Paternal Exposure to Immunosuppressive and/or Biologic Agents and Birth Outcomes in Patients With Immune-Mediated Inflammatory Diseases.

BACKGROUND & AIMS: We conducted a retrospective cohort study to inform the safety of exposure to immunosuppressive and/or biologic agents around conception in expectant fathers with immune-mediated inflammatory diseases (IMIDs) on birth outcomes. METHODS: Using a deidentified administrative claims database (OptumLabs Data Warehouse), we identified 7453 expectant fathers with IMIDs (inflammatory bowel diseases, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis) linked to newborns with periconception medication exposure between 38 and 60 weeks before the newborn birth date (34-58 weeks prior for preterm newborns) and neonatal follow-up for 3 months after the birth date. Through logistic regression adjusting for paternal age and race (and, in a subset, for maternal age, race, presence of IMIDs, and nonsingleton births), we compared the risk of major congenital malformations (primary outcome) and preterm birth and low birth weight in fathers exposed to thiopurines (n = 461), methotrexate (n = 171), tumor necrosis factor (TNF) α antagonists (n = 1082), or non-TNF-targeting biologic agents (n = 132) vs fathers not exposed to any of these medications (n = 5607). RESULTS: As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66-1.76), methotrexate (RR, 0.67; 95% CI, 0.21-1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non-TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80-3.24) was not associated with increased risk of major congenital malformations. No association was observed between paternal medication exposure and risk of preterm birth or low birth weight. Results were stable on subanalyses of linked father-mother-newborn triads. CONCLUSIONS: In a large cohort study of 7453 expectant fathers with IMIDs, exposure to immunosuppressive or biologic agents around conception was not associated with increased risk of adverse birth outcomes.

Rate, risk factors and causes of mortality in patients with Sjögren's syndrome: a systematic review and meta-analysis of cohort studies.

OBJECTIVES: There is conflicting evidence regarding prognosis in patients with primary SS (pSS). The aim of this study was to estimate the rate, risk factors and causes of mortality in patients with pSS through a systematic review and meta-analysis. METHODS: Through a systematic review of multiple databases through October 2014, we identified cohort studies reporting relative risk (compared with standardized population), risk factors and causes of mortality in patients with pSS. We estimated summary risk ratios (RRs) with 95% CIs using random effects model. RESULTS: We identified 10 studies with 7888 patients (91% females) with pSS, of whom 682 patients died over a median average follow-up of 9 years. The pooled standardized mortality ratio in patients with pSS was 1.38 (95% CI 0.94, 2.01). Leading causes of mortality were cardiovascular diseases, solid-organ and lymphoid malignancies and infections; however, it is unclear whether these observed causes were overrepresented in patients with pSS as compared with the general population. Risk factors associated with increased mortality were advanced age at diagnosis [RR 1.09 (95% CI 1.07, 1.12)], male sex [RR 2.18 (95% CI 1.45, 3.27)], parotid enlargement [RR 1.81 (95% CI 1.02, 3.21)], abnormal parotid scintigraphy [RR 2.96 (95% CI 1.36, 6.45)], extraglandular involvement [RR 1.77 (95% CI 1.06, 2.95)], vasculitis [RR 7.27 (95% CI 2.70, 19.57)], anti-SSB positivity [RR 1.45 (95% CI 1.03, 2.04)], low C3 [RR 2.14 (95% CI 1.38, 3.32)] and C4 [RR 3.08 (95% CI 2.14, 4.42)] and cryoglobulinaemia [RR 2.62 (95% CI 1.77, 3.90)]. CONCLUSION: pSS is not associated with an increase in all-cause mortality as compared with the general population. However, a subset of patients with extraglandular involvement, vasculitis, hypocomplementaemia and cryoglobulinaemia may be at increased risk of mortality and require close follow-up.

Cancer risk in cutaneous lupus erythematosus: a population-based cohort study.

