Recent advances in the management of rheumatoid arthritis

History

Patients have pain, stiffness, and limited joint movement. Presentation may be classic, with symmetrical polyarthritis of the small joints of the hands and feet, but monoarthritis or oligoarthritis, including large joints as first manifestation, is not uncommon.5 Observational studies suggest that patients who present with monoarthritis or oligoarthritis are as likely to develop progressive joint damage as those who present with polyarthritis^w2 Patients often report general symptoms, such as morning stiffness (not only in affected joints, lasting more than an hour), fatigue, fever, sweats, and weight loss.6 In early disease, functional limitations are determined by the presence of active synovitis, but in the long term joint damage is also a contributory factor.^w3

Examination

Synovitis can be clinically diagnosed by examination of the joints (box 2). Palpation shows swelling within the joint, sometimes with bulging and pain on pressure. Movement, particularly (over)extension or rotation, is limited, and force is reduced—for example, when making a fist. Because the small joints of the feet may be difficult to assess separately, inflammation may be easier to detect if the metatarsal joints are squeezed together. Heat and redness may be apparent, but absence of these signs does not preclude inflammation. In later stages of disease, rheumatic nodules or deformation might be seen, typically with ulnary deviation of the metacarpophalangeal joints. No single test or set of criteria is available to diagnose rheumatoid arthritis. Classification criteria have been developed for use in research populations only, although they are sometimes used in clinical practice. Until recently, the 1987 classification criteria of the American College of Rheumatology (ACR) were used (box 3).7 New classification criteria with a higher sensitivity in early disease were developed in 2010 (table⇓).5

Investigations by general practitioner

Patients with clinical signs and symptoms of arthritis should be referred to a rheumatologist as early as possible.6 More than a 12 week delay in referral is associated with a reduced chance of drug-free remission and increased risk for progressive joint damage.8 Radiographs and laboratory assessments are not necessary before referral and may delay treatment. Once the presence of arthritis is established, these tests may help identify monoarthritis or oligoarthritis in the early phases of disease.^w4

Investigations by a specialist

Investigations in newly diagnosed patients include measurement of acute phase reactants (to calculate disease activity), a full blood count, and autoantibody tests. When an infectious cause or crystal induced (poly)arthritis is suspected, aspiration of synovial fluid or synovial biopsy may be helpful. Ultrasound may show synovitis in joints that are clinically difficult to assess and may help guide synovial fluid aspiration. Additional radiological and laboratory assessments might be needed to exclude alternative diagnoses. Radiographs of hands, wrists, and feet are recommended early in the disease to assess early structural damage and should be repeated annually to monitor disease severity and response to treatment.6 In research settings, changes on ultrasound and magnetic resonance imaging seem to be predictive of future progression, but it is unclear if and how these modalities should be integrated into daily practice.^w5

Autoantibodies

Laboratory studies, observational trials, and randomised trials have shown that rheumatoid factor, directed against IgG, and antibodies against citrullinated proteins are seen in about two thirds of patients with rheumatoid arthritis. Several observational studies have shown that the presence of autoantibodies predicts a more severe disease course. In patients with undifferentiated arthritis, the presence of anti-citrullinated protein antibodies predicts progression to rheumatoid arthritis.9 10 Patients with and without these autoantibodies seem to differ genetically from one another, suggesting that anti-citrullinated protein positive and negative arthritis may be two distinct disease entities.^w6 Evidence from laboratory studies suggests that these antibodies play a pathogenic role in the disease, although the exact mechanism is unknown.^w7 Both types of autoantibody can be present years before onset of disease.^w8

Evaluation of treatment response

For decades treatment was adjusted on the basis of the doctor-patient interview and clinical examination. More objective ways of calculating disease activity have made it possible to set predefined goals and change drugs accordingly. Box 4, figs 1⇓ and 2⇓, and the web extra material (see bmj.com) show the most commonly used outcome measures in rheumatoid arthritis. The concept of tight control was introduced in the TICORA and CAMERA trials. Both trials found reduced disease activity and radiographic progression and increased function and clinical remission in patients whose treatment was regularly adjusted than in those treated conventionally.12 13 The BeSt study used a disease activity score of 2.4 or lower to guide all treatments, including drug tapering and discontinuation steps, while comparing four different treatment strategies. Patients starting with a combination of DMARDs and prednisone or infliximab showed earlier clinical improvement and reduced progression of joint damage.14

