Rituximab for the Treatment of Refractory Cardiac Sarcoidosis: A Single-Center Experience.

BACKGROUND: We sought to examine the effect of anti-B-cell therapy (rituximab) on cardiac inflammation and function in corticosteroid-refractory cardiac sarcoidosis. Cardiac sarcoidosis (CS) is a rare cause of cardiomyopathy characterized by granulomatous inflammation involving the myocardium. Although typically responsive to corticosteroid treatment, there is a critical need for identifying effective steroid-sparing agents for disease control. Despite increasing evidence on the role of B cells in the pathogenesis of sarcoidosis, there is limited data on the efficacy of anti-B-cell therapy, specifically rituximab, for controlling CS. METHODS AND RESULTS: We reviewed the clinical experience at a tertiary care referral center of all patients with CS who received rituximab after failing to improve with initial immunosuppression therapy, which included corticosteroids. Fluorodeoxyglucose positron emission tomography (FDG PET/CT) images before and after rituximab treatment were evaluated. All images were interpreted by 2 experienced nuclear medicine trained physicians. We identified 7 patients (5 men, 2 women; mean age at diagnosis, 49.0 ± 7.9 years) with active CS who were treated with rituximab. The median length of follow-up was 5.1 years. All individuals, but 1, had received prior steroid-sparing agents in addition to corticosteroids. Rituximab was administered either as 1000 mg intravenously ×1 or ×2 doses, separated by 2 weeks. Repeat dosing, if appropriate, was considered after 6 months. All tolerated the infusions well. Inflammation as assessed by maximum standardized uptake value on cardiac FDG PET/CT uptake significantly decreased in 6 of 7 patients (median 6.0-4.5, Wilcoxon signed rank z -1.8593, W 3), whereas the left ventricular ejection fraction improved or stabilized in 4 patients but decreased in 3. The mean left ventricular ejection fraction was 40.1% and 43.3% before and after treatment, respectively (P = .28). Three patients reported improved physical capacity, and 5 patients showed improved arrhythmic burden on Holter monitoring or implantable cardioverter-defibrillator interrogation. One patient subsequently developed a fungal catheter-associated infection and sepsis requiring discontinuation. CONCLUSIONS: Rituximab was well-tolerated and seemed to decrease inflammation, as assessed by cardiac FDG PET/CT in all but 1 patient with active CS. These data suggest that rituximab may be a promising therapeutic option for CS, which deserves merits further study.

Progression rate of severity of aortic stenosis in patients with rheumatoid arthritis.

OBJECTIVE: Valvular heart disease is common in patients with rheumatoid arthritis (RA). However, there is uncertainty about how often to perform echocardiographic surveillance in this population. The objective of this study was to assess the progression rate of mild and moderate aortic stenosis (AS) in patients with RA. METHODS: A population-based cohort of patients with RA and either mild (2.0-2.9 m/second) or moderate (3.0-3.9 m/second) AS was identified. Demographic, clinical, and echocardiographic data were collected. Annual progression rate of AS was then calculated for the study cohort and the impact of pertinent RA variables on progression rate determined. RESULTS: Sixty-eight patients with RA and mild or moderate AS met the inclusion requirements. Peak aortic valve (AV) velocity and mean AV gradient increased during the study period, whereas AV area decreased, consistent with progression of AS (P<.001). Mean (SD) annual increase in peak AV jet velocity was 0.05 m/second (0.01) and in mean AV gradient was 1.0 mm Hg (0.18). Mean annual decrease in AV area was 0.04 (0.01) cm2 . The progression rate of AS was higher in patients with increased erythrocyte sedimentation rates (ESR) (P=.001). CONCLUSIONS: The rate of AS progression in the RA population was higher in patients with increased ESR but less than that of the reported rate of AS progression in the general population. Although the cause for this finding is uncertain, these results suggest that patients with RA who have mild or moderate AS should undergo echocardiographic surveillance for disease progression similar to that of the general population.

Impact of Pregnancy and Gender on Internal Medicine Resident Evaluations: A Retrospective Cohort Study.

