The Utility of Laboratory Investigations for the Assessment and Management of Rheumatic Immune Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have greatly improved survival of several cancers with historically very poor prognosis. ICIs act by stimulating the patient's own immune system to fight cancer. Simultaneously, this immune activation can lead to immune-related adverse events (irAEs), including rheumatic manifestations (Rh-irAEs). Rh-irAEs mimic primary rheumatic diseases including arthritis, polymyalgia rheumatica, myositis, vasculitis, sarcoidosis, and sicca. This article summarizes the latest evidence regarding the utility of laboratory investigations in Rh-irAEs.

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.

Behavioural interventions delivered through interactive social media for health behaviour change, health outcomes, and health equity in the adult population.

BACKGROUND: Social networking platforms offer a wide reach for public health interventions allowing communication with broad audiences using tools that are generally free and straightforward to use and may be combined with other components, such as public health policies. We define interactive social media as activities, practices, or behaviours among communities of people who have gathered online to interactively share information, knowledge, and opinions. OBJECTIVES: We aimed to assess the effectiveness of interactive social media interventions, in which adults are able to communicate directly with each other, on changing health behaviours, body functions, psychological health, well-being, and adverse effects. Our secondary objective was to assess the effects of these interventions on the health of populations who experience health inequity as defined by PROGRESS-Plus. We assessed whether there is evidence about PROGRESS-Plus populations being included in studies and whether results are analysed across any of these characteristics. SEARCH METHODS: We searched CENTRAL, CINAHL, Embase, MEDLINE (including trial registries) and PsycINFO. We used Google, Web of Science, and relevant web sites to identify additional studies and searched reference lists of included studies. We searched for published and unpublished studies from 2001 until June 1, 2020. We did not limit results by language. SELECTION CRITERIA: We included randomised controlled trials (RCTs), controlled before-and-after (CBAs) and interrupted time series studies (ITSs). We included studies in which the intervention website, app, or social media platform described a goal of changing a health behaviour, or included a behaviour change technique. The social media intervention had to be delivered to adults via a commonly-used social media platform or one that mimicked a commonly-used platform. We included studies comparing an interactive social media intervention alone or as a component of a multi-component intervention with either a non-interactive social media control or an active but less-interactive social media comparator (e.g. a moderated versus an unmoderated discussion group). Our main outcomes were health behaviours (e.g. physical activity), body function outcomes (e.g. blood glucose), psychological health outcomes (e.g. depression), well-being, and adverse events. Our secondary outcomes were process outcomes important for behaviour change and included knowledge, attitudes, intention and motivation, perceived susceptibility, self-efficacy, and social support. DATA COLLECTION AND ANALYSIS: We used a pre-tested data extraction form and collected data independently, in duplicate. Because we aimed to assess broad outcomes, we extracted only one outcome per main and secondary outcome categories prioritised by those that were the primary outcome as reported by the study authors, used in a sample size calculation, and patient-important. MAIN RESULTS: We included 88 studies (871,378 participants), of which 84 were RCTs, three were CBAs and one was an ITS. The majority of the studies were conducted in the USA (54%). In total, 86% were conducted in high-income countries and the remaining 14% in upper middle-income countries. The most commonly used social media platform was Facebook (39%) with few studies utilising other platforms such as WeChat, Twitter, WhatsApp, and Google Hangouts. Many studies (48%) used web-based communities or apps that mimic functions of these well-known social media platforms. We compared studies assessing interactive social media interventions with non-interactive social media interventions, which included paper-based or in-person interventions or no intervention. We only reported the RCT results in our 'Summary of findings' table. We found a range of effects on health behaviours, such as breastfeeding, condom use, diet quality, medication adherence, medical screening and testing, physical activity, tobacco use, and vaccination. For example, these interventions may increase physical activity and medical screening tests but there was little to no effect for other health behaviours, such as improved diet or reduced tobacco use (20,139 participants in 54 RCTs). For body function outcomes, interactive social media interventions may result in small but important positive effects, such as a small but important positive effect on weight loss and a small but important reduction in resting heart rate (4521 participants in 30 RCTs). Interactive social media may improve overall well-being (standardised mean difference (SMD) 0.46, 95% confidence interval (CI) 0.14 to 0.79, moderate effect, low-certainty evidence) demonstrated by an increase of 3.77 points on a general well-being scale (from 1.15 to 6.48 points higher) where scores range from 14 to 70 (3792 participants in 16 studies). We found no difference in effect on psychological outcomes (depression and distress) representing a difference of 0.1 points on a standard scale in which scores range from 0 to 63 points (SMD -0.01, 95% CI -0.14 to 0.12, low-certainty evidence, 2070 participants in 12 RCTs). We also compared studies assessing interactive social media interventions with those with an active but less interactive social media control (11 studies). Four RCTs (1523 participants) that reported on physical activity found an improvement demonstrated by an increase of 28 minutes of moderate-to-vigorous physical activity per week (from 10 to 47 minutes more, SMD 0.35, 95% CI 0.12 to 0.59, small effect, very low-certainty evidence). Two studies found little to no difference in well-being for those in the intervention and control groups (SMD 0.02, 95% CI -0.08 to 0.13, small effect, low-certainty evidence), demonstrated by a mean change of 0.4 points on a scale with a range of 0 to 100. Adverse events related to the social media component of the interventions, such as privacy issues, were not reported in any of our included studies. We were unable to conduct planned subgroup analyses related to health equity as only four studies reported relevant data. AUTHORS' CONCLUSIONS: This review combined data for a variety of outcomes and found that social media interventions that aim to increase physical activity may be effective and social media interventions may improve well-being. While we assessed many other outcomes, there were too few studies to compare or, where there were studies, the evidence was uncertain. None of our included studies reported adverse effects related to the social media component of the intervention. Future studies should assess adverse events related to the interactive social media component and should report on population characteristics to increase our understanding of the potential effect of these interventions on reducing health inequities.

