Liyan Liu

Initiation of Tumor Necrosis Factor-α Antagonists and the Risk of Hospitalization for Infection in Patients With Autoimmune Diseases

CONTEXT Although tumor necrosis factor (TNF)-α antagonists are increasingly used in place of nonbiologic comparator medications, their safety profile remains incomplete. OBJECTIVES To determine whether initiation of TNF-α antagonists compared with nonbiologic comparators is associated with an increased risk of serious infections requiring hospitalization. DESIGN, SETTING, AND PATIENTS Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998-2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare. TNF-α antagonists and nonbiologic regimens were compared in disease-specific propensity score (PS)-matched cohorts using Cox regression models with nonbiologics as the reference. Baseline glucocorticoid use was evaluated as a separate covariate. MAIN OUTCOME MEASURE Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-α antagonists or nonbiologic regimens. RESULTS Study cohorts included 10,484 RA, 2323 IBD, and 3215 psoriasis and spondyloarthropathies matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91-1.21]). Among patients with IBD, rates were 10.91 (TNF-α antagonists) and 9.60 (comparator) per 100 person-years (aHR, 1.10 [95% CI, 0.83-1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-α antagonists) and 5.37 (comparator) per 100 person-years (aHR, 1.05 [95% CI, 0.76-1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07-1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02-1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections. CONCLUSION Among patients with autoimmune diseases, compared with treatment with nonbiologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.

Incidence and Mortality of Colorectal Adenocarcinoma in Persons With Inflammatory Bowel Disease From 1998 to 2010

BACKGROUND & AIMS The relationship between inflammatory bowel disease (IBD) and the incidence and mortality of colorectal adenocarcinoma (CRC) has not been evaluated recently. METHODS We calculated the incidence and standardized incidence and mortality rate ratios of CRC among adult individuals with intact colons using Kaiser Permanente of Northern Californias database of members with IBD and general membership data for the period of 1998 to June 2010 (data through 2008 were used to calculate mortality). We also evaluated trends in medication use and rates of cancer detection over time. RESULTS We identified 29 cancers among persons with Crohns disease (CD) and 53 among persons with ulcerative colitis (UC). Overall, the incidence rates of cancer among individuals with CD, UC, or in the general membership were 75.0, 76.0, and 47.1, respectively, per 100,000 person-years. In the general population, the incidence of CRC was 21% higher in 2007-2010 than in 1998-2001 (P for trend, <.0001), coincident with the growth of CRC screening programs. The incidence of CRC among individuals with CD or UC was 60% higher than in the general population (95% confidence interval [CI] for CD, 20%-200%; 95% CI for UC, 30%-200%) and was stable over time (P for trend was as follows: CD, .98; UC, .40). During 1998-2008, the standardized mortality ratio for CRC in individuals with CD was 2.3 (95% CI, 1.6-3.0) and 2.0 in those with UC (95% CI, 1.3-2.7). Over the study period, anti-tumor necrosis factor agents replaced other therapies for CD and UC; the rate of colonoscopy increased by 33% among patients with CD and decreased by 9% in those with UC. CONCLUSIONS From 1998 to 2010, the incidence of CRC in patients with IBD was 60% higher than in the general population and essentially stable over time.

Association Between the Initiation of Anti–Tumor Necrosis Factor Therapy and the Risk of Herpes Zoster

IMPORTANCE Herpes zoster reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates herpes zoster risk. OBJECTIVES To ascertain whether initiation of anti-TNF therapy compared with nonbiologic comparators is associated with increased herpes zoster risk. DESIGN, SETTING, AND PATIENTS We identified new users of anti-TNF therapy among cohorts of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared herpes zoster incidence between new anti-TNF users (n=33,324) and patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs) (n=25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007). Within these cohorts, we used Cox regression models to compare propensity score-adjusted herpes zoster incidence between new anti-TNF and nonbiologic DMARD users while controlling for baseline corticosteroid use. MAIN OUTCOME MEASURES Incidence of herpes zoster cases occurring after initiation of new anti-TNF or nonbiologic DMARD therapy. RESULTS Among 33,324 new users of anti-TNF therapy, we identified 310 herpes zoster cases. Crude incidence rates among anti-TNF users were 12.1 per 1000 patient-years (95% CI, 10.7-13.6) for RA, 11.3 per 1000 patient-years (95% CI, 7.7-16.7) for inflammatory bowel disease, and 4.4 per 1000 patient-years (95% CI, 2.8-7.0) for psoriasis, psoriatic arthritis, or ankylosing spondylitis. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk (adjusted hazard ratio [HR], 2.13 [95% CI, 1.64-2.75]) compared with no baseline use. For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR, 1.00 [95% CI, 0.77-1.29]) and comparable between all 3 anti-TNF therapies studied. Across all disease indications, the adjusted HR was 1.09 (95% CI, 0.88-1.36). CONCLUSION AND RELEVANCE Among patients with RA and other inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens.

Incidence and Prevalence of Inflammatory Bowel Disease in a Northern California Managed Care Organization, 1996–2002

OBJECTIVE:There are few estimates of the incidence and prevalence of inflammatory bowel disease in North American communities. We sought to estimate the incidence and prevalence of inflammatory bowel disease (IBD), including Crohns disease (CD), and ulcerative colitis (UC), among 3.2 million members of Kaiser Permanente, Northern California, for the period 1996–2002.METHODS:All health plan members who had one or more diagnoses of CD (ICD-9 code 555) or UC (ICD-9 code 556) on computerized records during the period 1996–2002 and with at least 12 months of membership were identified as possible IBD cases (N = 12,059). We randomly sampled 24% of these for chart review to confirm the diagnosis and obtain the initial diagnosis date. Incidence rates and the point prevalence on December 31, 2002 were standardized to the 2000 U. S. Census.RESULTS:The annual incidence rate per 100,000 persons was 6.3 for CD (95% confidence interval [CI], 5.6–7.0) and 12.0 for UC (CI, 11.0–13.0). The point prevalence per 100,000 on December 31, 2002 was 96.3 for CD (95% CI, 89.6–103.0) and 155.8 for UC (95% CI, 146.6–164.9), increasing to 100.3 and 205.8 per 100,000, respectively, when hospital discharge data from 1985 to 1995 were included. The age-specific incidence of CD was bimodal, while UC incidence rose in early adulthood and remained elevated with advancing age.CONCLUSIONS:The incidence we estimated for CD was similar to the previous U. S. estimate. Our incidence estimate for UC was much higher than the previous U.S. estimate, but similar to that of recent Canadian and European studies. The prevalence we estimated for CD was somewhat lower than previous estimates.

Mycobacterial diseases and antitumour necrosis factor therapy in USA

Objective In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown. Methods At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000–2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. Results Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). Conclusions Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.

Role of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease.

OBJECTIVES:The objective of this study was to assess inflammatory bowel disease (IBD) medications in relation to lymphoma risk.METHODS:Information on IBD and relevant medications and other utilization was obtained from the Kaiser Permanente IBD Registry, 1996–2009. Lymphoma cases were ascertained from the Kaiser Permanente Cancer Registry. Lymphoma incidence was compared between the IBD cohort and the general Kaiser Permanente population.RESULTS:Of the 16,023 IBD patients without human immunodeficiency virus followed an average 5.8 years, 43 developed lymphoma. IBD patients with and without lymphoma did not differ with respect to past IBD-related visits, procedures, or tests. The standardized incidence rate ratio (SIRR) for lymphoma among IBD patients with no dispensing of thiopurine or anti-tumor necrosis factor (TNF) was 1.0 (95% confidence interval (CI): 0.96–1.1). Of the 21,282 person-years involving exposure to thiopurine or anti-TNF, 81% involved thiopurine alone; 3%, anti-TNF alone; and 16%, combination therapy. Among patients with thiopurine but not anti-TNF dispensings, the SIRR was 0.3 (95% CI: 0.2–0.4) for past use and 1.4 for current use (95% CI: 1.2–2.7). Among patients with dispensing of anti-TNF (with and without thiopurine), the SIRR was 5.5 for past use (95% CI: 4.5–6.6) and 4.4 for current use (95% CI: 3.4–5.4). The most common lymphoma subtypes were diffuse large B-cell lymphoma (44%), follicular lymphoma (14%), and Hodgkins disease (12%).CONCLUSIONS:Our study provides evidence that IBD alone is not associated with the risk of lymphoma. Use of anti-TNF with thiopurine and current use of thiopurine alone were associated with increased risk, although the effect of disease severity merits further evaluation.

Clustering of Inflammatory Bowel Disease With Immune Mediated Diseases Among Members of a Northern California-Managed Care Organization

BACKGROUND AND AIMS:Previous studies provide evidence that some immune-mediated diseases occur at greater frequency among inflammatory bowel disease (IBD) patients than in the general population. The present study examined the co-occurrence of IBD with common immune-mediated disorders including asthma, psoriasis, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, vitiligo, autoimmune thyroiditis (Graves and Hashimotos), and chronic glomerulonephritis.METHODS:We conducted a cross-sectional study among members of the Kaiser Permanente Medical Care Program for the period 1996–2005. A total of 12,601 patients with at least two IBD diagnoses in computerized visit data were ascertained. Four persons without IBD were matched to each IBD patient on age, gender, and length of enrollment. Information on co-occurring diseases was obtained from computerized visit data for 1996–2005. Conditional logistic regression was used to estimate the odds ratio and 95% confidence interval for the association of IBD with immune-mediated disorders after adjusting for smoking.RESULTS:Seventeen percent of the IBD patients and 10% of the persons without IBD had a diagnosis for at least one immune-mediated disease. IBD patients were more likely to have asthma (1.5, 95% CI 1.4–1.6), psoriasis (1.7, 95% CI 1.5–2.0), rheumatoid arthritis (1.9, 95% CI 1.5–2.3), and multiple sclerosis (2.3, 95% CI 1.6–3.3).CONCLUSIONS:Among the immune-mediated diseases we studied, most were more common in IBD patients than in persons without IBD, suggesting that IBD shares common etiologic factors with other immune-mediated diseases.

