Checkpoint inhibitor immunotherapy induced inflammatory arthritis secondary to Nivolumab and Ipilimumab: a pediatric first.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature. CASE PRESENTATION: A 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy. CONCLUSIONS: To our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children.

Clinical Characteristics of Adolescents With Juvenile Idiopathic Arthritis Transitioning to Adult Rheumatology Care in Canada: Results From the CAPRI Registry.

OBJECTIVE: Using Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) juvenile idiopathic arthritis (JIA) registry data, we describe (1) clinical characteristics of patients with JIA transitioning to adult care, (2) prevalence of disease-related damage and complications, and (3) changes in disease activity during the final year prior to transfer. METHODS: Registry participants who turned 17 years between February 2017 and November 2021 were included. Clinical characteristics and patient-reported outcomes (PROs) at the last recorded pediatric rheumatology visit, and changes observed in the year prior to that visit were analyzed. Physicians completed an additional questionnaire characterizing cumulative disease-related damage and adverse events by age 17 years. RESULTS: At their last visit, 88 of 131 participants (67%) had inactive and 42 (32%) had active disease. Overall, 96 (73%) were on medications and 41 (31%) were on biologic disease-modifying antirheumatic drugs. Among 80 participants for whom the additional questionnaire was completed, 26% had clinically detected joint damage, 31% had joint damage on imaging, 14% had uveitis, and 7.5% had experienced at least 1 serious adverse event. During the final year, 44.2% of patients were in remission, 28.4% attained inactive disease, and 27.4% became or remained active. Mean scores of PROs were stable overall during that last year, but a minority reported marked worsening. CONCLUSION: A substantial proportion of youth with JIA transitioning to adult care in Canada had a high disease burden, which was reflected by their degree of disease activity, joint damage, or ongoing medication use. These results will inform pediatric and adult providers of anticipated needs during transition of care.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

All hands on deck: A multidisciplinary approach to SARS-CoV-2-associated MIS-C.

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious complication of SARS-CoV-2 infection with overlapping features of Kawasaki disease and toxic shock syndrome. In May 2020, a provincial multidisciplinary working group was established in anticipation of emerging cases following the first wave of SARS-CoV-2 infections. Methodology: Our centre established a multidisciplinary working group for MIS-C cases in British Columbia. The group developed guidelines using the World Health Organization MIS-C case definition. Guidelines were updated using quality improvement methods as new reports and our local experience evolved. We included all children who were evaluated in person or had samples sent to our centre for MIS-C evaluation from May 2020 to April 2021. We prospectively collected patient demographics, clinical and laboratory characteristics, and treatment. Results: Fifty-two children were included. Eleven were diagnosed as confirmed MIS-C. Ten of the 11 MIS-C cases presented with shock. Gastrointestinal and mucocutaneous involvement were also prominent. Common laboratory features included elevated C-reactive protein, D-dimer, troponin, and brain natriuretic peptide. Four out of 11 (36%) had myocardial dysfunction and 3/11 (27%) had coronary artery abnormalities. All 11 patients had evidence of SARS-CoV-2 infection. Ten out of 11 (91%) received intravenous (IV) immunoglobulin and IV corticosteroids. Conclusion: Our provincial cohort of MIS-C patients were more likely to present with shock and cardiac dysfunction, require ICU admission, and be treated with corticosteroids compared to ruled out cases. Our working group's evolving process ensured children with features of MIS-C were rapidly identified, had standardized evaluation, and received appropriate treatment in our province.

Development and validation of the Kids Disability Screen for children with juvenile idiopathic arthritis: results from the CAPRI Registry.

