Medical Care: Optimal care of patients with RA requires an integrated approach of pharmacologic and nonpharmacologic therapies.
" Nonpharmacologic
o Education is important in helping patients to understand their disease and to learn how to cope with its consequences.
o Physiotherapy and physical therapy are initiated to help improve and sustain range of motion, increase muscle strength, and reduce pain.
o Occupational therapy is initiated (1) to help patients to use joints and tendons efficiently without stressing these structures, (2) to help patients decrease tension on the joints through the use of specially designed splints, and (3) to help patients to cope with daily life through the use of adaptations to the patients' environment and the use of different aids.
o Orthopedic measures include reconstructive and replacement-type surgical measures.
" Pharmacologic
o The most important measure to successfully treat RA is the use of DMARDs. DMARDs can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function.
o Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications.
o Until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.
o DMARDs can be classified into xenobiotic and biologic agents.
o Xenobiotic agents
" The xenobiotic DMARDs, ie, gold salts (eg, aurothiomalate, auranofin, others), D-penicillamine, chloroquine and hydroxychloroquine, sulfasalazine (SSZ), methotrexate (MTX), azathioprine, and cyclosporin A, have been widely used to treat RA; some have been used for decades.
" MTX and SSZ are the most active compounds in terms of frequency of remissions and time to onset of action and provide the best risk-benefit ratios. MTX alone or in combination with other agents has become the standard of care for moderate-to-severe RA.
" Interest in the use of minocycline has recently been increasing because of its capacity to act as a DMARD.
" Leflunomide is the most recent addition to the xenobiotics and has an activity similar to that of SSZ and MTX.
" SSZ is dosed up to 2-4 g/d, while MTX is administered up to 25 mg once a week (PO, IV, IM, or SC). Both SSZ and MTX are started at low dosages and are increased to full dosages within approximately 4-6 weeks. Monitoring of CBC counts and liver enzymes is important because of the drugs' hematologic and hepatic toxicities. Approximately 1% of patients develop agranulocytosis to SSZ or pneumonitis to MTX. Leflunomide is usually initiated with a loading dose of 100 mg/d for 3 days and is then continued at 20 mg/d. CBC counts and liver enzymes also must be monitored. Most of these drugs have been shown to improve signs and symptoms (as well as quality of life) and to significantly retard radiographic progression of RA.
" Combination therapy appears to be helpful in patients whose RA insufficiently or completely fails to respond to monotherapy with a DMARD. Several compounds have been successfully combined without unexpected added risks; these usually include MTX as one of the drugs, ie, MTX plus cyclosporine A, MTX plus SSZ plus an antimalarial, MTX plus leflunomide, or MTX plus biologics. In general, the same precautions are needed as with the single compounds, although liver and bone marrow toxicity may be increased if compounds affecting these organs are combined.
" The most important and most common adverse events relate to liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Antimalarials may cause ocular toxicity. Nevertheless, these drugs, when used with appropriate clinical and laboratory control monitoring, are usually tolerated well. Adverse events typically become more rare after the first 2-3 months. Most adverse events are reversible with cessation of the drugs or with reduction of the doses.
" In clinical trials, 30-70% of patients using DMARDs, either alone or in combination therapy, achieve partial responses according to the American College of Rheumatology's disease activity score. Predicting which patients will not respond is impossible. In clinical practice, attempting to reduce disease activity as much as possible by (1) increasing the dose of medication (eg, MTX), (2) switching to other DMARDs in those who do not respond or in those with responses regarded as insufficient, or (3) initiating combination therapy is important. Because patients may require 2-3 months to achieve a full response to DMARDs, decisions regarding changes in medication are often delayed until that time.
o Biologic agents
" The recognition of TNF-alpha and IL-1 as central proinflammatory cytokines has led to the development of agents that block these cytokines or their effects. The TNF blockers include etanercept, infliximab, and adalimumab. Etanercept, a bivalent p75-TNF receptor linked to the Fc portion of human IgG, is administered at 25 mg SC twice weekly or 50 mg SC weekly, with or without concomitant MTX. Infliximab, a chimeric monoclonal antibody against TNF-alpha, is administered at doses of 3 mg/kg IV at weeks 0, 2, and 6 and then every 4-8 weeks, usually with MTX. Adalimumab, a recombinant human IgG1 monoclonal antibody specific for human TNF monoclonal antibody, is administered 40 mg SC every 2 weeks.
" These agents are expensive. Consensus statements do not recommend their use until at least one xenobiotic DMARD, usually MTX, has been administered without sufficient success. In clinical trials, up to 70% of patients achieve significant responses, but remissions are not usually observed.
" These agents bind TNF and thus prevent its interaction with its receptors; infliximab binds to cells that express membrane TNF, while etanercept binds lymphotoxin (formerly termed TNF-beta) in addition to soluble TNF-alpha. Failure to respond to one TNF blocker does not preclude response to another. As with xenobiotics, the decision to continue or stop biologic agents can often be made within 3 months after initiation of therapy.
" Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, emergence of antinuclear antibodies, occasional drug-induced lupuslike syndromes, and infections (including tuberculosis). Rarely, demyelinating disorders and bone marrow suppression may occur. Acute and chronic infections, demyelinating disorders, and recent malignancies are contraindications for TNF blockers. Thoroughly searching for latent tuberculosis using chest x-ray films and/or purified protein derivative (PPD) testing is recommended before starting these agents.
" Another biologic is anakinra (IL-1 receptor antagonist [IL-1ra]). IL-1ra occupies the IL-1 receptor without triggering it and prevents receptor binding of IL-1. It is given at a dose of 100 mg/d SC. In clinical trials, a significant response was observed in approximately 40% of patients with RA.
" Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CED86, thereby blocking CD28 interaction. CD28 interaction provides a signal needed for full T-cell activation that is implicated in RA pathogenesis. It is dosed according to body weight (vida infra); after initial infusion, repeat on week 2 and week 4, then every 4 weeks following.
" In addition to improving signs and symptoms and quality of life, all biologics significantly retard radiographic progression of joint erosions.
o Glucocorticoids
" Glucocorticoids are potent anti-inflammatory drugs and are commonly used in patients with RA to bridge the time until DMARDs are effective.
" Doses of up to 10 mg of prednisone per day are typically used, but some patients may require higher doses.
" Timely dose reductions and cessation are important because of the adverse effects associated with long-term steroid use.
o Nonsteroidal anti-inflammatory drugs
" NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. However, they do not retard joint destruction and, therefore, when used alone, are not sufficient to treat RA. Similar to glucocorticoids, they can be reduced in dose or discontinued with successful DMARD therapy.
" Several dozen NSAIDs are available and can be classified into different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac.
" In the early 1990s, 2 isoforms of COX were discovered, ie, COX-1 and COX-2. Traditional NSAIDs inhibit both COX-1 and COX-2.
" The coxibs (COX-2 inhibitors), a new group of compounds, have recently been developed. These compounds have a significant preference for COX-2 over COX-1. COX-1 has a protective role, particularly in the stomach, while COX-2 is strongly up-regulated during inflammation.
" Coxibs, with their selectivity for COX-2, have been shown to be clinically efficacious and are accompanied by significantly reduced GI toxicity, the major adverse event related to the use of nonselective COX inhibitors (ie, NSAIDs). Other adverse effects, such as water retention, hypertension, and abnormal transaminase levels, are observed with both nonselective and COX-2-selective drugs. Whether and to what degree nonaspirin NSAIDs, coxibs, or both have cardiovascular toxicity has not been definitively settled.
o Analgesics
" Acetaminophen/paracetamol, tramadol, codeine, opiates, and a variety of other analgesic medications can also be employed to reduce pain.
" These agents do not affect swelling or joint destruction.
o Experimental therapies
" Despite significant advances over the past decades, RA continues to be an incurable disease. The disease remains active in many patients whose conditions partially or completely fail to respond to DMARDs. Therefore, a vigorous search is underway for new therapeutic agents.
" Although not truly experimental because it has been approved for use in RA, an immunoadsorbent column (Prosorba) is used on occasion to treat patients with resistant disease. Weekly exchanges are given for 12 weeks.
" New TNF blockers are in clinical trials and include CDP 870, a Fab fragment of a humanized monoclonal antibody; and a pegylated version of the p55 TNF receptor.
" Biologics capable of blocking IL-6 or interfering with T-cell/non-T-cell interactions may also be promising.
" Xenobiotics directed at molecules involved in transduction of TNF or IL-1-mediated signals could prove helpful.
" Inhibition of matrix metalloproteinases, although initially unsuccessful, could prove to be efficacious, as could agents that inhibit activation of osteoclasts.
" Apheresis procedures are being investigated.
" High-dose immunosuppression combined with autologous stem cell transplantation has been used in study protocols for patients whose conditions are resistant to other therapies.
o Early therapy
" Many studies have revealed that early treatment of RA (ie, within 3-12 mo of onset) with DMARDs can not only more efficiently retard disease progression than later treatment, but also may induce more remissions. Thus, early therapy with DMARDs has become the standard of care.
" Importantly, note that patients with early forms of arthritis should be evaluated by, and if necessary, referred to physicians who are experienced in the diagnosis and treatment of this disease.
Surgical Care: Cervical spine involvement usually affects C1-C2 and may potentially cause serious neurological consequences. Patients who are to undergo intubation or procedures that may involve manipulation of the neck should have careful evaluation of the cervical spine.
Patients with RA often need multiple operations over time (eg, synovectomy, tendon corrections, joint replacements).