BACKGROUND: Pregnancy and its impact on graduate medical training are not well understood. OBJECTIVE: To examine the effect of gender and pregnancy for Internal Medicine (IM) residents on evaluations by peers and faculty. DESIGN: This was a retrospective cohort study. SUBJECTS: All IM residents in training from July 1, 2004-June 30, 2014, were included. Female residents who experienced pregnancy and male residents whose partners experienced pregnancy during training were identified using an existing administrative database. MAIN MEASURES: Mean evaluation scores by faculty and peers were compared relative to pregnancy (before, during, and after), accounting for the gender of both the evaluator and resident in addition to other available demographic covariates. Potential associations were assessed using mixed linear models. KEY RESULTS: Of 566 residents, 117 (20.7%) experienced pregnancy during IM residency training. Pregnancy was more common in partners of male residents (24.7%) than female residents (13.2%) (p = 0.002). In the post-partum period, female residents had lower peer evaluation scores on average than their male counterparts (p = 0.0099). CONCLUSIONS: A large number of residents experience pregnancy during residency. Mean peer evaluation scores were lower after pregnancy for female residents. Further study is needed to fully understand the mechanisms behind these findings, develop ways to optimize training throughout pregnancy, and explore any unconscious biases that may exist.

Pulmonary IgG4-related disease and colon adenocarcinoma: possible paraneoplastic syndrome.

Malignancy has a complicated association with immunoglobulin G4-related disease (IgG4-RD) both being an item in the differential diagnosis as well as malignancy occurring in the background of IgG4-RD in the same organ. However, recently there is evidence of higher rates of distant malignancy in patients with IgG4-RD. Here we report a case of pulmonary IgG4-RD potentially consistent with a paraneoplastic phenomenon which improved with treatment of the underlying colon adenocarcinoma.

Progressive Decline of Lung Function in Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: Interstitial lung disease (ILD) is associated with substantial morbidity in rheumatoid arthritis (RA), but very little is known about its long-term progression. This study was undertaken to investigate the progression of pulmonary disease using a large single-center cohort of patients with RA-associated ILD. METHODS: Records of all patients with RA-associated ILD seen at Mayo Clinic between 1998 and 2014, with at least 4 weeks follow-up and at least 1 pulmonary function test, were identified and manually screened for study inclusion. Progression was defined as a diffusing capacity for carbon monoxide (DLco) <40% predicted (or patients whose illness was too advanced to undergo screening) or a forced vital capacity (FVC) <50% predicted. Time to progression was analyzed using the Kaplan-Meier method. RESULTS: Of the 167 patients included in the study, 81 (49%) were female, with a mean ± SD age of 67 ± 10 years at diagnosis of ILD. Median follow-up time from diagnosis of ILD was 3.3 years (range 0.01-14.8). One-third of the patients required supplemental oxygen, 40% developed DLco <40% predicted, and 22% developed FVC <50% predicted within 5 years after ILD diagnosis. Usual interstitial pneumonia (UIP) versus nonspecific interstitial pneumonia (NSIP) was a risk factor for DLco progression (hazard ratio 3.29 [95% confidence interval 1.28-8.41]). Lower DLco and FVC at baseline increased the risk for progression to DLco <40% predicted and FVC <50% predicted, and higher rates of change in the first 6 months also increased the risk of progression. CONCLUSION: Progressive loss of pulmonary function is common in RA-associated ILD and is worse in patients with UIP than in those with NSIP. Predictors of progression in patients with RA-associated ILD may aid clinicians in identifying patients at highest risk for progression of ILD.

Patterns of interstitial lung disease and mortality in rheumatoid arthritis.

Objective: To characterize a cohort of patients with RA who have interstitial lung disease (ILD) and to assess the utility of previously developed mortality staging systems [gender, age, lung physiology (GAP) and ILD-GAP]. Methods: All patients with RA and ILD seen at the Mayo Clinic from 1998 to 2014 were identified and manually screened for study inclusion. RA disease characteristics and pulmonary findings including high-resolution CT and pulmonary function testing were evaluated. Survival was estimated using Kaplan-Meier methods. GAP and ILD-GAP models were evaluated using c-statistics and standardized incidence ratios. Results: The study included 181 patients with RA-associated ILD (96% Caucasian; 48% females; 37% never-smokers). The mean age at ILD diagnosis was 67.4 years ( s . d . 9.9). The median time from RA diagnosis to ILD was 4.9 years (range -10.9-48.1). The median follow-up was 3.1 years (range 0.01-14.8). Age, RA disease duration and low initial diffusing capacity for carbon monoxide were predictive of premature mortality in multivariate modelling. Sex, smoking status, obstructive lung disease, seropositivity and erosive disease were not associated with mortality. The 5-year survival rate was 59.7% (95% CI 51.5, 69.2). Survival did not differ between usual interstitial pneumonia, non-specific interstitial pneumonia and organizing pneumonia ( P = 0.42). The GAP model performed well in this cohort for both discrimination and calibration (c-statistic 0.71, standardized incidence ratio 0.97). Conclusion: In this large single-centre cohort of patients with RA-ILD, most patients were seropositive and had a history of smoking. ILD most commonly occurred after the RA diagnosis. Mortality was high and did not differ among the types. The GAP model may be useful in assessing mortality risk.

