Treatment of Calcinosis in Juvenile Dermatomyositis.

PURPOSE OF REVIEW: Juvenile dermatomyositis (JDM) is a rare autoimmune disease characterised by muscle and skin involvement. Calcinosis is a debilitating complication of JDM which is difficult to treat and may cause long-term morbidity. The purpose of this review is to provide an update for the treatment of JDM-associated calcinosis based on previously published studies. RECENT FINDINGS: Evidence-based studies are lacking for the management of calcinosis, and current treatment modalities have been largely based on case reports, case series, cohort studies, limited controlled studies and anecdotal clinical experience. The use of early aggressive therapy for resistant cases is strongly suggested to halt persistent disease activity which may help in reducing steroid use and their associated complications. Recent insights into disease pathogenesis, myositis-specific antibodies and genetic associations have led to identification of novel therapeutic targets such as Janus kinase (JAK) 1/2. Different treatment regimens with variable outcomes are in use for the treatment of refractory calcinosis; nevertheless, the level of evidence is not sufficient to propose specific guidelines. Recently, JAK 1/2 inhibitors have shown to be effective as an emerging therapeutic option highlighting that translational and clinical research is crucial to develop targeted treatment for JDM-associated calcinosis.

Retrospective analysis of infliximab and adalimumab treatment in a large cohort of juvenile dermatomyositis patients.

BACKGROUND: Anti-TNF treatment may be useful for the treatment of patients with refractory juvenile dermatomyositis (JDM). The aim of this study was to describe the use of infliximab and adalimumab therapy in juvenile dermatomyositis as an adjunctive treatment. METHODS: Sixty children recruited to the UK JDM Cohort and Biomarker Study that had received at least 3 months of anti-TNF treatment (infliximab or adalimumab) were studied. Childhood Myositis Assessment Scale (CMAS), Manual Muscle Testing (MMT8) and physician's global assessment (PGA) were recorded. Skin disease was assessed using the modified skin disease activity score (DAS). Data were analysed using Friedman's test for repeated measures analysis of variance. RESULTS: Compared to baseline, there were improvements at 6 and 12 months in skin disease (χ2(2) = 15.52, p = 0.00043), global disease (χ2(2) = 8.14, p = 0.017) and muscle disease (CMAS χ2(2) = 17.02, p = 0.0002 and MMT χ2(2) = 10.56, p = 0.005) in infliximab patients. For patients who switched from infliximab to adalimumab, there was improvement in global disease activity (χ2(2) = 6.73, p = 0.03), and trends towards improvement in CMAS, MMT8 and modified DAS. The median initial prednisolone dose was 6 [0-10] mg, and final was 2.5 [0-7.5] mg (p < 0.0001). Fifty-four per cent of patients had a reduction in the number and/or size of calcinosis lesions. Twenty-five per cent switched their anti-TNF treatment from infliximab to adalimumab. 66.7%of the switches were to improve disease control, 26.7% due to adverse events and 6.6% due to patient preference. A total of 13.9 adverse reactions occurred in 100 patient-years, of which 5.7 were considered serious. CONCLUSION: Reductions in muscle and skin disease, including calcinosis, were seen following treatment with infliximab and adalimumab.

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.

European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides - the SHARE initiative.

OBJECTIVES: The European initiative Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) aimed to optimize care for children with rheumatic diseases. Systemic vasculitides are very rare in children. Consequently, despite recent advances, paediatric-specific information is sparse. The lack of evidence-based recommendations is an important, unmet need. This study aimed to provide recommendations for diagnosing and treating children with rare forms of childhood systemic vasculitis. METHODS: Recommendations were developed by a consensus process in accordance with the European League Against Rheumatism standard operating procedures. A systematic literature review informed the recommendations, which were devised and evaluated by a panel of experts via an online survey, and two consensus meetings using nominal group technique. Recommendations were accepted when ⩾ 80% of experts agreed. RESULTS: Ninety-three relevant articles were found, and 78 recommendations were accepted in the two consensus meetings. General, cross-cutting recommendations and disease-specific statements regarding the diagnosis and treatment of childhood-onset PAN, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and Takayasu arteritis are provided. CONCLUSION: These Single Hub and Access point for paediatric Rheumatology in Europe recommendations were formulated through an evidence-based consensus process to support uniform, high-quality standard of care for children with rare forms of paediatric systemic vasculitis.

