eMedicine Specialties > Rheumatology > Rheumatoid Arthritis

Rheumatoid Arthritis: Treatment & Medication

Author: Howard R Smith, MD, Adjunct Professor of Medicine, Case Western Reserve University; Chief of Rheumatology, Director of The Herbert Bell Pain Management Center, Director of Research, Cleveland Clinic, Huron Hospital
Contributor Information and Disclosures

Updated: Oct 6, 2009

Treatment

Medical Care

The optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach of pharmacologic and nonpharmacologic therapies.

• Nonpharmacologic
  • Education is important in helping patients to understand their disease and to learn how to cope with its consequences.
  • Physiotherapy and physical therapy are initiated to help improve and sustain range of motion, to increase muscle strength, and to reduce pain.
  • Occupational therapy is initiated (1) to help patients to use joints and tendons efficiently without stressing these structures, (2) to help decrease tension on the joints with specially designed splints, and (3) to cope with daily life through adaptations to the patients' environment and the use of different aids.
  • Orthopedic measures include reconstructive and replacement-type surgical measures.
• Pharmacologic
  • The American College of Rheumatology is developing RA recommendations and algorithms for the use of nonbiological and biological DMARDs for patients with RA.
  • DMARDs represent the most important measure in the successful treatment of RA. DMARDs can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function.
  • Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications.
  • Until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.
  • DMARDs can be classified into xenobiotic and biological agents.
  • Xenobiotic agents include the following:
    • 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.
    • Minocycline may act as a DMARD through its action as a matrix metalloproteinase inhibitor.
    • Leflunomide is the most recent addition to the xenobiotics and has an activity that is 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 lower 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.
    • Visser et al (2009) conducted a systematic review to assess the evidence for the optimal treatment of RA with MTX. The study sought to establish the optimal dosage and route of administration of MTX. In the review of 1748 articles identified in the literature, 38 met inclusion criteria. The analysis concluded that an initial MTX dose of 15 mg/week orally with escalation of 5 mg/month to achieve target doses of 25-30 mg/week or maximum tolerable doses was the optimal, evidence-based dosing strategy. Starting at higher initial doses or too rapid of escalation is limited by toxicity. Conversion from oral to subcutaneous administration of MTX is suggested for patients who have an inadequate response to oral therapy.⁴
    • 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 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 well tolerated. Adverse events typically become rarer 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. Currently, predicting which patients will not respond is not possible. 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.
  • Biological agents include the following:
    • 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 p 75–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.⁵
    • 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 biological agents can often be made within 3 months after initiation of therapy.
    • Adverse effects associated with the biological 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 radiography and/or purified protein derivative (PPD) testing is recommended before these agents are started.
    • Another biological agent 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 CD86, thereby blocking their interaction with CD28. 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.
    • Fleischmann et al examined safety and efficacy of certolizumab monotherapy in 220 patients RA in whom DMARD therapy had failed. Patients were randomized 1:1 to receive certolizumab 400 mg or placebo every 4 weeks for 24 weeks. At 24 weeks, 45.5% of the certolizumab group achieved a 20% improvement according to the American College of Rheumatology criteria (ACR20), whereas 9.3% of the placebo group achieved ACR20 (P <0.001). Statistically significant differences between certolizumab and placebo were observed as early as week 1 through week 24 (P <0.001).⁶
    • Smolen et al evaluated the effect of certolizumab plus MTX versus placebo plus MTX in patients with RA. The primary endpoint was ACR20 response at week 24. Patients (n=619) were randomized to receive certolizumab 400 mg at weeks 0, 2, and 4 followed by 200 mg or 400 mg plus MTX every 2 weeks, or placebo plus MTX every 2 weeks. Significantly more patients who received certolizumab 200 mg or 400 mg achieved ACR20 compared with those who received placebo (P <0.001), with rates of 57.3%, 57.6%, and 8.7%, respectively. Radiographic progression was significantly inhibited with certolizumab 200 mg (0.2), 400 mg (-0.4) compared with placebo (1.2). When compared with placebo plus MTX, certolizumab plus MTX significantly relieved signs and symptoms, improved physical function, and inhibited radiographic progression in patients with RA.⁷
    • In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions.
    • Golimumab, a new human anti–TNF-alpha monoclonal antibody, inhibits TNF-alpha bioactivity, thereby modulating immune activity in patients with RA. Emery et al (2009) conducted a 52-week, randomized, double-blind, placebo-control study, followed by an open-label extension through 5 years to assess the safety and efficacy of golimumab in MTX-naive patients with RA. Patients (n=637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Intent-to-treat analysis showed no significant differences in the primary endpoint between group 1 and groups 3 and 4 combined, indicating efficacy of golimumab in RA. The incidence of serious adverse events was similar among all treatment groups.⁸
  • 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.
  • 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.
  • Analgesics
    • Acetaminophen/paracetamol, tramadol, codeine, opiates, and various other analgesic medications can also be used to reduce pain.
    • These agents do not affect swelling or joint destruction.
  • 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 RA. Weekly exchanges are given for 12 weeks.
    • New TNF blockers are in clinical trials and include certolizumab, a Fab pegylated fragment of a humanized monoclonal antibody.
    • Several new CD20 B-cell–targeted biologic agents are under investigation, including atacicept, AMG 623, B3-FCc, Br3-Fc, belimumab, epratuzumab, ofatumumab, ocrelizumab, and TRU-015.
    • Biologics capable of blocking IL-6 (tocilizumab) or interfering with T-cell/non–T-cell interactions look to be very promising.
    • Xenobiotics directed at molecules involved in transduction of TNF, those involved with the receptor for the lymphotoxin-b receptor, or IL-1–mediated signals (eg, AMG 108, an IL-1ra) 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.
  • Early therapy
    • Many studies have revealed that early treatment of RA (ie, within months of onset) with DMARDs can not only more efficiently retard disease progression than later treatment, but may also 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 RA.
    • In a study by van Vollenhoven et al, patients with early RA were administered MTX (up to 20 mg/wk). Study participants not achieving low disease activity after 3-4 months were randomized to receive either sulfasalazine and hydroxychloroquine or infliximab in addition to MTX. Of 487 patients who were initially enrolled, 258 had not achieved low disease activity with MTX and were then randomized to receive additional treatment (in addition to MTX) with sulfasalazine and hydroxychloroquine (n=130) or infliximab (n=128). In the sulfasalazine and hydroxychloroquine group, 32 of 130 (25%) achieved the primary outcome defined as a good response according to the European League Against Rheumatism (EULAR). In the infliximab group, 50 of 128 (39%) attained the primary outcome. The authors concluded that, in early RA that fails MTX treatment, the addition of a tumor necrosis factor antagonist is superior to addition of conventional DMARDs.⁹

