ARTHRITIS AND ITS TREATMENT
2. RHEUMATOID ARTHRITIS
RA is a chronic, progressive autoimmune inflammatory disease of unknown etiology that attacks the synovial tissue leading to irreversible joint damage (Figure 1), chronic pain, stiffness and functional impairment. It affects about 1% of adult population. It is prevalent across all ethnic groups and can occur at any age, although most cases are seen in adults between ages 30 and 60 years.
Women comprise 75% of all cases.
There has been a radical change in the treatment of RA since early 1990s with initiation of disease-modifying anti-rheumatic drugs (DMARDs) early in the disease rather than late. This has resulted from our understanding that RA is not
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Figure 1. Clinical Spectrum of Rheumatoid Arthritis
a benign but progressive disease and many DMARDs are not prohibitively toxic.
In addition to its considerable associated morbidity and economic costs (direct and indirect), RA leads to premature mortality (Reilly et al.,1990). A patient with RA is 2 times more likely to have a myocardial infarction, 70% more likely to have a stroke, 70% more likely to develop an infection, has a 25-fold increased incidence of lymphoma, mortality rates 41% higher for women and life expectancy decreased by 18 years. Since DMARDs alter the disease course in recent onset RA, early and aggressive treatment should be initiated to achieve remission.
There are several options for treating RA. These include traditional DMARDs such as hydroxychloroquine (or chloroquine), sulfasalazine (or salazopyrine), gold salts and methotrexate and newer agents such as lefluonmide and tumor necrosis factor inhibitor etanercept and infliximab. Evidence suggests that treatment with a combination of DMARDs is more effective than monotherapy (O’ Dell et al., 1996). It is a challenge to the management skills of the rheumatologist to determine the most efficacious regiment for a particular patient using a combination and even more importantly appropriate timing of pharmacologic therapy, which may include NSAID, DMARD(s), low dose prednisolone, local injection of gluco- corticoid, biologic agents, emotional and rehabilitation support and non-narcotic analgesics. An early consultation with a rheumatologist is of paramount importance to create a window of opportunity for early initiation of appropriate treatment.
Factors influencing the choice of treatment are efficacy, safety, convenience of treatment regimen, the patient’s disease activity, functional status, co-morbidities, life-style (e.g. child-bearing potential), work status and treatment reimbursement issues. Algorithm for achieving therapeutic success in RA is depicted in Figure2.
2.1 Nonpharmacologic treatment of RA
Management of RA involves more than drug therapy alone. Early in the course of the disease, the patients needs to know and accept to learn to live with RA and will also be required to become involved in decision making for the
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Figure 2. (Is Remission the Mission in RA?)(2005)+Methotrexate is chosen as the initial DMARD quite often, though others may also be used. DAS: Disease Activity Score. TNF: Tumor Necrosis Factor
treatment. Education regarding joint protection, energy conservation and arthritis home exercise programme (one such free exercise programme is available at www.healingtouchwebhelp.net/html/exerci.htm) with range of motion and strength- ening exercises are important for maintaining joint function.
Physical therapy and occupational therapy may help the patient who is compro- mised in activities of daily living. Regular dynamic and aerobic exercises improve joint mobility, muscle strength, aerobic fitness and psychological well being without increasing fatigue or joint symptoms.
2.2 Drug Therapy of RA
Drug therapy of RA often consists of NSAIDs, DMARDs, anti-TNF and/or gluco- corticoids. The initial therapy of RA usually involves use of salicyclates or NSAIDs to reduce joint pain and swelling and to improve joint function. NSAIDs have analgesic and anti-inflammatory properties but do not alter the disease course or alter joint destruction.
ARTHRITIS AND ITS TREATMENT 111 2.3 DMARDs
DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function and reduce total cost of health care and maintain economic productivity of RA patient (ACR Subcommittee on Rheumatoid Arthritis Guide- lines, 2002). The initiation of DMARDs therapy should not delayed beyond 3 months for any patient with established diagnosis who, despite adequate treatment with NSAIDs, has ongoing joint pain, significant morning stiffness or fatigue, active synovitis, persistent elevation of ESR or CRP level or radiographic joint damage (ACR Subcommittee on Rheumatoid Arthritis Guidelines,2002). In fact there is an emerging view that early onset RA should be considered as a medical emergency and early treatment (within 2 weeks of diagnosis) with DMARDs should be initiated as it provides better outcomes at 2 years (Lard et al.,2001). For any untreated patient with persistent synovitis and joint damage, DMARDs should be started promptly to prevent or slow further damage (ACR Subcommittee on Rheumatoid Arthritis Guidelines,2002) and ultimately to achieve remission.
The DMARDs commonly used in RA include hydroxychloroquine (HCQ), sulfasalazine (SSZ), methotrexate (MTX), and lefluonmide. Those used less frequently include azathioprine (AZA), D-penicillamine (D-Pen), gold salts, minocycline and cyclosporine.
Initial choice of DMARD for a particular patient is influenced by several consid- erations. Initial DMARD(s) is chosen based on its relative efficacy, convenience of administration, monitoring requirement, cost of drug and monitoring, time until expected benefit and adverse affects. Patient factors like compliance, co-morbidities, life-style (e.g. child-bearing potential), severity and prognosis of the patient’s disease also influence the choice. For women of child-bearing age, effective contra- ception is required with DMARDs.