Juvenile dermatomyositis: novel treatment approaches and outcomes.

PURPOSE OF REVIEW: The aim of this article is to provide a summary of the recent therapeutic advances and the latest research on outcome measures for juvenile dermatomyositis (JDM). RECENT FINDINGS: Several new international studies have developed consensus-based guidelines on diagnosis, outcome measures and treatment of JDM to standardize and improve patient care. Myositis-specific antibodies together with muscle biopsy histopathology may help the clinician to predict disease outcome. A newly developed MRI-based scoring system has been developed to standardize the use of MRI in assessing disease activity in JDM. New data regarding the efficacy and safety of rituximab, especially for skin disease, and cyclophosphamide in JDM support the use of these medications for severe refractory cases. SUMMARY: International network studies, new biomarkers and outcome measures have led to significant progress in understanding and managing the rare inflammatory myositis conditions such as JDM.

Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: the SHARE initiative.

BACKGROUND: In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is possibly its most devastating extra-articular manifestation. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment practices differ widely, within and between nations. OBJECTIVES: To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. METHODS: Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists). RESULTS: In total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations. CONCLUSIONS: The SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe.

2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as "possible IIM." CONCLUSION: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) 'probable IIM', had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to 'definite IIM'. A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50 to <55% as 'possible IIM'. CONCLUSIONS: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of 'definite', 'probable' and 'possible' IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

International validation of a urinary biomarker panel for identification of active lupus nephritis in children.

BACKGROUND: Conventional markers of juvenile-onset systemic lupus erythematosus (JSLE) disease activity fail to adequately identify lupus nephritis (LN). While individual novel urine biomarkers are good at detecting LN flares, biomarker panels may improve diagnostic accuracy. The aim of this study was to assess the performance of a biomarker panel to identify active LN in two international JSLE cohorts. METHODS: Novel urinary biomarkers, namely vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), lipocalin-like prostaglandin D synthase (LPGDS), transferrin (TF), ceruloplasmin, alpha-1-acid glycoprotein (AGP) and neutrophil gelatinase-associated lipocalin (NGAL), were quantified in a cross-sectional study that included participants of the UK JSLE Cohort Study (Cohort 1) and validated within the Einstein Lupus Cohort (Cohort 2). Binary logistic regression modelling and receiver operating characteristic curve analysis [area under the curve (AUC)] were used to identify and assess combinations of biomarkers for diagnostic accuracy. RESULTS: A total of 91 JSLE patients were recruited across both cohorts, of whom 31 (34 %) had active LN and 60 (66 %) had no LN. Urinary AGP, ceruloplasmin, VCAM-1, MCP-1 and LPGDS levels were significantly higher in those patients with active LN than in non-LN patients [all corrected p values (p c) < 0.05] across both cohorts. Urinary TF also differed between patient groups in Cohort 2 (p c = 0.001). Within Cohort 1, the optimal biomarker panel included AGP, ceruloplasmin, LPGDS and TF (AUC 0.920 for active LN identification). These results were validated in Cohort 2, with the same markers resulting in the optimal urine biomarker panel (AUC 0.991). CONCLUSION: In two international JSLE cohorts, urinary AGP, ceruloplasmin, LPGDS and TF demonstrate an 'excellent' ability for accurately identifying active LN in children.

Muscle Biopsy Findings in Combination With Myositis-Specific Autoantibodies Aid Prediction of Outcomes in Juvenile Dermatomyositis.

