2 Rheumatoid Arthritis Aggressive treatment can mitigate damage
Learning Objectives • to identify the causes of RA as well as its clinical and laboratory signs and symptoms of different stages of the disease • to provide concrete instances for referring patients to a rheumatologist • to describe the different available therapies for short- and long-term treatment, such as drug, physical and occupational
and never recurred. Three years CASE #1: later she experienced an allergic A 39-year-old woman, previously in reaction to the antibiotic Septra, good health, presents to her doctor which she was prescribed to treat a with a four-week history of pain persistent throat infection. and swelling in the MCP and PIP joints of her right hand, and in both wrists and knees. She has been experiencing morning stiffness that abates by mid-morning, and low energy, making it impossible for her to pursue her aerobics routine, which invariably exacerbates the pain. Fever has been absent but her appetite has been poor, causing her to lose five pounds. At the age of 28, while taking ibuprofen for a gallbladder attack, she had a gastric ulcer that was effectively treated Fig. 1: Rheumatoid arthritis of the hands
A maternal aunt with longstanding rheumatoid arthritis is the only known family member to have a history of arthropathy. CASE #2: A 71-year-old man presents to his doctor having noted a change in his long-standing rheumatoid arthritis. His condition had been under good control with hydroxychloroquine and occasional use of acetaminophen for breakthrough pain. However, in the past several months, he has noted increased joint pain, stiffness, and swelling in the small joints of his hands and in the wrists, knees, ankles and feet. His morning stiffness now lasts three to four hours and his energy level has fallen. Physical examination is consistent with active inflammatory arthritis. Additional positive findings include inspiratory crackles on chest auscultation and mild ankle swelling. Results of laboratory tests show a Hb level of 110 g/L (with the rest of the CBC being normal) and a creatinine level of 180 µmol/L. A normal Hb level range is 135 g/L to 180 g/L; the normal range for creatinine levels is 60 µmol/L to 130 µmol/L. A chest X-ray is consistent with early interstitial changes.
EPIDEMIOLOGY AND CLINICAL PRESENTATION A progressive, inflammatory, systemic disease that manifests itself most prominently in the joints, rheumatoid arthritis (RA) has a worldwide distribution and can occur at any age, with a peak incidence between 30 and 50. Depending on the stringency of criteria, prevalence estimates vary from about 3 per 1,000 to 15 per 1,000. Most evidence suggests that 1% of the population has RA. Women are about 2.5 times more likely to be affected than men. Although the possibility of a bacterial or viral etiology has been vigorously pursued and genetic factors are certainly involved, the cause of RA remains elusive. Onset is occasionally sudden but more typically develops over a period of several weeks, as in Case #1. The wrists are affected in virtually all RA patients. MCP and PIP joints are commonly affected, whereas DIP joints are often spared. Shoulder, elbow, knee, ankle, and MTP joint involvement is also common. Hip involvement is not unusual but may be difficult to detect because of radiation of pain into the buttocks, back and knee. The cervical spine may also be involved, but not the thoratic or lumbar spine. The pattern of joint involvement is often
symmetrical, though the symmetry may not be absolute. Morning stiffness is an almost universal feature of synovial inflammation in RA. In contrast to the brief period of stiffness seen in osteoarthritis, RA-induced morning stiffness usually lasts one hour or more and abates gradually with movement. Patients also experience soreness in affected joints, and often-chronic fatigue, loss of appetite and general malaise. Physical signs of synovitis may be obvious (warm, obviously swollen joints) or more subtle, especially in buried joints such as the hip or during periods when the disease is less active. Subcutaneous rheumatoid nodules (usually over pressure points) develop at some time in up to 50% of RA patients. Structural damage from synovitis often begins in the first year of disease, and much of the damage may occur in the first two years. Characteristic features are cartilage loss, erosion of periarticular bone and alterations in periarticular muscles and tendons. Clinically, this translates to progressive functional and anatomical deterioration. Joint deformity is also related to the patient’s inhibition of full range of motion in the joint(s) in question. Extra-articular manifestations of