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.

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.

Clinicopathologic and immunophenotypic characterization of lichen planopilaris and central centrifugal cicatricial alopecia: A comparative study of 51 cases.

BACKGROUND: The purpose of the study was to compare the histopathologic and immunophenotypic features of central centrifugal cicatricial alopecia (CCCA) and lichen planopilaris (LPP) to better characterize and differentiate these two clinical entities. CCCA remains an ill-defined and still-unsettled histologic entity and many hair loss experts regard CCCA to be histologically indistinguishable from LPP. Given the overlapping histologic features of these two lymphocyte-predominant cicatricial alopecias, and the lack of consensus regarding the significance of proposed distinctions, dermatopathologists face difficulty in providing clinicians and patients certainty with a definitive diagnosis of CCCA vs LPP. METHODS: We performed a retrospective review of 51 scalp biopsies of patients with either the clinical diagnosis of CCCA (27 cases) or LPP (24 cases). Clinical information, histologic features of hematoxylin-eosin-stained sections, and a panel of immunohistochemical markers were evaluated on scalp biopsies. Tested parameters were quantified, and statistical analysis was performed. RESULTS: Our study found no differences on either histologic assessment or immunophenotypic characterization between cases of classic LPP and CCCA. CONCLUSION: The conclusion of this study is that the inflammatory infiltrates in CCCA and LPP are not only histologically similar but also immunophenotypically indistinguishable.

Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis.

Immunotherapy for cancer treatment continues to evolve, and immune checkpoints have proven successful therapeutic targets. With success has come the challenge of managing the commonly associated immune-related toxicities. Arthralgias and arthritis are a common immune-related adverse event (IrAE), well described in the literature (Pardoll Nat Rev Cancer 12:252-264, 2012; Diesendruck and Benhar Drug Resist Updat 30:39-47, 2017; Cappelli et al. Arthritis Care Res 69:1751-1763, 2017; Brahmer et al. J Clin Oncol 36:1714-1768, 2018; Smith and Bass (2017). The optimal management of immune checkpoint inhibitor (ICI)-induced arthritis remains unclear. We describe the first series using hydroxychloroquine as a first-line disease-modifying antirheumatic drug (DMARD) for patients without pre-existing autoimmune disease, who developed arthritis secondary to ICI's. This was a single-center retrospective observational study reporting all patients evaluated by rheumatologists affiliated with the University of Alberta, a large tertiary health care center in Northern Alberta, Canada, deemed to have inflammatory arthritis (IA) following ICIs. We identified 11 patients, without pre-existing autoimmune disease, who developed IA following ICIs. Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy.

Inappropriateness of health care in Canada: a systematic review protocol.

