Rheumatoid arthritis (RA) is prevalent in 0.5% of adults in the US; it is about 2.5 times more common in women than in men. Guidelines for treatment of RA from the American College of Rheumatology were recently updated. The goal of treatment is to minimize disease activity and prevent irreversible joint damage.

View Expanded Table: Some Biologic Drugs and JAK Inhibitors for Rheumatoid Arthritis

View Expanded Table: Some Conventional DMARDs for Rheumatoid Arthritis

View the Flowchart: Rheumatoid Arthritis Treatment

The FDA has required updates to the boxed warnings in the labeling of the Janus kinase (JAK) inhibitors tofacitinib (Xeljanz, Xeljanz XR), baricitinib (Olumiant), and upadacitinib (Rinvoq) describing increased risks of major adverse cardiovascular events, malignancy, thrombosis, and death with their use. The new warnings were prompted by the results of a postmarketing safety trial with tofacitinib and were added to the labels of baricitinib and upadacitinib based on the presumption of a class effect. The tofacitinib package insert had contained a boxed warning about an increased risk of thrombosis and mortality with a dosage of 10 mg twice daily since 2019, but the new warnings are not limited by dose.

The FDA has approved upadacitinib (Rinvoq – Abbvie), an oral Janus kinase (JAK) inhibitor, for treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to or cannot tolerate methotrexate (Trexall, and others). Upadacitinib is the third JAK inhibitor to be approved in the US for treatment of RA; tofacitinib (Xeljanz, Xeljanz XR) and baricitinib (Olumiant) were approved earlier.

The FDA has approved Qmiiz ODT (TerSera), an orally disintegrating tablet formulation of the prescription NSAID meloxicam. Qmiiz ODT, like conventional oral meloxicam tablets (Mobic, and generics), is indicated for relief of the symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA) in adults and of juvenile RA in children who weigh ≥60 kg. Vivlodex, a low-dose capsule formulation of meloxicam, is FDA-approved only for management of OA pain.

The FDA has required updates to the labeling of the Janus kinase (JAK) inhibitor tofacitinib (Xeljanz, Xeljanz XR) based on interim results of a postmarketing safety trial that showed an increased risk of pulmonary thromboembolism and death with a dosage of 10 mg twice daily.1 Tofacitinib is approved for treatment of rheumatoid arthritis (RA),2 psoriatic arthritis, and ulcerative colitis.

In the postmarketing trial, RA patients ≥50 years old taking methotrexate who had at least one cardiovascular risk factor were randomized to receive add-on treatment with tofacitinib 5 mg twice daily (the FDA-approved dosage for RA and psoriatic arthritis), tofacitinib 10 mg twice daily (an approved dosage for ulcerative colitis), or a tumor necrosis factor (TNF) inhibitor. At the time of the interim analysis in January 2019 (~3900 patient-years of data in each group), pulmonary thromboembolism had occurred in 19 patients taking tofacitinib 10 mg twice daily and in 3 patients taking a TNF inhibitor; 45 patients taking tofacitinib 10 mg twice daily and 25 taking a TNF inhibitor had died. Interim data from the 5-mg twice daily group have not been made available by the FDA. After the interim analysis, patients taking the higher dose of tofacitinib were transitioned into the 5 mg twice daily group; the trial is ongoing.3

Serious, sometimes fatal thromboembolic adverse events have also occurred with use of baricitinib (Olumiant),4 another JAK inhibitor that is FDA-approved for treatment of RA. Whether an increased risk of thromboembolism is a class effect of JAK inhibitors remains to be determined; RA itself has been associated with an increased thromboembolic risk.5

The tofacitinib package insert now contains a boxed warning describing the increased risk of thrombosis and mortality with a dosage of 10 mg twice daily and emphasizes that this dosage or Xeljanz XR 22 mg once daily is not recommended for treatment of RA or psoriatic arthritis. For treatment of ulcerative colitis, tofacitinib is now only indicated in patients who have had an inadequate response or intolerance to TNF inhibitors; for these patients, the 10-mg twice daily dosage is still recommended as induction therapy for 8 weeks (can be continued for up to 16 weeks) and for maintenance treatment when there is loss of response to a dosage of 5 mg twice daily.

1. FDA drug safety communication: FDA approves boxed warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). July 26, 2019. Available at: www.fda.gov. Accessed August 15, 2019.
2. Tofacitinib for rheumatoid arthritis. Med Lett Drugs Ther 2013; 55:1.
3. FDA drug safety communication: Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. February 25, 2019. Available at: https://www.fda.gov. Accessed August 15, 2019.
4. Baricitinib (Olumiant) for rheumatoid arthritis. Med Lett Drugs Ther 2018; 60:120.
5. IC Scott et al. Thromboembolism with Janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk? Drug Saf 2018; 41:645.

