolism, so if these drugs are being used their

Gout     797

dose should be reduced to one-quarter if allop-

urinol is used concurrently.

The action of oral anticoagulants may also be potentiated, so particular attention needs to be paid to prothrombin time/INR measurements (see Chapter 11). However, the clinical significance of this interaction is doubtful.

Because   hydrogen   peroxide   is   produced,

rasburicase  may  produce  haemolytic  anaemia

and  methaemoglobinaemia  in  patients  with

G6PD  deficiency  or  hereditery  anaemia (see

Chapter 11). Consequently rasburicase treatment

should  be supervised by an experienced haema-

tological  oncologist.  Otherwise,  rasburicase  is

well-tolerated, sometimes causing fever and, less

commonly, gastrointestinal disturbances. Because

it is a protein, it may cause allergic reactions.

Increased renal excretion is achieved with the

uricosuric agent, sulfinpyrazone. This inhibits

renal tubular reabsorption of uric acid, and so is

ineffective   if   renal   function   is   impaired.

Although used less nowadays because it is more

toxic  than  allopurinol,  it  retains  a  place  for

patients intolerant of the latter. Initiation of

treatment is undertaken with the same precau-

tions as for allopurinol. Sulfinpyrazone may also be

used  in  addition  to  allopurinol  if  the  latter

provides  inadequate  control  of  serum  urate

levels.

Although probenecid has been used similarly to sulfinpyrazone, and is included in the BNF in the ‘gout’ section, it is now available only on a named-

patient basis for the prevention of nephrotoxicity associated with the antiviral drug cidofovir.

Side-effects and interactions.   Sulfinpyrazone is

generally well tolerated, but should be used care-

fully if patients have peptic ulceration or renal

impairment,   because   it   may   cause   gastro-

intestinal  distress  and  its  action  depends  on

adequate renal function. It must not be given

with aspirin or salicylates, which antagonize its

action in the renal tubules. The urine should be

alkalinized, e.g. with citrates, if the uric acid

level is high, to give the maximum solubility of

uric acid and prevent urate stone formation. A

night-time  dose  of  acetazolamide,  a  carbonic

anhydrase inhibitor and weak diuretic, has also

been used to alkalinize the urine (unlicensed

application).  Gastrointestinal  disorders  occur

most commonly, but hypersensitivity reactions

and blood dyscrasias may also occur: regular

blood counts are advisable with sulfinpyrazone.

A new uricosuric agent, benzbromarone, has the advantage that it retains its activity in moderate renal impairment. It is not currently licensed in theUK, but importation is available through the named-patient procedure.

Research is under way to see whether it is

possible to increase urate excretion by antago-

nizing the urate transporter-1 (URAT1) molecule that is responsible for the tubular reabsorption of urate in the kidney.

Pyrophosphate arthropathy

Pyrophosphate   arthropathy,   also   known   as

calcium   pyrophosphate   deposition   disease,

CPPD, pseudogout or chondrocalcinosis, results

from   the   excessive   deposition   of   calcium

pyrophosphate  in  joints.  Minor  deposits  are common  and  are  usually  asymptomatic.  The aetiology is usually not identified, but some

genetic and predisposing factors, e.g. age and hyperparathyroidism, are known. CPPD is about one-third as common as gout.

The calcium pyrophosphate crystals probably

form initially in cartilage and are shed into the

synovial fluid. Thus microscopic examination of

the latter gives a clear diagnosis. It is probable

that acute exacerbations of osteoarthritis are due

to   calcium   pyrophosphate   shedding   from

damaged cartilage.

The disease may present acutely, resembling acute gout, or as a degenerative chronic arthritis, sometimes with intermittent acute episodes.

Management resembles that of osteoarthritis,

but colchicine is as effective in CPPD as in gout.

Otherwise   there   is   no   specific   treatment:

NSAIDs are effective in acute attacks and intra-

articular injections of corticosteroids are highly

beneficial.

Autoimmune connective tissue disorders

There is currently no satisfactory classification for this group of chronic, progressive inflamma-

tory diseases, formerly called ‘collagen-vascular diseases’ or ‘multisystem disorders’. A possible grouping is given in Table 12.19. They share the following features:

•  Widespread   inflammation   of   organs   and

            systems   throughout   the   body,   notably

causing vasculitis and arthritis.

•  Autoimmune features, with circulating auto-

            antibodies and immune complex deposition.

•  Unknown aetiology.

Two types of antineutrophil cytoplasmic anti-

bodies (ANCA) are seen in the systemic vas-

culitides:   cytoplasmic,   proteinase       3   ANCA

(PR3-ANCA, formerly cANCA) and perinuclear,

myeloperoxidase ANCA (MPO-ANCA, formerly

pANCA). Both are anti-enzyme antibodies, so

causing an autoimmune state. There is an asso-

ciation  with  HLA  class  II  antigens  and  the

production of IgG autoantibodies (see Chapter

2). Mixed connective tissue diseases are strongly associated with the HLA-DR4 genotype.

Patients often show features of more than one of

these diseases. The syndrome described as ‘mixed

connective  tissue  disease’  may  be  a  distinct

entity, but is possibly a variant of scleroderma.

Because  fever  and  arthralgias  are  common presenting   symptoms,   patients   are   usually referred to rheumatologists.

Systemic lupus erythematosus

Definition and epidemiology

This non-organ-specific, multisystem, autoim-

mune disease primarily affects young women.

Systemic   lupus   erythematosis            (SLE)   occurs worldwide, and may affect up to 0.5% of Black women in North America and the West Indies and  women  in  the  Far  East.  There  are  over 30000 diagnosed patients in theUK.

Aetiology

There  is  an  inherited  tendency  for  SLE,  the

concordance rate for monozygotic twins being

about 25%, whereas that for dizygotic twins and

first-degree relatives of patients is about 3%. In

Caucasians,   this   is   linked   to   an   increased

frequency of HLA-B8 and DR3 genotypes, and in

Japanese with DR2.

Inherited deficiencies of a number of compo-

nents of the complement system occur, e.g. of C2, C4a and C4b in 83% of patients, these being linked to the HLA type.

There is a defect in T cell regulation of the

immune response, associated with B cell activa-

tion and a failure to clear the resultant immune

complexes.

Sex hormone status is also involved, because oophorectomy (ovary  removal)  or  treatment with androgens has relieved lupus-like symp-

toms in experimental animals. Also males with Klinefelter’s syndrome, who are genetically XXY or XXYY, are prone to SLE.