Surgical Care

Cervical spine involvement usually affects C1-C2 and may potentially cause serious neurologic consequences. Patients who are to undergo intubation or procedures that may involve manipulation of the neck should undergo careful evaluation of the cervical spine.

Patients with RA often need multiple operations over time (eg, synovectomy, tendon corrections, joint replacements).

Consultations

• Orthopedists
• Physical and rehabilitative medicine specialists

Medication

Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach of pharmacologic and nonpharmacologic therapies.

Disease-modifying antirheumatic drugs

Xenobiotics include gold salts (eg, aurothiomalate, auranofin, others), D-penicillamine, chloroquine and hydroxychloroquine, SSZ, MTX, azathioprine, and cyclosporin A and have been widely used to treat RA.

Leflunomide (Arava)

First new DMARD approved in more than 10 years. Blocks autoimmune antibodies and reduces inflammation. Inhibits dihydroorotate dehydrogenase, an enzyme in the de novo pyrimidine synthesis pathway. Studies indicate that it reduces symptoms, possibly better than MTX, and may even slow progression of RA. Use with caution in renal insufficiency

Methotrexate (Rheumatrex, Folex PFS)

Unknown mechanism of action in treatment of inflammatory reactions, although it is a known inhibitor of dihydrofolate reductase and causes extracellular release of adenosine, a known inhibitor of immune and inflammatory pathways. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Gradually adjust dose to attain satisfactory response.

Sulfasalazine (Azulfidine, Azulfidine EN-tabs)

Acts locally to decrease inflammatory response and systemically inhibits prostaglandin synthesis.

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils, inhibits locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate (200 mg) is equivalent to 155-mg hydroxychloroquine base and 250-mg chloroquine phosphate.

Biologicals

Various biologic agents are used to rheumatic actions on joints and may include TNF–alpha inhibition and targeted monoclonal antibodies.

Rituximab (Rituxan)

Chimeric IgG1-kappa monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The Fab domain of rituximab binds to CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Rituximab in combination with methotrexate is indicated to reduce signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF antagonist therapies.

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas. Used with MTX in patients who have inadequate response to MTX monotherapy.

Etanercept (Enbrel)

Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses.

Adalimumab (Humira)

Recombinant human IgG1 monoclonal antibody specific for human TNF. Indicated to reduce inflammation and inhibit progression of structural damage in moderate-to-severe rheumatoid arthritis. Reserved for those who experience inadequate response to one or more DMARDs. It can be used alone or in combination with MTX or other DMARDs. Binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors.

Golimumab (Simponi)

TNF-alpha inhibitor. Decreases inflammation caused by overproduction of TNF associated with chronic inflammatory diseases. Indicated for moderate-to-severe RA, active psoriatic arthritis, and active ankylosing spondylitis. Available as 50-mg/mL, single-dose Simponi SmartJect (Autoinjector) or a prefilled syringe.

