Recent Advances: Rheumatology

BMJ 1995;310:637-640 (11 March)

Education and debate

Recent Advances: Rheumatology

Anthony Bradlow, consultant,^a Joel David, consultant ^a

^a Department of Rheumatology, Battle Hospital, Royal Berkshire and Battle Hospitals NHS Trust, Reading RG3 1AG

Correspondence to: Dr Bradlow.

The changing philosophies affecting medicine as a whole areat the forefront of rheumatology. Many of the publications ofthe past year have centred on improving and increasing the safetyof drug treatment. There are now good grounds for hope thatseveral newer agents to ameliorate rheumatoid arthritis areavailable or are in trial phase. Attitudes to chronic back painand the chronic fatigue syndrome are more positive and treatmentis more proactive. Osteoporosis is recognised as an importantpublic health issue; the role of screening with bone densitometryhas become better defined.

Safety of individual non-steroidal anti-inflammatory drugs

The choice of non-steroidal anti-inflammatory drug for individualpatients has until recently depended on the doctor's experience,the class of drug, and the manufacturer's recommendations. Arecent publication by the Committee on Safety of Medicines hasgiven a new perspective to selecting them.¹ The committee assessedseveral years of reports of adverse drug reactions (yellow card)for the seven most widely used non-steroidal anti-inflammatorydrugs in the United Kingdom. Ibuprofen carried the lowest risk,naproxen, indomethacin, and diclofenac intermediate risk, andazapropazone the highest risk of serious adverse upper gastrointestinalevents at the doses in which these drugs are normally prescribed(fig 1). Furthermore, azapropazone had the highest number ofyellow card reports for renal, liver, haematological, and hypersensitivityreactions. The report recommends that azapropazone should beused only when other non-steroidal anti-inflammatory drugs havefailed, doses being restricted to a maximum of 600 mg dailyin patients over 60. Drugs with low risk should generally bepreferred, and these should be started in the lowest recommendeddose. Only one non-steroidal anti-inflammatory drug should beused at a time. The report concludes that all members of thisgroup are contraindicated in patients with peptic ulceration.This is controversial for patients with rheumatoid arthritis,who frequently have or have had peptic ulceration.

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FIG1--Reporting frequencies for gastrointestinal reactions associatedwith seven non-steroidal anti-inflammatory drugs reported throughBritish yellow card scheme, 1989-93. Frequencies are expressedas number of reactions reported per 100000 prescriptions correctedfor time trends in reporting¹

       Recent advances in rheumatology
-----------------------------------------------------
   * Ibuprofen is the safest non-steroidal anti-
   inflammatory drug when used at conventional
   doses

   * Treatment with a monoclonal antibody to
   tumour necrosis factor produces significant
   but temporary improvement in the severity of
   rheumatoid arthritis

   * Methotrexate is well tolerated and effective
   for very long periods in most patients with
   rheumatoid arthritis, but possible long term side
   effects on the liver give cause for concern

   * Specialist rheumatology nurse practitioners
   and day patient management of rheumatoid
   arthritis are likely to play an increasing part in
   the future

   * Patients with acute back pain should be
   mobilised as quickly as possible and continue to
   work

   * In patients with rheumatoid arthritis pred-
   nisolone treatment is associated with significant
   bone loss at doses below 5 mg daily and above
   7.5 mg daily

   * No infective cause for rheumatoid arthritis
   has yet been found

Tiaprofenic acid is also mentioned in the same report as a causeof severe cystitis; a recent editorial in the BMJ asked whetherthe time had now come to withdraw tiaprofenic acid from use.²Like oral preparations, topical non-steroidal anti-inflammatorydrugs have also recently been implicated in renal impairment.³

