Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: Results from the MYONET registry.

OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

DNA methylation patterns in CD4+ T-cells separate psoriasis patients from healthy controls, and skin psoriasis from psoriatic arthritis.

Background: Psoriasis is an autoimmune/inflammatory disorder primarily affecting the skin. Chronic joint inflammation triggers the diagnosis of psoriatic arthritis (PsA) in approximately one-third of psoriasis patients. Although joint disease typically follows the onset of skin psoriasis, in around 15% of cases it is the initial presentation, which can result in diagnostic delays. The pathophysiological mechanisms underlying psoriasis and PsA are not yet fully understood, but there is evidence pointing towards epigenetic dysregulation involving CD4+ and CD8+ T-cells. Objectives: The aim of this study was to investigate disease-associated DNA methylation patterns in CD4+ T-cells from psoriasis and PsA patients that may represent potential diagnostic and/or prognostic biomarkers. Methods: PBMCs were collected from 12 patients with chronic plaque psoriasis and 8 PsA patients, and 8 healthy controls. CD4+ T-cells were separated through FACS sorting, and DNA methylation profiling was performed (Illumina EPIC850K arrays). Bioinformatic analyses, including gene ontology (GO) and KEGG pathway analysis, were performed using R. To identify genes under the control of interferon (IFN), the Interferome database was consulted, and DNA Methylation Scores were calculated. Results: Numbers and proportions of CD4+ T-cell subsets (naïve, central memory, effector memory, CD45RA re-expressing effector memory cells) did not vary between controls, skin psoriasis and PsA patients. 883 differentially methylated positions (DMPs) affecting 548 genes were identified between controls and "all" psoriasis patients. Principal component and partial least-squares discriminant analysis separated controls from skin psoriasis and PsA patients. GO analysis considering promoter DMPs delivered hypermethylation of genes involved in "regulation of wound healing, spreading of epidermal cells", "negative regulation of cell-substrate junction organization" and "negative regulation of focal adhesion assembly". Comparing controls and "all" psoriasis, a majority of DMPs mapped to IFN-related genes (69.2%). Notably, DNA methylation profiles also distinguished skin psoriasis from PsA patients (2,949 DMPs/1,084 genes) through genes affecting "cAMP-dependent protein kinase inhibitor activity" and "cAMP-dependent protein kinase regulator activity". Treatment with cytokine inhibitors (IL-17/TNF) corrected DNA methylation patterns of IL-17/TNF-associated genes, and methylation scores correlated with skin disease activity scores (PASI). Conclusion: DNA methylation profiles in CD4+ T-cells discriminate between skin psoriasis and PsA. DNA methylation signatures may be applied for quantification of disease activity and patient stratification towards individualized treatment.

Classification and management strategies for paediatric chronic nonbacterial osteomyelitis and chronic recurrent multifocal osteomyelitis.

INTRODUCTION: Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disease that most commonly affects children and adolescents causing significant pain and damage to bones. The absence of diagnostic criteria and biomarkers, an incomplete understanding of the molecular pathophysiology, and lack of evidence from randomized and controlled trials make the diagnosis and care challenging. AREAS COVERED: This review provides an overview of the clinical and epidemiological features of CNO and displays diagnostic challenges and how they can be addressed following strategies used internationally and by the authors. It summarizes the molecular pathophysiology, including pathological activation of the NLRP3 inflammasome and IL-1 secretion, and how these observations can inform future treatment strategies. Finally, it provides a summary of ongoing initiatives aiming at classification criteria (ACR/EULAR) and outcome measures (OMERACT) that will enable the generation of evidence through clinical trials. EXPERT OPINION: Scientific efforts have linked molecular mechanisms to cytokine dysregulation in CNO, thereby delivering arguments for cytokine blocking strategies. Recent and ongoing collaborative international efforts are providing the basis to move toward clinical trials and target directed treatments for CNO that find approval by regulatory agencies.

Juvenile idiopathic inflammatory myositis: an update on pathophysiology and clinical care.

The childhood-onset or juvenile idiopathic inflammatory myopathies (JIIMs) are a heterogenous group of rare and serious autoimmune diseases of children and young people that predominantly affect the muscles and skin but can also involve other organs, including the lungs, gut, joints, heart and central nervous system. Different myositis-specific autoantibodies have been identified that are associated with different muscle biopsy features, as well as with different clinical characteristics, prognoses and treatment responses. Thus, myositis-specific autoantibodies can be used to subset JIIMs into sub-phenotypes; some of these sub-phenotypes parallel disease seen in adults, whereas others are distinct from adult-onset idiopathic inflammatory myopathies. Although treatments and management have much improved over the past decade, evidence is still lacking for many of the current treatments and few validated prognostic biomarkers are available with which to predict response to treatment, comorbidities (such as calcinosis) or outcome. Emerging data on the pathogenesis of the JIIMs are leading to proposals for new trials and tools for monitoring disease.