Population-based study of outcomes of patients with juvenile idiopathic arthritis (JIA) compared to non-JIA subjects.

OBJECTIVE: Evaluate healthcare utilization and occurrence of comorbidities in a population-based cohort of patients of juvenile idiopathic arthritis (JIA) with an age- and sex-matched comparator group. METHODS: Prevalent cases of JIA in 1994-2013 were identified in Olmsted County, Minnesota, along with age- and sex-matched non-JIA comparators. Surgeries, hospitalizations, pregnancies, and comorbidities were identified by medical record review. Poisson methods were used to generate rate ratios (RR) with 95% confidence intervals (CI) to compare outcomes between JIA and non-JIA cohorts separately during childhood (age < 18 years) and adulthood (age ≥ 18 years). RESULTS: A total of 89 JIA and 89 non-JIA comparators were identified [64% female; mean (SD) age 8.6 (5.1) years at JIA incidence/index date and mean follow-up in childhood 6.3 (4.4) years for JIA; similar for comparators]. Among them, 38 pairs had follow-up into adulthood with mean follow-up of 8.0 (5.5) years for JIA. Children with JIA were more likely to have joint surgery (RR = 3.93, 95% CI: 1.18-24.94), non-joint surgery (RR = 1.90, 95% CI: 1.05-3.67), and hospitalizations (RR = 2.25, 95% CI: 1.04-5.53) than non-JIA comparators. As adults only joint surgeries remained significantly different (RR = 8.5, 95% CI: 2.27-120.1). Depression during childhood was more common in JIA (RR = 2.49, 95% CI: 1.01-6.13). There were no differences in educational achievement, employment status, or pregnancy outcomes between the 2 groups. CONCLUSIONS: In a population-based cohort, inpatient healthcare utilization is higher for patients with JIA including surgery and hospitalization during childhood but not extending into adulthood. Understanding long-term comorbidities and healthcare needs for patients with JIA is necessary to provide comprehensive care.

Management of rheumatoid arthritis during pregnancy: challenges and solutions.

Rheumatoid arthritis, a chronic inflammatory autoimmune disease with significant physical disability, affects women three times more frequently than men, often in their childbearing years. Parenthood decisions can be challenging, often affected by perceptions of their disease state, health care needs, and complex pharmacological treatments. Many women struggle to find adequate information to guide them on pregnancy planning, lactation, and early parenting in relation to their chronic condition. The expanded availability and choice of pharmacotherapies have supported optimal disease control prior to conception and enhanced physical capabilities for women to successfully overcome the challenges of raising children but require a detailed understanding of their risks and safety in the setting of pregnancy and breastfeeding. This review outlines the various situational challenges faced by rheumatologists in providing care to men and women in the reproductive age group interested in starting a family. Up to date evidence-based solutions particularly focusing on the safe use of disease-modifying antirheumatic drugs and biologic response modifiers to assist rheumatologists in the care of pregnant and lactating women with RA are reviewed.

Risk of serious infection in patients with rheumatoid arthritis-associated interstitial lung disease.

The objective of this study is to assess the occurrence of and risk factors for serious infections in rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). All patients with RA-ILD (ACR 1987 criteria for RA) seen at a single center from 1998 to 2014 were identified and manually screened for study inclusion. Follow-up data were abstracted until death or December 31, 2015. Serious infection was defined as requiring antimicrobial therapy and hospitalization. Risk of infection was analyzed by person-year (py) methods using time-dependent covariates started when the medication was first used and stopped 30 days after the medication was discontinued. Of the 181 included patients, 87 (48 %) were female. The mean age at ILD diagnosis was 67.4 (±9.9) years, and median follow-up time was 3.1 (range: 0.01 to 14.8) years. Higher infection rates were observed during the first year after ILD diagnosis (14.1 per 100 py) than subsequently (5.7 per 100 py; p = 0.001). Pneumonia was the most common (3.9 per 100 py). Overall infection risk was higher in organizing pneumonia (OP) (27.1 per 100 py) than usual interstitial pneumonia (7.7 per 100 py) or non-specific interstitial pneumonia (5.5 per 100 py) (p < 0.001). The highest infection rate observed was with a daily prednisone use >10 mg per day (15.4 per 100 py). Patients with RA-ILD are at risk of serious infection. Prednisone use >10 mg per day was associated with higher rates of infection. Immunosuppressive drug use governed by concern for risk of infection in patients with ILD resulting in channeling bias cannot be excluded.

Opioid use in patients with rheumatoid arthritis 2005-2014: a population-based comparative study.