Pathology and diagnosis

SLE damages a wide range of tissues. Damage

to cells is known to release DNA, and this may

provoke  the  formation  of  anti-dsDNA  anti-

body.  Plasma  DNA  has  a  high  affinity  for

the  collagen  in  the  glomerular  basement

membrane, so binding of DNA in this region

may be expected to lead to the formation of

immune   complexes      (ICs),   triggering   local

inflammation.  These  observations  provide  an

explanation for two of the features of SLE: the

presence of antinuclear antibodies (see below)

and   renal   involvement.   A   further   reason

for  glomerular  involvement  in  SLE  is  local

glomerular   hypertension,   which   promotes

extravasation  of  cells  and  nuclei  from  the

circulation,  which  can  then  attach  to  the

basement membrane.

Fluorescent  antibody  studies  show  wide-

spread  IC  deposition  in  cellular  basement

membranes.  This  probably  accounts  for  most

of the manifestations of the disease, especially

the  vasculitis  in  the  arterioles  and  capillaries.

Although these ICs may be formed in all indi-

viduals,  SLE  sufferers  may  be  unable  to  clear

them  because  of  complement  deficiencies,

notably C2 and C4.

The  standard  screening  test  is  the  fluores-

cent  antinuclear  antibody  test (ANA;  ANF,

antinuclear  factor),  which  detects  antinuclear antibodies  and  is  positive  in  virtually  all

patients  with  SLE.  However,  the  ANA  test  is

not  specific (some 3%  of  the  population  is

ANF-positive, but only about 3% of these have

SLE) and so is used only as a routine screening

test. More confidence can be placed in dsDNA

binding  tests,  though  some  15%  of  patients

are falsely negative in these, especially in early

or  mild  disease.  Because  this  test  is  applied

only  to  patients  who  are  strongly  positive  in

the ANA test this type of result does not give

rise to ambiguities.

Despite the inflammation, the CRP is not raised, though the ESR is usually high in concordance with disease activity. The criteria for diagnosis are given in Table 12.20.

Some people have the immunological markers of SLE but do not have overt disease.

Drug-induced SLE

Many drugs are capable of producing a lupus-like

syndrome (Table 12.21), but this is usually rela-

tively mild, rarely provoking renal involvement,

and tends to remit when the drug is withdrawn.

It is doubtful whether this is related to true SLE.

Drugs may trigger attacks only in susceptible

subjects,   and   all   pharmacotherapy   in   SLE patients needs careful supervision. A history of drug  allergies  is  common  in  patients  with

drug-induced SLE.

Clinical features

SLE may affect almost any organ, though the

liver   is   rarely   involved.   The   approximate

percentage frequencies of the principal organs

involved are: joints, 95%; skin, 80%; CNS, 60%;

kidneys, 50%; lungs, 40% and heart, 40%. Fever,

arthralgias and myalgias are common, accompa-

nied  by  headaches,  depression,  malaise  and

tiredness.

There is often a symmetrical facial ‘butterfly’-

shaped  rash,  giving  a  wolf-like  appearance; hence the name ‘lupus’. The occurrence of the rash  may  be  triggered  by  sunlight,  with  or without photosensitizing drugs. If rash is the

principal presenting symptom, patients may be referred initially to a dermatologist.

Although  an  episodic  course  is  usual,  some

patients  have  chronic  disease  with  exacerba-

tions and complete remissions occurring over a

very variable time period. The pattern of estab-

lished  disease  is  usually  apparent  in  its  early

stages. SLE used to be represented as a relent-

lessly progressive, fatal condition, but the 10-

year  survival  rate  is  now  about 90%.  Severe

problems are unlikely if they have not devel- oped within this time: most patients now do            the scalp, hands and feet may also be affected.

reasonably well.

Management

General

Because of the potential widespread and diverse

nature of symptoms, patients need to be coun-

selled carefully and told to report any new symp-

toms as they occur. Reassurance is appropriate

for most. They should be warned of the need to

protect   themselves   from   bright   sunshine,

because of photosensitivity, and of the potential

for drug allergies.

Pregnancy is not contra-indicated, except in severe disease, but specialist gynaecological care is essential.

Pharmacotherapy

Corticosteroids

These are the mainstay of treatment, using high doses  in  acute  severe  episodes  and  low-dose maintenance therapy in most patients. Their

well-known side-effects make it important to

step down the dose to about 7.5 mg/day of pred-

nisolone, or less if possible, once symptoms are controlled.   However,   not   all   patients   need continuous maintenance therapy.

Immunosuppressants

Azathioprine or cyclophosphamide are often used

for their steroid-sparing effect and to control

renal involvement or severe symptoms. Other

treatment is supportive and symptomatic, e.g.

renal dialysis.

Mild disease confined to the joints can usually be controlled with NSAIDs. Hydroxychloroquine is useful if these are inadequate and for the control of skin lesions.

Chronic discoid lupus erythematosus

Clinical features and pathology

Chronic discoid lupus erythematosus (CDLE) is a

benign,  chronic,  episodic,  erythematous  skin

disorder that mostly affects the face, although

The rash may be symmetrical (like SLE) or asym-

metrical. The lesions are sharply defined, slightly

scaly,  erythematous  discs  about 5-10 mm  in

diameter, sometimes slightly larger. If a scale is

removed,  the  underside  will  show  a ‘hairy’

appearance due to the adherent pilosebaceous

plugs that filled the underlying hair follicles: this

sign is pathognomonic. Older lesions tend to

heal with scarring and hair loss. Pigmentation

may occur in white skin and depigmentation is

common in coloured skin. Usually, there are no

systemic features with CDLE, but about 5% of

patients eventually develop SLE.

Similarly to SLE, the lesions are caused by the

deposition of ICs, in this case in the basal layer

of the skin, causing cell destruction. There may

be a high ESR and cells usually associated with

SLE or similar diseases (LE cells) occur in the

serum.

Pharmacotherapy

High protection factor sunblock preparations are

used for photosensitivity. CDLE is one of the few

indications for the use on the face of potent or

moderately potent corticosteroids, e.g. clobetasol:

intralesional injections are sometimes used.

If this does not achieve control, antimalarials

may be helpful, as in SLE. Antimycobacterial

drugs are sometimes used because they have

anti-inflammatory properties. The antileprotic

drug clofazimine is preferred to rifampicin, so as

not to prejudice the use of the latter for TB.

