Immune Checkpoint Inhibitor-Associated Remitting Seronegative Symmetrical Synovitis With Pitting Edema: Description of a New Entity by CanRIO.

OBJECTIVE: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is characterized by symmetrical synovitis with pitting edema and negative rheumatoid factor (RF). It has been described in a setting of malignancy, suggesting a paraneoplastic association. With the increasing use of immune checkpoint inhibitors (ICIs) for the treatment of cancers and emergence of immune-related adverse events (irAEs), our objective was to identify and describe cases of ICI-associated RS3PE (ICI-RS3PE) and compare them to non-ICI-RS3PE. METHODS: The Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) network is a collaboration of Canadian rheumatologists with experience in the management of patients with rheumatic irAEs (Rh-irAEs). Standardized data on adult patients with Rh-irAE have been collected as part of retrospective and prospective cohorts. In this study, detailed information on all cases of ICI-RS3PE from both cohorts were extracted and analyzed. RESULTS: We identified 11 cases of ICI-RS3PE. The most frequently observed malignancy was nonsmall cell lung cancer (4 of 11), followed by malignant melanoma (2 of 11) and cutaneous squamous cell carcinoma (2 of 11). The median time to onset of ICI-RS3PE was 26 weeks from ICI start and 52 weeks from diagnosis of malignancy. Seven patients had stable cancer prior to onset of ICI-RS3PE, 3 had partial response, and 1 had complete response. All patients received glucocorticoids. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) were needed in 10 patients. CONCLUSION: ICI-RS3PE may be an independent Rh-irAE, separate from paraneoplastic RS3PE. The symptoms of ICI-RS3PE responded well to glucocorticoids, but concomitant treatment with csDMARDs may be necessary.

IgG4-related prostatitis manifesting as urinary obstruction in a 28-year-old male.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a systemic lymphoproliferative disorder characterized by elevated serum IgG4 levels and tumefactive lesions that can involve nearly every organ system. Involvement of the prostate is rare but has been reported in limited cases. CASE PRESENTATION: A 28-year-old man of Asian descent with a history of sinusitis and priapism presented to hospital with rigors and voiding symptoms. He was diagnosed with IgG4-RD one month prior to presentation, following pathological analysis of a submandibular mass that demonstrated chronic sclerosing sialadenitis. On presentation, white blood cell count, C-reactive protein, and prostate serum antigen levels were all within normal limits. Examination was notable for a large, firm prostate, and a foley catheter was inserted. Contrast CT of the abdomen was unremarkable. Further workup revealed elevated serum IgG4 levels (9.22 g/L) and he was subsequently started on prednisone 35 mg daily. Imaging to screen for systemic IgG4-RD involvement demonstrated paravertebral soft tissue involvement and he was given rituximab 1000 mg IV × 2 doses. MRI revealed diffuse prostatitis. Five days after starting prednisone and one day after his first dose of rituximab, he successfully passed trial of void and was discharged home. CONCLUSIONS: IgG4-related prostatitis is a rare and underrecognized manifestation of IgG4-RD. Our case highlights the need to consider IgG4-related prostatitis as an etiology of urinary obstruction in young individuals. Resolution of symptoms following treatment with steroids may be diagnostic of IgG4-related prostatitis, and may potentially avoid the need for invasive diagnostic procedures such as prostate biopsy.

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.

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Vaccination Guidelines for Patients With Immune-Mediated Disorders on Immunosuppressive Therapies.

