Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis

William G Dixon, Michal Abrahamowicz, Marie-Eve Beauchamp, David W Ray, Sasha Bernatsky, Samy Suissa, Marie-Pierre Sylvestre, William G Dixon, Michal Abrahamowicz, Marie-Eve Beauchamp, David W Ray, Sasha Bernatsky, Samy Suissa, Marie-Pierre Sylvestre

Abstract

Objectives: To explore the relationship of serious infection risk with current and prior oral glucocorticoid (GC) therapy in elderly patients with rheumatoid arthritis (RA).

Methods: A case-control analysis matched 1947 serious infection cases to five controls, selected from 16207 RA patients aged ≥ 65 between 1985-2003 in Quebec, Canada. Adjusted odds ratios for infection associated with different GC patterns were estimated using conventional models and a weighted cumulative dose (WCD) model.

Results: The WCD model predicted risks better than conventional models. Current and recent GC doses had highest impact on current risk. Doses taken up to 2.5 years ago were also associated with increased risk, albeit to a lesser extent. A current user of 5mg prednisolone had a 30%, 46% or 100% increased risk of serious infection when used continuously for the last 3 months, 6 months or 3 years, respectively, compared to a non-user. The risk associated with 5mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month. Discontinuing a two-year course of 10mg prednisolone six months ago halved the risk compared to ongoing use.

Conclusions: GC therapy is associated with infection risk in older patients with RA. The WCD model provided more accurate risk estimates than conventional models. Current and recent doses have greatest impact on infection risk, but the cumulative impact of doses taken in the last 2-3 years still affects risk. Knowing how risk depends on pattern of GC use will contribute to an improved benefit/harm assessment.

Conflict of interest statement

Competing interests None.

Figures

Figure 1
Figure 1
Estimated weight function (solid curve) and pointwise 95% bootstrap CI (dotted curves) for the final weighted cumulative dose model of the association between previous oral glucocorticoid exposure and serious infection. The final WCD model used 3 degrees of freedom to model the weight function (see Supplementary Online Materials). Relative risks associated with specific exposure patterns are derived from the weighted sum of past doses, with weights shown on the y-axis. Accordingly, the total impact of continuing exposure (in terms of log OR) during a given time period corresponds to the area under the weight curve (over the corresponding time interval).

References

    1. Caplan L, Wolfe F, Russell AS, et al. Corticosteroid use in rheumatoid arthritis: prevalence, predictors, correlates, and outcomes. J Rheumatol 2007;34:696–705
    1. Thiele K, Buttgereit F, Huscher D, et al. Current use of glucocorticoids in patients with rheumatoid arthritis in Germany. Arthritis Rheum 2005;53:740–7
    1. Gøtzsche PC, Johansen HK. Meta-analysis of short-term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. BMJ 1998;316:811–18
    1. Kirwan JR, Bijlsma JW, Boers M, et al. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev 2007;1:CD006356
    1. Hoes JN, Jacobs JW, Buttgereit F, et al. Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nat Rev Rheumatol 2010;6:693–702
    1. Hoes JN, Jacobs JW, Boers M, et al. EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2007;66:1560–7
    1. Thomas E, Symmons DP, Brewster DH, et al. National study of cause-specific mortality in rheumatoid arthritis, juvenile chronic arthritis, and other rheumatic conditions: a 20 year followup study. J Rheumatol 2003;30:958–65
    1. Cutolo M, Seriolo B, Pizzorni C, et al. Use of glucocorticoids and risk of infections. Autoimmun Rev 2008;8:153–5
    1. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 1989;11:954–63
    1. Dixon WG, Suissa S, Hudson M. The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis: systematic review and meta-analyses. Arthritis Res Ther 2011;13:R139.
    1. Choy EH, Smith CM, Farewell V, et al. ; CARDERA (Combination Anti-Rheumatic Drugs in Early Rheumatoid Arhritis) Trial Group Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis 2008;67:656–63
    1. Franklin J, Lunt M, Bunn D, et al. Risk and predictors of infection leading to hospitalisation in a large primary-care-derived cohort of patients with inflammatory polyarthritis. Ann Rheum Dis 2007;66:308–12
    1. Lacaille D, Guh DP, Abrahamowicz M, et al. Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis. Arthritis Rheum 2008;59:1074–81
    1. Smitten AL, Choi HK, Hochberg MC, et al. The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol 2008;35:387–93
    1. Schneeweiss S, Setoguchi S, Weinblatt ME, et al. Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 2007;56:1754–64
    1. Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis. Rheumatology (Oxford) 2007;46:1157–60
    1. Saag KG, Koehnke R, Caldwell JR, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med 1994;96:115–23
    1. Abrahamowicz M, Bartlett G, Tamblyn R, et al. Modeling cumulative dose and exposure duration provided insights regarding the associations between benzodiazepines and injuries. J Clin Epidemiol 2006;59:393–403
    1. Sylvestre MP, Abrahamowicz M. Flexible modeling of the cumulative effects of time-dependent exposures on the hazard. Stat Med 2009;28:3437–53
    1. Health Canada Drug Product Database Online Query: 2010 [cited 2010 23/4/2010]; Available from: (accessed 23 April 2010)
    1. Ting G, Schneeweiss S, Katz JN, et al. Performance of a rheumatoid arthritis records-based index of severity. J Rheumatol 2005;32:1679–87
    1. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292:1955–60
    1. Abrahamowicz M, MacKenzie TA. Joint estimation of time-dependent and non-linear effects of continuous covariates on survival. Stat Med 2007;26:392–408
    1. Akaike H. A new look at the statistical model identification. IEEE Trans Automat Contr 1974;19:716–23
    1. Quantin C, Abrahamowicz M, Moreau T, et al. Variation over time of the effects of prognostic factors in a population-based study of colon cancer: comparison of statistical models. Am J Epidemiol 1999;150:1188–200
    1. Curtis JR, Patkar N, Xie A, et al. Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum 2007;56:1125–33
    1. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 2006;54:628–34
    1. McMaster A, Ray DW. Drug insight: selective agonists and antagonists of the glucocorticoid receptor. Nat Clin Pract Endocrinol Metab 2008;4:91–101
    1. Doran MF, Crowson CS, Pond GR, et al. Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002;46:2294–300
    1. Dixon WG, Kezouh A, Bernatsky S, et al. The influence of systemic glucocorticoid therapy upon the risk of non-serious infection in older patients with rheumatoid arthritis: a nested case-control study. Ann Rheum Dis 2011;70:956–60
    1. Abrahamowicz M, Beauchamp ME, Sylvestre MP. Comparison of alternative models for linking drug exposure with adverse effects. Stat Med. Published Online First: 17 November 2011. doi:10.1002/sim.4343

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe