Background/Purpose: The incidence of opportunistic infections (OIs) in patients on biologics is low, but may approach several cases per 100 person-years (PY). Data on risks for OIs associated with newer biologics and in those switching biologics among rheumatoid arthritis (RA) patients are limited.

Methods:

Using data from 1998-2011 from the U.S. Veteran’s Health Administration we identified a cohort of rheumatologist-diagnosed RA patients (n=36,433).  Patients eligible for this analysis started anti-TNF therapy (adalimumab, infliximab, etanercept) after previous anti-TNF exposure, or rituximab (RTX) or abatacept (ABA). To minimize confounding from channeling of patients to certain biologics, those patients with a history of hematologic malignancy in the past year were excluded.  Potential OIs were identified using ICD-9 codes and/or available laboratory results (cultures, serology). With the exception of zoster, where ICD-9 code alone identified a case, all other OIs were confirmed by chart review using standardized case definitions. Patients were censored at first OI event. Baseline co-morbidities were defined in the 1-year period prior to treatment initiation. Exposure was “as treated” on the basis of days supply or usual dosing intervals. Exposure was extended 60 days after the end of the day’s supply; RTX exposure was assumed to be 12 months after infusion. Frequencies of OIs were calculated and crude OI incidence rates were estimated using a Poisson distribution.

Results:

A total of 2917 unique RA patients contributed 3774 treatment episodes (ABA 338; RTX 511, TNFs 2925). Two-thirds of TNF use was adalimumab.  Mean age of the cohort was 60.8 ± 10.7 years; 87% were male.  Hypertension (55.5%), diabetes (25.6%) and COPD (14.2%) were common. Overall, 84 OIs (2.9%) in 2917 patients were identified, yielding an overall rate of 1.5 (95% CI 1.2, 1.9) OIs per 100 PY(Table). The most common OIs were zoster, rate 1.17 (0.9, 1.5) per 100 PY and tuberculosis, rate 0.05 (0.02, 1.6) per 100 PY. Crude rates of OIs per 100 PY among TNFs, ABA and RTX users were 1.5 (1.2, 1.9); 1.1 (0.4, 2.6), and 1.8 (1.0, 3.2), respectively.  Among TNFs, rates per 100 PY were infliximab 0.8 (0.3, 2.1), adalimumab 1.6 (1.2, 2.2) and etanercept 1.6 (1.0. 2.5). For the 19 confirmed OIs other than zoster, 7 (37%) were identified by screening lab data and were not identified by ICD-9 codes.   

Table: Frequency of Physician-Confirmed Opportunistic Infections (OIs) by Biologic Exposure

Opportunistic Infection	Abatacept N=338 PY=486	Adalimumab N=1826 PY=2727	Etanercept N=741 PY=1181	Infliximab N=358 PY=511	Rituximab N=511 PY=651	TOTAL  N=3774 PY=5538
Zoster	5	38	16	2	4	65
Tuberculosis	0	0	2	0	1	3
Pneumocystosis	0	0	0	0	3	3
Legionellosis	0	3	0	0	0	3
Coccidioidomycosis	0	0	1	0	2	3
Histoplasmosis	0	1	0	1	0	2
Non-tuberculous mycobacteria	0	1	0	0	1	2
Salmonellosis	0	1	0	0	1	2
Nocardiosis	0	0	0	1	0	1
Total OIs	5	44	19	4	12	84
IR (95% CI) per 100 p-years	1.1(0.4, 2.6)	1.6 (1.2, 2.2)	1.6 (1.0, 2.5)	0.8 (0.3, 2.1)	1.8 (1.0, 3.2)	1.5 (1.2, 1.9)

OI=opportunistic infection; IR=incidence rate

Conclusion:

In US veterans with RA, overall crude OI rates were low and similar among biologics. The most common OI was zoster. The availability of serologic and culture data for OI screening yielded a meaningfully higher proportion of OI cases compared to administrative data alone.

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