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Disease-modifying antirheumatic drugs (DMARDs) are used for initial treatment of rheumatoid arthritis (RA) to achieve clinical remission and prevent irreversible joint damage (see Table 1). DMARDs generally do not have an immediate analgesic effect, but over time they can control symptoms and have been shown to delay and possibly stop progression of the disease. Methotrexate (Trexall, and others) is generally the drug of choice; it can be used for patients with low, moderate, or high disease activity. For mild disease, some clinicians prefer to start with hydroxychloroquine (Plaquenil, and generics) and/or sulfasalazine (Azulfidine, and others).

View Expanded Table: Biologic Agents for Rheumatoid Arthritis

View Expanded Table: Conventional DMARDs for Rheumatoid Arthritis

The FDA has approved the Janus kinase (JAK) inhibitor baricitinib (Olumiant – Lilly) for oral treatment of adults with moderately to severely active rheumatoid arthritis (RA) that has not responded adequately to one or more tumor necrosis factor (TNF) inhibitors. Baricitinib is the second JAK inhibitor to be approved for treatment of RA; tofacitinib (Xeljanz, Xeljanz XR) was the first.

View the Comparison Table: Some Nonopioid Analgesics for Pain

Nonopioid drugs can be used in the treatment of many nociceptive and neuropathic pain conditions. Use of opioids for pain will be reviewed in a future issue.

The FDA has approved the interleukin-6 (IL-6) receptor antagonist tocilizumab (Actemra – Genentech) for subcutaneous (SC) treatment of giant cell arteritis in adults. It is the first drug to be approved in the US for this indication. Tocilizumab is also approved for treatment of rheumatoid arthritis, polyarticular or systemic juvenile idiopathic arthritis, and cytokine release syndrome.

The FDA has approved the interleukin (IL)-6 inhibitor sarilumab (Kevzara – Sanofi) for second-line treatment of adults with moderately to severely active rheumatoid arthritis (RA). It is the second IL-6 inhibitor to be approved for this indication; tocilizumab (Actemra) was approved earlier.

The FDA has approved infliximab-dyyb (Inflectra – Pfizer; marketed as Remsima in some countries), as a biosimilar of the TNF inhibitor infliximab (Remicade). Infliximab-dyyb was approved in the European Union (EU) in 2013 and in Canada in 2014. It is the second biosimilar to be approved by the FDA. Filgastrim-sndz (Zarxio), a recombinant human granulocyte colony-stimulating factor, was the first.

Psoriatic arthritis is a chronic inflammatory arthropathy that develops in up to 40% of patients with psoriasis. Several guidelines for treatment of psoriatic arthritis have been published.

For initial treatment of rheumatoid arthritis, most expert clinicians prescribe a disease-modifying antirheumatic drug (DMARD) and add a nonsteroidal anti-inflammatory drug (NSAID) or a corticosteroid to control symptoms. Methotrexate is generally the DMARD of choice...

DMARDs
Disease-modifying antirheumatic drugs (DMARDs) are used early in the treatment of rheumatoid arthritis (RA) to achieve clinical remission, prevent irreversible damage to joints, and minimize toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. DMARDs generally do not have an immediate analgesic effect, but over time can control symptoms and have been shown to delay and possibly stop progression of the disease. Methotrexate (Rheumatrex, and others) is generally the first DMARD prescribed; it can be used to treat mild, moderate, or severe RA. For mild disease, some clinicians prefer to start with hydroxychloroquine (Plaquenil, and generics) and/or sulfasalazine (Azulfidine, and others).

The FDA has approved a new injectable formulation of methotrexate (Otrexup – Antares) for use in rheumatoid arthritis and polyarticular juvenile idiopathic arthritis, and for severe psoriasis in adults. On its web site (www.otrexup.com), the manufacturer states: "Otrexup is the first subcutaneous (SC) methotrexate (MTX) for self-administration delivered once weekly by auto-injector." Methotrexate has been available as a once-weekly injection (IM or SC) for these indications for many years,1 but not specifically for self-administration and not in a single-dose auto-injector. Methotrexate is generally given orally, but injectable formulations may be helpful for patients who have adverse gastrointestinal effects from the oral formulation or lose benefit over time because of poor absorption.

Otrexup auto-injectors are available in strengths of 10, 15, 20, and 25 mg of methotrexate per 0.4 mL. The usual dosage of methotrexate for patients with rheumatoid arthritis ranges from 7.5 to 25 mg once weekly. Otrexup should be administered SC in the abdomen or thigh. Four 25-mg auto-injectors cost $548.00, compared to $5.00 for a single 4-mL vial of generic methotrexate containing 25 mg/mL.2 Nevertheless, some patients with rheumatoid arthritis who find it difficult to draw up methotrexate solution from a vial and inject it with a syringe may prefer Otrexup.

