Confidence Scale

The confidence ratings in this guide are derived from a systematic review of the literature. The level of confidence is based on the overall quantity and quality of clinical evidence.

High: There are consistent results from good quality studies. Further research is very unlikely to change the conclusions.

Medium: Findings are supported, but further research could change the conclusions.

Low: There are very few studies, or existing studies are flawed.

DMARDs

DMARDs (synthetic or biologic) are thought to work by suppressing an overactive immune system. Although synthetic DMARDs have been available longer than biologics, their exact mechanisms of action are unknown. The biologics, however, target components of the immune system by blocking specific immune cytokines. Adalimumab, etanercept, and infliximab are all tumor necrosis factor (TNF) inhibitors. Other biologics work by blocking other cytokines or by directly suppressing lymphocytes.

Corticosteroids

Corticosteroids are used for RA because of their anti-inflammatory and immunosuppressive effects. They are commonly used as an adjunct to DMARDs, particularly early in treatment.

Monotherapy

To reduce joint swelling and tenderness and improve function:

• Methotrexate works as well as adalimumab or etanercept (two of the TNF-inhibitors) for people with early RA who have not previously taken methotrexate. However, adalimumab and etanercept give better 2-year radiographic outcomes.
  Level of confidence
• Leflunomide and sulfasalazine work as well as methotrexate. There is no difference in 2-year radiographic outcomes.
  Level of confidence
• All of the TNF-inhibitors (adalimumab, etanercept, and infliximab) work equally well.
  Level of confidence
• Anakinra does not work as well as any of the TNF-inhibitors (adalimumab, etanercept, or infliximab).
  Level of confidence

Evidence is insufficient to compare:

• Hydroxychloroquine, leflunomide, and sulfasalazine with the biologics.
• Hydroxychloroquine with the other synthetic DMARDs.
• Abatacept, rituximab, or corticosteroid monotherapy with the other DMARDs.

Combination Therapy

To reduce joint swelling and tenderness and improve function:

• Combining a biologic with methotrexate works better than using either drug alone.
  Level of confidence
• Combining prednisone with hydroxychloroquine, methotrexate, or sulfasalazine works better than using these synthetic DMARDs alone. It also gives better 2-year radiographic outcomes.
  Level of confidence
• A triple combination of hydroxychloroquine, methotrexate, and sulfasalazine works better than a two-drug combination (methotrexate with either drug) for people previously on monotherapy.
  Level of confidence
• Combining sulfasalazine with methotrexate does not work better than monotherapy with either drug alone for people with early RA.
  Level of confidence
• Evidence is insufficient to determine whether combining two biologics works better than monotherapy with a biologic.
• Research has not addressed whether combining a corticosteroid with a biologic works better than monotherapy with a biologic.

Infection

• Most biologics and methotrexate increase the risk of serious infections that require antibiotic treatment or hospitalization.
• TNF-inhibitors increase the risk of reactivating latent tuberculosis.
• About 2 percent of people taking a biologic for 3–12 months will develop a serious infection.
• The likelihood of serious infection is greater with combinations of two biologics than with just one biologic.
  Level of confidence

Other Serious Risks

• Methotrexate increases the risk of hepatotoxicity, including fibrosis and cirrhosis.
• Methotrexate increases the risk of interstitial lung disease and malignant lymphomas.
• Methotrexate and sulfasalazine increase the risk of bone marrow suppression.
• Corticosteroids have several well-known side effects. Long-term use of corticosteroids increases the risk of adrenal suppression, osteoporosis, obesity, diabetes, cataracts, and infection.

Injection and Infusion Reactions

• Biologics administered subcutaneously (anakinra, etanercept, and adalimumab) can cause painful injection site reactions. Reactions are more common with anakinra (67 percent) than with the TNF-inhibitors etanercept (22 percent) and adalimumab (18 percent).
  Level of confidence
• Biologics administered intravenously (abatacept, infliximab, and rituximab) can cause infusion reactions (dizziness, nausea, or fever) in up to 50 percent of people. About 2 percent of people discontinue therapy due to these reactions.
• Biologics administered intravenously can also cause rare but life-threatening infusion reactions resembling anaphylaxis or seizures. Evidence is insufficient to determine if the risk of infusion reactions differs among these DMARDs.

Reproductive Risks for Women and Men

• Leflunomide and methotrexate should not be taken during pregnancy. Both drugs can cause congenital abnormalities, and methotrexate can also cause fetal death. Both women and men taking these drugs should be counseled about reproductive risks.
• There are not enough data to determine the reproductive risks of other DMARDs.

Initial Drug Choice

• No single DMARD is superior as an initial treatment for RA.
• Methotrexate, the best known and one of the least costly DMARDs, slows disease progression as well as other drugs used as monotherapy.

Adjusting Medication

• Combining methotrexate with a biologic is a better strategy than combining two synthetic DMARDs or two biologics.
• When monotherapy with a synthetic DMARD isn’t working well enough, consider a triple combination of hydroxychloroquine, methotrexate, and sulfasalazine. It works better than a two-drug combination (methotrexate with either drug).
• Adding prednisone to a synthetic DMARD can reduce inflammation and pain, but long-term use of prednisone can cause adverse effects.
• Combination therapy (except with two biologics) does not increase the likelihood of discontinuation due to adverse effects.

Cost

The cost of RA drugs may be a barrier. Drugs, doses, and prices are listed below. Intravenous drugs incur additional expense. The oral agents are all available as generics, but biologics are not.

If your patients need help paying for RA drugs, consider a prescription assistance program. The Partnership for Prescription Assistance provides information on 475 public and private programs. Web site: www.pparx.org. Phone: 1-888-477-2669.