Kevin Haynes

Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study

OBJECTIVE: To determine whether childhood antianaerobic antibiotic exposure is associated with the development of inflammatory bowel disease (IBD). METHODS: This retrospective cohort study employed data from 464 UK ambulatory practices participating in The Health Improvement Network. All children with ≥2 years of follow-up from 1994 to 2009 were followed between practice enrollment and IBD development, practice deregistration, 19 years of age, or death; those with previous IBD were excluded. All antibiotic prescriptions were captured. Antianaerobic antibiotic agents were defined as penicillin, amoxicillin, ampicillin, penicillin/β-lactamase inhibitor combinations, tetracyclines, clindamycin, metronidazole, cefoxitin, carbapenems, and oral vancomycin. RESULTS: A total of 1 072 426 subjects contributed 6.6 million person-years of follow-up; 748 developed IBD. IBD incidence rates among antianaerobic antibiotic unexposed and exposed subjects were 0.83 and 1.52/10 000 person-years, respectively, for an 84% relative risk increase. Exposure throughout childhood was associated with developing IBD, but this relationship decreased with increasing age at exposure. Exposure before 1 year of age had an adjusted hazard ratio of 5.51 (95% confidence interval [CI]: 1.66–18.28) but decreased to 2.62 (95% CI: 1.61–4.25) and 1.57 (95% CI: 1.35–1.84) by 5 and 15 years, respectively. Each antibiotic course increased the IBD hazard by 6% (4%–8%). A dose-response effect existed, with receipt of >2 antibiotic courses more highly associated with IBD development than receipt of 1 to 2 courses, with adjusted hazard ratios of 4.77 (95% CI: 2.13–10.68) versus 3.33 (95% CI: 1.69–6.58). CONCLUSIONS: Childhood antianaerobic antibiotic exposure is associated with IBD development.

Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study

Objectives We aimed to quantify the risk of major adverse cardiovascular events (MACE) among patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA) and psoriasis without known PsA compared with the general population after adjusting for traditional cardiovascular risk factors. Methods A population-based longitudinal cohort study from 1994 to 2010 was performed in The Health Improvement Network (THIN), a primary care medical record database in the UK. Patients aged 18–89 years of age with PsA, RA or psoriasis were included. Up to 10 unexposed controls matched on practice and index date were selected for each patient with PsA. Outcomes included cardiovascular death, myocardial infarction, cerebrovascular accidents and the composite outcome (MACE). Cox proportional hazards models were used to calculate the HRs for each outcome adjusted for traditional risk factors. A priori, we hypothesised an interaction between disease status and disease-modifying antirheumatic drug (DMARD) use. Results Patients with PsA (N=8706), RA (N=41 752), psoriasis (N=138 424) and unexposed controls (N=81 573) were identified. After adjustment for traditional risk factors, the risk of MACE was higher in patients with PsA not prescribed a DMARD (HR 1.24, 95% CI 1.03 to 1.49), patients with RA (No DMARD: HR 1.39, 95% CI 1.28 to 1.50, DMARD: HR 1.58, 95% CI 1.46 to 1.70), patients with psoriasis not prescribed a DMARD (HR 1.08, 95% CI 1.02 to 1.15) and patients with severe psoriasis (DMARD users: HR 1.42, 95% CI 1.17 to 1.73). Conclusions Cardiovascular risk should be addressed with all patients affected by psoriasis, PsA or RA.

Rates of malignancy associated with juvenile idiopathic arthritis and its treatment

OBJECTIVE To determine the relative rates of incident malignancy among children with juvenile idiopathic arthritis (JIA) with respect to treatment as compared to children without JIA. METHODS Using national Medicaid data from 2000 through 2005, we identified cohorts of children with JIA and without JIA according to the diagnosis codes used by their physicians and the medication prescriptions that were dispensed. Study followup began after a 6-month lag period to exclude prevalent and misdiagnosed malignancies. Treatment with methotrexate (MTX) and tumor necrosis factor (TNF) inhibitors was categorized as ever exposed or never exposed. Malignancy outcomes were identified using an adapted version of a previously validated algorithm. Incident malignancies were categorized as possible, probable, or highly probable based on a comprehensive review of all claims. Malignancy rates were standardized to the age, sex, and race distribution of the overall JIA cohort. Standardized incidence ratios (SIRs) were calculated using children with attention deficit hyperactivity disorder (n = 321,821) (one of two comparator groups included) as the referent group. RESULTS The JIA cohort included 7,812 children with a total followup time of 12,614 person-years; 1,484 of these children contributed 2,922 person-years of TNF inhibitor exposure. For all children with JIA versus children without JIA, the SIR was 4.4 (95% confidence interval [95% CI] 1.8-9.0) for probable and highly probable malignancies. For those taking MTX without TNF inhibitor use, the SIR was 3.9 (95% CI 0.4-14). Following any use of TNF inhibitors, no probable or highly probable malignancies were identified (SIR 0 [95% CI 0-9.7]). CONCLUSION Children with JIA appeared to have an increased rate of incident malignancy compared to children without JIA. The treatment for JIA, including TNF inhibitors, did not appear to be significantly associated with the development of malignancy.