OBJECTIVE: The aim of this study was to develop and validate a brief disability screen for children with JIA, the Kids Disability Screen (KDS). METHODS: A total of 216 children enrolled in the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry in 2017-2018 formed a development cohort, and 220 children enrolled in 2019-2020 formed a validation cohort. At every clinic visit, parents answered two questions derived from the Childhood Health Assessment Questionnaire (CHAQ): 'Is it hard for your child to run and play BECAUSE OF ARTHRITIS?' ('Hard' 0-10), and 'Does your child usually need help from you or another person BECAUSE OF ARTHRITIS?' ('Help', 0-10). We used 36-fold cross-validation and tested nine different mathematical methods to combine the answers and optimize psychometric properties. The results were confirmed in the validation cohort. RESULTS: Expressed as the mean of the two answers, KDS best balanced ease of use and psychometric properties, while a LASSO regression model combining the two answers with other patient characteristics [estimated CHAQ [eCHAQ]) had the highest responsiveness. In the validation cohort, 22.7%, 25.9% and 28.6% of patients had a score of 0 at enrolment for the KDS, eCHAQ and CHAQ, respectively. Responsiveness was 0.67, 0.74 and 0.62, respectively. Sensitivity to detect a CHAQ > 0 was 0.90 and specificity 0.56, KDS detecting some disability in 44% of children with a CHAQ = 0. CONCLUSION: This simple KDS has psychometric properties comparable with those of a full CHAQ and may be used at every clinic visit to identify those children who need a full disability assessment.

Impact of the COVID-19 pandemic on juvenile idiopathic arthritis presentation and research recruitment: results from the CAPRI registry.

OBJECTIVE: The COVID-19 pandemic has disrupted healthcare delivery and clinical research worldwide, with data from areas most affected demonstrating an impact on rheumatology care. This study aimed to characterize the impact of the pandemic on the initial presentation of JIA and JIA-related research in Canada. METHODS: Data collected from the Canadian Alliance of Pediatric Rheumatology Investigators JIA Registry from the year pre-pandemic (11 March 2019 to 10 March 2020) was compared with data collected during the first year of the pandemic (11 March 2020 to 10 March 2021). Outcomes included time from symptom onset to first assessment, disease severity at presentation and registry recruitment. Proportions and medians were used to describe categorical and continuous variables, respectively. RESULTS: The median time from symptom onset to first assessment was 138 (IQR 64-365) days pre-pandemic vs 146 (IQR 83-359) days during the pandemic. The JIA category frequencies remained overall stable (44% oligoarticular JIA pre-pandemic, 46.8% pandemic), except for systemic JIA (12 cases pre-pandemic, 1 pandemic). Clinical features, disease activity (cJADAS10), disability (CHAQ) and quality of life (JAQQ) scores were similar between the two cohorts. Pre-pandemic, 225 patients were enrolled, compared with 111 in the pandemic year, with the greatest decrease from March to June 2020. CONCLUSIONS: We did not observe the anticipated delay in time to presentation or increased severity at presentation, suggesting that, within Canada, care adapted well to provide support to new patient consults without negative impacts. The COVID-19 pandemic was associated with an initial 50% decrease in registry enrolment but has since improved.

SARS-CoV-2 Infection and COVID-19 Outcomes in Rheumatic Diseases: A Systematic Literature Review and Meta-Analysis.

OBJECTIVE: The relative risk of SARS-CoV-2 infection and COVID-19 disease severity among people with rheumatic and musculoskeletal diseases (RMDs) compared to those without RMDs is unclear. This study was undertaken to quantify the risk of SARS-CoV-2 infection in those with RMDs and describe clinical outcomes of COVID-19 in these patients. METHODS: We conducted a systematic literature review using 14 databases from January 1, 2019 to February 13, 2021. We included observational studies and experimental trials in RMD patients that described comparative rates of SARS-CoV-2 infection, hospitalization, oxygen supplementation/intensive care unit (ICU) admission/mechanical ventilation, or death attributed to COVID-19. Methodologic quality was evaluated using the Joanna Briggs Institute critical appraisal tools or the Newcastle-Ottawa scale. Risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated, as applicable for each outcome, using the Mantel-Haenszel formula with random effects models. RESULTS: Of the 5,799 abstracts screened, 100 studies met the criteria for inclusion in the systematic review, and 54 of 100 had a low risk of bias. Among the studies included in the meta-analyses, we identified an increased prevalence of SARS-CoV-2 infection in patients with an RMD (RR 1.53 [95% CI 1.16-2.01]) compared to the general population. The odds of hospitalization, ICU admission, and mechanical ventilation were similar in patients with and those without an RMD, whereas the mortality rate was increased in patients with RMDs (OR 1.74 [95% CI 1.08-2.80]). In a smaller number of studies, the adjusted risk of outcomes related to COVID-19 was assessed, and the results varied; some studies demonstrated an increased risk while other studies showed no difference in risk in patients with an RMD compared to those without an RMD. CONCLUSION: Patients with RMDs have higher rates of SARS-CoV-2 infection and an increased mortality rate.