Successful integration of an automated patient-reported outcome measure within a hospital electronic patient record.

Objectives: The objective of this evaluation was to assess the feasibility of implementing a fully integrated, automated, electronic patient-reported outcome measures (ePROM) system into a hospital electronic patient record (EPR; hospital-based clinical record). Additional objectives included evaluating the effect of the system on patient-reported outcome measures (PROM) completion rates and investigating the acceptability of the ePROM. Methods: The evaluation was conducted in a rheumatology clinic in a specialist children's hospital in the UK. Paper-based childhood HAQ PROMs were already used in the clinic, and an EPR was the main hospital information system. The technical feasibility of introducing the ePROM technology was assessed using a case study approach; the effect of the system on PROM completion rates was investigated using a before-after design; and acceptability was assessed using semi-structured questionnaires and a focus group. Results: An automated and integrated ePROM system was implemented successfully in April 2021. After implementation, ∼500 automated SMS text messaging invitations to complete ePROMs were sent to care-givers each month. PROM completion rates increased from 33 of 100 (33%) to 47 of 65 (72%) after the introduction of the ePROM system (χ2 = 11.51; P < 0.05). The ePROM system was highly acceptable to patients and clinical staff. Some clinical staff expressed a concern that an electronic system might represent a barrier to care for families with more limited resources. Conclusion: High levels of automation and integration with existing technology systems seemed to be key contextual factors associated with the successful implementation and adoption of the ePROM intervention in a paediatric rheumatology clinic.

Juvenile dermatomyositis. Where are we now?

Juvenile onset idiopathic inflammatory myopathy (IIM) has many similarities and distinct differences from adult-onset disease. This review will focus on recent developments in understanding and treatment of juvenile dermatomyositis (JDM), the most common disease sub-type of IIM in childhood. JDM is a systemic immune mediated vasculopathy, increasingly recognised as a group of distinct phenotypes with variable presentation and outlook. This overview will describe long-term outlook and disease course including health-related quality of life and emerging treatments.

Mapping the current psychology provision for children and young people with juvenile dermatomyositis.

OBJECTIVES: Juvenile Dermatomyositis (JDM) is a rare, chronic autoimmune condition of childhood, with known psychosocial implications. In this study, we sought to establish current psychological support for children and young people across the UK with rheumatic conditions, with a specific focus on those with JDM. METHODS: Electronic surveys were distributed to the 15 centres that belong to the JDM Research Group in the UK, collecting responses from health-care professionals in the fields of medicine, nursing and psychology. RESULTS: One hundred per cent of professionals from medicine and nursing replied from all 15 centres. Of these, 7 (47%) did not have a named psychologist as part of their rheumatology team, despite the majority [13 (87%)] having >200 paediatric rheumatology patients. Of the remaining centres, hospital psychology provision varied considerably. When rating their service, only 3 (8%) of 40 professionals scored their service as five (where one is poor and five is excellent); there were wide discrepancies in these scores. Many challenges were discussed, including limited psychology provision, lack of time and difficulties in offering support across large geographical areas. CONCLUSION: Many of the challenges discussed are applicable to other centres worldwide. Suggestions have been proposed that might help to improve the situation for children and young people with rheumatic conditions, including JDM. Based on these findings, we suggest that rheumatology teams maximize use of these data to advocate and work toward more comprehensive psychology provision and support in their individual centres.

Developmentally appropriate transitional care during the Covid-19 pandemic for young people with juvenile-onset rheumatic and musculoskeletal diseases: the rationale for a position statement.

BACKGROUND: The importance of developmentally appropriate transitional care in young people with juvenile-onset rheumatic and musculoskeletal disease is well recognised. The Paediatric Rheumatology European Society (PReS) / European League Against Rheumatism (EULAR) Taskforce has developed international recommendations and standards for transitional care and a growing evidence base supports the positive benefits of such care. However, there is also evidence that universal implementation has yet to be realised. In 2020, against this background the COVID-19 pandemic arrived with significant impact on all our lives, young and old, patient, public and professional alike. The unfortunate reality of the pandemic with potential for unfavourable outcomes on healthcare provision during transition was acknowledged by the PReS working groups in a position statement to support healthcare professionals, young people and their caregivers. AIM: The aim of this review is to present the literature which provides the rationale for the recommendations in the PReS Position Statement. The following areas are specifically addressed: the prime importance of care coordination; the impact of the pandemic on the various aspects of the transition process; the importance of ensuring continuity of medication supply; the pros and cons of telemedicine with young people; ensuring meaningful involvement of young people in service development and the importance of core adolescent health practices such as routine developmental assessment psychosocial screening and appropriate parental involvement during transitional care.

Chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO).

Chronic nonbacterial osteomyelitis (CNO) is an inflammatory bone disorder that most frequently affects children and adolescents. Chronic recurrent multifocal osteomyelitis (CRMO) is a severe form of CNO, usually characterized by symmetrical inflammatory bone lesions and its waxing and waning character. Sometimes severe and chronic pain can significantly affect the quality of life and psychosocial development of individuals affected. In the absence of prospectively tested and widely accepted diagnostic criteria or disease biomarkers, CNO remains a diagnosis of exclusion, and infections, malignancy and other differentials require consideration (1). The pathophysiology of CNO is not fully understood, but imbalanced cytokine expression and increased inflammasome activation in monocytes from CNO patients contribute to a pro-inflammatory phenotype that contributes to bone inflammation (2). Currently, no medications are licensed for the use in CNO. Most patients show at least some response to nonsteroidal anti-inflammatory drugs, others require more aggressive treatment that can include corticosteroids, cytokine-blocking agents and/or bisphosphonates (3). While under the care of an experienced team and sufficient treatment, the prognosis is good, but some patients will develop sequalae which can include vertebral compression fractures (1).

Limited sensitivity and specificity of the ACR/EULAR-2019 classification criteria for SLE in JSLE?-observations from the UK JSLE Cohort Study.

OBJECTIVES: This study aimed to test the performance of the new ACR and EULAR criteria, that include ANA positivity as entry criterion, in JSLE. METHODS: Performance of the ACR/EULAR-2019 criteria were compared with Systemic Lupus International Collaborating Clinics (SLICC-2012), using data from children and young people (CYP) in the UK JSLE Cohort Study (n = 482), with the ACR-1997 criteria used as reference standard. An unselected cohort of CYP positive for ANA (n = 129) was used to calculate positive/negative predictive values of the criteria. RESULTS: At both first and last visits, the number of patients fulfilling the different classification criteria varied significantly (P < 0.001). The sensitivity of the SLICC-2012 criteria was higher when compared with that of the ACR/EULAR-2019 criteria at first and last visits (98% vs 94% for first visit, and 98% vs 96% for last visit; P < 0.001), when all available CYP were considered. The ACR/EULAR-2019 criteria were more specific when compared with the SLICC-2012 criteria (77% vs 67% for first visit, and 81% vs 71% for last visit; P < 0.001). Significant differences between the classification criteria were mainly caused by the variation in ANA positivity across ages. In the unselected cohort of ANA-positive CYP, the ACR/EULAR-2019 criteria produced the highest false-positive classification (6/129, 5%). CONCLUSION: In CYP, the ACR/EULAR-2019 criteria are not superior to those of the SLICC-2012 or ACR-1997 criteria. If classification criteria are designed to include CYP and adult populations, paediatric rheumatologists should be included in the consensus and evaluation process, as seemingly minor changes can significantly affect outcomes.

Identification and prediction of novel classes of long-term disease trajectories for patients with juvenile dermatomyositis using growth mixture models.

OBJECTIVES: Uncertainty around clinical heterogeneity and outcomes for patients with JDM represents a major burden of disease and a challenge for clinical management. We sought to identify novel classes of patients having similar temporal patterns in disease activity and relate them to baseline clinical features. METHODS: Data were obtained for n = 519 patients, including baseline demographic and clinical features, baseline and follow-up records of physician's global assessment of disease (PGA), and skin disease activity (modified DAS). Growth mixture models (GMMs) were fitted to identify classes of patients with similar trajectories of these variables. Baseline predictors of class membership were identified using Lasso regression. RESULTS: GMM analysis of PGA identified two classes of patients. Patients in class 1 (89%) tended to improve, while patients in class 2 (11%) had more persistent disease. Lasso regression identified abnormal respiration, lipodystrophy and time since diagnosis as baseline predictors of class 2 membership, with estimated odds ratios, controlling for the other two variables, of 1.91 for presence of abnormal respiration, 1.92 for lipodystrophy and 1.32 for time since diagnosis. GMM analysis of modified DAS identified three classes of patients. Patients in classes 1 (16%) and 2 (12%) had higher levels of modified DAS at diagnosis that improved or remained high, respectively. Patients in class 3 (72%) began with lower DAS levels that improved more quickly. Higher proportions of patients in PGA class 2 were in DAS class 2 (19%, compared with 16 and 10%). CONCLUSION: GMM analysis identified novel JDM phenotypes based on longitudinal PGA and modified DAS.

Presentation, Treatment Response and Short-Term Outcomes in Paediatric Multisystem Inflammatory Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS).