Monoclonal   antibodies   against   the   CD40 ligand (see Chapter 2) are undergoing trial.

Sjögren’s syndrome (keratoconjunctivitis sicca)

Definition

Classically, Sjögren’s syndrome is defined as a triad of:

•  Xerophthalmia (dry eyes).

•  Xerostomia (dry mouth).

•  A connective tissue or rheumatoid disease,

            usually RA.

If only the first two of these symptoms occur,

this is described as the ‘primary’ form, some-

times called ‘sicca syndrome’, which also causes

symptoms resembling mild SLE. It is not known

whether this represents a complication of occult

connective tissue disease or whether the two

conditions are triggered by a common agent.

There is an association of sicca syndrome with

lymphoid hyperplasia and high levels of circu-

lating antibody, suggesting the presence of a

distinct autoimmune disease.

However,   Sjögren’s   syndrome   is   usually secondary, occurring in about 20% of those with other autoimmune and connective tissue diseases, e.g. RA, SLE or systemic sclerosis (see below).

Overall,  about  0.5%  of  adult  females  are affected, the female:male ratio being 9:1.

A similar condition occurs in association with HIV infection, so investigation needs to exclude this possibility.

Pathology

This is a chronic autoimmune disease causing destruction of exocrine glands, due to lympho-

cytic infiltration. The aetiology is unknown, but there is an association with an HLA-DR3 and other HLA genotypes.

There is also hyperactivity of B cells, shown by

auto-antibodies, e.g. RFs and antibodies to small

RNA-protein complexes. Levels of IgG are very

high.

Clinical features

The general drying up of exocrine secretions

may  cause  effects  on  many  organ  systems,

though in most patients the disease remains a

minor mouth and eye problem. These effects

include:

•  Eyes:   grittiness,   irritation,   morning   lid

            stickiness and conjunctivitis.

•  Mouth: there is difficulty in chewing and swal-

            lowing food; inability to speak continuously; a

            smooth,   erythematous,   sensitive   tongue;

greatly  increased  dental  caries  and  parotid gland  enlargement.  Candidal  infection  is common.

•  Respiratory  tract:  the  failure  of  secretion

            predisposes to infection.

•  Genital    tract:    atrophic    vaginitis    and

            dyspareunia  (difficult or painful coitus) in

premenopausal women.

•  Kidneys: some patients develop nephritis, but

            major renal pathology is rare.

•  Raynaud’s syndrome (in 25% of patients; see

            below).

•  Non-erosive arthritis (33%).

•  Vasculitis, causing purpura and sometimes

            glomerulonephritis.

Other features may be seen, e.g. leg ulceration and an increased tendency to hypersensitivity reactions. Patients with persistent parotid gland enlargement may develop non-Hodgkin’s B cell lymphoma, but this can be predicted by the

presence   of   circulating   cryoglobulins (IgMs precipitated at low temperatures).

Management

In secondary disease this consists of managing the  underlying  condition,  plus  symptomatic relief as in the primary syndrome.

Treatment of primary Sjögren’s syndrome is solely symptomatic, and focuses on replacement of secretions, thus minimizing discomfort and any damaging effects. Treatment includes:

•  Eye   drops:   frequent   use   of   preparations

            containing hypromellose, polyvinyl alcohol  or

acetylcysteine (‘artificial tears’). •  Mouth problems:

-  Scrupulous attention to dental hygiene to

            minimize premature, gross dental caries.

-  Mouthwash  solution  tablets,  compound

sodium mouthwash or more potent anti-

septic   mouthwashes,   e.g.   chlorhexidine gluconate, if toothbrushing is painful.

-  Commercial ‘artificial saliva’ preparations,

and   sugar-free   demulcent   pastilles,   to

alleviate dryness; pilocarpine may also help.

-  Fluconazole or itraconazole for oropharyngeal            dysfunction   and   sometimes   a   rapidly

candidiasis.

•  Hydroxychloroquine for joint problems.

•  Corticosteroids or cytotoxic immunosuppres-

sants,   e.g.   cyclophosphamide,   for   severe systemic problems, e.g. vasculitis.

•  Lymphoma; normal treatment (see Chapter

            10).

Diuretics  and  anticholinergic  drugs  aggravate the lack of secretions and should be avoided.

Systemic sclerosis and scleroderma

Definition

Scleroderma  is  characterized  by  widespread

tissue fibrosis. There is a dense hardening of skin

collagen, especially of the hands and face, giving

a tense, shiny appearance to the affected skin

and  puckering  around  the  mouth.  Vascular

abnormalities  and  degenerative  changes  also

occur.

If the internal organs are affected, the term

systemic sclerosis is more appropriate, but the terms tend to be used interchangeably. Systemic sclerosis may lead to renal, pulmonary or cardiac failure. Dermal collagen is also normal.

Clinical features and pathology

The disease is uncommon (UKannual incidence

about 10 per million,USAslightly higher) and

occurs principally in women aged 30-50 years,

with an overall female:male ratio about 3:1.

The symptoms described above are the result of three features:

•  Vascular damage: Raynaud’s syndrome (see

            below) occurs in nearly all patients, often

months or years before other symptoms. This, and finger joint arthropathy, are common

presenting features.

•  Fibrosis: from the deposition of collagen and

            adhesive proteins (e.g. fibronectin), produced

            by   fibroblasts.   This   causes   oesophageal

progressive visceral involvement.

•  An  activated  immune  system:  the  active

            fibroblasts  are  associated  with  TH (CD4 )

lymphocytes,  macrophages  and  degranula-

tion  of  mast  cells.  About  75%  of  systemic sclerosis  patients  have  antinuclear  Igs,  e.g. antinucleolar or anticentromere.

A  genetic  susceptibility  has  been  mapped  to

MHC genes. Intriguingly, nucleic acid similarity

between  the  target  of  some  antiscleroderma

auto-antibodies,   DNA   topoisomerase-1,   and

some mammalian retroviruses raises the possi-

bility that scleroderma is triggered by viral infec-

tion. However, exposure to industrial chemicals

(e.g.  vinyl  chloride  and  trichloethylene)  and

bleomycin (a cytotoxic antibiotic) may cause a

similar syndrome.

Some 60% of sufferers have a limited cutaneous

form of scleroderma that starts with Raynaud’s

syndrome, sometimes years before other symp-

toms appear. In the other 40% the systemic symp-

toms  appear  either  at  the  same  time  as  the

Raynaud’s syndrome or shortly afterwards.