Antirheumatic Disease Therapies for the Treatment of COVID-19: A Systematic Review and Meta-Analysis.

OBJECTIVE: Antirheumatic disease therapies have been used to treat coronavirus disease 2019 (COVID-19) and its complications. We conducted a systematic review and meta-analysis to describe the current evidence. METHODS: A search of published and preprint databases in all languages was performed. Included studies described ≥1 relevant clinical outcome for ≥5 patients who were infected with severe acute respiratory syndrome coronavirus 2 and were treated with antirheumatic disease therapy between January 1, 2019 and May 29, 2020. Pairs of reviewers screened articles, extracted data, and assessed risk of bias. A meta-analysis of effect sizes using random-effects models was performed when possible. RESULTS: The search identified 3,935 articles, of which 45 were included (4 randomized controlled trials, 29 cohort studies, and 12 case series). All studies evaluated hospitalized patients, and 29 of the 45 studies had been published in a peer-reviewed journal. In a meta-analysis of 3 cohort studies with a low risk of bias, hydroxychloroquine use was not significantly associated with mortality (pooled hazard ratio [HR] 1.41 [95% confidence interval (95% CI) 0.83, 2.42]). In a meta-analysis of 2 cohort studies with some concerns/higher risk of bias, anakinra use was associated with lower mortality (pooled HR 0.25 [95% CI 0.12, 0.52]). Evidence was inconclusive with regard to other antirheumatic disease therapies, and the majority of other studies had a high risk of bias. CONCLUSION: In this systematic review and meta-analysis, hydroxychloroquine use was not associated with benefit or harm regarding COVID-19 mortality. The evidence supporting the effect of other antirheumatic disease therapies in COVID-19 is currently inconclusive.

Determinants of scholarly project completion in a paediatric resident program in Canada.

BACKGROUND: The primary aims of this study were to: 1) assess barriers and facilitators of completing scholarly projects from residents and faculty mentor perspectives, 2) determine the perceived value of new initiatives designed to support resident scholarly projects and 3) determine if these initiatives led to changes in resident publications. DESIGN AND METHODS: Between June and September 2014, we surveyed 18 paediatric residents and 41 faculty mentors regarding barriers to resident scholarly project completion and the value of new initiatives to support scholarly activity. We also tracked scientific publications by residents before and after implementation of these initiatives. RESULTS: The primary perceived barriers to research for residents and faculty were lack of protected time (64.3% versus 68.6%, respectively), lack of resident interest in scholarly activity (50.0% versus 60.0%, respectively) and lack of mentor motivation. Mentors and residents did not agree that lack of proper training in research (29% versus 54%, respectively) and faculty motivation (29% versus 17%, respectively) were barriers to completing a project. A dedicated research coordinator (71.4% versus 70.6%, respectively), a revised research curriculum (71.4% versus 41.2%, respectively) and works in progress sessions (50.0% versus 61.8%, respectively) were perceived as valuable initiatives to the program. These initiatives were not associated with changes in annual resident publication rates. CONCLUSIONS: Lack of time and competing clinical training are primary barriers to scholarly project completion for residents in addition to a lack of motivation on the part of faculty members. Improving program support was perceived as positive changes to address these barriers but did not increase resident publication rates. The information provided here could be used to tailor future resident research programs and highlight the value of gathering input from resident and faculty when designing initiatives to enhance resident research productivity.

Specific allergen immunotherapy for the treatment of atopic eczema.