OBJECTIVE: Immune dysregulation associated with chronic autoimmune diseases, such as SLE, has been associated with increased cancer risk. It is unclear whether isolated cutaneous lupus erythematosus (CLE) modifies cancer risk. We estimated the cumulative incidence of cancer in a population-based CLE cohort and compared the risk with a matched non-CLE cohort. METHODS: All incident cases of CLE in Olmsted County, MN, USA between 1965 and 2005 were identified and followed to December 2013. Estimates for the cumulative incidence of any cancer and skin cancer in patients with CLE were derived and compared with an age-, sex- and calendar-year-matched non-CLE cohort using Cox models. RESULTS: There were a total of 155 patients with CLE [age at diagnosis, 48 (sd 16) years; 65% females; BMI, 26.3 (sd 7.1) kg/m2; 40% smokers, 9% with diabetes]. During a median follow-up of 14.6 years, we observed 35 cases of incident cancer (including 10 cases of skin cancer). The cumulative 1-, 5- and 10-year incidence of any cancer after diagnosis of CLE was 1.4, 7.5 and 11.6%, respectively. Compared with matched non-CLE controls, the overall risk of malignancies was not increased in patients with CLE (smoking-adjusted hazard ratio = 1.29; 95% CI: 0.78, 2.13; P = 0.31). There was also no significant increase in risk of any skin cancer in patients with CLE (hazard ratio = 2.51; 95% CI: 0.91, 6.96; P = 0.16). CONCLUSION: CLE is not associated with an increased risk of any cancers, including skin cancers, compared with the general population. However, the number of events was small, limiting the power of the study.

Burden, Causes, and Outcomes of Hospitalization in Patients With Giant Cell Arteritis: A US National Cohort Study.

OBJECTIVE: Giant cell arteritis (GCA) has a relapsing-remitting course and is associated with a high burden of comorbidities, leading to repeated hospitalizations. This study was undertaken to investigate the burden, risk factors, causes, and outcomes of hospitalization and readmission in GCA patients in a US national cohort. METHODS: Using the 2017 US National Readmission Database, we identified adults ≥50 years of age hospitalized with GCA between January and June 2017, with at least 6 months of follow-up. We estimated the burden of hospitalization including 6-month risk of readmission, total days spent in hospital, and costs, annually. We examined patient-, hospital-, and index hospitalization-related factors for 6-month readmission and total days of hospitalization using binomial logistic regression. RESULTS: Our study included 1,206 patients hospitalized with GCA (70% women, median age 77 years), with 13% of patients experiencing GCA-related ophthalmologic complications at index hospital admission. On follow-up, 3% died, and 34% of patients were readmitted within 6 months, primarily for infections (23%) and cardiovascular diseases (CVDs) (15%). Charlson comorbidity index (CCI) of ≥1, smoking, and obesity were associated with readmission. GCA patients spent a median of 5 days/year in hospital (interquartile range [IQR] 3-11), with those in the top quartile spending 19 days/year in hospital (IQR 14-26). CONCLUSION: GCA patients frequently experience unplanned health care utilization, with 1 in 3 patients experiencing readmission within 6 months, and 3% dying within the follow-up period. Infection and CVDs are common causes of readmission and may be related to glucocorticoid exposure. Population health management strategies are required in these vulnerable GCA patients.

Lipidomic Profiling in Synovial Tissue.

The analysis of synovial tissue offers the potential for the comprehensive characterization of cell types involved in arthritis pathogenesis. The studies performed to date in synovial tissue have made it possible to define synovial pathotypes, which relate to disease severity and response to treatment. Lipidomics is the branch of metabolomics that allows the quantification and identification of lipids in different biological samples. Studies in animal models of arthritis and in serum/plasma from patients with arthritis suggest the involvement of different types of lipids (glycerophospholipids, glycerolipids, sphingolipids, oxylipins, fatty acids) in the pathogenesis of arthritis. We reviewed studies that quantified lipids in different types of tissues and their relationship with inflammation. We propose that combining lipidomics with currently used "omics" techniques can improve the information obtained from the analysis of synovial tissue, for a better understanding of pathogenesis and the development of new therapeutic strategies.

Comparative Risk of Cardiovascular Events With Biologic and Synthetic Disease-Modifying Antirheumatic Drugs in Patients With Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the comparative effects of tumor necrosis factor inhibitors (TNFi), non-TNFi biologics, and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on cardiovascular risk in rheumatoid arthritis (RA). METHODS: Using a systematic search through May 8, 2018, we included 14 observational studies in adults with RA treated with TNFi, non-TNFi biologics, tofacitinib, or csDMARDs, reporting the risk of major adverse cardiovascular events (MACE) or stroke. Only studies reporting active comparators were included. We performed random effects meta-analysis and estimated odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: As compared to TNFi, tocilizumab was associated with a decreased risk of MACE (OR 0.59 [95% CI 0.34-1.00]), whereas csDMARDs were associated with an increased risk of MACE (csDMARDs including methotrexate OR 1.45 [95% CI 1.09-1.93]; without methotrexate OR 2.57 [95% CI 1.32-5.00]), without heterogeneity (I2 = 0%); there was no difference in risk of MACE between abatacept and TNFi (OR 0.89 [95% CI 0.71-1.11]), or between tocilizumab and abatacept (OR 0.81 [0.57-1.16]). Based on 11 cohorts (n = 135,053 patients), as compared to TNFi, csDMARDs were associated with an increased risk of stroke (OR 1.17 [95% CI 1.01-1.36]); there was no difference in risk of stroke between different biologics (tocilizumab versus TNFi OR 0.98 [95% CI 0.59-1.61]; abatacept versus TNFi OR 1.08 [0.86-1.34]; tocilizumab versus abatacept OR 0.73 [95% CI 0.39-1.38]), without heterogeneity (I2 = 0%). No comparative studies on cardiovascular risk with tofacitinib were identified. CONCLUSION: Based on meta-analysis, as compared to TNFi, tocilizumab may be associated with a reduced risk of MACE, whereas csDMARDs may be associated with an increased risk of MACE and stroke.

