Preexisting autoimmune disease and immune-related adverse events associated with anti-PD-1 cancer immunotherapy: a national case series from the Canadian Research Group of Rheumatology in Immuno-Oncology.

BACKGROUND: Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). METHODS: Retrospective study of patients with PAD referred for rheumatologic evaluation prior to starting or during immunotherapy between January 2013 and July 2019 from 10 academic sites across Canada. Data were extracted by chart review using a standardized form. RESULTS: Twenty-seven patients with PAD on ICI therapy were identified. The most common PADs were rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (IBD, 15%) and axial spondyloarthritis (11%), and the most frequently observed cancers were lung cancer and melanoma. All patients received anti-PD-1 therapies, and 2 received additional sequential anti-CTLA-4 therapy. PAD exacerbations occurred in 52% over a median (IQR) follow-up of 11.0 (6.0-17.5) months, with 14% being severe, 57% requiring corticosteroids, 50% requiring immunosuppression and 14% requiring ICI discontinuation. Flares were generally more frequent and severe in patients who previously required more intensive immunosuppression (i.e., biologics). Flares occurred despite background immunosuppression at the time of ICI initiation. In patients with preexisting psoriasis, IBD and axial spondyloarthritis, rheumatic immune-related adverse events (irAEs), mostly polyarthritis and tenosynovitis, were frequently observed. Tumor progression was not associated with exposure to immunosuppressive drugs before or after ICI initiation and was numerically less frequent in patients with irAEs. CONCLUSION: PAD exacerbations in the context of ICI treatment are common, although generally mild, and occur despite background immunosuppression. Exacerbations are more frequent and severe in patients on more intensive immunosuppressive therapies pre-immunotherapy.

Anxiety and Mood Disorders in Systemic Lupus Erythematosus: Current Insights and Future Directions.

PURPOSE OF REVIEW: Optimal management of anxiety and mood disorders in patients with systemic lupus erythematosus (SLE) is limited by an incomplete understanding of their pathophysiology and a lack of treatment guidelines. This review aims to critically synthesize recent literature on these conditions in adults with SLE, focusing on their etiology, assessment, and management. RECENT FINDINGS: Along with psychosocial factors, there is growing evidence for a bidirectional interaction between inflammatory pathways and SLE-associated anxiety and mood disorders. Direct immune-mediated mechanisms via autoantibodies may also play a role in some cases. With a growing number of tools used in SLE for the assessment of these conditions, the search continues for the ideal instrument to use in all future investigations to allow comparisons across studies. There is data supporting psychological interventions, but a dearth of literature on pharmacotherapy for the treatment of anxiety and mood disorders in SLE. There is a clear need for further research in anxiety and mood disorders in SLE, particularly with respect to diagnostic tools and medications, which could inform much-needed updates to current guidelines.

Polypharmacy and Potentially Inappropriate Medication Use in Older Adults With Systemic Lupus Erythematosus.

OBJECTIVE: To assess the prevalence and potential risk factors for polypharmacy and prescribing of the potentially inappropriate medications, opioids and benzodiazepines/Z-drugs, in older adults with systemic lupus erythematosus (SLE). METHODS: The study population comprised adults age ≥50 years meeting American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria followed at a tertiary care rheumatology clinic. Information on prescriptions filled in the 4 months preceding chart review was obtained from the Manitoba Drug Program Information Network. Clinical data, including age, sex, Charlson Comorbidity Index (CCI) score, Systemic Lupus Erythematosus Disease Activity Index 2000 score, prednisone use, SLE duration, and rural residence were abstracted from electronic medical records. Logistic regression analyses were performed to assess any association between polypharmacy (using 2 definitions: ≥5 and ≥10 medications), potentially inappropriate medication use, and clinical features. RESULTS: A total of 206 patients (mean age 62 years, 91% female, 36% rural) were included: 148 (72%) filled ≥5 medications, 71 (35%) filled ≥10 medications, 63 (31%) used benzodiazepines/Z-drugs, and 50 (24%) used opioids. Among the 77 patients age ≥65 years, 57 (74%) filled ≥5 medications, and 26 (34%) filled ≥10 medications, compared to 30% and 4%, respectively, of Manitobans age ≥65 years (National Prescription Drug Utilization Information System, 2016). The odds of polypharmacy were greater with prednisone use (adjusted odds ratio [OR] 3.70 [95% confidence interval (95% CI) 1.40-9.79] for ≥5 medications), CCI score (adjusted OR 1.62 [95% CI 1.20-2.17]), and rural residence (adjusted OR 2.05 [95% CI 1.01-4.18]). Odds of benzodiazepine/Z-drug use were increased with polypharmacy (adjusted OR 4.35 [95% CI 1.69-11.22]), and odds of opioid use were increased with polypharmacy (adjusted OR 6.75 [95% CI 1.93-23.69]) and CCI score (adjusted OR 1.29 [95% CI 1.08-1.54]). CONCLUSION: The prevalence of polypharmacy in this SLE cohort was higher than in the general Manitoban population. Polypharmacy is a strong marker for use of prescription benzodiazepines/Z-drugs and opioids.

