Context Although tumor necrosis factor alpha (TNF-α) antagonists are increasingly used in place of non-biologic comparator medications, their safety profile remains incomplete. Objectives To determine whether initiation of TNF-α antagonists compared with non-biologic comparators is associated with an increased risk of serious infections. 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 (PsO-PsA-AS) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid and National Medicaid/Medicare. TNF-α antagonists and non-biologic regimens were compared in disease specific-propensity score (PS) matched cohorts using Cox regression models with non-biologics as 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 non-biologic regimens. Results Study cohorts included 10484 RA, 2323 IBD and 3213 PsO-PsA-AS PS-matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1171 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among RA patients, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR]: 1.07 (95% CI: 0.93–1.23)). Among IBD patients, rates were 10.91 and 9.60 per 100 person-years (aHR: 1.13, (0.85–1.50)). Among PsO-PsA-AS patients, rates were 5.41 and 5.19 per 100 person-years (aHR: 1.10, (0.80–1.53)). Among RA patients, infliximab was associated with a significant increase in serious infections compared with etanercept and adalimumab (aHRs: 1.27 (1.08–1.49) and 1.23 (1.02–1.48)). Baseline glucocorticoid use was associated with a dose-dependent increase in infections. Conclusions Among patients with autoimmune diseases, compared to treatment with non-biologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.
A single-nucleotide polymorphism (SNP), identified at nucleotide position −844 in the 5′ promoter of the FasL gene, lies within a putative binding motif for CAAT/enhancer-binding protein β (C/EBPβ). Electrophoretic mobility shift and supershift assays confirmed that this element binds specifically to C/EBPβ and demonstrated that the two alleles of this element have different affinities for C/EBPβ. In luciferase reporter assays, the −844C genotype had twice the basal activity of the −844T construct, and basal expression of Fas ligand (FasL) on peripheral blood fibrocytes was also significantly higher in −844C than in −844T homozygous donors. FasL is located on human chromosome 1q23, a region that shows linkage to the systemic lupus autoimmune phenotype. Analysis of 211 African American systemic lupus erythematosus patients revealed enrichment of the −844C homozygous genotype in these systemic lupus erythematosus patients compared with 150 ethnically matched normal controls (p = 0.024). The −844C homozygous genotype may lead to the increased expression of FasL, to altered FasL-mediated signaling in lymphocytes, and to enhanced risk for autoimmunity. This functionally significant SNP demonstrates the potential importance of SNPs in regulatory regions and suggests that differences in the regulation of FasL expression may contribute to the development of the autoimmune phenotype.
Objective To evaluate the risks of herpes zoster (HZ) and herpes simplex virus infection (HSV) associated with tofacitinib compared to biologic agents among patients with rheumatoid arthritis (RA). Methods Using health plan data from 2010–2014, RA patients initiating tofacitinib or biologics with no history of HZ or HSV were identified. Incident cases of HZ or HSV within this cohort were identified. Crude incidence rates were calculated by drug exposure. Cox proportional hazards models evaluated the adjusted association between tofacitinib and HZ, and a composite outcome of HZ or HSV. Results A total of 2,526 patients initiating tofacitinib were compared with initiations of other biologics: anti-TNF (n=42,850), abatacept (n=12,305), rituximab (n=5,078), and tocilizumab (n=6,967). Tofacitinib patients were somewhat younger (mean age 55 years) versus those on other biologics, and somewhat less likely to use concomitant MTX (39% vs. 43–56%, depending on drug). Crude incidence of HZ associated with tofacitinib was 3.87/100py. After multivariable adjustment, HZ risk was significantly elevated, hazard ratio [HR] 2.01 (95%CI 1.40–2.88) compared to abatacept. Rates and adjusted HRs for all other RA biologics were comparable to each other and abatacept. Older age, female sex, prednisone >7.5mg/day, prior outpatient infection, and greater number of hospitalizations were also associated with increased HZ risk Incidence rates for the combined outcome were greatest for tofacitinib (7.61/100py) and significantly elevated after adjustment (HR=1.40, 95%CI 1.09–1.81). Conclusion The rate of zoster associated with tofacitinib was approximately double that observed in patients using biologics.