Cytokines and rheumatic disease

Cytokines such as interleukin-1, interleukin-6, tumour necrosisfactor alpha, and granulocyte-macrophage colony stimulatingfactor have an important role in inflammatory arthritis as theypromote systemic and local inflammation, which in rheumatoidarthritis may damage joints.⁴ Individual cytokines interactwith one another to amplify the inflammatory process. Betweenattacks of gout low grade inflammation modulated by cytokinesand proteins bound to crystals may play a part in joint destruction.⁵

Trials of monoclonal antibodies against cytokines have beenunder way for some years⁶; in an open study chimeric monoclonalantibody to tumour necrosis factor alpha given to patients withrheumatoid arthritis improved the severity of arthritis andreduced laboratory measures of inflammation.⁷ A multicentrerandomised double blind placebo controlled trial of treatmentwith this monoclonal antibody in "moderately severe" rheumatoidarthritis has been published.⁸ This study assessed the effectsof two dose regimens (1 mg/kg or 10 mg/kg); at four weeks aftera single infusion of the antibody both regimens were effective,the higher dose regimen impressively so. Repeated infusion ofthe antibody was effective in some patients,⁹ although adverseeffects were more common than in the double blind study. Treatmentwith chimeric monoclonal antibody to tumour necrosis factoralpha has promise, although more information about risks isrequired before it can be considered to be a viable treatmentfor rheumatoid arthritis.

Further developments in treating rheumatoid arthritis

Methotrexate--A feature of the past year has been the increasein the use of methotrexate to treat rheumatoid arthritis. Thedrug seems to be well tolerated; almost two thirds of the 123patients with rheumatoid arthritis enrolled in a recent studywere still taking methotrexate five years later.¹⁰ Few of thosewho stopped taking the drug did so because it was ineffective.However, unwanted effects, particularly liver cirrhosis, areworrying. Protocols for monitoring methotrexate treatment inrheumatoid arthritis have recently been published,¹¹ and theBritish Society for Rheumatology is shortly to introduce itsown guidelines for monitoring methotrexate and other secondline drug treatments for rheumatoid arthritis.

Cyclosporin was licensed in 1994 in the United Kingdom for treatingrheumatoid arthritis.¹²

Tenidap is being considered for treating rheumatoid arthritis.¹³It modulates cytokine bioactivity and inhibits leukotriene synthesis.

Treatment of systemic vasculitis--Systemic vasculitis (includingthat associated with rheumatoid arthritis) may have a high deathrate. Combinations of high dose steroids and cyclophosphamidehave been shown to be useful.¹⁴ Rheumatoid vasculitis (fig 2)may not be recognised because the classic signs--skin infarcts,neuropathy, and episcleritis--may be lacking. The only indicationsof this potentially treatable complication of the disease inpatients with rheumatoid arthritis may be rapid weight loss,fever, malaise, and a persistently raised erythrocyte sedimentationrate and C reactive protein concentration.¹⁵ A clinical scoreto grade activity of rheumatoid and other forms of vasculitis(including systemic lupus erythematosus)¹⁶ correlates well withother scores of vasculitis activity and provides a useful monitorof the disease's activity and response to treatment.

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FIG2--Rheumatoid vasculitis

Oral desensitisation of rheumatoid arthritis has long been agoal of rheumatologists. A three month placebo controlled doubleblind study of soluble chicken type II collagen has previouslydemonstrated significant improvement in disease activity.¹⁷Studies are continuing into other oral desensitising agents.¹⁸

Second line drugs--There has long been doubt about the efficacyof second line drugs in preventing the progression of rheumatoidarthritis.¹⁹ Nevertheless, second line treatment continues tobe used from an early stage in the disease.²⁰ A partly reassuringmessage has recently emerged. Good disease control and improvedfunction was achieved in the long term in almost a third ofpatients treated with sulphasalazine, penicillamine, or injectablegold.²¹ Possibly even better results will be shown with methotrexateand combinations of second line drugs.