Time Trends in Therapies and Outcomes for Adult Inflammatory Bowel Disease, Northern California, 1998–2005

BACKGROUND & AIMS The management of inflammatory bowel disease (IBD) has become increasingly complicated, and it is unknown whether poor outcomes (prolonged steroid use, hospitalizations, and surgery) have declined in the general population. METHODS This multilevel study used computerized clinical data. The study comprised 2892 adults with Crohns disease (CD) and 5895 with ulcerative colitis (UC) who received care at 16 medical centers within an integrated care organization in Northern California between 1998 and 2005. RESULTS Time trends included (1) a shift in gastroenterology-related visits from the gastroenterology division to primary care; (2) increased use of IBD-related drugs, except for a 7% decline in use of 5-aminosalicylate in CD and no change in steroid use for CD; (3) for the prevalence of prolonged steroid exposure (120 days of continuous use), a 36% decline for CD with a 27% increase for UC; (4) declines in the hospitalization rates of 33% for CD and 29% for UC; and (5) for the surgery rate, no significant change for CD with a 50% decline for UC. CONCLUSIONS Declines in prolonged steroid exposure and the hospitalization rate for CD and in the hospitalization and surgery rate for UC are encouraging; however, the increase in prolonged steroid exposure for UC merits concern and further investigation. The variability in care patterns observed in this study suggests lack of standardization of care and the opportunity to identify targets for quality improvement. These findings should stimulate research to quantify the effect of current trends in IBD management.

Estimation of the period prevalence of inflammatory bowel disease among nine health plans using computerized diagnoses and outpatient pharmacy dispensings

Background: There are few contemporary estimates of prevalence rates for inflammatory bowel disease (IBD) in diverse North American communities. Methods: We estimated the period prevalence of IBD for January 1, 1999, through June 30, 2001, among 1.8 million randomly sampled members of nine integrated healthcare organizations in the US using computerized diagnoses and outpatient pharmaceutical dispensing. We also assessed the positive predictive value (PPV) and sensitivities of 1) the case‐finding algorithm, and 2) the 30‐month sampling period using medical chart review and linkage to a 78‐month dataset, respectively. Results: The PPV of the case‐finding algorithm was 81% (95% confidence interval [CI], 78–87) and 84% (95% CI, 79–89) in two different organizations. In both, the sensitivity of the optimal algorithm, compared with the most inclusive, exceeded 90%. The sensitivity of the 30‐month sampling period compared with 78 months was 61% (95% CI, 57–64) in one organization. Applying a slightly more sensitive case‐finding algorithm, the average period prevalence of IBD across the nine organizations, standardized to the age‐ and gender‐distribution of the US population, 2000 census, was 388 cases (95% CI, 378–397) per 100,000 persons (range 209–784 per 100,000; average follow‐up 26 months). The prevalence of Crohns disease, ulcerative colitis, and unspecified IBD was 129, 191, and 69 per 100,000, respectively. Conclusions: The observed average prevalence was similar to prevalence proportions reported for other North American populations (369–408 per 100,000). Additional research is needed to understand differences in the occurrence of IBD among diverse populations as well as practice variation in diagnosis and treatment of IBD.

Incidence, prevalence, and time trends of pediatric inflammatory bowel disease in Northern California, 1996 to 2006.

OBJECTIVE To examine the incidence and prevalence of pediatric inflammatory bowel disease (IBD) during 1996-2006 in a community-based health-care delivery system. STUDY DESIGN Members of Kaiser Permanente Northern California aged 0 to 17 years with IBD were identified by use of computerized medical information with confirmation obtained through review of the medical record. RESULTS The average annual incidence of IBD per 100000 was 2.7 (95% confidence interval [CI], 2.3-3.1) for Crohns disease (CD) and 3.2 (CI, 2.8-3.6) for ulcerative colitis (UC). During the 11-year study period, the annual incidence per 100000 increased from 2.2 to 4.3 for CD (P = .09) and from 1.8 to 4.9 for UC (P < .001). The ratio of incident CD cases to incident UC cases was 0.9 in non-Hispanic whites, 1.6 in African Americans (P = .12), 0.3 in Hispanics (P < .001) and 0.4 in Asians (P = .04). The average length of enrollment during the 11-year study period exceeded 8 years. The point prevalence on December 31, 2006, per 100000 was 12.0 for CD (CI, 9.6-14.4) and 19.5 (CI, 16.5-22.6) for UC. CONCLUSIONS In this population the incidence of UC increased significantly by 2.7-fold and CD increased 2.0-fold without reaching statistical significance. Hispanic and Asian children had development of UC more often than CD, suggesting possible etiologic differences across racial and ethnic groups.