BACKGROUND:: Patients with immune-mediated diseases on immunosuppressive therapies have more infectious episodes than healthy individuals, yet vaccination practices by physicians for this patient population remain suboptimal. OBJECTIVES:: To evaluate the safety and efficacy of vaccines in individuals exposed to immunosuppressive therapies and provide evidence-based clinical practice recommendations. METHODS:: A literature search for vaccination safety and efficacy in patients on immunosuppressive therapies (2009-2017) was conducted. Results were assessed using the Grading of Recommendation, Assessment, Development, and Evaluation system. RESULTS:: Several immunosuppressive therapies attenuate vaccine response. Thus, vaccines should be administered before treatment whenever feasible. Inactivated vaccines can be administered without treatment discontinuation. Similarly, evidence suggests that the live zoster vaccine is safe and effective while on select immunosuppressive therapy, although use of the subunit vaccine is preferred. Caution regarding other live vaccines is warranted. Drug pharmacokinetics, duration of vaccine-induced viremia, and immune response kinetics should be considered to determine appropriate timing of vaccination and treatment (re)initiation. Infants exposed to immunosuppressive therapies through breastmilk can usually be immunized according to local guidelines. Intrauterine exposure to immunosuppressive agents is not a contraindication for inactivated vaccines. Live attenuated vaccines scheduled for infants and children ⩾12 months of age, including measles, mumps, rubella, and varicella, can be safely administered as sufficient time has elapsed for drug clearance. CONCLUSIONS:: Immunosuppressive agents may attenuate vaccine responses, but protective benefit is generally maintained. While these recommendations are evidence based, they do not replace clinical judgment, and decisions regarding vaccination must carefully assess the risks, benefits, and circumstances of individual patients.

Remote assessment via video evaluation (RAVVE): a pilot study to trial video-enabled peer feedback on clinical performance.

BACKGROUND: Video review processes for evaluation and coaching are often incorporated into medical education as a means to accurately capture physician-patient interactions. Compared to direct observation they offer the advantage of overcoming many logistical challenges. However, the suitability and viability of using video-based peer consultations for professional development requires further investigation. This study aims to explore the acceptability and feasibility of video-based peer feedback to support professional development and quality improvement in patient care. METHODS: Five rheumatologists each provided four videos of patient consultations. Peers evaluated the videos using five-point scales, providing annotations in the video recordings, and offering recommendations. The rheumatologists reviewed the videos of their own four patient interactions along with the feedback. They were asked to document if they would make practice changes based on the feedback. Focus groups were conducted and analysed to explore the effectiveness of video-based peer feedback in assisting physicians to improve clinical practice. RESULTS: Participants felt the video-based feedback provided accurate and detailed information in a more convenient, less intrusive manner than direct observation. Observations made through video review enabled participants to evaluate more detailed information than a chart review alone. Participants believed that reviewing recorded consultations allowed them to reflect on their practice and gain insight into alternative communication methods. CONCLUSIONS: Video-based peer feedback and self-review of clinical performance is an acceptable and pragmatic approach to support professional development and improve clinical care among peer clinicians. Further investigation into the effectiveness of this approach is needed.

The effect of rheumatoid arthritis-associated autoantibodies on the incidence of cardiovascular events in a large inception cohort of early inflammatory arthritis.

Objective: . RA is associated with an increased risk of cardiovascular events (CVEs). The objective was to estimate independent effects of RA autoantibodies on the incident CVEs in patients with early RA. Methods: Patients were enrolled in the Canadian Early Inflammatory Arthritis Cohort, a prospective multicentre inception cohort. Incident CVEs, including acute coronary syndromes and cerebrovascular events, were self-reported by the patient and partially validated by medical chart review. Seropositive status was defined as either RF or ACPA positive. Multivariable Cox proportional hazards survival analysis was used to estimate the effects of seropositive status on incident CVEs, controlling for RA clinical variables and traditional cardiovascular risk factors. Results: . A total of 2626 patients were included: the mean symptom duration at diagnosis was 6.3 months ( s . d . 4.6), the mean age was 53 years ( s . d . 15), 72% were female and 86% met classification criteria for RA. Forty-six incident CVEs occurred over 6483 person-years [incidence rate 7.1/1000 person-years (95% confidence interval 5.3, 9.4)]. The CVE rate did not differ in seropositive vs seronegative subjects and seropositivity was not associated with incident CVEs in multivariable Cox regression models. Baseline covariates independently associated with incident CVEs were older age, a history of hypertension and a longer duration of RA symptoms prior to diagnosis. Conclusion: The rate of CVEs early in the course of inflammatory arthritis was low; however, delays in the diagnosis of arthritis increased the rate of CVEs. Hypertension was the strongest independent risk factor for CVEs. Results support early aggressive management of RA disease activity and co-morbidities to prevent severe complications.