   Pathogenesis of anaemia of chronic
   disease²³

   Decreased production of red cells

   * Inadequate iron supply:
        Impaired absorption and transport
        Failure to release iron stores

   * Erythropoietin:
        Decreased concentrations
        Increased marrow resistance

   * Ineffective erythropoiesis
   * Abnormal development of erythroid progenitor
       cells

   Increased destruction of red cells
   * Not an important factor

Anaemia--In rheumatoid arthritis anaemia is due to a combinationof factors, including gastrointestinal blood loss caused bynon-steroidal anti-inflammatory drugs and the "anaemia of chronicinflammation"²² (box). Human recombinant erythropoietin is effectivein raising haemoglobin concentrations in patients with activerheumatoid arthritis who have been adequately pretreated withiron.²⁴ The patients' energy improves significantly but nottheir indicators of disease activity.

Specialist nurse practitioners--Rheumatologists who work inassociation with specialist nurse practitioners believe thatsuch nurses increase the effectiveness of practice, particularlyin terms of giving information to and counselling patients.Patients with rheumatoid arthritis monitored by a nurse practitionershowed greater improvement in measures of pain, knowledge, andsatisfaction than patients receiving care only from a consultantrheumatologist.²⁵

Day patient v inpatient management--Under increasing pressureto reduce hospital inpatient episodes, rheumatologists haveexamined whether patients with active rheumatoid arthritis hithertoadmitted to hospital can be treated successfully as outpatients.A pilot study found comparable clinical outcome with inpatientand day case treatment, day case treatment being significantlycheaper.²⁶ As the authors concede, however, many patients withactive rheumatoid arthritis need to be treated as inpatients;the study excluded patients admitted as emergencies, those withmedical complications of rheumatoid arthritis, and those livingtoo far from hospital to attend daily. The results of a largerstudy are awaited.

Chronic back pain and soft tissue rheumatism

Successful treatment of chronic back pain remains as elusiveas the cause in most cases. An editorial reviewed recent discoveriesabout the possible role of cerebral factors and of sensitisationof the dorsal horn of the spinal cord in perpetuating pain,even when no direct cause for the pain can be found.²⁷ Treatmentsthat lead to a reduction in cerebral activation of the sensitiseddorsal horn may thus be the most effective way of dealing withchronic low back pain. Prevention of chronic low back pain byearly mobilisation of patients with acute back pain is an approachincreasingly favoured²⁸ and has been confirmed in the recentrecommendations from the government's Clinical Standards AdvisoryGroup.²⁹

Uncritical acceptance of the significance of abnormalities inscans from magnetic resonance imaging of the lumbar spine hasbeen dented by the discovery that many people without low backpain have disc bulges on such scans (fig 3).³⁰ An accompanyingeditorial emphasises the hazards of scans taken "just in case,"pointing out that this type of undirected investigation encouragesillness related behaviour.³¹ Such a state of affairs is familiarto rheumatologists, who are frequently called on to reassurepatients with abnormal results in inappropriately performedtests for rheumatoid factor and antinuclear antibody.

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FIG3--Magnetic resonance imaging scan showing disc bulges, posteriorlybetween lower lumbar vertebrae. These were previously thoughtto cause back pain

Whatever the appearance on magnetic resonance imaging, disabilitydue to low back pain remains a major problem; return to workis governed as much by the sufferer's job and his or her compensationstatus as by the severity of the pain.³² This confirms the needfor doctors to avoid abetting the sick role and illness behaviourat an early stage in patients with back pain if there is tobe any hope that chronic back pain can be avoided.

Similarly, the development of the chronic fatigue syndrome mightbe related not only to the patient's tendency to somatise symptomsbut also to the doctor's providing a sick note and expressinguncertainty about the diagnosis.³³

Such patients are often "difficult to help"--a term coined toreplace pejorative names such as heartsink.³⁴ Patients withmedically unexplained symptoms, severe untreatable illness,and coexisting social problems who are long term attenders atoutpatient departments are particularly difficult to help. Sincemany patients attending rheumatology clinics fall into one ormore of these categories, rheumatologists may be doomed notto satisfy a number of such patients.

