Recent Advances in Rheumatology

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Rheumatology Recent advances: Clinical review

BMJ 2000;321:882-885 ( 7 October )

http://bmj.com/cgi/content/full/321/7265/882

Rajan Madhok, consultant rheumatologist, Kerr, specialist

registrar in rheumatology, A Capell, consultant rheumatologist.

Centre for Rheumatic Diseases, Royal Infirmary, Glasgow G4 0SF

Correspondence to: H A Capell gcl101@...

***(Sections on Osteoarthritis, Osteoporosis and References snipped for

space ... but available at website)***

The health consequences and fiscal burden of musculoskeletal diseases

has been acknowledged but never fully addressed. An agenda unveiled by

the World Health Organization to redress the balance sets specific goals

for the next 10 years (the bone and joint decade). These include a 25%

reduction in the expected increase in morbidity from rheumatoid

arthritis, osteoporosis, and osteoarthritis.

Methods

We have reviewed advances in rheumatology that can be easily integrated

into routine clinical practice and highlighted areas where appropriate

treatment has been shown to prevent later disability or morbidity.

References are supplied for published trials and systematic reviews.

Non-steroidal anti-inflammatory drugs are the most commonly prescribed

drugs in the management of rheumatic disease. Gastrointestinal ulcers

occur in 15-20% of patient taking non-steroidal anti-inflammatories, 70%

of them in the stomach. Around 2-4% of patients develop ulcer related

complications, mainly bleeding and perforation. Women, especially those

aged over 70 years with coexisting cardiac disease and previous peptic

ulcers, are at greatest risk. These risk factors are additive.

Options to prevent complications include H2 receptor antagonists, proton

pump inhibitors, and misoprostol. More recently, selective and specific

cyclo-oxygenase-2 inhibitors have become available. A two part

comparative study of omeprazole and misoprostol in patients taking

non-steroidal anti-inflammatory drugs found that omeprazole healed more

gastric and duodenal ulcers than misoprostol. In the maintenance phase

omeprazole prevented more duodenal ulcers than misoprostol but not

gastric ulcers. No comment on ulcer related complications can be made.13

Two cyclo-oxygenase isoforms are recognised: cyclo-oxygenase-1 is

fundamental to normal function (expressed in the gastrointestinal tract,

kidneys, and platelets), whereas cyclo-oxygenase-2 is induced during

inflammation. Two specific cyclo-oxygenase-2 inhibitors are currently

available, rofecoxib (licensed for osteoarthritis only) and celecoxib

(licensed for osteoarthritis and rheumatoid arthritis). Both are as

effective as conventional non-steroidal anti-inflammatory drugs in

arthritic patients. 14 15 Dyspepsia occurs in similar numbers of

patients as with conventional non-steroidal anti-inflammatories. The

incidence of endoscopic ulcer with cyclo-oxygenase-2 inhibitors,

however, is similar to that in the placebo group.

To examine the issue of ulcer related complications, Langman et al

conducted a pooled analysis of eight studies comparing conventional

non-steroidal anti-inflammatory drugs with placebo and rofecoxib in

patients with osteoarthritis (total sample size, 5435).16 Although the

number of complications (perforation, painful ulcer, and bleeding) was

small, fewer arose with rofecoxib than with other non-steroidals

(ibuprofen and diclofenac; no complications were attributed to

nabumetone but numbers treated were small).16

Rheumatoid arthritis

Early disease modifying antirheumatic treatment improves subjective and

objective markers of severity of rheumatoid arthritisthat is, joint

pain, swelling, and tenderness; duration and severity of morning

stiffness; patient wellbeing and function; and inflammatory markers such

as erythrocyte sedimentation rate and C reactive protein. Early

treatment also improves outcome measures such as disability, quality of

life, and radiological progression.17

Advances have focused on defining when treatment should begin, how long

to continue, if one drug is better than others, if combinations confer

additional benefit, and the evidence for the more expensive biological

drugs. The double edged sword of oral corticosteroid treatment remains

under scrutiny 50 years after its introduction by Hench et al.18

When should treatment be started?