Opioid prescriptions have seen an increase across the USA, Canada, Europe, and the UK. In the USA, they have quadrupled from 1999 to 2010. Opioid use among patients with rheumatoid arthritis (RA) over time is not well described. This study examined trends of opioid use in patients with RA. Retrospective prescription data was examined from 2005 to 2014 in a population-based incidence cohort of patients with RA by 1987 ACR criteria and comparable non-RA subjects. Differences in opioid use were examined with Poisson models. A total of 501 patients with RA (71 % female) and 532 non-RA subjects (70 % female) were included in the study. Total and chronic opioid use in 2014 was substantial in both cohorts 40 % RA vs 24 % non-RA and 12 % RA vs. 4 % non-RA, respectively. Opioid use increased by 19 % per year in both cohorts during the study period (95 % confidence interval [CI] 1.15, 1.25). Relative risk (RR) of chronic opiate use for RA patients compared to non-RA subjects was highest in adults aged 50-64 years (RR 2.82; 95 % CI 1.43-6.23). RA disease characteristics, biologic use at index, treated depression/fibromyalgia, education, and smoking status were not significantly associated with chronic opiate use. Over a third of patients with RA use opioids in some form, and in more than a tenth use is chronic. Use has increased in recent years. Patients aged 50-64 with RA use substantially more opioids than their non-RA counterparts.

Treatment of patients with juvenile idiopathic arthritis (JIA) in a population-based cohort.

A population-based cohort was utilized to evaluate medications and intra-articular injection utilization for patients with juvenile idiopathic arthritis (JIA) to inform clinical practice and further research. In a geographically defined population, all incident cases of JIA cases were identified between January 1, 1994 and December 31, 2013 based first on diagnosis code followed by medical chart confirmation. Medications and intra-articular glucocorticoid injections were abstracted. Predictors of the first disease-modifying antirheumatic drug (DMARD)/biologic and injections were reported as a hazard ratio (HR) with 95 % confidence intervals (CIs) adjusted for age and sex. Kaplan-Meier methods evaluated therapy at 6 months and 1 year. Injections were reported per 100 person-years (py) with 95 % CI using the Poisson methods. Seventy-one incident cases were identified. Forty-two (59 %) were female with mean age (standard deviation) at diagnosis of 8.2 (5.3) years. Twenty-six (37 %) utilized at least one DMARD or biologic, in which 77 % of these were prescribed in the first 6 months. Subtype of JIA was significantly associated with DMARDs/biologics (p < 0.001). Intra-articular injections were performed in 48 %. The rate of intra-articular injections was 20.7 per 100 py (95 % CI 16.5, 25.6). The rate of joint injections was higher in the first year after diagnosis (p < 0.001) and more common in recent years (p < 0.001). The majority of patients with JIA in a modern population-based cohort do not require DMARDs or biologics. In those who do, the majority receives these within the first 6 months. Intra-articular injections were utilized in almost half of patients with JIA and were increasingly used.

Juvenile Idiopathic Arthritis in Olmsted County, Minnesota, 1960-2013.

OBJECTIVE: To evaluate the incidence and prevalence of juvenile idiopathic arthritis (JIA) in Olmsted County, Minnesota in 1994-2013 and trends in juvenile rheumatoid arthritis (JRA) in 1960-2013. METHODS: Cases of arthritis in 1994-2013 were identified by diagnosis code with medical chart review to confirm diagnosis separately for JIA and JRA. Overall incidence rates with 95% confidence intervals (95% CIs) were age and sex adjusted to the 2010 US white population. Comparisons were made with an earlier (1960-1993) cohort from this same population. RESULTS: Seventy-one incident cases of JIA in 1994-2013 were identified, with an overall age- and sex-adjusted incidence rate of 10.3 per 100,000 (95% CI 7.9-12.7). Forty-two (59%) were female, with an incidence of 12.4 per 100,000 (95% CI 8.6-16.2), as compared to 8.3 per 100,000 (95% CI 5.2-11.3) in males. The most common subtype was oligoarthritis (63%). The mean ± SD age at diagnosis was 8.2 ± 5.3 years. The prevalence of JIA on January 1, 2000 and January 1, 2010 was 51.0 per 100,000 (95% CI 25.2-76.8) and 57.6 per 100,000 (95% CI 31.0-94.5), respectively. When the annual incidence of JRA was compared over time from 1960 to 2013, there was no significant change in incidence overall; however, the incidence decreased among females (P = 0.003). A cyclic pattern of incidence was observed, with peaks approximately every 10 years. Similar to the findings with regard to incidence, prevalence did not change overall, but decreased among females (P = 0.048). There were 4 deaths in the cohort of JRA patients diagnosed in 1960-2013; the standardized mortality ratio was 1.50 (95% CI 0.41-3.83). CONCLUSION: Incidence of juvenile arthritis overall in Olmsted County, Minnesota has not changed significantly in the past 53 years. A consistent cyclic pattern was noted.