The association between childhood maltreatment and pain catastrophizing in individuals with immune-mediated inflammatory diseases.

OBJECTIVE: Childhood maltreatment is associated with pain catastrophizing. Both childhood maltreatment and pain catastrophizing are prevalent in certain immune-mediated inflammatory disease (IMID) populations. However, it is unknown whether childhood maltreatment contributes to the high rates of pain catastrophizing in IMID cohorts. We assessed the relationship between childhood maltreatment and pain catastrophizing in individuals with IMID, and whether this differed across IMID. METHODS: Between November 2014 and July 2016 we recruited individuals with multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA). Participants completed the Childhood Trauma Questionnaire-Short Form, the Pain Catastrophizing Scale, and Hospital Anxiety and Depression Scale. We tested the association between childhood maltreatment and pain catastrophizing using multivariable logistic regression. RESULTS: We included 577 individuals with IMID (MS: 232, IBD: 215, RA: 130). Overall, 265 (46%) participants with IMID reported any childhood maltreatment, with the most common type of maltreatment being emotional neglect. Childhood maltreatment was associated with pain catastrophizing (OR 3.32; 95% CI 1.89-5.85) independent of other risk factors, including sociodemographics and symptoms of anxiety and depression. CONCLUSION: Pain catastrophizing is highly prevalent in our IMID population, and strongly associated with childhood maltreatment in this population. Interventions that consider childhood maltreatment and pain catastrophizing should be incorporated into the clinical management of IMID patients.

Rheumatic immune-related adverse events associated with cancer immunotherapy: A nationwide multi-center cohort.

OBJECTIVE: Although immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, their use is associated with immune toxicities referred to as immune-related adverse events (irAE). Here we describe the clinical presentation and management of rheumatic immune-related adverse events (Rh-irAE) in a national multi-center cohort. METHODS: All patients presenting with Rh-irAE at 9 academic sites across Canada between January 2013 and January 2019 were identified and included in this retrospective cohort study. Standardized data were extracted by chart review. RESULTS: 117 patients who developed 136 Rh-irAE were identified. The most frequent Rh-irAE was symmetric polyarthritis (n = 45). Other Rh-irAE included non-inflammatory musculoskeletal symptoms (n = 18), polymyalgia rheumatica (n = 17) and myositis (n = 9). Prednisone was the most commonly used treatment (n = 76) with a mean maximum dose of 60 ± 74 mg/d and duration of treatment of 8.4 ± 11 months. Forty-two patients required conventional synthetic disease-modifying anti-rheumatic drugs (DMARD) and two required biologic DMARD to control the Rh-irAE. ICI was discontinued due to the Rh-irAE in 22 patients. There were no deaths related to Rh-irAE. Treatment of the Rh-irAE did not appear to negatively impact the tumor response to immunotherapy with 23 patients experiencing tumor progression prior to treatment of the Rh-irAE and 13 following treatment. CONCLUSION: In this largest multi-center cohort of Rh-irAE described to date, symmetric polyarthritis was the most common Rh-irAE. There was considerable heterogeneity of treatment, although this did not appear to negatively impact the anti-tumor response. This study can inform the development of evidence-based recommendations to optimize Rh-irAE and cancer outcomes in patients treated with ICI.

