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Original article

Bernatsky S et al. (2007) Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis. Rheumatology 46: 1157–1160   PubMed

Synopsis

Background

Disease-modifying antirheumatic drugs (DMARDs), such as anti-tumor necrosis factor (TNF) agents and glucocorticoids, are most commonly used to treat patients with rheumatoid arthritis (RA). Increased risk of infection is a major concern in patients who use these drugs, especially considering that patients with RA are already immunocompromised.

Objective

The objective of this study was to determine the risk of serious infection associated with the use of DMARDs and glucocorticoids in patients with RA.

Design and intervention

Patients from a Canadian rheumatology clinic were studied between 1 January 1980 and 31 December 2003, using a nested case–control design. Matching for age and sex, and adjusting for comorbidity and physician use, conditional logistic regression was used to estimate the effect of specific drugs on the rate ratio (RR) for infections that required hospitalization.

Outcome measures

The primary outcome measure of this study was the occurrence of a first serious infection leading to hospitalization, identified using hospital discharge records.

Results

A total of 23,733 patients with RA, who had received a prescription for DMARD treatment and had no history of infection, were screened for this study. DMARD prescriptions included the following agents: methotrexate, hydroxychloroquine, azathioprine, leflunomide and anti-TNF agents. Overall, the total risk of all infections that required hospitalization seemed to be most elevated in patients who were being treated with cyclophosphamide (RR 3.26, 95% CI 2.28–4.67) and those receiving treatment with systemic glucocorticoid agents (RR 2.56, 95% CI 2.29–2.85). It was shown that treatment with azathioprine was associated with a moderately increased risk of serious infection (RR 1.52, 95% CI 1.18–1.97). The authors observed a trend towards increased risk of pneumonia in patients treated with methotrexate (RR 1.16, 95% CI 1.02–1.33); however, this was not significant. It was also observed that all results were similar for the period before and after the commencement of therapy with anti-TNF agents. The RR point estimate for anti-TNF agents suggested about a twofold increased risk for all infections, but the estimate was imprecise.

Conclusion

The authors conclude that patients who receive treatment with glucocorticoids and immunosuppressive DMARDs are at the most heightened risk of developing serious infections. Thus, the assessment of infection risk should be carefully considered in studies of new and emerging therapies.

Commentary

This study by Bernatsky et al. provides further insight into the risk of serious infection associated with the use of antirheumatic drugs. Since anti-TNF therapy is the latest DMARD to be widely used, we will limit our comments to this treatment modality.

Anti-TNF agents have provided substantial benefit to patients with RA and other inflammatory conditions. As TNF has a significant role in host defenses, however, there is concern that anti-TNF treatment might lead to an increased risk of serious infections. The absolute risk is unclear, as patients with rheumatological diseases already have an increased risk of infection because of underlying conditions and the use of other DMARDs (especially steroids).

In order to define the risk of serious infection more clearly, a recent meta-analysis and other observational surveillance studies from patient-use registries have been evaluated, with mixed results.^{1, 2, 3} In this study, Benartsky et al. found no significantly increased risk of serious infection. As recently reviewed by Dixon et al., however, observational data sets are limited by a number of potential confounding biases related to selection factors that are difficult to identify.⁴ In a previous report from the British Society for Rheumatology Biologics Register, Dixon et al. found no increased risk of serious infection associated with anti-TNF treatment.² By using a more extended analysis, however, the authors found an adjusted incidence ratio for serious infection of 4.6 (95% CI 1.8–11.9) associated with anti-TNF therapy when including follow-up to 90 days and beyond.⁴

Despite the findings of Bernartsky et al., we believe that careful examination of the available data does support a clear, but small, increase in risk of serious infection associated with anti-TNF use, which is relevant to practicing rheumatologists. Accumulated data showing that the use of the TNF monoclonal antibody agents, such as infliximab, is associated with a high incidence of reactivation of granulomatous infection—most specifically tuberculosis, but also endemic mycosis and intracellular bacterial infections—is of concern. The most frequently reported site-specific serious infections are lower respiratory tract infections, skin and subcutaneous tissue infections, and bone and joint infections (the latter often observed after joint surgery).

In light of this trend toward increased infection associated with the use of anti-TNF therapy, appropriate measures for prevention and early treatment of serious infections should be implemented by the practicing rheumatologist. As has been previously proposed, we recommend a systematic approach to each patient when considering anti-TNF use.^{5, 6} Patients should be screened for a history of previous or latent infections, and therapy for latent infection should be initiated prior to treatment with anti-TNF. Patients should be educated regarding infection avoidance. Preventive vaccines (e.g. influenza and pneumococcal) should ideally be administered before anti-TNF administration; vaccines are, however, still effective when administered in the presence of anti-TNF treatment. Live vaccines, such as the zoster vaccine, should be avoided during anti-TNF therapy. Finally, clinicians and patients need to be aware that treatment with anti-TNF might modulate signs and symptoms of infection, so serious infections might have atypical presentation. Many infections encountered in the clinical setting are minor (e.g. upper respiratory tract infections) and can be treated without interrupting anti-TNF therapy. Vigilance must be maintained to detect the development of more serious infections, particularly when patients develop unexplained fever and symptoms; in such cases, anti-TNF therapy should be paused while evaluation is conducted.

Acknowledgments

The synopsis was written by Jasmine Farsarakis, Associate Editor, Nature Clinical Practice.

References

1. Bongartz T et al. (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infection and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295: 2275–2285 | Article | PubMed | ISI | ChemPort |
2. Dixon WG et al. (2006) Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 54: 2368–2376 | Article | PubMed | ISI | ChemPort |
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4. Dixon WG et al. (2007) Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum 56: 2896–2904 | Article | PubMed | ChemPort |
5. Saketkoo LA and Espinoza LR (2006) Impact of biologic agents on infectious diseases. Infect Dis Clin N Am 20: 931–961 | Article |
6. Strangfeld A and Listing J (2006) Infections and musculoskeletal conditions: bacterial and opportunistic infections during anti-TNF therapy. Best Pract Res Clin Rheumatol 20: 1181–1195 | Article | PubMed | ChemPort |

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Subject areas under which this article appears: Clinical trials | Rheumatoid arthritis