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Contraindications

Conditions considered to be therapeutic contraindications for using nonbiologic and biologic DMARDs were defined primarily on the basis of evidence from observational studies, and to a lesser extent on evidence from randomized clinical trials (Table 2).¹

Table 2. Recommendations for contraindications to nonbiologic and biologic DMARD in rheumatoid arthritis.¹ (Click image to view larger)

Infectious diseases and pneumonitis. Therapy with leflunomide, methotrexate, or biologic agents should not be initiated, nor should therapy with these agents be resumed, in patients with infectious diseases or pneumonitis. Such conditions include active bacterial infection or bacterial infection requiring antibiotic therapy, active tuberculosis or latent tuberculosis prior to preventive therapy, active herpes zoster infection, or active life-threatening fungal infections.¹ In general, patients with RA have an elevated risk for herpes zoster relative to the general population (3 cases per 1,000 person-years), but the level of risk is similar to that for people with depressed immunity from human immunodeficiency virus (HIV) infection, transplantation, cancer, or other immunosuppressive disorders and treatments (12–14 cases per 1,000 person-years).⁷ Use of oral corticosteroids and of biologic and traditional DMARDs is associated with a slight increase in the risk of herpes zoster (odds ratio [OR] = 1.54 for biologics and 1.37 for traditional DMARDs).⁸ In patients with severe upper respiratory tract infections (viral or bacterial) or nonhealed skin ulcers, use of biologic agents is contraindicated.¹ A recent meta-analysis of clinical trials in which RA patients were treated with anti-tumor necrosis factor (anti-TNF) antibodies found an elevated incidence of serious bacterial infections, ie, requiring antimicrobial therapy or hospitalization.⁹ Risk of serious infection was significantly increased with high doses of anti-TNF therapy (OR versus placebo = 2.3; 95% CI, 1.5–3.6) but only reached borderline significance for low doses (OR verus placebo = 1.8; 95% CI, 1.1–3.1).⁹ The Task Force Panel made no recommendations for or against using DMARDs in patients with HIV infection. Methotrexate was contraindicated in cases of RA-associated pneumonitis or interstitial lung disease of unknown cause.¹

Hematologic and oncologic conditions. For patients in whom lymphoproliferative disease or myelodysplasia has been diagnosed or treated within the previous 5 years, methotrexate, leflunomide, and anti-TNF agents are contraindicated.¹ The meta-analysis of anti-TNF trials noted above reported a significant dose-dependent effect for malignancy-related adverse effects with the use of these agents.⁹ In comparisons with placebo, the OR was higher for high-dose anti-TNF therapy (OR = 4.3; 95% CI, 1.6–11.8) than for low-dose anti-TNF therapy (OR = 1.4; 95% CI, 0.3–5.7).⁹ The ACR Task Force Panel did not endorse any specific recommendations regarding other malignancies and the use of biologic or nonbiologic DMARDs.¹ A recent study suggests that anti-TNF therapy does not increase the risk for nonhematologic or lymphoproliferative malignancies in RA patients.⁹ If white blood cell counts are <3,000/mm³, methotrexate and leflunomide are contraindicated, except in cases in which large granular lymphocyte syndrome accompanies RA.¹

Cardiac conditions. Cardiac contraindications for DMARDs are limited to patients who have moderate or severe heart failure (New York Heart Association class III or IV). Only anti-TNF therapies are specifically contraindicated in patients with moderate or severe heart failure; this recommendation is based on level B evidence from the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) and Randomized Etanercept Worldwide Evaluation (RENEWAL) trials, in which patients treated with high doses of anti-TNF therapy for moderate to severe chronic heart failure experienced a worsening in their clinical status.^10,11

Hepatitis. In patients with acute hepatitis B or C, treatment with methotrexate, leflunomide, sulfasalazine, minocycline, and biologic agents is contraindicated, because of the risk of increased activation of the virus as a result of immune suppression.^1,12 In patients with chronic liver disease (including hepatitis B and C) Child-Pugh score, which reflects the severity of liver impairment, is the key factor in clinical decision making.¹ Methotrexate and leflunomide are contraindicated for patients in all Child-Pugh classes.¹ Biologic therapy, minocycline, and sulfasalazine are contraindicated for Child-Pugh class B and C regardless of hepatitis treatment status.¹

Neurologic conditions. In patients with multiple sclerosis or demyelination disorders, anti-TNF agents are contraindicated, based on limited observations from randomized controlled trials.^1,13,14