Four recent studies emphasised the importance of early treatment for

maximum benefit and to reduce future disability. Two retrospective

analyses showed patients treated early were more likely to maintain

vital functional benefit at five years. 19 20 An open randomised

controlled trial in 238 consecutive patients allocated to immediate or

delayed introduction of disease modifying treatment found that the group

given immediate treatment had significant advantages in functional

disability, patient score, and radiological progression at one year.21

The fourth study in 199 patients reported better pain and physical

outcomes at three years for patients given early treatment compared with

patients in whom treatment was delayed for nine months.22

Is it necessary to continue treatment once a response is achieved?

A study of 285 patients who had shown a sustained response to disease

modifying treatment over five years found that more flares occurred in

the group randomised to placebo than in those who continued the drug

over one year.23 This finding was confirmed by a study that randomised

112 patients to treatment or placebo. Flares occurred in 42 patients, 33

of whom were in the placebo group. Fifty two people refused to

participate because they did not wish to be exposed to the chance of

receiving placebo.24 These results shows that treatment is effective, of

greater benefit if introduced early, and needs to be sustained

indefinitely.

Which drug to use? How much benefit should be expected?

Sulfasalazine and methotrexate are widely used anchor drugs.

Intramuscular gold and penicillamine are more toxic than the other

drugs, and hydroxychloroquine and auranofin confer less benefit. The

future roles of leflunomide (a recently introduced immunomodulatory drug

that inhibits synthesis of pyrimidine and has a similar benefit to

sulfasalazine and methotrexate)25 and minocycline (effective in

rheumatoid arthritis but not licensed) have yet to be established.

Concerns about long term cumulative toxicity with systemic

corticosteroids and the short term relief of symptoms (average nine

months) has limited their widespread use, despite favourable

radiological data.26 In the combination study by Boers et al, the dose

of corticosteroid (60 mg) was too high to be maintained without

unacceptable toxicity.27

Along with drugs against tumour necrosis factor , the choice of

antirheumatic drugs is now wider. Thus all patients with rheumatoid

arthritis should have access to an effective drug early in the course of

their disease. A 50% improvement in symptoms and acute phase reactants

should be achieved.

Targeted immunotherapy

Tumour necrosis factor , a product of macrophages, acts on the immune

system to induce the production of other pro-inflammatory mediators. Two

drugs that inhibit tumour necrosis factor activity have recently been

licensed for treatment of rheumatoid arthritis, infliximab and

etanercept. Infliximab is a chimeric monoclonal antibody given as an

intravenous infusion at 0, 2, and 6 weeks and then every 8 weeks.

Infliximab cross links tumour necrosis factor bound to T cells, thus

inactivating or destroying it. A double blind study of infliximab in

addition to methotrexate showed considerable benefit. Side effects

include short lived early and late infusion reactions. One patient

receiving infliximab died of infection during the study.28

Etanercept is a tumour necrosis factor receptor fusion protein designed

to bind circulatory tumour necrosis factor . It is given as a

subcutaneous injection of 25 mg twice weekly, either alone or with

methotrexate. Results from placebo controlled studies are encouraging.29

Although no major complications were seen in clinical trials, serious

and fatal infections have been reported during postmarketing

surveillance in the United States.

Current limitations of treatment

There are concerns that continued inhibition of pro-inflammatory

molecules may increase the risk of infection and cancer, particularly

lymphoproliferative malignancies. Currently there is no such evidence.

Unless these drugs prove more effective than existing treatments, their

greater costs may preclude widespread early use.

Ongoing research studies

Osteoarthritis: effects of glucosamine and chondroitin on outcome

(National Institutes of Health study)

Non-steroidal anti-inflammatory drugs: do cyclo-oxygenase-2 selective

drugs reduce gastrointestinal toxicity in " true to life " setting?

Rheumatoid arthritis:

Value of combination treatments

Role of targeted immunotherapy

Osteoporosis:

New methods of delivery of bisphosphonates including nasal inhalation

Role of combination treatments

The recent observation that inhibition of hydroxymethylglutaryl coenzyme

A reductase may reduce the risk of fracture raises the possibility that

patients requiring statin for cardiovascular disease may derive

additional benefit in terms of osteoporosis.37