Obesity and response to anti-tumor necrosis factor-α agents in patients with select immune-mediated inflammatory diseases: A systematic review and meta-analysis.

OBJECTIVES: We sought to evaluate the association between obesity and response to anti-tumor necrosis factor-α (TNF) agents, through a systematic review and meta-analysis. METHODS: Through a systematic search through January 24, 2017, we identified randomized controlled trials (RCTs) or observational studies in adults with select immune-mediated inflammatory diseases-inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), spondyloarthropathies (SpA), psoriasis and psoriatic arthritis (PsA)-treated with anti-TNF agents, and reporting outcomes, stratified by body mass index (BMI) categories or weight. Primary outcome was failure to achieve clinical remission or response or treatment modification. We performed random effects meta-analysis and estimated odds ratios (OR) and 95% confidence interval (CI). RESULTS: Based on 54 cohorts including 19,372 patients (23% obese), patients with obesity had 60% higher odds of failing therapy (OR,1.60; 95% CI,1.39-1.83;I2 = 71%). Dose-response relationship was observed (obese vs. normal BMI: OR,1.87 [1.39-2.52]; overweight vs. normal BMI: OR,1.38 [1.11-1.74],p = 0.11); a 1kg/m2 increase in BMI was associated with 6.5% higher odds of failure (OR,1.065 [1.043-1.087]). These effects were observed across patients with rheumatic diseases, but not observed in patients with IBD. Effect was consistent based on dosing regimen/route, study design, exposure definition, and outcome measures. Less than 10% eligible RCTs reported outcomes stratified by BMI. CONCLUSIONS: Obesity is an under-reported predictor of inferior response to anti-TNF agents in patients with select immune-mediated inflammatory diseases. A thorough evaluation of obesity as an effect modifier in clinical trials is warranted, and intentional weight loss may serve as adjunctive treatment in patients with obesity failing anti-TNF therapy.

Risk of Cerebrovascular Accidents and Ischemic Heart Disease in Cutaneous Lupus Erythematosus: A Population-Based Cohort Study.

OBJECTIVE: It is unclear whether isolated cutaneous lupus erythematosus (CLE) affects cardiovascular risk. We estimated the cumulative incidence and mortality of cardiovascular diseases in a population-based CLE cohort and compared the risk with a matched non-CLE cohort. METHODS: All incident cases of CLE in Olmsted County, Minnesota, between 1965 and 2005 were followed until December 2013. The cumulative incidence of cerebrovascular accidents (CVAs [including stroke and transient ischemic attack]), ischemic heart disease (IHD [including coronary artery disease, myocardial infarction, and angina pectoris]), heart failure, and peripheral arterial disease (PAD) was derived and compared to an age-, sex-, and calendar year-matched non-CLE cohort using Cox models. RESULTS: There were 155 patients with CLE (mean ± SD age at diagnosis 48 ± 16 years, 65% female, mean ± SD BMI 26.3 ± 7.1 kg/m2 , 40% smokers, 9% with diabetes mellitus). During a median followup of 14.6 years, 41 CLE patients had cardiovascular events (15 patients with CVAs, 32 patients with IHD), with a 20-year cumulative incidence of 31.6%. As compared to non-CLE subjects, the risk of CVAs (smoking-adjusted hazard ratio [HR] 2.97 [95% confidence interval (95% CI) 1.13-7.78]) and PAD (HR 2.06 [95% CI 0.99-4.32]) was increased in patients with CLE, but the risk of IHD was not increased (HR 0.94 [95% CI 0.57-1.54]). There was no increase in cardiovascular mortality (HR 1.68 [95% CI 0.76-3.75]). The magnitude of risk for any cardiovascular outcome was not significantly influenced by the extent of cutaneous involvement. CONCLUSION: CLE may be associated with an increased risk of CVAs and PAD, but not IHD. Factors contributing to increased CVA risk in patients with CLE merit evaluation.