Arterial events in persons with dermatomyositis and polymyositis.

OBJECTIVE: To assess arterial events in dermatomyositis (DM) and polymyositis (PM), and associated factors. METHODS: We studied a cohort of persons with DM and PM, assembled from provincial administrative databases. New cases of ischemic heart disease, cerebrovascular accidents (CVA), and peripheral arterial disease were ascertained from billing and hospitalization data. We performed case-control analyses to assess the effects of clinical factors and medication exposures. RESULTS: Incident arterial events occurred in 80 subjects, including 34 acute myocardial infarctions (13.8/1000 person-years) and 13 CVA (5.1/1000); these rates are higher than available Canadian figures. Nested case-control analyses, with risk-set sampling, revealed an increased incidence of arterial events associated with hypertension [adjusted rate ratio (RR) 2.6; 95% confidence interval (CI) 1.2-5.5] and lipid disorders (adjusted RR 2.6, 95% CI 1.0-6.5), whereas nonsteroid immunomodulators (methotrexate, azathioprine, antimalarial agents, or cyclophosphamide) were inversely associated with arterial events (adjusted RR 0.5, 95% CI 0.2-1.0). CONCLUSION: We found a high incidence of arterial events in this cohort of persons with inflammatory myopathy. Traditional risk factors, particularly hypertension and lipid disorders, were predictors of arterial events, while nonsteroid immunomodulators were inversely associated. Our work suggests a rationale for aggressive risk reduction strategies in persons with inflammatory myopathies.

Association between serum total cholesterol level and renal outcome in systemic lupus erythematosus.

OBJECTIVE: To determine whether an elevated serum total cholesterol level in a first-available sample obtained at a systemic lupus erythematosus (SLE) clinic is associated with worse renal outcome in patients with SLE. METHODS: Survival analysis methods were used on prospectively gathered data on 1,060 patients with SLE who were registered in the University of Toronto Lupus Databank. The effect of total cholesterol and 15 additional variables on the outcomes of renal deterioration, end-stage renal disease (ESRD), and death was assessed using Cox proportional hazards methods. RESULTS: In 474 (45%) of the 1,060 patients, the total cholesterol level exceeded 5.2 mmoles/liter. In the entire study group, the median total cholesterol level was 5.1 mmoles/liter (range 1.6-17.1). During a mean followup period of 8.8 years, 93 patients (9%) experienced renal deterioration, 42 patients (4%) had ESRD, and 161 deaths occurred, 48 (30%) of which were associated with renal dysfunction (renal death), and 113 (70%) of which were not associated with renal dysfunction (nonrenal death). Kaplan-Meier survival estimates for each outcome were statistically significantly different between patients with normal versus those with elevated total cholesterol levels (cutoff 5.2 mmoles/ liter), with a worse outcome observed among those with an elevated total cholesterol concentration. In multivariate analyses, total cholesterol level (hazard ratio [HR] 1.17, 95 confidence interval [95% CI] 1.01-1.36), serum creatinine level (HR 1.06, 95% CI 1.04-1.07), proteinuria (HR 2.44, 95% CI 1.25-4.76), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (HR 1.44, 95% CI 1.16-1.80), and corticosteroid dose (HR 1.01, 95% CI 1.00-1.02) were associated with renal deterioration. Significant predictors of ESRD were baseline proteinuria (HR 6.24, 95% CI 1.96-19.88) and serum creatinine level (HR 1.15, 95% CI 1.08-1.22). The total cholesterol level was correlated with death (HR 1.20, 95% CI 1.11-1.29), retaining statistical significance for renal death (HR 1.33, 95% CI 1.20-1.47) but not for nonrenal death (HR 1.12, 95% CI 0.99-1.25). CONCLUSION: Those results indicate that an elevated serum total cholesterol level in a first-available sample obtained at an SLE clinic is associated with adverse renal outcomes and mortality.