Advances in understanding genetic influences in rheumatoid arthritis

Understanding of the genetic influences on rheumatoid arthritishas developed slowly. Conclusions are hampered by problems withdefining rheumatoid arthritis, the more frequent occurrenceof the disease in siblings and twins of patients with severerheumatoid arthritis than in those with mild disease, and thecross sectional design of existing studies.³⁵ Uncertainty alsopersists about how much of the inheritance of rheumatoid arthritisis through HLA-DR or other genes.³⁶ Several groups think thatHLA-DR genes constitute about 30% of the genetic componentsof rheumatoid arthritis.³⁷

Osteoporosis

Osteoporosis deserves a review of its own.³⁸ The value of bonedensitometry as a research tool is established; it is now availablefor clinical use and rheumatologists are frequently asked toadvise on its results. The indications for densitometry includeknown oestrogen deficiency, vertebral deformity or a historyof multiple low trauma fractures, radiographic osteopenia, andsteroid treatment.³⁹ Serial bone densitometry measurements maybe indicated for monitoring the effects of bone sparing treatment.

Bone densitometry has yielded important information in patientswith rheumatoid arthritis; generalised bone loss occurs earlyin the disease and reflects disease activity.⁴⁰ The resultsalso point to a narrow therapeutic window for steroid treatmentin patients with rheumatoid arthritis: bone loss is high atprednisolone doses of less than 5 mg daily, probably owing topoor disease suppression, and over 7.5 mg daily.⁴¹

Future directions for rheumatology

Infection and inflammatory arthritis--Researchers have longbelieved that rheumatoid arthritis may be a consequence of infection;evidence for this has been lacking. The infective nature ofLyme disease, parvovirus B19 arthritis, and discoveries aboutreactive arthritis⁴² have boosted hopes that infection may beimplicated in the aetiopathogenesis of rheumatoid arthritisand Still's (systemic) disease.

Kawasaki syndrome continues to fascinate paediatricians andrheumatologists. No bacterial infection has been found to explainthis syndrome; agents such as rickettsia, parvovirus, and retrovirushave been suggested. One hypothesis is that microbiologicaltoxins acting as superantigens may stimulate the Vß² regionof the immunoglobulin molecule and T cells.⁴³ Staphylococciand streptococci that produce toxins similar to those of thetoxic shock syndrome have been found in children with the Kawasakisyndrome. Thus the effectiveness of intravenous immunoglobulinin treating the Kawasaki syndrome could be the result of itsneutralising effect on the toxin.

Neuropeptides--The role of neuropeptides (particularly substanceP) in perpetuating synovitis is being examined.⁴⁴ To date moststudies have been performed in animals.

Free radicals--The role of free radicals (including nitric oxideand hydrogen peroxide) in inflammation awaits further clarification.⁴⁵

Long term studies in rheumatoid arthritis--Valid conclusionsabout the natural course and efficacy of treatment of rheumatoidarthritis require studies extending over decades. Much existinglong term knowledge is based on studies using outmoded treatmentsand means of assessment. The results of long term studies basedon more modern methods such as the health assessment questionnaire⁴⁶will appear in increasing numbers, giving a more accurate pictureof the progression of rheumatoid arthritis.

Conclusion

A first glance through the published work of the past year mightsupport the cynical argument that there have been no significantrecent advances in rheumatology. Rheumatoid arthritis remainsincurable, its mechanisms poorly understood, and its cause unknown.Back pain continues to cause major disability and economic loss.The need for hip and knee replacements for osteoarthritis remainsas high as ever. This apparent gloom conceals, however, informationthat has led to improvements and greater safety in individualpractice and benefit to patients. A spirit of encouraging patientswith back pain not to take to their beds or to take time offwork seems to be growing. In the future, rheumatologists arecertain to face increasing questioning from their patients aboutthe wisdom of treatment with corticosteroids and nonsteroidalanti-inflammatory drugs.