Pregnancy-related issues in women with systemic lupus erythematosus.

While fertility is preserved in females with systemic lupus erythematosus (SLE), it is well established that pregnancy in these patients is associated with adverse maternal and fetal outcomes, including pregnancy loss, pre-eclampsia, preterm delivery and intrauterine growth retardation, as well as neonatal mortality. Mechanisms underlying these adverse outcomes are poorly understood, and better understanding of these would allow development of targeted and personalized treatment strategies. Established risk factors for adverse pregnancy outcomes include active disease within 6 months prior to conception and during pregnancy, active nephritis, maternal hypertension, antiphospholipid antibodies and hypocomplementemia. While intensive monitoring is recommended, the comparative effectiveness of appropriate management strategies is unclear. While current strategies are able to achieve live births in 85-90% of pregnancies, certain aspects such as prevention of preterm birth, treatment of congenital heart block due to neonatal lupus and recurrent pregnancy loss despite best management, remains challenging. Pregnancy is also associated with an increased risk of flare of lupus, particularly in patients with active disease at time of conception or within 6 months prior to conception. Pregnant patients with SLE should be followed in a high-risk obstetric clinic, and care should be closely coordinated between the obstetrician and rheumatologist.

Visual manifestations in giant cell arteritis: trend over 5 decades in a population-based cohort.

OBJECTIVE: To evaluate clinical characteristics, treatment, and outcomes of patients with visual changes from giant cell arteritis (GCA) and to examine trends over the last 5 decades. METHODS: We reviewed the medical records of a population-based cohort of patients with GCA diagnosed between 1950 and 2004. The clinical, ophthalmological, and laboratory features of patients with visual manifestations attributable to GCA were compared to patients without visual complications. Trends over time were examined using logistic regression modeling adjusted for age and sex. RESULTS: In a cohort of 204 cases of GCA (mean age 76.0 ± 8.2 yrs, 80% female), visual changes from GCA were observed in 47 patients (23%), and 4.4% suffered complete vision loss. A higher proportion of patients with visual manifestations reported jaw claudication than did patients without visual changes (55% vs 38%, p = 0.04). Over a period of 55 years, we observed a significant decline in the incidence of visual symptoms due to GCA. There was a lower incidence of ischemic optic neuropathy in the 1980-2004 cohort vs 1950-1979 (6% vs 15%, p = 0.03). Patients diagnosed in later decades were more likely to recover from visual symptoms (HR 1.34, 95% CI 1.06-1.71). Chances of recovery were poor in patients with anterior ischemic optic neuropathy or complete vision loss. CONCLUSION: Incidence of visual symptoms has declined over the past 5 decades, and chances of recovery from visual symptoms have improved. However, complete loss of vision is essentially irreversible. Jaw claudication is associated with higher likelihood of development of visual symptoms.

YouTube for information on rheumatoid arthritis--a wakeup call?

OBJECTIVE: Rheumatoid arthritis (RA) is a common debilitating autoimmune disease, with unmet need for knowledge among patients and the general population. YouTube is a popular, consumer-generated, video-sharing website, which can be a source of information on RA. We investigated the quality of information on RA on YouTube and analyzed audience interaction. METHODS: YouTube was searched using the term "Rheumatoid Arthritis," for videos uploaded on RA. Two physicians independently classified videos as useful, misleading, or patient views, and rated them on a 5-point global quality scale (GQS; 1 = poor quality, 5 = excellent quality). Useful videos were rated for reliability and content, on a 5-point scale (higher scores represent more reliable and comprehensive videos). Source of videos was also noted. Audience interaction was assessed through video viewership. RESULTS: A total of 102 relevant videos were identified; 54.9% were classified as useful (GQS 2.9 ± 1.0) and 30.4% deemed misleading (GQS 1.3 ± 1.6). Mean reliability and content score of useful videos was 3.2 (± 1.0) and 2.5 (± 1.2), respectively. All videos uploaded by university channels and professional organizations provided useful information but formed only 12.7% of total videos, whereas 73.9% of medical advertisements and videos by for-profit organizations were misleading. There was no difference in the viewership/day (10.0 vs 21.5; p = nonsignificant) of useful and misleading information. CONCLUSION: YouTube is a source of information on RA, of variable quality, with wide viewership and potential to influence patients' knowledge and behavior. Physicians and professional organizations should be aware of and embrace this evolving technology to raise awareness about RA, and empower patients to discriminate useful from misleading information.