Fig 1 Overview of swollen and tender joint counts as components of disease activity scores. Part (A) shows the joints assessed for swelling in the 44 swollen joint count (white and dark purple; assessed for the presence (score 1) or absence (0) of swelling). For the 28 swollen and tender joint counts only the joints depicted in dark purple (A) are assessed for the presence or absence of swelling or tenderness. Part B shows the Ritchie articular index. For each joint, tenderness is graded from 0 to 3 (0=not tender, 1=pain on pressure, 2=winced; 3=winced and withdrew). With this index joints are grouped, and for each colour the highest score is used. The white joints count as separate joints

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Fig 2 Several methods are available to quantify joint damage on radiographs of hands and feet. The modified Sharp method is well validated and often used in clinical trials.15 In total, 44 joints of hands and feet are assessed for erosions (part A; score range per joint 0-5 in hands, 0-10 in feet) and 42 joints of hands and feet for joint space narrowing (part B; range per joint 0-4). The maximum score is 448. An increase in total score of 5 in one year is considered to be rapid radiological progression and carries a poor prognosis

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Current treatment strategies can achieve a mean Health Assessment Questionnaire score of 0.6, 43% clinical remission, and 13% drug-free remission.16 Recently, an international taskforce published 10 recommendations on targeted treatment, which were based on high level evidence and expert opinion.17 It recommended that clinicians base treatment on a shared decision between patient and rheumatologist; maximise long term health related quality of life through control of symptoms, prevention of structural damage, normalisation of function and social participation, particularly through “abrogation of inflammation”; and target treatment by measuring disease activity and adjusting treatment accordingly.17

Conventional disease modifying anti-rheumatic drugs

Many synthetic DMARDs are available for the treatment of rheumatoid arthritis, but methotrexate is the first line treatment. A recent meta-analysis found that it improves clinical and radiological outcomes; has an acceptable long term toxicity profile; is acceptable to patients, with good adherence rates; and is cost effective.6 11 19 EULAR guidelines published in 2010 consider methotrexate to be safe and effective in combination with other DMARDs.11 Methotrexate also seems to increase the efficacy of biological agents when given concurrently. The most common side effects are gastrointestinal problems and reversible liver toxicity, which can be reduced by subcutaneous administration and dose reduction or concomitant use of folic acid, according to recent international consensus guidelines.20 Other synthetic DMARDs that may be useful are sulfasalazine, leflunomide, hydroxychloroquine, and less often injectable gold, ciclosporin, and azathioprine. As with methotrexate, all conventional DMARDs need regular monitoring for safety.21 A recent systematic review and meta-analysis found that leflunomide was as effective as methotrexate; that sulfasalazine and injectable gold reduced signs and symptoms of rheumatoid arthritis and structural damage; and that ciclosporin, minocycline, tacrolimus, and hydroxychloroquine showed some efficacy in reducing the number of swollen joints.22

Corticosteroids

A systematic review of randomised controlled trials found that low to moderate dose (7.5-15 mg/day) oral glucocorticoids reduce joint destruction and improve symptoms.22 Glucocorticoids reduce disease activity quickly, so are useful as “bridging drugs” when treatment begins. Adding glucocorticoids to DMARD monotherapy or combinations of synthetic DMARDs retards the clinical course of disease and inhibits radiographic progression,6 22 an effect that can last for years.^{w11 w12} Randomised controlled trials have shown that temporary treatment with prednisolone combined with methotrexate and sulfasalazine (and hydroxychloroquine) early in the disease induces more rapid reduction of inflammation and, as a result, earlier reduction of clinical symptoms and prevention of radiological damage than DMARD monotherapy.14 23 24 Intra-articular glucocorticosteroids in combination with methotrexate can reduce local symptoms and may also prevent progression of joint damage.^w13 The optimal dose of glucocorticoids in combination treatment is unknown.

Because long term use of glucocorticoids may increase risk of cardiovascular disease, the occurrence of mood disturbances, and osteoporosis, experts advise cautious use of these drugs, with tapering as soon as symptoms are controlled.6 11 In 2007, a EULAR taskforce published recommendations for the use of oral glucocorticoids in rheumatoid arthritis, with a focus on toxicity.^w14

Biological agents

Several drugs have been developed that target cytokines and cells of the immune system that play a role in the disease process. These new treatments are generally referred to as “biologicals” (box 5).