1. Drugs for rheumatoid arthritis. Treat Guidel Med Lett 2012; 10:37.

2. Approximate wholesale acquisition cost (WAC). Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) March 5, 2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.

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The FDA has approved the interleukin-1 (IL-1) beta inhibitor canakinumab (Ilaris – Novartis) for treatment of systemic juvenile idiopathic arthritis (sJIA; formerly called juvenile rheumatoid arthritis or Still’s disease) in children ≥2 years old. Canakinumab was approved earlier for treatment of cryopyrin-associated periodic syndromes (CAPS). Tocilizumab (Actemra), an interleukin-6 (IL-6) inhibitor that has been available since 2010 for treatment of rheumatoid arthritis in adults, was also recently approved by the FDA for sJIA. Canakinumab is the only IL-1 inhibitor approved for this indication.

The FDA has approved tofacitinib (toe” fa sye’ ti nib; Xeljanz – Pfizer), an oral Janus kinase (JAK) inhibitor, for treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to or are intolerant of methotrexate. Ruxolitinib (Jakafi) is the only other JAK inhibitor available in the US; it is FDA-approved for treatment of myelofibrosis.

The FDA has approved a delayed-release oral formulation of prednisone (Rayos – Horizon Pharma). Rayos is not labeled for any specific indication, but the only published studies of the new product have been in patients with rheumatoid arthritis (RA).

Disease-modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA) to achieve clinical remission, prevent irreversible damage to joints, and minimize toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. DMARDs (Table 1) generally do not have an immediate analgesic effect, but over time can control symptoms and have been shown to delay and possibly stop progression of the disease. NSAIDs have immediate analgesic and antiinflammatory effects, but may not affect the disease process. Oral corticosteroids can relieve joint symptoms and control systemic manifestations, but their chronic use can cause many complications. Judicious use of intra-articular corticosteroids can rapidly decrease inflammation in acute joints with few, if any, adverse effects.

The FDA has approved Duexis (Horizon), a fixed-dose combination of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and the H2-receptor antagonist (H2RA) famotidine, for symptomatic relief of osteoarthritis and rheumatoid arthritis and to decrease the risk of developing gastric and duodenal ulcers in patients at risk for NSAID-associated ulcers. Vimovo, a combination of the NSAID naproxen and the proton pump inhibitor (PPI) esomeprazole, is also approved by the FDA for prevention of NSAID-associated gastric ulcers.

The FDA has approved the marketing of Vimovo (AstraZeneca), a fixed-dose combination of the nonsteroidal anti-inflammatory drug (NSAID) naproxen and the proton pump inhibitor (PPI) esomeprazole, for symptomatic relief of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk for NSAID-associated ulcers.

The FDA has approved tocilizumab (Actemra – Genentech; RoActemra in Europe) for intravenous (IV) treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to tumor necrosis factor (TNF) inhibitors.

The FDA has approved five tumor necrosis factor (TNF) inhibitors for treatment of moderately to severely active rheumatoid arthritis (RA). TNF-α is a pro-inflammatory cytokine involved in the pathogenesis of many systemic inflammatory disorders.

Golimumab (Simponi - Centocor), a fully humanized anti-tumor necrosis factor (TNF)-a antibody, has been approved by the FDA for the treatment of: (1) moderate to severe active rheumatoid arthritis (RA) in combination with methotrexate; (2) active psoriatic arthritis (PsA) alone or in combination with methotrexate; and (3) active ankylosing spondylitis (AS).

Disease-modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA) to prevent irreversible damage to joints and minimize toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids.

Rituximab (Rituxan - Genentech), an anti-CD20 monoclonal antibody already marketed for treatment of B-cell non-Hodgkin's lymphoma, is now FDA-approved for use concurrently with methotrexate to treat moderate to severe rheumatoid arthritis in patients who have had an inadequate response to one or more tumor necrosis factor (TNF) inhibitors. Rituximab selectively depletes CD20+ B cells, which apparently play a role in the autoimmune response and in the chronic synovitis associated with rheumatoid arthritis.

Atacept (Orencia - Bristol-Myers Squibb), an inhibitor of T-cell activation, has been approved by the FDA for treatment of moderate to severe rheumatoid arthritis (RA) in patients who have not responded to one or more disease-modifying anti-rheumatic drugs (DMARDs).