Based on consideration of safety, convenience and cost many rheumatol- ogists select HCQ or SSZ first, but for patient with very active disease or with indicators of a poorer prognosis MTX or combination therapy would be preferred. For patients in whom MTX is contraindicated or has failed to achieve satisfactory disease control either because of lack of efficacy (in doses upto 25 mg/week) or intolerance, treatment with biologic agents or with other DMARDs, either alone or in combination is indicated (ACR Subcommittee on Rheumatoid Arthritis Guidelines,2002).
Controversy remains about whether to initiate DMARD in a sequential ‘step- up’ approach in patients with persistently active disease in whom single agent has failed or whether to initiate combination DMARDs therapy early in the disease course and then apply a ‘step-down’ approach once adequate disease control is attained (Williams et al.,1992). However, there is emerging data (FIN-RACo trial (Mottosen et al.,1999), COBRA (Boers Met et al.,1997)) that combination therapy may be more effective in early RA and should be considered as induction therapy early especially in those with poor prognostic signs (extra-articular manifestations e.g. cutaneous ulcers, vasculitic rash, neuropathy, scleritis, subcutaneous nodules;
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female gender; poor functional score (HAQ >1 at 1 year of disease); multiple joint involvement especially >12 joints; early radiographic evidence of erosive changes; advanced age at onset; high rheumatoid factor titres, anti-cyclic citrullated peptide antibodies; sustained elevation of acute-phase reactants e.g. ESR, CRP, low socioeconomic status/educational level).
2.4 Glucocorticoids
Low dose oral steroids (less than 10 mg/day prednisone) and local steroid injections are highly effective for relieving symptoms in patients with active RA. However, many RA patients become steroid dependent despite DMARD therapy. Evidence suggests that low-dose steroids slow the rate of joint damage and therefore appeared to have disease-modifying potential (ACR Subcommittee on Rheumatoid Arthritis Guidelines, 2002). However, the benefits of low-dose steroids should always be weighed against their adverse effects.
2.5 Biological Agents
These agents bind and neutralize TNF which is an important inflammatory mediator.
The three anti-TNF agents used in RA include etanercept, infliximab and adali- mumab. The timing of use of biologic agents in treating RA is controversial. In the past, these agents were used only when therapy with DMARDs had failed. However, recent studies (TEMPO, ASPIRE, BeST, PREMIER) have evaluated the role of biologic therapy with anti-TNF agents early in the course of disease, making their early use more favorable, even perhaps as first-line agents. Overall, these studies suggest that early therapy with a combination of methotrexate and an anti-TNF agent is likely lead to improved outcomes in RA over therapies without anti-TNF agents. However, the high-cost of the anti-TNF agents may limit their early use, although we may find that if disease activity is controlled early, long-term costs of RA in terms of disability may be averted.
Also, it may be found that combination therapy with methotrexate and an anti- TNF agent can be used up front to control disease, and once disease activity is minimal, the anti-TNF agent can be discontinued and methotrexate used as monotherapy.
It is now being recognized that radiographic progression can occur even during remission in RA (Esmeralda et al., 2004). If a patient is in constant remission and has no other risk factor (that risk factor is defined as a positive rheumatoid factor or baseline damage already present), then no radiographic progression can be expected (Paco et al., 2004). But in those patients in clinical remission who are either rheumatoid factor positive or have a high baseline radiographic score, radiographic progression is still possible (Paco et al.,2004).
ARTHRITIS AND ITS TREATMENT 113 2.6 Is remission in RA a cure?
Using the armamentarium of DMARDs and anti-TNF agents early and aggressively, remission is possible in RA. Does remission mean a cure and can the treatment be discontinued after achieving remission? When patients in remission shifted from active treatment to placebo, they had much higher incidence of flares compared with those who received continued treatment (Saskia et al.,1997). If these patients with flare are again treated with the previously successful regimen they may not achieve the same level of control but actually run a certain risk of getting disease that is worse than they had in the beginning.
2.7 Emerging Concepts in RA Management
It has been found in 2 very large studies that patients destined to develop RA will develop evidence of autoimmunity several years before the onset of their first clinical symptom (Darcy et al.,2003). In fact, up to 40% of RA patients will have either rheumatoid factor and/or anticyclic citrullinated peptide (anti-CCP) antibodies in the preclinical phase of their disease. It’s also known that for the 2 years prior to the onset of their first clinical symptom, they will have an increase in their C-reactive protein (CRP), albeit in the normal range, but it will slowly start to increase, indicating subtle inflammation is occurring, much like what is seen with CRP and atherosclerosis patients.
When they do develop their first symptoms of synovitis? If a biopsy is done in asymptomatic joints, one will find evidence of asymptomatic synovitis in those joints that look clinically normal. This actually means that RA is already a chronic disease at the onset of first symptom. The reason this is important to realize is that if we’re going to cure RA, we may actually need to develop strategies to identify high-risk patients and intervene before they develop a clinical phase. This in fact is being strategized by several investigators presently.