The most common adverse effects of belimumab are nausea, diarrhea, and respiratory tract infection. As with other bDMARDs, there is a slight increase in the risk of infection including serious infections. Cases of depression and suicide have been reported in patients receiving belimumab, although these patients may have had neurologic SLE, thus confounding the causal relationship. Infusion reactions including anaphylaxis are among the other adverse effects. A very small percentage of patients develop antibodies toward belimumab; their clinical significance is not clear.
In a 1998 survey, approximately half of North American rheumatologists treated moderately aggressive RA with combination therapy, and the use of drug combinations is probably much higher now. Combinations of DMARDs can be designed rationally on the basis of complementary mechanisms of action, nonoverlapping pharmacokinetics, and nonoverlapping toxicities.
When added to methotrexate background therapy, cyclosporine, chloroquine, hydroxychloroquine, leflunomide, infliximab, adalimumab, rituximab, and etanercept have all shown improved efficacy. Triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine appears to be as effective as etanercept and methotrexate. In contrast, azathioprine or sulfasalazine plus methotrexate results in no additional therapeutic benefit. Other combinations have occasionally been used.
While it might be anticipated that combination therapy could result in more toxicity, this is often not the case. Combination therapy for patients not responding adequately to monotherapy is now the rule in the treatment of RA.
The general pharmacology of corticosteroids, including mechanism of action, pharmacokinetics, and other applications, is discussed in Chapter 39.
Corticosteroids have been used in 60–70% of RA patients. Their effects are prompt and dramatic, and they are capable of slowing the appearance of new bone erosions. Corticosteroids may be administered for certain serious extra-articular manifestations of RA such as pericarditis or eye involvement or during periods of exacerbation. When prednisone is required for long-term therapy, the dosage should not exceed 7.5 mg daily, and gradual reduction of the dose should be encouraged. Alternate-day corticosteroid therapy is usually unsuccessful in RA.
Other rheumatic diseases in which the corticosteroids’ potent anti-inflammatory effects may be useful include vasculitis, SLE, Wegener’s granulomatosis, PA, giant cell arteritis, sarcoidosis, and gout. Intra-articular corticosteroids are often helpful to alleviate painful symptoms and, when successful, are preferable to increasing the dosage of systemic medication.
Some of the symptoms of RA, especially morning stiffness and joint pain, follow a circadian rhythm, probably due to an increase in proinflammatory cytokines in the early morning. A recent approach uses delayed-release prednisone for the treatment of early morning stiffness and pain in RA. The tablet contains an inactive outer layer and a core of the active drug. The outer layer dissolves over 4–6 hours, releasing the prednisone. Taking the drug at 9–10 pm results in a small pulse of prednisone at 2–4 am, decreasing the circadian inflammatory cytokines. At low doses of 3–5 mg prednisone, the adrenal-pituitary axis does not seem to be impacted.
Prolonged use of corticosteroids leads to serious and disabling toxic effects as described in Chapter 39. Many of these adverse effects occur at doses below 7.5 mg prednisone equivalent daily and many experts believe that even 3–5 mg/d can cause adverse effects in susceptible individuals when this class of drugs is used over prolonged periods.