OBJECTIVE: Juvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositis-specific autoantibodies (MSAs) have prognostic significance in juvenile DM. METHODS: Muscle biopsy samples (n = 101) from patients in the UK Juvenile Dermatomyositis Cohort and Biomarker Study were stained, analyzed, and scored for severity of histopathologic features. In addition, autoantibodies were measured in the serum or plasma of patients (n = 90) and longitudinal clinical data were collected (median duration of follow-up 4.9 years). Long-term treatment status (on or off medication over time) was modeled using generalized estimating equations. RESULTS: Muscle biopsy scores differed according to MSA subgroup. When the effects of MSA subgroup were accounted for, increased severity of muscle histopathologic features was predictive of an increased risk of remaining on treatment over time: for the global pathology score (histopathologist's visual analog scale [hVAS] score), 1.48-fold higher odds (95% confidence interval [95% CI] 1.12-1.96; P = 0.0058), and for the total biopsy score (determined with the standardized score tool), 1.10-fold higher odds (95% CI 1.01-1.21; P = 0.038). A protective effect was identified in patients with anti-Mi-2 autoantibodies, in whom the odds of remaining on treatment were 7.06-fold lower (95% CI 1.41-35.36; P = 0.018) despite muscle biopsy scores indicating more severe disease. In patients with anti-nuclear matrix protein 2 autoantibodies, anti-transcription intermediary factor 1γ autoantibodies, or no detectable autoantibody, increased histopathologic severity alone, without adjustment for the effect of MSA subtype, was predictive of the risk of remaining on treatment: for the hVAS global pathology score, 1.61-fold higher odds (95% CI 1.16-2.22; P = 0.004), and for the total biopsy score, 1.13-fold higher odds (95% CI 1.03-1.24; P = 0.013). CONCLUSION: Histopathologic severity, in combination with MSA subtype, is predictive of the risk of remaining on treatment in patients with juvenile DM and may be useful for discussing probable treatment length with parents and patients. Understanding these associations may identify patients at greater risk of severe disease.

Eosinophilic granulomatosis with polyangiitis in childhood: retrospective experience from a tertiary referral centre in the UK.

OBJECTIVE: To describe the presenting clinical features, treatment and outcome in children with eosinophilic granulomatosis with polyangiitis (EGPA) and to define factors that predicted mortality. METHODS: A retrospective case notes review of patients fulfilling the Chapel Hill Consensus Conference definition and/or ACR criteria for EGPA seen at Great Ormond Street Hospital, London. Demographics, clinical features, histopathology, treatment and outcomes were recorded. Descriptive statistics were expressed as median and range. Fisher's exact test was used for group comparisons. The Paediatric Vasculitis Activity Score and Paediatric Vasculitis Damage Index (PVDI) were calculated. RESULTS: Thirteen children (38% female) aged at diagnosis 14.1 (4-15.6) years were identified. The median time to diagnosis was 2 (0-7.3) years. History of asthma was documented in 76%. The most common presenting features were pulmonary (69%), skin (61%), gastrointestinal (46%), cardiac involvement (46%), paranasal sinus abnormality (38%), arthritis/arthralgia (38%) and neurological involvement (15%). Paediatric Vasculitis Activity Score at presentation was 8/63 (2-25/63); ANCA was negative in all 10/13 patients tested. Treatment included corticosteroids in all, combined with CYC in 38% or AZA in 23%. PVDI at 12 (3-48) months follow-up was 3/72 (0-13/72). Relapses were recorded in 46%. Mortality was 15%; cardiomyopathy and PVDI scores ⩾5 significantly associated with mortality risk (P = 0.012). CONCLUSION: EGPA in the paediatric population is a rare and potentially life-threatening vasculitis. Increased awareness is essential to secure a timely diagnosis and to promptly initiate treatment since our data emphasize a high mortality, particularly in those with cardiac involvement and significant accrued damage.

Histopathological features of gastrointestinal mucosal biopsies in children with juvenile idiopathic arthritis.

