How Serious Are Serious Infections in Lupus? A Nationwide Analysis

Apr 28, 2014

The first step in reducing the burden of infection during lupus nephritis is understanding where and how it happens.

Up to 50% of patients with systemic lupus erythematosus (SLE) have a severe infection during their disease course, and these are among the leading causes of hospitalization and mortality in lupus.1-10 Patients with lupus nephritis (LN) appear to be particularly vulnerable.6,9,11-22

How can we reduce the burden of this complication? First, it’s important to understand it.

Previous randomized trials and cohort studies have described infection rates in this population, but they have been limited by small sample sizes, exclusions and restrictions, and short follow-up periods.10,23-33 In the interests of improving early detection and treatment of these infections, we have studied the distribution of SLE and LN in a large racially and ethnically diverse nationwide cohort, the Medicaid Analytic eXtract (MAX) dataset, with billing claims and demographic information for Medicaid enrollees from 47 states and Washington, DC from 2000-2006.34-35

We identified 28,803 SLE patients and 5,140 with LN who were new users of (e.g. had not used within the prior six months) hydroxychloroquine (HCQ), oral or intravenous corticosteroids (CS), or immunosuppressants.

Here’s what we have found:

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In this Medicaid population, serious infections requiring hospitalization were most common in
 
•  older patients (51-64 years);
•  those who are White, African American and Native American;
•  those living in the Midwest,
•  those with low socioeconomic status; and
•  patients with multiple SLE-related comorbidities.

Predominant infectious conditions were as follows:

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Bacterial: pneumonia, cellulitis and bacteremia
Fungal:  systemic candidiasis
Viral:  herpes zoster
Mycobacterial: tuberculosis.

We found that new use of corticosteroids is associated with the highest rates of serious infections in patients with SLE or LN. These rates are significantly higher than those for patients taking HCQ alone.

•  The incidence rate of infections in SLE patients newly receiving corticosteroids was 21 per 100 person-years (4.2 times higher than those receiving HCQ alone).

•  The incidence rate of infections in LN patients receiving corticosteroids was 44 per 100 person-years  (nearly 3 times higher than those receiving HCQ alone).

•  Compared to rheumatoid arthritis patients receiving corticosteroids in a similar size cohort, incident rates among SLE patients were nearly 5 times higher and among those with LN, fully 10 times higher.36

What needs to be done next?

We intend to:

  • account for confounding by indication in drug prescribing using propensity score adjusted analyses
  • compare incidence rates of infections among SLE and LN patients by specific medication use, and
  • assess corticosteroid use by administration route, dose, and duration.

 

References:

1.   Feng X, Zou Y, Pan W, et al.Prognostic indicators of hospitalized patients with systemic lupus erythematosus: a large retrospective multicenter study in China.  The Journal of Rheumatology (2011) 38:1289-1295.

2.    Lee J, Dhillon N, Pope J. All-cause hospitalizations in systemic lupus erythematosus from a large Canadian referral centre. Rheumatology (2013) 52:905-909.

3.   Sciascia S, Ceberio L, Garcia-Fernandez C, et al. Systemic lupus erythematosus and infections: clinical importance of conventional and upcoming biomarkers. Autoimmunity Reviews (2012) 12:157-163.

4.    Juarez M, Misischia R, Alarcon GS. Infections in systemic connective tissue diseases: systemic lupus erythematosus, scleroderma, and polymyositis/dermatomyositis. Rheumatic diseases clinics of North America (2003) 29:163-184.

5.    Zandman-Goddard G, Shoenfeld Y. Infections and SLE.Autoimmunity (2005) 38:473-485.

6.    Ginzler E, Diamond H, Kaplan D, et al.Computer analysis of factors influencing frequency of infection in systemic lupus erythematosus. Arthritis and Rheumatism (1978) 21:37-44.

7.   Duffy KN, Duffy CM, Gladman DD. Infection and disease activity in systemic lupus erythematosus: a review of hospitalized patients.The Journal of Rheumatology  (1991) 18:1180-1184.

8   Liam CK, Wang F. Pneumocystis carinii pneumonia in patients with systemic lupus erythematosus.Lupus (1992) 1:379-385.

9    Lee P, Urowitz MB, Bookman AA, et al. Systemic lupus erythematosus. A review of 110 cases with reference to nephritis, the nervous system, infections, aseptic necrosis and prognosis.The Quarterly Journal of Medicine (1977) 46:1-32.