The disease follows a chronic, highly variable

course. Acute renal hypertension, lung fibrosis

and hypertension, and cardiac problems may

occur.

Management

Management of scleroderma is primarily symp-

tomatic. Corticosteroids may be used to suppress

synovitis. Cytotoxic immunosuppressants and

antithymocyte globulin, if given early enough,

may be helpful. They also help to spare the

steroid dose. ACEIs have vastly improved the

morbidity and mortality from renal involvement

(see Chapters 4 and 14), and the usual cause of

death is now pulmonary fibrosis. Penicillamine

and IFN-gamma have been used experimentally

to stem fibrosis.

The survival rate at 7 years after diagnosis is about 50%, but in some patients the disease

stabilizes  or  regresses  at  about  this  time.  In limited   cutaneous   disease   the   comparable survival is about 75%.

Raynaud’s syndrome

Definition and epidemiology

The nomenclature of this condition is confused.

The  primary  (idiopathic)  form,  which  occurs

without any underlying rheumatoid or connec-

tive tissue disorder, has been called ‘Raynaud’s

disease’, that secondary to other diseases being

called ‘Raynaud’s phenomenon’. This division

seems  artificial,  not  least  because  Raynaud’s

disease may precede the onset of symptoms of

an underlying disease by many years and is then

seen to be a prodrome of that disease. In this text

the   neutral   term ‘Raynaud’s   syndrome’   is

preferred  for  both.  However,  the  distinction

is important because it is essential to identify

any   underlying   disease   state   and   institute

appropriate treatment.

Primary  Raynaud’s  syndrome,  which  espe-

cially affects young women, is due to spasm of

the arterioles and small arteries, especially in the

fingers   and   toes,   resulting   in   intermittent

blanching of the overlying skin. Occasionally

other extremities (e.g. the nose, tongue and ears)

may  be  involved.  About 5%  of  people  are

affected.

The secondary form (Table 12.22) may reflect

local nerve damage (e.g. in miners and dispatch

riders), similarly causing vasospasm, or the use of   vasospastic   drugs,   but   may   be   due   to inflammation, e.g. vasculitis.

Clinical features

The primary form causes intermittent, reversible attacks,  precipitated  by  exposure  to  cold  or emotional  upset.  The  hands  are  most  often affected, but attacks rarely involve the thumb. The affected fingers go white and may even

become cyanosed and finally red as rewarming occurs. Paraesthesias, e.g. numbness, tingling or burning are common, and pain may be severe during circulatory recovery.

The primary disease is a common condition that affects 5% of the population. It usually

causes  bilateral  symptoms  whereas  secondary disease may produce unilateral, irreversible ones, the affected area being permanently sensitive to adverse conditions, especially cold.

Recurrent   severe   episodes   may   eventually cause small infarcts in the affected digits, but the condition is usually non-progressive.

Diagnosis

The symptoms described above are pathogno-

monic.    However,    attacks    of    secondary

Raynaud’s syndrome may precede the onset of

symptoms  due  to  the  underlying  disease,  e.g.

RA,  scleroderma  or  carpal  tunnel  syndrome

(p. 809), by months or years. It is thus essential

to  look  carefully  for  the  markers  of  any

underlying disease.

Management

General measures

In secondary Raynaud’s syndrome, treatment is that of the underlying disease. The most useful basic approaches, whether or not the condition is primary are:

•  To avoid:

-  Cold; keep warm locally and generally.

-  Peripherally  vasoconstricting  drugs,  e.g.

ergotamine, beta-blockers.

-

Smoking.

-

•  To be scrupulous about hand hygiene, cuts,

-

            etc. and skin care.

-

•  Physiotherapy needs to be started at the onset

-

            and  performed  regularly  to  promote  good

-

circulation.

-

Pharmacotherapy

-

Drugs are widely used, but most drug use is

-

empirical. The following may help.

-

•           Vasodilators:

-

-           Calcium  channel  blockers  (see  Chapter

-

4)  are  sometimes  effective.  Nifedipine  is

-

the  only  one  licensed  for  this  purpose

-

in  the UK,  but  nicardipine,  and  possibly

-

amlodipine  and  felodipine,  may  also  be

-

useful.  They  tend  to  cause  headache,

-

flushing  and  dizziness  and  tachycardia.

-

Reports   of   efficacy   are    somewhat

-

contradictory.

-

-           Other vasodilators  (see Chapter  4) may

-

help,  such  as  ACEIs  (e.g.  captopril  and

-

enalapril). Naftidofuryl  and inositol nicoti-

-

nate are other possibly helpful agents but may cause postural hypotension and the

-

side-effects described for CCBs.

-

-           Cinnarizine,  moxisylyte,  pentoxifylline  and

-

prazosin have not proved to be useful.

-

-           Epoprostenol, an antiplatelet drug, is also a

-

potent vasodilator and has been used if

-

there are seriously compromised ischaemic

-

areas. It must be given by continuous IV

-

infusion because of its very short half-life

-

of 3 min. Epoprostenol  may cause severe

-

flushing, headache and hypotension and

-

so its use must be supervised closely. It is

-

unsuitable for patients with IHD because

-

the   vasodilatation   diverts   blood   from

-

ischaemic   areas   and   aggravates   the

-

problem. Its more stable analogue iloprost

-

may be preferred if epoprostenol is not toler-

-

ated (unlicensed use).

-

•           Other  agents:  gamolenic  acid,  in  evening

-

primrose oil, and halibut liver oil have been

-

reported to be helpful.

-

•           Nitric oxide, generated topically by mixing

-

sodium nitrite and ascorbic acid gels, has been reported to improve the microcirculation.

-

Vasculitides      805

-

Surgery

-

This may help, for example to relieve median nerve compression in associated carpal tunnel syndrome (p. 809). Sympathectomy has been

-

used if there is a risk of digital gangrene, but the long-term outcome is uncertain.

-

Vasculitides

-

Vasculitis is inflammation of blood vessel walls.

-

Because of the prime importance of blood vessel

-

function  these  conditions  may  have  serious,

-

widespread effects. The classification is debated:

-

that used here is widely accepted. The features of

-

the  primary  conditions  and  some  associated

-

ones are given below. There is overlap between

-

the types.

-

Antineutrophil cytoplasmic antibodies (PR3-

-

ANCA and MPO-ANCA) are found in some of the

-

acute vasculitides. PR3-ANCA is present in the

-

serum of 90% of patients with Wegener’s granu-

-

lomatosis (see below). MPO-ANCA antibodies

-

occur in up to 60% of other vasculitides, other

-

rheumatic diseases and IBD (see Chapter 3).

-

Large-vessel vasculitis

-

Giant cell arteritis

-

Clinical features

-

Giant cell arteritis (GCA) usually involves only

-

the carotid arterial tree. Patients present with

-

fever, severe malaise, weight loss, facial pain and

-

jaw pain on chewing that forces rest (claudica-

-

tion). Polymyalgia rheumatica (see below) is a

-

frequently associated condition. Most patients

-

are over 60 years of age, and women are affected

-

more than men. Severe, localized headache is

-

common, usually unilateral (temporal or occip-

-

ital), with marked tenderness of the temple or

-

scalp, e.g. when combing the hair, hence the

-

alternative   names   temporal    (or   cranial)

-

arteritis. Doubtful cases may be resolved by

-

temporal artery biopsy, but this is performed

-

only occasionally.

-

The ESR is very high, 50-120 mm/h (normal

-

÷20 mm/h), as is the CRP level. One very serious

complication is sudden, reversible or irreversible,

unilateral or bilateral blindness (25% risk). Rarer

complications include ischaemia of the brain-

stem, cranial and peripheral nerves, and major

arteries.

Pharmacotherapy

High-dose corticosteroids, e.g. 60-100 mg pred-

nisolone daily, are essential to prevent blindness,

and  should  be  commenced  immediately  the

diagnosis is suspected. The dose may be reduced

after 1 month, depending on the condition of

the patient and the reduction in ESR. Some

consultants favour lower starting doses of 40 mg.

The headache usually remits within 48 h of the

first dose, and this rapid response may be helpful

diagnostically.

The     disease     usually     remits   within

24-36 months’   treatment   in   about 75%   of

patients, but the remainder require maintenance

low-dose steroids, e.g. 10 mg prednisolone daily,

because the risk of visual loss persists for several

years. Recurrence of symptoms, or increased ESR

or CRP, at any stage, dictate a return to full

steroid dosage.

Patients need to be taught to manage their

disease and to increase the corticosteroid dose immediately according to an agreed protocol if their condition deteriorates. They should then see their doctor as soon as possible. A prompt reaction to deterioration may pre-empt the need for more aggressive treatment later.

Polymyalgia rheumatica

Aetiology and epidemiology

Polymyalgia rheumatica (PMR) is defined by its

clinical features. Some cases are associated with

GCA, though most show quite distinct features

and  more  widespread  arteritis.  PMR  occurs

mainly in the elderly, with two-thirds of patients

being aged over 60 years, and is uncommon

before   the   age   of 50   or   above 80.   The

female:male ratio is 2:1.

PMR is more common in Northern Europe.

There are marked seasonal variations in inci-

dence (about 70 per 100 000 in the over-60s),

and these have prompted a search for infective

causes,  but  without  success.  Because  PMR  is

unusual  in  patients’  partners,  environmental factors are unlikely to be implicated.

Clinical features

The principal symptoms are stiffness and aching,

principally in the shoulder and pelvic girdles,

e.g. the neck, shoulders, upper arm, buttocks and

thighs.  There  is  prolonged  and  severe  early

morning stiffness lasting more than 1 h, malaise,

depression  and  weight  loss.  Onset  may  be

sudden and dramatic (e.g. overnight), but in

most cases occurs gradually over about 2 weeks.

In  the  latter  case,  it  may  all  too  easily  be

dismissed as part of ‘ageing’.

Pharmacotherapy

Symptoms respond rapidly to moderate doses of

prednisolone, e.g. 15-25 mg daily. If there is any

evidence of vasculitis, the higher doses used for

GCA  should  be  used  because  of  the  risk  of

sudden blindness (see above). The dose is gradu-

ally reduced to the minimum required to control

symptoms and normalize the ESR. It is possible

to withdraw steroids completely in about 75% of

patients  within 2-3 years.  In  the  remainder,

disease duration may be 7-10 years and the risks

of prolonged corticosteroid treatment have to be

weighed   against   those   associated   with   the

disease, notably blindness.

Azathioprine is often used for its steroid-sparing effect,   and   dapsone,   cyclophosphamide   and antimalarials have also been used.

The  same  considerations  apply  to  patient self-management as in GCA.

Medium- and small-vessel vasculitis

Polyarteritis nodosa

This  intense  inflammation  of  the  small  and

medium arteries, e.g. in coronary, pulmonary,

kidney,   muscular   and   mesenteric   arteries,

commonly occurs at the junctions of vessels,

causing characteristic aneurysms that are visible

in the retina. The widespread distribution of the

lesions leads to correspondingly extensive and

severe symptoms.

Polyarteritis nodosa (PAN) is a rare disease that

affects  middle-aged  men  more  than  women

(male:female ratio about 2.5:1). In about 20%

of patients PAN is associated with hepatitis B

infection.  A  small  number  of  cases  appear  to

be associated with hypersensitivity reactions to

penicillins and sulphonamides. These observa-

tions point to the possibility of the inflamma-

tion   being   triggered   by   immune   complex

deposition  in  arterial  walls (see  Chapters 2

and  14).  However,  the  aetiology  is  generally

unknown.

There is infiltration of all the layers of the

affected arteries by inflammatory cells, leading

to degeneration of the arterial walls, and to

ischaemia. Inflammation and thrombosis may

lead to tissue infarction in almost any organ.

The clinical features are the result of wide-

spread ischaemic organ damage, involving the

skin, cardiovascular and nervous systems, kidney

and lungs, associated with non-specific symp-

toms, e.g. polyarthritis, myalgia, fever, weight

loss and malaise. The ESR and CRP are raised.

Such  extensive  symptoms  clearly  indicate  a

severe and alarming disease. Joint involvement

is common, but is rarely serious. The disease runs

a very variable course from a mild cutaneous

vasculitis to severe, life-threatening involvement

of major organs.

Management is with high-dose corticosteroids,

immunomodulators,    e.g.    azathioprine    or

cyclophosphamide, and appropriate symptomatic

support.