BACKGROUND: The association between inflammatory bowel disease and joint involvement is well established. There is a paucity of data describing histopathological features of the gut in relation to juvenile idiopathic arthritis (JIA). METHODS: We retrospectively identified 33 (21 male) children aged 3-16 y with JIA (11 with oligoarthritis, 5 with polyarthritis, 8 with systemic onset arthritis, 8 with enthesitis-related arthritis (ERA), and 1 with psoriatic arthritis) with significant gastrointestinal (GI) symptoms who underwent upper and/or lower endoscopy. The histopathological findings were reviewed in addition to presence of autoantibodies and concomitant treatment. RESULTS: The most common GI indications for endoscopy were persistent abdominal pain (14/33 (42%)) and diarrhea (10/33 (30%)). Of the 33 children, 28 (85%) had gut mucosal inflammation, mostly affecting the colon (80%). Active inflammation of the gut was found in 5 of 28 (17%) children, and 15 of 28 (53%) children showed mild nonspecific inflammation. Eight patients (27%) had predominantly an eosinophilic infiltrate. Twenty-six patients had previously received treatment for JIA. There was a negative association with the use of immunomodulators and the presence of eosinophil inflammation. CONCLUSION: The majority of children with JIA and GI symptoms have histological evidence of mild nonspecific inflammation, but some having active colitis and prominent eosinophil infiltrate.

Analysis of Published Criteria for Clinically Inactive Disease in a Large Juvenile Dermatomyositis Cohort Shows That Skin Disease Is Underestimated.

OBJECTIVE: The Pediatric Rheumatology International Trials Organisation (PRINTO) recently published criteria for classification of patients with juvenile dermatomyositis (DM) as having clinically inactive disease. The criteria require that at least 3 of 4 conditions be met, i.e., creatine kinase level ≤150 units/liter, Childhood Myositis Assessment Scale score ≥48, Manual Muscle Testing in 8 muscles score ≥78, and physician's global assessment of overall disease activity (PGA) ≤0.2. The present study was undertaken to test these criteria in a UK cohort of patients with juvenile DM. METHODS: We assessed 1,114 patient visits for the 4 items in the PRINTO criteria for clinically inactive disease. Each visit was analyzed to determine whether skin disease was present. The Disease Activity Score (DAS) for juvenile DM was determined in 59 patients. RESULTS: At 307 of the 1,114 visits, clinically inactive disease was achieved based on the 3 muscle criteria (but with a PGA of >0.2); rash was present at 65.8% of these visits and nailfold capillary abnormalities at 35.2%. When PGA ≤0.2 was one of the 3 criteria that were met, the frequency of skin signs was significantly lower (rash in 23.1% and nailfold capillary abnormalities in 8.7%). If PGA was considered an essential criterion for clinically inactive disease (P-CID), patients with active skin disease were less likely to be categorized as having clinically inactive disease (a median DAS skin score of 0 [of a possible maximum of 9] in visits where the PGA was ≤0.2, versus a median DAS skin score of 4 in patients meeting the 3 muscle criteria [with a PGA of >0.2]; P < 0.001). Use of the P-CID led to improvements in the positive predictive value and the positive likelihood ratio (85.4% and 11.0, respectively, compared to 72.9% and 5.1 with the current criteria). CONCLUSION: There was a high frequency of skin disease among patients with juvenile DM who did not meet the PGA criterion for inactive disease but met the other 3 criteria. Incorporating PGA as an essential criterion for clinically inactive disease helps prevent the misclassification of patients with active skin disease.

The vascular phenotype of children with systemic lupus erythematosus.