10.   Petri M, Genovese M. Incidence of and risk factors for hospitalizations in systemic lupus erythematosus: a prospective study of the Hopkins Lupus Cohort.The Journal of Rheumatology (1992) 19:1559-65.

11.   Jarrett MP, Santhanam S, Del Greco F. The clinical course of end-stage renal disease in systemic lupus erythematosus.Archives of Internal Medicine (1983) 143:1353-1356.

12.   Correia P, Cameron JS, Ogg CS, et al. End-stage renal failure in systemic lupus erythematosus with nephritis. Clinical Nephrology (1984) 22:293-302.

13.   Pollock CA, Ibels LS. Dialysis and transplantation in patients with renal failure due to systemic lupus erythematosus. The Australian and New Zealand experience. Australian and New Zealand Journal of Medicine (1987) 17:321-325.

14.   Yap DY, Tang CS, Ma MK, et al. Survival analysis and causes of mortality in patients with lupus nephritis.Nephrology, Dialysis, Transplantation (2012) 27:3248-3254.

15.   Harisdangkul V, Nilganuwonge S, Rockhold L. Cause of death in systemic lupus erythematosus: a pattern based on age at onset. Southern Medical Journal  (1987) 80:1249-1253.

16.   Karsh J, Klippel JH, Balow JE, Decker JL. Mortality in lupus nephritis. Arthritis and Rheumatism (1979) 22:764-769.

17.   Staples PJ, Gerding DN, Decker JL, Gordon RS, Jr. Incidence of infection in systemic lupus erythematosus. Arthritis and Rheumatism (1974) 17:1-10.

18.   Yuhara T, Takemura H, Akama T, et al.Predicting infection in hospitalized patients with systemic lupus erythematosus.Intern Med (1996) 35:629-636.

19.   Kimberly RP, Lockshin MD, Sherman RL, et al. "End-stage" lupus nephritis: clinical course to and outcome on dialysis. Experience with 39 patients. Medicine (1981) 60:277-287.

20.   Correia P, Cameron JS, Lian JD, et al.Why do patients with lupus nephritis die?Br Med J (Clin Res Ed) (1985) 290:126-131.

21.   Ginzler EM, Diamond HS, Weiner M, et al. A multicenter study of outcome in systemic lupus erythematosus. I. Entry variables as predictors of prognosis. Arthritis and Rheumatism (1982) 25:601-611.

22.   Rosner S, Ginzler EM, Diamond HS, et al. A multicenter study of outcome in systemic lupus erythematosus. II. Causes of death. Arthritis and Rheumatism (1982) 25:612-617.

23.   Gladman DD, Hussain F, Ibanez D, Urowitz MB. The nature and outcome of infection in systemic lupus erythematosus. Lupus (2002) 11:234-239.

24.   Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.The New England Journal of Medicine (2005) 353:2219-2228.

25.   Ong LM, Hooi LS, Lim TO, et al. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.Nephrology  (2005) 10:504-510.

26.   Pryor BD, Bologna SG, Kahl LE. Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus.Arthritis and Rheumatism (1996) 39:1475-1482.

27.   Chakravarty E, Michaud K, Katz R, Wolfe F. Increased incidence of herpes zoster among patients with systemic lupus erythematosus.Lupus (2013) 22:238-244

28.   Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Journal of the American Society of Nephrology (2009) 20:1103-1112.

29.   Contreras G, Tozman E, Nahar N, Metz D. Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide.Lupus (2005) 14 Suppl 1:s33-38.

30.   Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group.The New England journal of Medicine (2000) 343:1156-1162.

31.   Chan TM, Tse KC, Tang CS, et al.Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. Journal of the American Society of Nephrology (2005) 16:1076-1084.

32.   Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. The New England Journal of Medicine (2011) 365:1886-1895.

33.   Houssiau FA, D'Cruz D, Sangle S, et al.Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial.Annals of the Rheumatic Diseases (2010) 69:2083-2089.

34.   Feldman CH, Hiraki LT, Liu J, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among U.S. adults with Medicaid coverage, 2000-2004. Arthritis and Rheumatism (2012)

35.   Chibnik LB, Massarotti EM, Costenbader KH. Identification and validation of lupus nephritis cases using administrative data. Lupus (2010) 19:741-743.

36.   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 and Rheumatism (2007) 56:1754-1764.

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