Wegener’s granulomatosis

This  rare  disease  mostly  affects  adults  over

40 years of age, causing widespread small vessel

granulomatous  arteritis.  Pulmonary,  renal  and

sometimes eye lesions occur. The initial symp-

toms may be severe rhinorrhoea, cough and pleu-

ritic pain, so patients usually present to chest

clinics. Some 85% of patients have nephritis (see

Chapter 14) that is rapidly progressive without

prompt diagnosis and treatment, and is a sign of

widespread systemic disease. The ESR is raised

and MPO-ANCAs are usually present.

The  aetiology  is  unknown,  but  it  has  been

suggested that drugs may be involved, though no

consistent associations have been demonstrated.

Other multisystem diseases  807

Pharmacotherapy

The condition, once uniformly fatal, responds

well  to  high-dose  prednisolone  plus  cyclophos-

phamide. The latter is given as pulsed intermit-

tent IV therapy or as continuous low-dose oral

treatment.

at about 3-6 months, the cyclophosphamide  is

usually replaced with azathioprine, to minimize

toxicity.

Other multisystem diseases

Amyloidosis

This is the deposition of abnormal, extracellular,

fibrous protein in various tissues throughout the

body. The proteins include Ig fragments and

precursors of normal serum proteins and are

resistant  to  proteolysis  in  vitro.  The  deposits

may be localized or widely distributed. Several

different forms are distinguished, depending on

the structure of the protein chains. It may be

inherited or acquired.

The  commonest  inherited  form  is  due  to autosomal-dominant mutant genes coding for variants of the protein transthyretin. This is the retinol-binding and thyroxine-binding transport globulin that is mostly synthesized in the liver. Over 50 different amino acid substitutions are known. Other forms of amyloid are derived from fibrinogen and lysozyme chains.

Because   many   organs   may   be   involved,

patients may present with any of a diverse range

of   symptoms,   e.g.   heart   failure,   nephrotic

syndrome, purpura, peripheral neuropathy and

weight loss.

In  secondary  amyloidosis  the  deposits  are

formed from abnormal serum amyloid A (SAA),

an acute phase protein. It may be associated

with   dialysis   arthropathy,   diabetes   mellitus,

Alzheimer’s  disease (the  commonest  form  of

senile dementia), Creutzfeldt-Jakob disease, RA,

JIA and any of the systemic connective tissue

diseases (see above). It usually presents with

renal syndromes (proteinuria) or heart failure. In

the Third World it may accompany TB and other

chronic infections. The primary disorder must be

identified and treated, if possible.

Once   regarded   as   relentlessly   progressive,

many patients can now be managed effectively,

e.g.   with   prednisolone,   the   alkylating   agent

melphalan (see   Chapter 10),   colchicine (for

familial Mediterranean fever, triggered by rick-

ettsial  infection),  or  combinations  of  these.

Transplantation of almost any affected organ,

especially the liver, may be curative. Patients

who respond to treatment show gradual regres-

sion of amyloid deposits. Transplant patients do

little worse than others without amyloid, but

surgery may be complicated by haemorrhagic

problems and poor wound healing.

Sarcoidosis

Epidemiology and clinical features

This  is  a  relatively  common  (UK  prevalence

about 20 per 100 000) granulomatous disorder,

mostly affecting young adults aged 20-40 years,

with widespread non-caseating granulomas in

lymph nodes, liver, lungs, eyes and skin. They

are less common in the joints, muscles, heart

and CNS. Eye lesions occur in 25% of cases

and  skin  lesions  in  about 10%  (see  below).

Afro-Caribbeans usually have a more severe form

of sarcoidosis, but it is less common in Asians.

It  usually  presents  with  a  restrictive  lung

defect (see   Chapter 5)   and   bilateral   hilar

lymphadenopathy, often detected on routine X-

ray, or small joint, tendon and associated soft

tissue   swelling,   occurring   in   about 5%   of

patients. The picture may strongly resemble RA,

but this frank arthritis is usually associated with

lung problems or erythema nodosum (a florid,

painful, dusky red rash on the lower limbs, espe-

cially in the lower shins and ankles). Cardiac

symptoms may occur rarely, in isolation.

The underlying abnormality appears to be the

sequestration  of  T-lymphocytes  in  the  lungs,

causing depression of T cell function, but there is

no evidence of CMI involvement (see Chapter

2). Spontaneous recovery is common.

Löfgren’s syndrome is characterized by the abrupt onset of malaise, fever, large joint arthritis, erythema nodosum and lung symptoms.

Management and pharmacotherapy

About  65%  of  patients  do  well  simply  with

NSAIDs. Those with Löfgren’s syndrome usually

respond similarly, though symptoms may take

up to 3 months to resolve, and lung lesions up to

18 months.

Corticosteroids are the mainstay of treatment

for lung, cardiac, CNS, liver and spleen involve-

ment. They may also help for hypercalcaemia,

but if this is severe ample IV fluids, and some-

times disodium pamidronate, are required. Severe

disease may necessitate the use of second-line

drugs, e.g. methotrexate or hydroxychloroquine, as

in RA. Ciclosporin has been used experimentally

but its value has been disputed, so it is usually

reserved  for  non-responders  to  conventional

treatment.

Eye problems (uveitis) are usually treated with topical corticosteroids, e.g. dexamethasone or clobe-

tasone (lower risk of glaucoma), but also require mydriatics, e.g. cyclopentolate. They may be severe enough to require systemic corticosteroids.

Combined heart-lung and kidney transplanta-

tion has been used in end-stage non-responders, but the disease is likely to affect the transplanted organs subsequently.

Other rheumatic disorders

Reactive arthritis

This is an ill-defined entity, but the term is usually

used to describe arthritis that follows an identifi-

able infection, often rheumatic fever or enteric

infections, e.g. Campylobacter infection, dysen-

tery, Salmonella food poisoning, AAC (see Chapter

8), and some sexually-acquired infections.

Reiter’s syndrome

Definition

This multi-system disorder is usually characterized

by:

•  Urethritis.

•  Seronegative spondarthritis (p. 789). •  Conjunctivitis.

•  Skin lesions.

These may follow sexually transmitted diseases,

e.g.  non-specific  urethritis  or  cervicitis.  The

acronym ‘SARA’,  Sexually  Acquired  Reactive

Arthritis, has been coined for this condition,

about 50%   of   cases   being   associated   with

Chlamydia trachomatis or Ureaplasma urealyticum

‘non-specific’   urethritis.   Gut   infections,   e.g.

bacillary dysentery, may also be involved.