Objective. The herpes zoster (HZ) vaccine is recommended for adults in the US ages ‡60 years who do not have weakened immune systems. It is unclear how the risk of HZ varies according to age and disease conditions in younger patients with autoimmune or inflammatory (AI) diseases. This study was undertaken to evaluate the age-stratified incidence of HZ in patients with AI diseases as compared to older adults for whom the HZ vaccine is currently recommended by the US Centers for Disease Control and Prevention.Methods. Using linked data obtained from patients who were insured by US commercial and government health care plans during the period 2007-2010, 7 cohorts of patients with AI diseases were assembled: systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (PsO), ankylosing spondylitis (AS), and gout. Two comparator cohorts were also assembled as controls: adult patients with diabetes and adult subjects without AI diseases or diabetic conditions. HZ was identified using diagnostic codes. Age-specific incidence rates (IRs) of HZ were calculated and compared to the IRs of HZ in control subjects ages 61-70 years who were without AI diseases or diabetic conditions.Results. After review of the linked data, the following number of enrollment periods were identified: 8,395 for patients with SLE, 7,916 for patients with IBD, 50,646 for patients with RA, 2,629 for patients with PsA, 4,299 for patients with PsO, 1,019 for patients with AS, 58,934 for patients with gout, 214,631 for control patients with diabetes, and 330,727 for control subjects without AI diseases and diabetic conditions. The respective highest and lowest IRs of HZ during the study were 19.9 per 1,000 person-years in the SLE cohort and 6.8 per 1,000 person-years in the gout cohort, as compared to an IR of 5.3 per 1,000 person-years in control subjects without AI diseases or diabetic conditions. The age-specific IRs of HZ in patients with RA and those with SLE ages ‡40 years were 1.5-2 times greater than those observed in
Objective Compare the incidence of hospitalized bacterial infections among children with and without juvenile idiopathic arthritis (JIA) and examine the effects of selected medications Methods Using national U.S. Medicaid data from 2000–2005, we identified a JIA cohort and a comparator cohort of children with attention-deficit hyperactivity disorder (ADHD). Exposures to methotrexate (MTX), TNF inhibitors, and oral glucocorticoids were determined using pharmacy claims. Hospitalized bacterial infections were identified using coded discharge diagnoses. We calculated adjusted hazard ratios (aHR) to compare infection incidence rates while adjusting for relevant covariates. Results We identified 8,479 JIA patients with 13,003 person-years of follow-up; 42% used MTX and 17% used TNF inhibitors. Compared with ADHD patients, JIA patients without current MTX or TNF inhibitor use had an increased rate of infection (aHR 2.0; 95%CI 1.5–2.5). Among JIA patients not using TNF inhibitor therapy, MTX users had a similar rate of infection compared with those without current MTX use (aHR 1.2; 95%CI 0.9–1.7). TNF inhibitor use (irrespective of MTX) resulted in a similar rate of infection compared to MTX without TNF inhibitor (aHR 1.2; 95%CI 0.8–1.8). With adjustment for MTX and TNF inhibitor use, high-dose glucocorticoid use (≥10 mg of prednisone daily) increased the rate of infection compared with no glucocorticoid use (aHR 3.1; 95%CI 2.0–4.7). Conclusions Children with JIA had an increased rate of infection compared to children with ADHD. Among children with JIA, the rate of infection was not increased with MTX or TNF inhibitor use, but was significantly increased with high-dose glucocorticoid use.
To investigate whether functional polymorphisms exist in the C-reactive protein (CRP) gene, i.e., ones that contribute directly to differences in baseline CRP among individuals, we sequenced a 1,156-nucleotide-long stretch of the CRP gene promoter in 287 ostensibly healthy people. We identified two single-nucleotide polymorphisms (SNPs), a bi-allelic one at nucleotide -409 (G-->A), and a tri-allelic one at -390 (C-->T-->A), both resident within the hexameric core of transcription factor binding E-box elements. Electrophoretic mobility shift assays confirmed that the SNP within the sequence (-412)CACGTG(-407) (E-box 1) modulates transcription factor binding, and that the one within (-394)CACTTG(-389) (E-box 2) supports transcription factor binding only when the -390 T allele is present. The commonest of four E-box 1/E-box 2 haplotypes (-409G/-390T) identified in the population supported highest promoter activity in luciferase reporter assays, and the rarest one (-409A/-390T) supported the least. Importantly, serum CRP in people with these haplotypes reproduced this rank order, i.e., people with the -409G/-390T haplotype had the highest baseline serum CRP (mean +/- SEM 10.9 +/- 2.25 microg/ml) and people with the -409A/-390T haplotype had the lowest (5.01 +/- 1.56 microg/ml). Furthermore, haplotype-associated differences in baseline CRP were not due to differences in age, sex, or race, and were still apparent in people with no history of smoking. At least two other SNPs in the CRP promoter lie within E-box elements (-198 C-->T, E-box 4, and -861 T-->C, E-box 3), indicating that not only is the quality of E-box sites in CRP a major determinant of baseline CRP level, but also that the number of E-boxes may be important. These data confirm that the CRP promoter does encode functional polymorphisms, which should be considered when baseline CRP is being used as an indicator of clinical outcome. Ultimately, development of genetic tests to screen for CRP expression variants could allow categorization of healthy people into groups at high versus low future risk of inflammatory disease.
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