BACKGROUND: The increased risk of cardiovascular disease (CVD) in adults with systemic lupus erythematosus (SLE) has been known since the 1970s, but studies in juvenile-onset SLE (JSLE) have reported conflicting results and more data are needed. The aim of this cross-sectional study was to establish the baseline risk of CVD in a cohort of UK patients with JSLE. METHODS: Data were collected to establish disease duration, disease activity, medication use and activity levels, as well as demographic data, including family history of CVD. Vascular phenotype was established using well-validated measures of carotid intima media thickness (cIMT) and pulse wave velocity (PWV). RESULTS: In total, 45 children (39 female; mean age 13.5 ± 2.9 years) with JSLE were recruited to the study. Of these, 24 had a history of biopsy-proven lupus nephritis and five had an estimated glomerular filtration rate of <90 ml/min/1.73 m(2). Comparison of these JSLE patients with healthy controls previously scanned at our hospital revealed that the cIMT value was significantly higher in the former (0.45 vs. 0.37 mm, respectively; p < 0.0001). This difference was associated with the use of antihypertensives (p = 0.04) and higher or lower doses of prednisolone (p < 0.0001). PWV was not significantly different in the patient and control group (5.27 vs. 5.34 m/s, respectively; p = 0.77). In the patient group, the mean body mass index percentile was 65.63 ± 28.8, and the median physical activity score was 1,773 (676-2,854) metabolic equivalents of task (METs). None of the patients admitted to cigarette smoking, and ten had a positive family history of cardiovascular disease (CVD). CONCLUSION: This study shows that our patients with JSLE had increased cIMT without an increase in PWV, suggesting possible early adaptive changes in JSLE. Follow-up data are needed to determine whether these changes result in clinically significant CVD.

Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.

OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM.

Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study.

INTRODUCTION: The aim of this study was to define the frequency and associated clinical phenotype of anti-MDA5 autoantibodies in a large UK based, predominantly Caucasian, cohort of patients with juvenile dermatomyositis (JDM). METHODS: Serum samples and clinical data were obtained from 285 patients with JDM recruited to the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-MDA5 antibodies was determined by immunoprecipitation and confirmed by ELISA using recombinant MDA5 protein. Results were compared with matched clinical data, muscle biopsies (scored by an experienced paediatric neuropathologist) and chest imaging (reviewed by an experienced paediatric radiologist). RESULTS: Anti-MDA5 antibodies were identified in 7.4% of JDM patients and were associated with a distinct clinical phenotype including skin ulceration (P = 0.03) oral ulceration (P = 0.01), arthritis (P <0.01) and milder muscle disease both clinically (as determined by Childhood Myositis Assessment Score (P = 0.03)) and histologically (as determined by a lower JDM muscle biopsy score (P <0.01)) than patients who did not have anti-MDA5 antibodies. A greater proportion of children with anti-MDA5 autoantibodies achieved disease inactivity at two years post-diagnosis according to PRINTO criteria (P = 0.02). A total of 4 out of 21 children with anti-MDA5 had interstitial lung disease; none had rapidly progressive interstitial lung disease. CONCLUSIONS: Anti-MDA5 antibodies can be identified in a small but significant proportion of patients with JDM and identify a distinctive clinical sub-group. Screening for anti-MDA5 autoantibodies at diagnosis would be useful to guide further investigation for lung disease, inform on prognosis and potentially confirm the diagnosis, as subtle biopsy changes could otherwise be missed.

Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study.

BACKGROUND: In juvenile-onset systemic lupus erythematosus (JSLE), renal involvement (lupus nephritis) is frequently seen and can result in long-term morbidity. This prospective longitudinal study aimed to identify the utility of standard and/or novel biomarkers for monitoring and predicting lupus nephritis in a real world setting. METHODS: Using an unselected JSLE cohort, urine samples were collected during routine clinical review. Protein concentrations of urinary monocyte chemo-attractant protein 1 (uMCP1) and neutrophil gelatinase-associated lipocalin (uNGAL) were analysed along with standard disease activity markers, and were compared with current and subsequent disease activity. RESULTS: JSLE patients (n = 64; median age 14.1 years) were seen at 3 (interquartile range: 2-5) clinical reviews over 364 (182-532) days. Multivariate analysis demonstrated uMCP1 and serum C3 as independent variables (p < 0.001) for active renal disease at the time of the current review. uMCP1 was an excellent predictor of improved renal disease over time (AUC: 0.81; p = 0.013). uNGAL was a good predictor of worsened renal disease activity (AUC 0.76; p = 0.04) over time. CONCLUSION: Biomarkers (uMCP1, serum C3) can indicate current renal involvement in JSLE, whilst uMCP1 and uNGAL are able to predict subsequent renal disease activity changes. Moving towards biomarker-led monitoring may improve the renal outcome for our patients.