BACKGROUND: Specific allergen immunotherapy (SIT) is a treatment that may improve disease severity in people with atopic eczema (AE) by inducing immune tolerance to the relevant allergen. A high quality systematic review has not previously assessed the efficacy and safety of this treatment. OBJECTIVES: To assess the effects of specific allergen immunotherapy (SIT), including subcutaneous, sublingual, intradermal, and oral routes, compared with placebo or a standard treatment in people with atopic eczema. SEARCH METHODS: We searched the following databases up to July 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 7, 2015), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), Web of Science™ (from 2005), the Global Resource of EczemA Trials (GREAT database), and five trials databases. We searched abstracts from recent European and North American allergy meetings and checked the references of included studies and review articles for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of specific allergen immunotherapy that used standardised allergen extracts in people with AE. DATA COLLECTION AND ANALYSIS: Two authors independently undertook study selection, data extraction (including adverse effects), assessment of risk of bias, and analyses. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 12 RCTs for inclusion in this review; the total number of participants was 733. The interventions included SIT in children and adults allergic to either house dust mite (10 trials), grass pollen, or other inhalant allergens (two trials). They were administered subcutaneously (six trials), sublingually (four trials), orally, or intradermally (two trials). Overall, the risk of bias was moderate, with high loss to follow up and lack of blinding as the main methodological concern.Our primary outcomes were 'Participant- or parent-reported global assessment of disease severity at the end of treatment'; 'Participant- or parent-reported specific symptoms of eczema, by subjective measures'; and 'Adverse events, such as acute episodes of asthma or anaphylaxis'. SCORing Atopic Dermatitis (SCORAD) is a means of measuring the effect of atopic dermatitis by area (A); intensity (B); and subjective measures (C), such as itch and sleeplessness, which we used.For 'Participant- or parent-reported global assessment of disease severity at the end of treatment', one trial (20 participants) found improvement in 7/9 participants (78%) treated with the SIT compared with 3/11 (27%) treated with the placebo (risk ratio (RR) 2.85, 95% confidence interval (CI) 1.02 to 7.96; P = 0.04). Another study (24 participants) found no difference: global disease severity improved in 8/13 participants (62%) treated with the SIT compared with 9/11 (81%) treated with the placebo (RR 0.75, 95% CI 0.45 to 1.26; P = 0.38). We did not perform meta-analysis because of high heterogeneity between these two studies. The quality of the evidence was low.For 'Participant- or parent-reported specific symptoms of eczema, by subjective measures', two trials (184 participants) did not find that the SIT improved SCORAD part C (mean difference (MD) -0.74, 95% CI -1.98 to 0.50) or sleep disturbance (MD -0.49, 95% CI -1.03 to 0.06) more than placebo. For SCORAD part C itch severity, these two trials (184 participants) did not find that the SIT improved itch (MD -0.24, 95% CI -1.00 to 0.52). One other non-blinded study (60 participants) found that the SIT reduced itch compared with no treatment (MD -4.20, 95% CI -3.69 to -4.71) and reduced the participants' overall symptoms (P < 0.01), but we could not pool these three studies due to high heterogeneity. The quality of the evidence was very low.Seven trials reported systemic adverse reactions: 18/282 participants (6.4%) treated with the SIT had a systemic reaction compared with 15/210 (7.1%) with no treatment (RR 0.78, 95% CI 0.41 to 1.49; the quality of the evidence was moderate). The same seven trials reported local adverse reactions: 90/280 participants (32.1%) treated with the SIT had a local reaction compared with 44/204 (21.6%) in the no treatment group (RR 1.27, 95% CI 0.89 to 1.81). As these had the same study limitations, we deemed the quality of the evidence to also be moderate.Of our secondary outcomes, there was a significant improvement in 'Investigator- or physician-rated global assessment of disease severity at the end of treatment' (six trials, 262 participants; RR 1.48, 95% CI 1.16 to 1.88). None of the studies reported our secondary outcome 'Parent- or participant-rated eczema severity assessed using a published scale', but two studies (n = 184), which have been mentioned above, used SCORAD part C, which we included as our primary outcome 'Participant- or parent-reported specific symptoms of eczema, by subjective measures'.Our findings were generally inconclusive because of the small number of studies. We were unable to determine by subgroup analyses a particular type of allergen or a particular age or level of disease severity where allergen immunotherapy was more successful. We were also unable to determine whether sublingual immunotherapy was associated with more local adverse reactions compared with subcutaneous immunotherapy. AUTHORS' CONCLUSIONS: Overall, the quality of the evidence was low. The low quality was mainly due to the differing results between studies, lack of blinding in some studies, and relatively few studies reporting participant-centred outcome measures. We found limited evidence that SIT may be an effective treatment for people with AE. The treatments used in these trials were not associated with an increased risk of local or systemic reactions. Future studies should use high quality allergen formulations with a proven track record in other allergic conditions and should include participant-reported outcome measures.