Risk of moderate to advanced kidney disease in patients with psoriasis: population based cohort study.

Objective To determine the risk of chronic kidney disease in patients with psoriasis. Design Population based cohort study and nested cross sectional study. Setting Electronic medical records database based in United Kingdom. Participants Cohort study: patients with psoriasis aged 18-90 each matched to up to five patients without psoriasis based on age, practice, and time of visit. Nested study: patients with psoriasis aged 25-64 with confirmed data on psoriasis severity, each matched to up to 10 patients without psoriasis based on age and practice. Main outcome measures Cohort study: incident moderate to advanced (stage 3 through 5) chronic kidney disease. Nested study: baseline prevalence of chronic kidney disease. Results 136 529 patients with mild psoriasis and 7354 patients with severe psoriasis based on treatment patterns were matched to 689 702 unaffected patients. The adjusted hazard ratios (95% confidence intervals) for incident chronic kidney disease were 1.05 (1.02 to 1.07), 0.99 (0.97 to 1.02), and 1.93 (1.79 to 2.08) in the overall, mild, and severe psoriasis groups, respectively. Age was a significant effect modifier in the severe psoriasis group, with age specific adjusted hazard ratios (95% confidence intervals) of 3.82 (3.15 to 4.64) and 2.00 (1.86 to 2.17) for patients aged 30 and 60, respectively. In the nested analysis of 8731 patients with psoriasis with measurements of affected body surface area matched to 87 310 patients without psoriasis, the adjusted odds ratios (95% confidence intervals) for chronic kidney disease were 0.89 (0.72 to 1.10), 1.36 (1.06 to 1.74), and 1.58 (1.07 to 2.34) in the mild, moderate, and severe psoriasis groups, respectively. Conclusions Moderate to severe psoriasis is associated with an increased risk of chronic kidney disease independent of traditional risk factors.

Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases†

OBJECTIVE To compare the incidence of cancer following tumor necrosis factor α (TNFα) inhibitor therapy to that with commonly used alternative therapies across multiple immune-mediated diseases. METHODS The Safety Assessment of Biological Therapeutics study used data from 4 sources: national Medicaid and Medicare databases, Tennessee Medicaid, pharmacy benefits plans for Medicare beneficiaries in New Jersey and Pennsylvania, and Kaiser Permanente Northern California. Propensity score-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were computed to estimate the relative rates of cancer, comparing those treated with TNFα inhibitors to those treated with alternative disease-modifying therapies. The cancer-finding algorithm had a positive predictive value ranging from 31% for any leukemia to 89% for female breast cancer. RESULTS We included 29,555 patients with rheumatoid arthritis (RA) (13,102 person-years), 6,357 patients with inflammatory bowel disease (1,508 person-years), 1,298 patients with psoriasis (371 person-years), and 2,498 patients with psoriatic arthritis (618 person-years). The incidence of any solid cancer was not elevated in RA (HR 0.80 [95% CI 0.59-1.08]), inflammatory bowel disease (HR 1.42 [95% CI 0.47-4.26]), psoriasis (HR 0.58 [95% CI 0.10-3.31]), or psoriatic arthritis (HR 0.74 [95% CI 0.20-2.76]) during TNFα inhibitor therapy compared to disease-specific alternative therapy. Among RA patients, the incidence of any of the 10 most common cancers in the US and of nonmelanoma skin cancer was not increased with TNFα inhibitor therapy compared to treatment with comparator drugs. CONCLUSION Short-term cancer risk was not elevated among patients treated with TNFα inhibitor therapy relative to commonly used therapies for immune- mediated chronic inflammatory diseases in this study.

Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN)