BACKGROUND: There is increasing recognition in Canada and globally that a substantial proportion of health care delivered is inappropriate as evidenced by (1) harmful and/or ineffective practices being overused, (2) effective clinical practices being underused, and (3) other clinical practices being misused. Inappropriate health care leads to negative patient experiences, poor health outcomes, and inefficient use of scarce health care resources. The purpose of this study is to conduct a systematic review of inappropriate health care in Canada. Our specific objectives are to (1) systematically search and critically review published and grey literature for studies on inappropriate health care in Canada; (2) estimate the nature and magnitude of inappropriate health care in Canada and its provincial and territorial jurisdictions. METHODS: We will include all quantitative study designs reporting objective or subjective measurements of inappropriate health care in Canada over the last 10 years. We will search the following online databases: MEDLINE, Cochrane Central Register of Controlled Trials, EconLit, and ISI-Web of Knowledge, which contains Web of Science Core Collection-Citation Indexes, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and Conference Proceedings Citation Index-Social Science & Humanities. We will also search grey literature sources to identify provincial and national audits of inappropriate health care. Two authors will independently screen, assess data quality, and extract data for synthesis. Study findings will be synthesized narratively. We will organize our data into three care categorizations: preventive care, acute care, and chronic care. We will provide a compendium of inappropriate health care for each care category for Canada and each Canadian province and territory, where sufficient data exists, by calculating (1) overall medians of underuse, overuse, and misuse of clinical practices and (2) the range of medians of underuse, overuse, and misuse for each clinical practice investigated. DISCUSSION: This review will result in the first-ever evidence-based compendium of inappropriate health care in Canada. We will also develop detailed reports of inappropriate health care for each Canadian province and territory. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018093495.

Ustekinumab in psoriatic arthritis and related phenotypes.

Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease. Ustekinumab, is a fully human monoclonal immunoglobulin (Ig)G1 antibody that binds specifically to the p40 subunit of IL-12 and IL-23, primarily inhibiting downstream Th-17 signalling pathways. Ustekinumab produced consistent and sustained clinical efficacy in two phase III clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-tumour necrosis factor (TNF) agents, whereas PSUMMIT-2 also included anti-TNF experienced patients. Similarly, ustekinumab produced consistent clinical efficacy in two phase III clinical trials in psoriasis, PHOENIX-1 and PHOENIX-2, and in both induction and maintenance of moderate-to-severe Crohn's disease, UNITI-1, UNITI-2 and IM-UNITI, without an increased safety signal. Currently, ustekinumab is used in the treatment of PsA following the failure of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (DMARDs), and as an alternative to, or after failure of an anti-TNF agent.

Central hair loss in African American women: incidence and potential risk factors.

BACKGROUND: Although central scalp hair loss is a common problem in African American women, data on etiology or incidence are limited. OBJECTIVE: We sought to determine the frequency of various patterns and degree of central scalp hair loss in African American women and to correlate this with information on hair care practices, family history of hair loss, and medical history. METHODS: Five hundred twenty-nine subjects at six different workshops held at four different sites in the central and/or southeast United States participated in this study. The subjects' patterns and degree of central scalp hair loss were independently assessed by both subject and investigator using a standardized photographic scale. Subjects also completed a detailed questionnaire and had standardized photographs taken. Statistical analysis was performed evaluating answers to the questionnaire relative to pattern of central hair loss. RESULTS: Extensive central scalp hair loss was seen in 5.6% of subjects. There was no obvious association of extensive hair loss with relaxer or hot comb use, history of seborrheic dermatitis or reaction to a hair care product, bacterial infection, or male pattern hair loss in fathers of subjects; however, there was an association with a history of tinea capitis. LIMITATIONS: There was no scalp biopsy correlation with clinical pattern of hair loss and further information on specifics of hair care practices is needed. CONCLUSIONS: This central scalp photographic scale and questionnaire provide a valid template by which to further explore potential etiologic factors and relationships to central scalp hair loss in African American women.

Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks.

New therapeutic options would benefit patients with actinic keratosis (AK), a precancerous condition that is a significant health concern. The efficacy and safety of a microsphere-based formulation of 0.5% fluorouracil cream were evaluated in a randomized, double-blind, multicenter, parallel-group study. Patients (N= 177) were randomized to receive 0.5% fluorouracil or vehicle once daily for 1, 2, or 4 weeks. Efficacy was assessed by lesion counts and clearance. Safety was evaluated by monitoring adverse events, including facial irritation. Significant improvements were seen from baseline to posttreatment follow-up in all efficacy variables for all fluorouracil regimens compared with vehicle. Patients treated for one week experienced significant improvements compared with vehicle, although efficacy increased with increasing treatment duration. Most patients experienced mild to moderate facial irritation of predictable onset and duration. Once-daily administration of 0.5% fluorouracil cream for 1, 2, or 4 weeks is safe and effective for the treatment of AKs.