more advanced disease include eye inflammation or dryness, laryngeal dysfunction and pericarditis. Cervical spine instability, when present, is particularly worrisome due to the potential for spinal cord impingement. DIFFERENTIAL DIAGNOSIS Despite the suggestiveness of the symptoms in Case #1, a diagnosis of RA cannot be made until symptoms have been present for at least six weeks. This criterion makes the possibility of a viral infection (e.g. mumps, rubella, parvovirus) less likely, which could cause a postviral arthropathy with RA-like symptoms. The presence of morning stiffness or of joint warmth or swelling helps exclude fibromyalgia, which may be suspected if the patient perceives the soreness as diffuse and generalized. However, fibromyalgia may coexist with RA so its presence does not preclude the diagnosis of RA. Documentation of inflammatory synovitis is essential for a diagnosis. Other causes of synovitis to rule out include systemic lupus erythematosus (SLE) and the seronegative spinal arthropathies (e.g. ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease). These forms of arthritis
RA DIAGNOSIS AT A GLANCE
WHEN TO REFER
• • •
Symptoms: Pain, tenderness, stiffness, long-duration morning stiffness Physical findings: Joint warmth and swelling, rheumatoid nodules Laboratory findings: Positive RF, elevated ESR Differentiate from: Viral infection, lupus, polymyalgia rheumatica, seronegative spinal arthropathies, gout, pseudogout, erosive inflammatory OA
may be indistinguishable from RA until the development (or absence) of characteristic extra-articular features allows a differential diagnosis. If a palpable effusion is detected, joint aspiration can confirm the presence of synovial fluid leukocytes and exclude the presence of the crystals found in gout or pseudogout. LABORATORY TESTING While no laboratory finding can establish a diagnosis of RA, a rheumatoid factor (RF) test can reinforce a strongly suspected diagnosis, as 85% of RA patients test positive for RF. When a patient is known to be RF-positive, there is little value in repeating the test because serial titers do not reflect
RA diagnosis is suspected and needs to be established or confirmed • The patient has been newly diagnosed • X-rays reveal the appearance or progression of erosions • Disease progresses rapidly and/or causes significant functional deterioration • Disease engenders extraarticular complications (e.g. cardiovascular, renal, pulmonary, ocular, cutaneous) • Drug treatment is being initiated or changed • Drug treatment is ineffective or drug toxicity/intolerance occur NOTE: In some cases, after the initial referral, the family physician can take over the day-to-day treatment (in consultation with the rheumatologist as necessary). Most patients benefit from at least one annual assessment by a rheumatologist.
clinical disease progression. Erythrocyte sedimentation rate (ESR), a measurement of the rate at which red blood cells settle, varies widely between patients but generally correlates with the degree of synovial inflammation. As such, it
is useful in following the course of inflammatory activity in an individual patient, as is the C-reactive protein test. Patients on parenteral gold or penicillamine require routine CBC and urinalysis. Those on methotrexate and sulfasalazine require periodic CBC and liver enzymes. Ophthalmologists should examine every six months for those on hydroxychloroquine. Radiography is useful in tracking the progression of joint damage. Joint space narrowing, bony erosions and decalcification are characteristic X-ray findings in more advanced disease. EXPECTED COURSE & MANAGEMENT In most patients, RA is a chronic disorder that predictably leads to joint damage and functional limitations. More encouragingly, recent studies have found that the severity of RA appears to be decreasing. Factors that predict a more severe course include the presence of RF and of rheumatoid nodules. It is now known that the greatest damage from RA occurs in the first two years. Early diagnosis and therapy are thus crucial, and the “progressive” model of treatment — begin with weaker medications and move up the potency ladder as
needed — has yielded to a more aggressive approach. Disease-modifying anti-rheumatic drugs (DMARDs), which slow the joint damage caused by RA, are often prescribed upon diagnosis (see Table 1 in Summary on page 26). They include hydroxychloroquine, methotrexate and sulfasalazine; cyclosporine and azathioprine are usually reserved for severe, refractory RA. Parenteral gold and penicillamine are also used in some situations and have a long history of use. Leflunomide has recently been approved for use in RA and is indicated for disease of moderate intensity; diarrhea may limit its tolerability and hepatotoxicity must be monitored. Most DMARDs can cause toxicity and require regular blood and/or urine monitoring. The recently available ‘biologics’ etanercept and infliximab, each targeted to a key pathogenic step in an immune pathway, are highly potent but their use may be limited because of their high cost. Increasing (though mixed) evidence that two or more DMARDs can act synergistically has led to a greater emphasis on combination therapy, often including hydroxychloroquine because of its benign safety profile. While sulfasalazine is a good choice for early, mild-to-moderate disease, it is contraindicated for patients