To prevent irreversible damage to joints and minimize toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, disease modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA). The DMARDs listed in the table on page 84 have no immediate analgesic effects, but can control symptoms and have been shown to delay and possibly stop progression of the disease. The NSAIDs listed in the table on page 88 have analgesic and anti-inflammatory effects, but may not affect the disease process. Oral corticosteroids can rapidly relieve joint symptoms and control systemic manifestations, but their chronic use is associated with many complications.

Patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) may be asking their health care providers if they should continue, and some may be asking for alternatives. For most patients taking nonspecific NSAIDs, it would be reasonable to continue. For those who are taking the COX-2 selective celecoxib (Celebrex) because they cannot tolerate the gastrointestinal (GI) effects of nonspecific NSAIDs, it seems reasonable to continue at doses no higher than 100 mg b.i.d. or 200 mg once daily; at these dosages cardiovascular risk has been no higher than with placebo. All NSAIDs, including COX-2 inhibitors, can decrease renal blood flow and cause fluid retention, hypertension and renal failure, especially in the elderly and in patients who take diuretics. The unpublished study that led to an FDA alert on an increased cardiovascular risk with naproxen (Naprosyn, and others) was conducted in patients older than 70. See NSAID addendum

Adalimumab (Humira - Abbott), a tumor necrosis factor alpha (TNF-α) inhibitor, has been approved by the FDA for treatment of moderate to severe rheumatoid arthritis (RA). A genetically engineered human IgG1 monoclonal antibody, adalimumab is approved for subcutaneous (SC) injection in adults who have failed at least one disease-modifying anti-rheumatic drug (DMARD), for use either alone or with other DMARDs such as methotrexate (Rheumatrex, and others). Two other TNF-α antagonists, etanercept (Enbrel) and infliximab (Remicade), are already on the market for treatment of RA (Treatment Guidelines from The Medical Letter 2003; 1:25).

Many different drugs are now used to treat rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs), listed in the table on page 26, have analgesic and anti-inflammatory effects, but may not affect the disease process. Corticosteroids can provide rapid relief of joint symptoms and control of systemic manifestations, but chronic use is associated with many complications. The "disease-modifying" anti-rheumatic drugs (DMARDs), listed on page 29, have no immediate analgesic effects, but can control symptoms and may delay progression of the disease (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, Arthritis Rheum 2002; 46:328). Interactions of anti-rheumatic drugs with other drugs are listed in The Medical Letter Handbook of Adverse Drug Interactions, 2003.

Valdecoxib (Bextra - Pharmacia/Pfizer), a selective cyclooxygenase (COX-2) inhibitor similar to celecoxib (Celebrex) and rofecoxib (Vioxx), was recently approved by the FDA for treatment of osteoarthritis, rheumatoid arthritis and primary dysmenorrhea.

Meloxicam, a nonsteroidal anti-inflammatory drug (NSAID) with some cyclooxygenase-2 (COX-2) selectivity in vitro, has been approved by the FDA for treatment of osteoarthritis.

Leflunomide (Arava - Hoechst Marion Roussel), which inhibits pyrimidine synthesis, and etanercept (Enbrel - Immunex/Wyeth-Ayerst), which blocks the action of tumor necrosis factor (TNF), have been approved by the FDA for treatment of rheumatoid arthritis. A third drug, infliximab (Remicade - Centocor), which also blocks TNF and has been used to treat rheumatoid arthritis, was approved earlier for treatment of Crohn's disease. Its use in Crohn's disease will be reviewed in a future issue.

Many different drugs are now used to treat rheumatoid arthritis. Apirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) listed in the table on page 102 have analgesic and anti-inflammatory effects, and they are relatively safe. The second-line drugs listed on page 106 have no immeadiate analgesic effects, but they can control symptoms and may delay progression of the disease. NSAIDs usually are taken concurrently with the slower acting second-line drugs, which, with the exception of methotrexate, may take months to produce a therapeutic response (JM Cash and JH Klippel, N Engl J Med, 330:1368, May 12, 1994).

Many different drugs are now used to treat rheumatoid arthritis. Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen (Motrin; and others), Naproxen (Naprosyn; and others) and, most recently, diclofenac (Voltaren - Medical Letter, 30:110, 1988), have immediate analgesic and anti-inflammatory effects, and they are relatively safe. The second-line of drugs used for treatment of rheumatoid arthritis include hydroxychloroquine, gold, penicillamine, azathioprine, sulfasalazine and methotrezate. These agents, which have no immediate analgesic effects, can control symptoms and may possibly delay progression of the disease, but they can also cause severe adverse effects. NSAIDs are usually taken concurrently with the slower acting second-line drugs, which may take months to produce a therapeutic response. but may not affect the disease process.