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the pathogen responsible for Coronavirus Disease 2019 (COVID-19). Whilst most children and young people develop mild symptoms, recent reports suggest a novel paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Case definition and classification are preliminary, treatment is empiric and disease-associated outcomes are unclear. Here, we report 29 patients with PIMS-TS who were diagnosed, admitted and treated in the English North West between March and June 2020. Consistent with patterns observed internationally, cases peaked approximately 4 weeks after the initial surge of COVID-19-like symptoms in the UK population. Clinical symptoms included fever (100%), skin rashes (72%), cardiovascular involvement (86%), conjunctivitis (62%) and respiratory involvement (21%). Some patients had clinical features partially resembling Kawasaki disease (KD), toxic shock syndrome and cytokine storm syndrome. Male gender (69%), black, Asian and other minority ethnicities (BAME, 59%) were over-represented. Immune modulating treatment was used in all, including intravenous immunoglobulin (IVIG), corticosteroids and cytokine blockers. Notably, 32% of patients treated with IVIG alone went into remission. The rest required additional treatment, usually corticosteroids, with the exception of two patients who were treated with TNF inhibition and IL-1 blockade, respectively. Another patient received IL-1 inhibition as primary therapy, with associated rapid and sustained remission. Randomized and prospective studies are needed to investigate efficacy and safety of treatment, especially as resources of IVIG may be depleted secondary to high demand during future waves of COVID-19.

Short-term outcome of surgical arthrodiastasis of the ankle with Ilizarov frame in a cohort of children and young people with juvenile idiopathic arthritis.

OBJECTIVES: Despite medical advances, life-changing articular damage may still occur in patients with JIA. We report a cohort with destructive arthropathy of the ankle treated by surgical arthrodiastasis. METHODS: Eight patients (nine ankles) received arthrodiastasis by means of an Ilizarov frame between 2009 and 2013. Patient- and clinician-reported outcome measures were collated prospectively, with retrospective analysis of demographics, disease and pre-surgical treatment. RESULTS: Pre-surgery, all patients received IA CS (mean 0.8 injections/year) and MTX (mean diagnosis to treatment 3.8 years; two of eight started within 3 months). Seven of eight patients received biologic drugs. Pain scores improved by 56 and 29% (P < 0.005) at 6 and 12 months post-frame removal. American Academy Orthopaedic Foot and Ankle Society ankle-hindfoot scale, Oxford Ankle Foot Questionnaire-Child and Oxford Ankle Foot Questionnaire-Parent scores improved by 171, 62 and 80%, respectively (P < 0.005) at 12 months post-frame removal. Patients remained satisfied with surgical treatment for a mean of 13.3 months. There was transient pin site infection in three patients, and all patients had radiological improvement in joint space. CONCLUSION: Arthrodiastasis with an Ilizarov frame is a safe, well-tolerated technique that should be considered as a short-term joint-preserving procedure to improve pain and function when damage has occurred. Delays to systemic medical treatment in this cohort would be considered out-with standard modern practice but, although less prevalent, destructive ankle arthropathy continues to occur in JIA, and we believe this study to be relevant. The ankle is particularly susceptible to damage and, even if localized, should be treated early and aggressively with DMARDs and rapid progression to biologic therapies. LEVELOF EVIDENCE: Level IV.

European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative.

OBJECTIVES: IgA vasculitis (IgAV, formerly known as Henoch-Schönlein purpura) is the most common cause of systemic vasculitis in childhood. To date, there are no internationally agreed, evidence-based guidelines concerning the appropriate diagnosis and treatment of IgAV in children. Accordingly, treatment regimens differ widely. The European initiative SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) aims to optimize care for children with rheumatic diseases. The aim therefore was to provide internationally agreed consensus recommendations for diagnosis and treatment for children with IgAV. METHODS: Recommendations were developed by a consensus process in accordance with the EULAR standard operating procedures. An extensive systematic literature review was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of 16 international experts via online surveys and subsequent consensus meeting, using nominal group technique. Recommendations were accepted when ⩾80% of experts agreed. RESULTS: In total, 7 recommendations for diagnosis and 19 for treatment of paediatric IgAV were accepted. Diagnostic recommendations included: appropriate use of skin and renal biopsy, renal work-up and imaging. Treatment recommendations included: the importance of appropriate analgesia and angiotensin-converting enzyme inhibitor use and non-renal indications for CS use, as well as a structured approach to treating IgAV nephritis, including appropriate use of CS and second-line agents in mild, moderate and severe disease along with use of angiotensin-converting enzyme inhibitors and maintenance therapy. CONCLUSION: The SHARE initiative provides international, evidence-based recommendations for the diagnosis and treatment of IgAV that will facilitate improvement and uniformity of care.