allergic to sulfonamide drugs, as in Case #1. The recommendation for this patient, who appears to have moderately severe disease, would be to start with methotrexate and possibly experiment with combination therapy. Case #2 would warrant a trial of a DMARD more potent than hydroxychloroquine, bearing in mind that sulfasalazine is contraindicated because of renal insufficiency. Again, methotrexate would be an appropriate first-line choice. Nonsteroidal anti-inflammatory drugs (NSAIDs) and (if necessary) oral or injected steroids provide short-term relief while waiting for DMARDs to take effect (several weeks for methotrexate and the biologics, several months for most other DMARDs). The risk of NSAID gastrointestinal toxicity increases in patients susceptible to GI bleeding (as in Case #1) and the risk of renal toxicity increases in patients with renal dysfunction (as in Case #2). Elderly patients are also at inherently increased risk. For high-risk patients, an approved NSAID belonging to the coxib class can markedly reduce the incidence of serious GI adverse effects. Gastrointestinal protection can also be obtained with the synthetic prostaglandin misoprostol, proton pump inhibitors, and possibly highdose H2 blockers (which may relieve
symptoms, but are not necessarily gastroprotective). Still, all NSAIDs need to be used with caution and regular monitoring in such patients. Physical and occupational therapy have a significant impact on joint strength and function. Typical rehabilitation for RA includes: hand and wrist splints to rest swollen joints and to support joints during activity; semi-rigid orthotics inserts to support proper foot alignment; and graduated exercises to maintain ROM, strength and aerobic capacity. Psychosocial interventions promote individual and family adjustment to the disease. If severe damage and/or discomfort persist despite appropriate drug and non-drug therapy, surgical intervention ranging from wrist fusion and tendon repair to total joint replacement can put an end to the pain and partially restore function. Treatment • For long-term mitigation of destruction: sulfasalazine (unless contraindicated), hydroxychloroquine or oral gold for mild-tomoderate disease; methotrexate (oral or parenteral), parenteral gold, or other DMARDs for moderate-to-severe disease • If response inadequate or toxicity occurs: experiment with other individual DMARDs and/or
combination therapy • For short-term symptomatic relief: full-dose nonsteroidal anti-inflammatory drug (coxib if patient has risk factors for UGI bleeding or ulcer disease), possibly with concomitant anti-ulcer
medication; oral and/or injected steroids if necessary • Non-drug therapy: physical and occupational therapy, exercises, rest, psychosocial support • If disease refractory to therapy: consider referral for surgery
DIAGNOSTIC & TREATMENT SUMMARY Criteria for Rheumatoid Arthritis: Four or more of the following seven criteria (the first four for at least six weeks): • •
Morning stiffness in and around joints, lasting at least an hour Arthritis, including soft tissue swelling or fluid, in three or more of 14 joint areas (right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP) Arthritis in at least one hand joint
• • •
(wrist, MCP, or PIP) Symmetric arthritis (partial or absolute) Subcutaneous rheumatoid nodules Elevated serum rheumatoid factor Radiographic changes typical of rheumatoid arthritis, including erosions or bony decalcification
POTENCY AND TOXICITY PROFILES OF DRUGS USED IN RA
Steroids (short-term) Parenteral gold
Steroids (short-term) Parenteral gold
Hydroxychloroquine Sulfasalazine Steroids (short-term) Penicillamine Parenteral gold NSAIDs Methotrexate Azathioprine
NSAIDs Methotrexate* Azathioprine Leflunomide Combination therapy Daily steroids Cyclosporine
NSAIDs Methotrexate* Azathioprine Leflunomide Combination therapy Daily steroids Cyclosporine Biologics: Infliximab Etanercept
Fairly High High
*consider parenteral dose up to 25 mg
QUESTIONS 1. What are some of the characteristic features of joint involvement in RA? The most commonly affected joints in RA are in the wrists (almost always), MCP and PIP joints of the hand, elbows, knees, ankles, and MTP joints of the foot. Shoulder, cervical spine, or hip involvement is not uncommon, though more difficult to establish because of the ‘deeper’ location of these joints. The same joint areas are often involved on both sides of the body, though the symmetry is not necessarily absolute — for example, MCP and PIP joints may be affected bilaterally but the wrist only on one side.
Hydroxychloroquine appears to be the least toxic DMARD, followed by methotrexate and gold. Azathioprine is more toxic — its toxicity profile resembles that of the most toxic NSAID, indomethacin — and generally reserved for patients with moderate-to-severe disease. The use of cyclosporine, which can cause irreversible renal toxicity, is generally limited to RA refractory to leflunomide and other DMARDs. To date, the toxicity profiles of the new “biologic” DMARDs have not been established definitively.
2. What are the key considerations guiding the choice of DMARD for treating RA? In prescribing DMARDs, physicians must weigh drug toxicity profiles with disease severity and individual risk factors. The optimal choice combines a high degree of disease-modifying capacity, minimal toxicity, and high probability that a patient will be able to continue the drug for two to five years.