OBJECTIVE This study was conducted to determine if type 1 diabetes is associated with an increased risk of fracture across the life span. RESEARCH DESIGN AND METHODS This population-based cohort study used data from The Health Improvement Network (THIN) in the U.K. (data from 1994 to 2012), in which 30,394 participants aged 0–89 years with type 1 diabetes were compared with 303,872 randomly selected age-, sex-, and practice-matched participants without diabetes. Cox regression analysis was used to determine hazard ratios (HRs) for incident fracture in participants with type 1 diabetes. RESULTS A total of 334,266 participants, median age 34 years, were monitored for 1.9 million person-years. HR were lowest in males and females age <20 years, with HR 1.14 (95% CI 1.01–1.29) and 1.35 (95% CI 1.12–1.63), respectively. Risk was highest in men 60–69 years (HR 2.18 [95% CI 1.79–2.65]), and in women 40–49 years (HR 2.03 [95% CI 1.73–2.39]). Lower extremity fractures comprised a higher proportion of incident fractures in participants with versus those without type 1 diabetes (31.1% vs. 25.1% in males, 39.3% vs. 32% in females; P < 0.001). Secondary analyses for incident hip fractures identified the highest HR of 5.64 (95% CI 3.55–8.97) in men 60–69 years and the highest HR of 5.63 (95% CI 2.25–14.11) in women 30–39 years. CONCLUSIONS Type 1 diabetes was associated with increased risk of incident fracture that began in childhood and extended across the life span. Participants with type 1 diabetes sustained a disproportionately greater number of lower extremity fractures. These findings have important public health implications, given the increasing prevalence of type 1 diabetes and the morbidity and mortality associated with hip fractures.

Risk of mortality in patients with psoriatic arthritis, rheumatoid arthritis and psoriasis: a longitudinal cohort study

Background There are conflicting reports in the literature of the mortality risk among patients with psoriatic arthritis (PsA). The objective of this study was to examine the risk of mortality in patients with PsA compared with matched controls, patients with psoriasis and those with rheumatoid arthritis (RA). Methods A longitudinal cohort study was performed in a large UK medical record database, The Health Improvement Network, among patients with PsA, rheumatoid arthritis (RA) or psoriasis with data from 1994 to 2010. Unexposed controls were matched on practice and start date within the practice for each patient with PsA. Cox proportional hazards models were used to calculate the relative hazards for death. Results Patients with PsA (N=8706), RA (N=41 752), psoriasis (N=138 424) and unexposed controls (N=82 258) were identified; 1 442 357 person-years were observed during which 21 825 deaths occurred. Compared with population controls, patients with PsA did not have an increased risk of mortality after adjusting for age and sex (disease-modifying antirheumatic drug (DMARD) users: HR 0.94, 95% CI 0.80 to 1.10; DMARD non-users: HR 1.06, 95% CI 0.94 to 1.19) whereas patients with RA had increased mortality (DMARD users: HR 1.59, 95% CI 1.52 to 1.66; DMARD non-users: HR 1.54, 95% CI 1.47 to 1.60). Patients with psoriasis who had not been prescribed a DMARD had a small increased risk of mortality (HR 1.08, 95% CI 1.04 to 1.12) while those who had been prescribed a DMARD, indicating severe psoriasis, were at increased risk (HR 1.75, 95% CI 1.56 to 1.95). Conclusions Patients with RA and psoriasis have increased mortality compared with the general population but patients with PsA do not have a significantly increased risk of mortality.

Comparative Effectiveness of Infliximab and Adalimumab for Crohn's Disease

BACKGROUND & AIMS Antibodies against tumor necrosis factor-α are widely used to treat patients with Crohns disease (CD). This study compared the effectiveness of infliximab and adalimumab, the 2 most commonly used anti-tumor necrosis factor agents, in patients with CD. METHODS We conducted a retrospective cohort study by using U.S. Medicare data from 2006 through 2010. Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871) after January 31, 2007, were included. Patients older than age 85 and those with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis were excluded. The primary outcome measures were disease persistence on therapy at week 26, surgery (including bowel resection, creation of an ostomy, or surgical treatment of a perforation or abscess), and hospitalization for CD. Propensity score-adjusted logistic and Cox regression were used to compute adjusted odds ratios or hazard ratios and 95% confidence intervals (CIs). RESULTS After 26 weeks of treatment, 49% of patients receiving infliximab remained on drug, compared with 47% of those receiving adalimumab (odds ratio, 0.98; 95% CI, 0.81-1.19). Fewer patients treated with infliximab underwent surgery than those treated with adalimumab, but this difference was not statistically significant (5.5 vs 6.9 surgeries per 100 person-years; hazard ratio, 0.79; 95% CI, 0.60-1.05). Rates of hospitalization did not differ between groups (hazard ratio, 0.88; 95% CI, 0.72-1.07). CONCLUSIONS We observed similar effectiveness of infliximab and adalimumab for CD on the basis of 3 clinically important outcome measures.

Cancer incidence in The Health Improvement Network.

The utility of electronic medical record databases for clinical research relies on the validity and completeness of the recorded medical diagnoses. This study assessed whether the recorded incidence of cancer among patients in The Health Improvement Network (THIN) database is comparable to that expected in the UK based on national cancer registry data.

Validity of The Health Improvement Network (THIN) for epidemiologic studies of hepatitis C virus infection.

Before using computerized databases to study hepatitis C virus (HCV) epidemiology, the validity of the diagnosis must be assessed. We determined the accuracy of HCV diagnostic codes within The Health Improvement Network (THIN), an electronic database containing medical record data from general medical practices in the United Kingdom.