This is largely a male problem (80-95%), with most patients aged 16-35 years. There is a strong association with HLA-B27 (between 60% and 95% in various reports) that suggests the existence of a genetic susceptibility to an infection-triggered, immune-mediated disease.

Clinical features

Typically, there is a low-grade fever, conjunc-

tivitis, arthritis and urinary-tract symptoms. The

arthritis tends to affect a few joints asymmetri-

cally, primarily in the lower limbs, and usually

remits after a few weeks or months. Sacroiliitis

and spondylitis can occur at any stage, usually in

severe cases associated with sexually-acquired infection. About 50% of patients experience a single  episode,  but  recurrences  occur  in  the remainder  over  a  period  of  years,  probably following repeated gastrointestinal or urinogen-

ital infections. Repeated attacks lead to joint

damage, which is sometimes severe.

Management

Management of Reiter’s syndrome involves:

•  Physiotherapy to reduce possible ankylosis.

•  Early, aggressive treatment of any infection,

e.g. tetracyclines for most urinogenital infec-

tions,   including   Chlamydia,   may   reduce arthropathy.

•  NSAIDs.

•  Corticosteroids for severe systemic complica-

      tions, or for injection into isolated, badly

affected joints.

•  Aspiration of badly swollen joints.

•  Surgery in late disease, as for AS (p. 789).

Soft tissue rheumatism

This section describes briefly the most common minor non-arthritic soft tissue lesions. They are relatively   common   and   treatable.   Topical therapy with creams and liniments is popular

(p. 811).  Physical  treatments,  e.g.  physio-

therapy, osteopathy, chiropractic and acupunc-

ture, are widely used, and help to relieve pain and associated muscle spasm.

Carpal tunnel syndrome (CTS)

Definition

This  entrapment  neuropathy  is  the  result  of

compression of the median nerve at the wrist,

where it passes between the tendons and the

transverse ligament (Figure 12.11).

Aetiology and epidemiology

CTS may be idiopathic or occur in association with  many  diseases  or  conditions,  e.g.  RA, Raynaud’s syndrome, fluid accumulation (preg-

nancy,    premenstrual    or    postmenopausal), tenosynovitis (e.g. sports injury, overuse of the wrist, repetitive strain injury and local trauma), obesity,   diabetes   mellitus,   hypothyroidism, amyloidosis and acromegaly. The condition may occur at any age, mostly in women.

Clinical features

These include:

•  Paraesthesias, e.g. tingling, sensory loss and

      numbness in the first three-and-a-half digits of

the hand (Figure 12.11(a)), i.e. in the area of

distribution of the median nerve, although

symptoms may be rather diffuse. The patient

often wakes at night and hangs the arm over

the bedside or wrings the hand to obtain relief.

Pain in the hand, wrist or forearm.

•  Weakness of the hand and wasting of the ball

of the thumb.

Management

This comprises:

•  Management of any underlying disease or

      predisposing condition.

•  Local injection of corticosteroids. •  Splinting.

•  Nerve decompression by surgical division of

      the transverse ligament of the wrist. However,

a precise diagnosis is an essential prerequisite;

this procedure will give no benefit if the root

of  the  problem  lies  elsewhere,  e.g.  nerve

compression at the elbow, neck or shoulder.

Tendonitis and tenosynovitis

Tendonitis is tendon inflammation. It is rarely

diagnosed  precisely  in  general  practice,  and

many   syndromes   are   enthesopathies.   The

aetiology is uncertain but may be associated with an inflammatory arthropathy or minor repeti-

tive trauma. The most common lesions include:

•  Supraspinous  tendonitis,  characterized  by

      pain on straight arm raising.

•  Frozen shoulder, a more serious condition,

      occurring at any age in adult life, but mostly in

older  patients;  it  may  cause  restriction  of

shoulder movement and severe pain, especially

at night.

•  Tennis elbow, with pain occurring over the

      lateral (outer) aspect of one elbow joint.

•  Golfer’s elbow  causes pain on the medial

(inner) side of an elbow.

•  Achilles tendonitis, behind the ankle.

•  Plantar fasciitis gives pain in the sole of the

foot.

Tenosynovitis is inflammation and swelling of the tendon sheaths. It is commonly caused by trauma and overuse injury, but it is also a frequent accompaniment to RA and other inflammatory arthropathies. Type II hyperlipoproteinaemia (see Chapter 4) is a predisposing factor.

The use of quinolone antibiotics (see Chapter

8) has occasionally been associated with tendon

rupture, especially in the Achilles tendon, but

also in the shoulder and hand. This rare side-

effect has also been reported in those taking

corticosteroids and may occur within 48 h of

starting  treatment.  Elderly  patients  are  more

prone to tendonitis. Patients should be warned

that  if  they  experience  any  tendon  pain  or

discomfort, especially of the Achilles tendon,

they should stop taking the antibiotic and see

their doctor immediately.

Management

Rest and the application of heat or cold, as the

patient  finds  most  effective,  and  NSAIDs  are

used. Local injection of corticosteroids is used

in resistant cases, under consultant supervision,

because it is important not to inject the tendon

itself: injection into a tendon may itself cause

rupture.  Physical  therapies  are  used  progres-

sively  as  the  condition  improves,  and  are

helpful  for  preventing  adhesions.  Surgery  to

divide  tendon  sheaths  or  remove  calcified

deposits may be needed in persistent cases, and

may be curative.

Soft tissue rheumatism         811

Topical NSAIDs are popular, partly because

when patients rub in the product they feel that

they are contributing to their own treatment and

because the massage also stimulates local blood

supply and interferes with pain signal transmis-

sion, so contributing to healing. Penetration into

joints  has  been  demonstrated  and  a  meta-

analysis found that topical forms of diclofenac,

ibuprofen, ketoprofen and piroxicam gave at least

50% pain reduction in acute soft tissue trauma,

sprains and strains. Similar benefits were seen in

chronic conditions, e.g. tendonitis and osteo-

arthritis.   Although   they   avoid   the   gastro-

intestinal   side-effects   associated   with   oral

dosing, the use of large amounts of topical prod-

ucts and occlusive bandaging may cause exces-

sive penetration and systemic effects, e.g. renal

impairment, especially in older patients, and

those with inflammatory skin problems. These

POM products are unlikely to be beneficial in

RA, but may give some benefit to those with OA

(see above) and soft tissue rheumatism.