Systemic polyarteritis nodosa in the young: a single-center experience over thirty-two years.

OBJECTIVE: Polyarteritis nodosa (PAN) is a rare disease of childhood. The aims of this study were to describe the clinical features, treatment, and outcome of systemic childhood PAN and to identify predictors of relapse. METHODS: A single-center retrospective medical records review of children with PAN fulfilling the European League Against Rheumatism (EULAR)/Paediatric Rheumatology European Society (PRES)/Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria who were seen over a 32-year period was performed. Data on demographic and clinical features, treatments, relapses (recurrence of clinical signs/symptoms or occurrence of new symptoms after initial remission requiring escalation or resumption of immunosuppressive therapy), and deaths were recorded. A disease activity score was retrospectively assigned using the Paediatric Vasculitis Activity Score (PVAS) instrument. Cox regression analysis was used to identify significant predictors of relapse. RESULTS: Sixty-nine children with PAN were identified; 55% were male, and their median age was 8.5 years (range 0.9-15.8 years). Their clinical features at presentation were fever (87%), myalgia (83%), skin (88%), renal (19%), severe gastrointestinal (GI) (10%), and neurologic (10%) involvement. The PVAS at presentation was 9 of 63 (range 4-24). Histopathologic analysis of the skin showed necrotizing vasculitis in biopsy samples from 40 of 50 children. Results of selective visceral arteriography suggested the presence of PAN in 96% of patients. Treatment included cyclophosphamide and corticosteroids (83%), plasma exchange (9%), and biologic agents (after 2002; 13%). The relapse rate was 35%, and the mortality rate was 4%. Severe GI involvement was associated with increased risk of relapse (P = 0.031), while longer time to induce remission (P = 0.022) and increased cumulative dose of cyclophosphamide (P = 0.005) were associated with lower relapse risk. CONCLUSION: Childhood PAN is a severe inflammatory disease of insidious onset and variable clinical presentation. Relapses occurred more frequently in those with severe GI involvement. A higher cumulative dose of cyclophosphamide was associated with a lower risk of relapse.

Limb girdle muscular dystrophy type 2B masquerading as inflammatory myopathy: case report.

Limb girdle muscular dystrophy type 2B is a rare subtype of muscular dystrophy, the predominant feature of which is muscle weakness. The disease is caused by an autosomal recessively inherited reduction/absence of muscle dysferlin due to a mutation in dysferlin gene at 2p12-14. We report a 10 year old boy who presented with severe non-transient right knee pain and swelling, which later became bilateral. His pain was worst in the morning and during rest. Blood tests revealed markedly raised creatine kinase values (highest 22, 297 U/l), raising the possibility of an inflammatory myositis. MRI showed bilateral asymmetrical muscle involvement of thighs and calves with oedematous changes mimicking the imaging appearances of inflammatory myositis. CRP and ESR levels were consistently within normal limits. Over several months his knee pain worsened and limited walking. Muscle biopsy revealed a severe reduction of dysferlin immunostaining, indicating the diagnosis, which was confirmed by 2 compound heterozygous pathogenic mutations in the dysferlin gene. It is not unusual for this subtype of the disease to mimic myositis: however, significant pain is a rare presenting symptom. Given the significant overlap between this form of muscular dystrophy and inflammatory myopathies, a high index of suspicion is needed to ensure an accurate and timely diagnosis. Furthermore, characteristic inflammatory-related morning pain should not rule out consideration of non-inflammatory causes.