Nonsteroidal anti-inflammatory drugs

These agents interfere with prostaglandin synthesis through inhibition of the COX enzyme, thus reducing swelling and pain. However, they do not retard joint destruction and alone are not sufficient to treat RA. As with glucocorticoids, dose can be reduced or drug discontinued with successful DMARD therapy. Coxibs have been given a "black box" warning by the US Food and Drug Administration regarding their potential for increased serious cardiovascular thrombotic events.

Several dozen NSAIDs are available, which can be classified into different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac.

Selective COX-2 inhibitors may be considered for patients at risk for GI bleeding.

Ibuprofen (Motrin, Advil)

Indicated for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Celecoxib (Celebrex)

Primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased. Seek lowest dose for each patient.

Ketoprofen (Orudis, Oruvail)

For relief of mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses of more than 75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response.

Naproxen (Naprosyn)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.
NSAIDs decrease intraglomerular pressure and decrease proteinuria.

Piroxicam (Feldene)

Decreases activity of cyclo-oxygenase, which in turn inhibits prostaglandin synthesis. These effects decrease formation of inflammatory mediators.

Diclofenac (Voltaren)

Designated chemically as 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt, with an empirical formula of C14 H10 Cl2 NO2 NA. One of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. Believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment.
Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation.Delayed-release, enteric-coated form is diclofenac sodium, and immediate release form is diclofenac potassium. Has relatively low risk for bleeding GI ulcers.

Analgesics

Acetaminophen/paracetamol, tramadol, codeine, opiates, and various other analgesic medications can be used to reduce pain. These agents do not affect swelling or joint destruction.

Acetaminophen (Tylenol, Feverall, Tempra)

Used for analgesia in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.

Tramadol (Ultram)

Inhibits ascending pain pathways, altering perception of and response to pain. Also inhibits reuptake of norepinephrine and serotonin.

Immunomodulators

These agents interfere with cytokine actions responsible for inflammation.

Anakinra (Kineret)

Competitively and selectively inhibits IL-1 binding to type I receptor (IL-1RI). IL-1 is found in excess in patients with RA and is produced in response to inflammatory stimuli. By blocking IL-1 binding, inflammation and pain associated with RA are inhibited. Indicated for RA in patients in whom one or more DMARDs have failed. Should be administered at approximately the same time every day.

Abatacept (Orencia)

Selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking CD28 interaction. CD28 interaction provides a signal needed for full T-cell activation that is implicated in RA pathogenesis. Indicated for reducing signs and symptoms of RA, slowing progression of structural damage, and improving physical function in adults with moderate-to-severe RA who have inadequate response to DMARDs, methotrexate, or TNF antagonists. May be used as monotherapy or with DMARDs (other than TNF antagonists, because of increased risk of serious infections [4.4% vs 0.8%]). Not recommended for concomitant use with anakinra (insufficient experience).

Glucocorticoids

These agents are potent anti-inflammatory drugs commonly used in patients with RA to bridge the time until DMARDs are effective. Doses of up to 10 mg/d of prednisone are typically used, but some patients may require higher doses. Adverse events associated with long-term steroid use make dose reductions and cessation important in due course.

Prednisone (Deltasone, Meticorten, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

• Search for CME/CE on This Topic »

• Rheumatoid Arthritis (Physical Medicine and Rehabilitation)
• Juvenile Rheumatoid Arthritis (Orthopedic Surgery)
• Juvenile Rheumatoid Arthritis (Pediatrics: General Medicine)
• Rheumatoid Arthritis and Pregnancy (Rheumatology)

• Arthritis Center
• Rheumatoid Arthritis Overview
• Rheumatoid Arthritis Causes
• Rheumatoid Arthritis Symptoms
• Rheumatoid Arthritis Treatment
• Juvenile Rheumatoid Arthritis Overview
• Chronic Fatigue Syndrome Overview
• Chronic Pain
• Muscle Disorders Center
• Understanding Rheumatoid Arthritis Medications

• Chinese Herb Effective for Rheumatoid Arthritis
• Rheumatoid Arthritis Activity Does Not Affect Myocardial Infarction Risk
• Long-Term Methotrexate Monotherapy for Rheumatoid Arthritis Appears Safe

• Monocytes are Essential for Inhibition of Synovial T-cell Glucocorticoid-mediated Apoptosis in Rheumatoid Arthritis
• Vasculitis in Rheumatoid Arthritis
• American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease Modifying Antirheumatic Drugs in Rheumatoid Arthritis

• Rheumatoid Arthritis Resource Center
• Spinal Disorders Resource Center