They should be applied with gentle massage

only, not used on abraded skin or large areas and

should not be occluded. Women who are pregnant

or breastfeeding should avoid these products.

OTC products may contain an NSAID or sali-

cylate plus a rubefacient and should not be used overenthusiastically, as above.

Bursitis

This  is  inflammation  of  a  bursa,  the  most

common  sites  being  the  large  toe (bunion),

shoulder, lower pelvis (‘tailor’s bottom’), knee

(‘housemaid’s knee’, shop workers’ knee, from

kneeling on hard floors), and elbow (‘miner’s or

‘students’ elbow’).

The aetiology is often unknown but is usually

the result of trauma. Other possible causes are

inflammation   of   adjacent   joints,   gout   or

infection.

There   is   pain   and   local   tenderness,   and swelling is a feature of the last two conditions mentioned above. Occasionally, chronic bursitis may follow repeated trauma, e.g. from shoes

(bunions), unresolved infection or gout.

Management includes rest, with or without

splinting,  and  high-dose  NSAIDs  plus  local injection of corticosteroids in severe or persistent cases: NSAIDs alone are of limited value. Physical therapies are used progressively as the pain and inflammation subside.

Inflamed   bursae   sometimes   continue   to enlarge  and  require  surgical  dissection,  with excellent results.

Fibrositis and fibromyalgia

This  is  a  group  of  non-specific  conditions

presenting  with  diffuse  pain,  tenderness  and

stiffness of muscles and their connective tissues,

with  local  tender  points.  Pain  is  felt  most

frequently in the back, neck, shoulders, chest

and buttocks.

There is no specific disease entity. It is assumed

to be due to trauma, exposure to cold, viral infec-

tion or stress. Management is purely sympto-

matic with analgesics, and topical and physical

treatments.

Low back pain

Definition

This is pain in the lower lumbar, lumbosacral

and sacroiliac regions. It is sometimes accompa-

nied  by  sciatica,  which  is  neurological  pain

occurring in the distribution of the sciatic nerve,

i.e. in the buttocks and the lateral (outer) aspect

of the leg and the foot. It can be very severe and

incapacitating.

Aetiology

The pain is mostly the result of ‘degenerative’

joint disease (OA) and so is very common in the

elderly (50% of the 60        age group). However,

buttock pain in younger patients may be due to

AS (see above). A first attack of mechanical low

back pain is unusual below 20 years of age or after

50 and raises the possibility of an organic cause.

A common cause is a prolapsed interverte-

bral disc (PID, ‘slipped disc’), when the capsule

of an intervertebral disc ruptures or herniates

under strain (e.g. lifting, bending stress, sports

trauma and sneezing) and the nucleus pulposus

(pulpy centre) is extruded into the spinal canal

to press on a nerve root. A strong longitudinal

vertebral ligament usually prevents the extruded

pulp  pressing  directly  on  the  spinal  cord,  so

pressure  is  normally  directed  to  one  side  to

give  unilateral  symptoms  (see  Figure  12.3(b)).

There is associated muscle spasm, which exac-

erbates the condition. A new PID is uncommon

in the elderly.

One iatrogenic cause is prolonged systemic corticosteroid therapy, leading to osteoporosis and collapse of one or more vertebrae (crush

fractures),  often  causing  bilateral  nerve  root compression and severe pain.

Pregnancy or obesity may also cause strain and low back pain.

Diagnosis

Frequently, no abnormality can be demonstrated

with X-rays, so it may be difficult to make a

precise diagnosis, unless there is a fracture, dislo-

cation or PID. MRI scanning is the preferred

procedure and is justified if symptoms are severe.

A full blood count, ESR or blood biochemistry

are  appropriate  if  an  inflammatory  lesion,  a

metabolic origin or malignancy are thought to

be likely.

More invasive investigations are rarely justi-

fied. However a myelogram (i.e. X-ray following

injection of a radio-opaque dye to visualize the

spinal cord) may be done in difficult cases to

determine the extent of spinal cord damage,

though MRI is less invasive and will usually

show this. This is important if there is evidence

of neurological deficit, e.g. leg paraesthesias or

loss of control of bladder or bowels, or to direct

possible surgery.

Management

Acute back pain

Management   is   conservative   because   most

patients  recover  completely  in 6-8 weeks  of

partial rest with warmth, plus analgesic support.

However, excessive rest is undesirable, causing

muscle wasting and delaying recovery. If pain is severe, recovery is prolonged or there are neuro-

logical   signs,   active   treatment   is   indicated, including:

•  Local  injections  of  pethidine  (meperidine),

local anaesthetics or a long-acting cortico-

steroid, if there is severe, acute pain. Oral

pethidine is ineffective (see Chapter 7).

•  Muscle relaxants, e.g. diazepam or meproba-

mate, to relieve muscle spasm.

•  Manipulation, provided it is certain that there

      is  no  PID  or  fracture,  otherwise  serious

neurological damage may be caused.

•  Traction  and  surgery  may  occasionally  be

indicated for persistent motor weakness, and as a matter of urgency if there is loss of

control of bladder or bowel function.

•  NSAIDs  are  often  used  in  the  community

but are seldom superior to simple or opioid analgesics.

Chronic back pain

No generally satisfactory treatment is available. Orthodox management includes:

•  Weight reduction.

•  Treatment of any underlying disease.

•  Analgesics appropriate to pain severity.

•  Patient education on the avoidance of back

strain and poor posture, including advice on working conditions and suitable seating.

•  Carefully graded exercises and physiotherapy

to   strengthen   the   back   muscles   and   so improve joint stability.

•  Spinal supports (corsets, belts) in an acute

      exacerbation, but prolonged use is undesir-

able  because  muscle  tone,  and  therefore support, is lost.

•  Occasionally,  surgical  removal  of  the  disc

      (discectomy,  usually  percutaneously)  or  a

vertebral arch (laminectomy). Enzyme injec-

tions are sometimes used to dissolve the disc

pulp (chemonucleolysis, e.g. with chymopa-

pain  from  the  papaya  plant),  but  are  less

satisfactory because of allergic reactions.

•  Spinal fusion is undertaken rarely.

Other physical modalities, e.g. osteopathy, chiro-

practic,  are  of  undoubted  benefit  to  many

References and further reading        813

sufferers, who tend to seek a variety of ‘alternative’

medical treatments, sometimes in desperation at

the unsatisfactory outcome of orthodox medical

treatment.