Thresholds for the 28-joint disease activity score (DAS28) using C-reactive protein are lower compared to DAS28 using erythrocyte sedimentation rate in early rheumatoid arthritis.

OBJECTIVES: The 28-Joint Disease Activity Score (DAS28) using C-reactive protein (CRP) and DAS28 using erythrocyte sedimentation rate (DAS28-ESR) may not be interchangeable. We sought to compare and estimate optimal thresholds for the DA28-CRP for use in early rheumatoid arthritis (ERA). METHODS: Patients from the Canadian Early Arthritis Cohort with baseline and 12 months' data for both DAS28-ESR and DAS28-CRP were examined for correlations and differences between DAS28-CRP and DAS28-ESR across their range of values. Receiver operating characteristic analysis identified thresholds for DAS28-CRP that best corresponded to established thresholds for the DAS28-ESR using the total sample, then stratified by age and sex. Agreement between DAS28-CRP and DAS28-ESR thresholds was assessed with the kappa statistic. RESULTS: The sample included 995 patients with mean (SD) age of 53.7 (14.5) years, 5.8 (2.9) months of symptom duration and 74% were female. DAS28-CRP and DAS28-ESR scores were highly correlated (r= 0.92, p<0.0001), however DAS28-CRP values were consistently lower than DAS28-ESR values. Calculated thresholds for DAS28-CRP were lower with 2.5 for remission, 2.9 for low disease activity, and 4.6 for high disease activity but showed moderate agreement with the DAS28-ESR thresholds (kappa=0.70). CONCLUSIONS: In this large sample of ERA patients, newly estimated thresholds for DAS28-CRP were consistently lower than DAS28-ESR thresholds across the spectrum of disease activity. This may have important clinical implications if inflammatory markers are used interchangeably. Additional external validation of our findings is needed.

The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis.

OBJECTIVE: To determine the comparative effectiveness of oral versus subcutaneous methotrexate (MTX) as initial therapy for patients with early rheumatoid arthritis (ERA). METHODS: Patients with ERA (symptoms ≤1 year) initiating MTX therapy were included from a multicentre, prospective cohort study. We compared the effectiveness between starting with oral versus subcutaneous MTX over the first year. Longitudinal multivariable models, adjusted for potential baseline and time-varying confounders, were used to compare treatment changes due to inefficacy or toxicity and treatment efficacy (Disease Activity Score-28 (DAS-28), DAS-28 remission and Health Assessment Questionnaire-Disability Index (HAQ-DI)). RESULTS: 666 patients were included (417 oral MTX, 249 subcutaneous MTX). Patients prescribed subcutaneous MTX were prescribed a higher dose of MTX (mean dose over first three months 22.3 mg vs 17.2 mg/week). At 1 year, 49% of patients initially treated with subcutaneous MTX had changed treatment compared with 77% treated with oral MTX. After adjusting for potential confounders, subcutaneous MTX was associated with a lower rate of treatment failure ((HR (95% CI) 0.55 (0.39 to 0.79)). Most treatment failures were due to inefficacy with no difference in failure due to toxicity. In multivariable models, subcutaneous MTX was also associated with lower average DAS-28 scores (mean difference (-0.38 (95% CI -0.64 to -0.10)) and a small difference in DAS-28 remission (OR 1.2 (95% CI 1.1 to 1.3)). There was no significant difference in sustained remission or HAQ-DI (p values 0.43 and 0.75). CONCLUSIONS: Initial treatment with subcutaneous MTX was associated with lower rates of treatment changes, no difference in toxicity and some improvements in disease control versus oral MTX over the first year in patients with ERA.