Determinants of Disability in Rheumatoid Arthritis: A Community-Based Cohort Study.

Longitudinal care of a community-based cohort of patients with rheumatoid arthritis (RA) was evaluated retrospectively. Candidate determinants of disability included visual analog scales (VAS) for patient global assessment and pain, comorbidities, and medications. The outcome was the 'patient-acceptable symptom state' for disability as defined by the Health Assessment Questionnaire (HAQ) disability index, using a cutoff of <1.04. Two-sample t tests and multivariable logistic regression were used to determine odds ratios (OR) for associations between predictor variables and disability. Out of a total of 99 patients, 28 (28%) patients had HAQ ≥1.04 at their last visit. The greatest odds of not attaining the patient-acceptable symptom state in a multivariable model was associated with corticosteroids (OR: 5.1; p=0.02), antidepressants (OR: 5.3; p=0.02), and female sex (OR: 6.5; p=0.05). In the era of biologic therapy, female sex, corticosteroids, and antidepressants remain profound determinants of disability highlighting the need to understand the underlying mechanisms.

Use of DMARDs and biologics during pregnancy and lactation in rheumatoid arthritis: what the rheumatologist needs to know.

Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease of synovial joints, can lead to chronic pain and structural joint damage, as well as other organ involvement, especially if not adequately controlled. Because it can affect women in their reproductive years, care of pregnant women with RA requires a delicate balance of maintaining disease control while limiting potential toxicity to the fetus and neonate. While most women experience a substantial improvement in disease activity during pregnancy, for some women their RA remains active. It can even manifest itself for the first time during pregnancy or early in the post-partum period. Optimizing disease control prior to conception is key, but utilizing disease-modifying treatments effectively and safely throughout pregnancy and lactation requires open dialogue and shared decision making. This review provides evidence-based recommendations for use of disease-modifying antirheumatic drugs (DMARDs) and biologic response modifiers to guide rheumatologists in their care of pregnant and lactating women with RA and serves as a guide to counsel male patients with RA on family planning decisions.

Perioperative management of the patient with rheumatoid arthritis.

A multidisciplinary approach is required to care for patients with rheumatoid arthritis (RA) in the perioperative period. In preparation for surgery, patients must have a cardiovascular risk assessment performed due to the high risk of heart disease in patients with RA. Treatment of RA is with immunomodulatory medications, which present unique challenges for the perioperative period. Currently, there is no consensus on how to manage disease modifying antirheumatic drug (DMARD) therapy in the perioperative setting. Much of the data to guide therapy is based on retrospective cohort data. Choices regarding DMARDs require an individualized approach with collaboration between surgeons and rheumatologists. Consensus regarding biologic therapy is to hold the therapy in the perioperative period with the length of time dictated by the half-life of the medication. Special attention is required at the time of surgery for potential need for stress dose steroids. Further, there must be close communication with anesthesiologists in terms of airway management particularly in light of the risk for cervical spine disease. There are no consensus guidelines regarding the requirement for cervical spine radiographs prior to surgery. However, history and exam alone cannot be relied upon to identify cervical spine disease. Patients with RA who undergo joint replacement arthroplasty are at higher risk for infection and dislocation compared to patients with osteoarthritis, necessitating particular vigilance in postoperative follow up. This review summarizes available evidence regarding perioperative management of patients with RA.

Differentiating scleroderma renal crisis from other causes of thrombotic microangiopathy in a postpartum patient.

Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and scleroderma renal crisis (SRC) all present with features of thrombotic microangiopathy. Distinguishing among these entities is critical, however, as treatments differ and may be mutually exclusive. We describe the case of a 25-year-old woman with an undefined mixed connective tissue disease who presented 6 weeks post-partum with fever, transient aphasia, thrombocytopenia, hemolytic anemia, and acute kidney injury eventually requiring initiation of hemodialysis. Renal biopsy revealed thrombotic microangiopathy. Renal function did not improve despite immediate initiation of plasma exchange, and an angiotensin-converting enzyme (ACE) inhibitor was initiated following discontinuation of plasma exchange. At last follow up, she remained dialysis dependent. Due to the myriad causes of thrombotic microangiopathy and potential for diagnostic uncertainty, the patient's response to therapy should be closely monitored and used to guide modification of therapy.