Infections requiring hospitalization in the abatacept clinical development program: an epidemiological assessment.
BACKGROUND
Patients with rheumatoid arthritis (RA) have an increased risk of infection and this risk appears to be higher with anti-TNF (tumor necrosis factor) agents. We pooled data from the cumulative abatacept RA clinical development program, both double-blind and open-label periods, to estimate the incidence rates (IRs) of infections requiring hospitalization including pneumonia and opportunistic infections, in comparison with RA patients treated with non-biologic disease-modifying antirheumatic drugs (DMARDs) from several reference cohorts.


METHODS
Infections reported in seven abatacept clinical trials of RA patients (double-blind and open-label periods) were tabulated. Comparisons were made between the observed IRs in abatacept-treated patients and those in over 133,000 patients exposed to non-biologic DMARDs in six reference RA cohorts. Age- and sex-adjusted IRs of infections requiring hospitalization, including pneumonia (most frequent hospital infection), were used to estimate the expected IRs with abatacept by the method of indirect adjustment. Standardized incidence ratios (SIR) and 95% CI were calculated comparing incidence in the cumulative abatacept experience with incidence in each RA cohort.


RESULTS
A total of 1,955 (double-blind period) and 4,134 (double-blind + open-label periods with a cumulative exposure of 8,392 person-years) abatacept-treated RA patients were analyzed. Observed IRs for infections requiring hospitalization during the double-blind period were 3.05 per 100-patient years for abatacept-treated patients and 2.15 per 100 patient years for placebo. In the cumulative population, observed IR for infections requiring hospitalization was 2.72 per 100-patient years. Rates for abatacept were similar to expected IRs based on other RA non-biologic DMARD cohorts.


CONCLUSIONS
IRs of infections requiring hospitalization and pneumonia in abatacept trials are consistent with expected IRs based on reference RA DMARD cohorts. RA patients are at higher risk of infection compared with the general population, making the RA DMARD cohorts an appropriate reference group. The safety of abatacept, including incidence of infections requiring hospitalization, will continue to be monitored in a post-marketing surveillance program.
Simon
Teresa A
TA
Global Health Economics and Outcomes Research, Bristol-Myers Squibb, Route 206 and Province Line Roads, Lawrenceville, NJ 08540, USA. teresa.simon@bms.com
Askling
Johan
J
Lacaille
Diane
D
Franklin
Jarrod
J
Wolfe
Frederick
F
Covucci
Allison
A
Suissa
Samy
S
Hochberg
Marc C
MC
D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000453:epidemiology*; D015897:Comorbidity; D004311:Double-Blind Method; D005060:Europe / Q000453:epidemiology; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009656:North America / Q000453:epidemiology; D009894:Opportunistic Infections / Q000453:epidemiology* / Q000209:etiology; D016032:Randomized Controlled Trials as Topic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
D018501:Antirheumatic Agents; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept
Control Clin Trials. 1986 Sep;7(3):177-88
3802833
Arthritis Rheum. 2007 Sep;56(9):2896-904
17763441
Ann Rheum Dis. 2008 Aug;67(8):1096-103
18055472
J Immunol. 1984 Jun;132(6):2883-7
6609962
Ann Rheum Dis. 2008 Apr;67(4):547-54
17921185
Arthritis Rheum. 2005 Aug;52(8):2263-71
16052582
JAMA. 2006 May 17;295(19):2275-85
16705109
Arthritis Rheum. 2006 Sep;54(9):2807-16
16947384
Curr Opin Rheumatol. 2008 Mar;20(2):138-44
18349742
J Rheumatol. 2008 Mar;35(3):387-93
18260176
Ann Rheum Dis. 2006 Jun;65(6):707-12
16414975
Arthritis Rheum. 2002 Sep;46(9):2287-93
12355475
Arthritis Rheum. 2008 Aug 15;59(8):1074-81
18668604
Proc Natl Acad Sci U S A. 1931 Dec;17(12):684-8
16577411
Arthritis Rheum. 2007 Dec;56(12):4226-7
18050253
J Exp Med. 1993 Jan 1;177(1):165-73
7678111
Arthritis Rheum. 2005 Nov;52(11):3403-12
16255017
N Engl J Med. 2005 Sep 15;353(11):1114-23
16162882
Arthritis Rheum. 2005 Apr 15;53(2):241-8
15818655
Ann Rheum Dis. 2009 Jan;68(1):25-32
18203761
Arthritis Rheum. 2002 Sep;46(9):2294-300
12355476
Arthritis Rheum. 2006 Feb;54(2):628-34
16447241
Ann Rheum Dis. 1982 Oct;41(5):490-4
6181746
Clin Exp Rheumatol. 2003 Sep-Oct;21(5 Suppl 31):S94-9
14969058
N Engl J Med. 2003 Nov 13;349(20):1907-15
14614165
Rev Infect Dis. 1989 Nov-Dec;11(6):954-63
2690289
Ann Intern Med. 2006 Jun 20;144(12):865-76
16785475
J Manag Care Pharm. 2007 Jan;13(1 Suppl):S7-18
17378700
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9203-8
10922071
Arthritis Rheum. 2002 Jun;46(6):1470-9
12115176
Ann Rheum Dis. 2009 Nov;68(11):1708-14
19074911