Juvenile Idiopathic Inflammatory Myopathy Research Articles

Assessing the sensitivity and specificity of myositis-specific and associated autoantibodies: a sub-study from the MyoCite cohort.

Myositis-specific and associated autoantibodies are important biomarkers in routine clinical use. We assessed local testing performance for myositis autoantibodies by comparing line immunoassay (LIA) to protein radio-immunoprecipitation and identifying clinical characteristics associated with each myositis autoantibody in the MyoCite cohort. Serum samples from patients within the MyoCite cohort, a well-characterised retro-prospective dataset of adult and juvenile idiopathic inflammatory myopathy (IIM) patients in Lucknow, India (2017-2020), underwent LIA at Sanjay Gandhi Postgraduate Institute of Medical Science (SGPGIMS), Lucknow. Immunoprecipitation of 147 IIM patient serum samples (125 adult-onset, 22 juvenile-onset) was conducted at the University of Bath, with researchers blind to LIA results. LIA performance was assessed against Immunoprecipitation as the reference standard, measuring sensitivity, specificity, and inter-rater agreement. Univariate and multivariate logistic regression determined clinical associations for specific MSA. Immunoprecipitation identified myositis autoantibodies in 56.5% (n = 83) of patient samples, with anti-Jo1 (n = 16; 10.9%) as the most common, followed by anti-MDA5 (n = 14, 9.5%). While LIA showed good agreement for anti-Jo1, anti-PL7 and anti-PL12 (Cohen's κ 0.79, 0.83, and 1, respectively), poor agreement was observed in other subgroups, notably anti-TIF1γ (Cohen's κ 0.21). Strongly positive samples, especially in myositis-specific autoantibodies, correlated more with immunoprecipitation results. Overall, 59 (40.1%) samples exhibited non-congruence on LIA and Immunoprecipitation, and κ values for LIA's for anti-TIF1γ, anti-Ku, anti-PmScl, anti-Mi2, and anti-SAE ranged between 0.21-0.60. While LIA reliably detected anti-Jo1, anti-PL7, anti-PL12, anti-MDA5, and anti-NXP-2, it also displayed false positives and negatives. Its effectiveness in detecting other autoantibodies, such as anti-TIF1γ, was poor.

42 Egyptian evidence-based consensus recommendations for diagnosis and targeted management of juvenile dermatomyositis. An initiative by the Egyptian College of Pediatric Rheumatology

BackgroundJuvenile dermatomyositis (JDM) is the most common type of juvenile idiopathic inflammatory myopathy mainly affecting the skin and proximal muscles. To date, there are no Egyptian nationally agreed, evidence-based guidelines concerning the diagnosis and management of JDM in children and treatment is often based on clinical expertise. These facts prompted us to develop clinical practice guidance for JDM suitable for patients in Egypt. This work was an initiative by the Egyptian College of Pediatric Rheumatology aiming at optimizing the management approaches for children and young adults with JDM.ObjectiveTo provide evidence-based consensus recommendations for diagnosis and management of JDM.MethodsThis study was carried out to achieve an Egyptian expert consensus on a management strategy for JDM using Delphi technique. A multistep process strategy was adopted, which started by developing 16 key clinical questions by scientific committee according to the Patient/Population, Intervention, Comparison, Outcomes and Time (PICOT) approach. The core leadership team identified clinicians and researchers with expertise in pediatric rheumatology all over Egypt. An evidence-based, systematic, literature review was conducted to compile evidence for the JDM management. Delphi process was implemented (3-rounds) to reach a consensus.ResultsTwenty-five expert panel participated in the 3 rounds with response rate 100%. A total of 22 recommendations, categorized into 15 domains (Targeted population, diagnostic criteria, high risk patients, diagnostic criteria, definition of disease activity status, differences between JDM and DM in adults, lab tests, treatment targets, treatment, monitoring, resisted cases, drug tapering, comorbidities, prognosis, vaccination and transition program. The Agreement with the recommendations (rank 7–9) ranged from 85.2–95.2%. The Consensus was reached (i.e. ≥75% of respondents strongly agreed or agreed) on all the clinical standards. Algorithm for management has also been developed.ConclusionThis work provided an updated management approach for JDM patients. This evidence-based informed consensus process is expected to support uniform, high quality standards of care for children with JDM in EgyptThe implication to policy, practice, research and advocacyto provide updated recommendations for better management of JDM.

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.

Anti-MDA5 juvenile idiopathic inflammatory myopathy with second-degree heart block but no skin or lung involvement: a case report

BackgroundPatients with idiopathic inflammatory myopathy and autoantibodies directed against melanoma differentiation-associated protein 5 (MDA5) characteristically have interstitial lung disease, severe cutaneous involvement, arthritis, and relatively mild myositis. Cardiac involvement in idiopathic inflammatory myopathy can occur and has been associated with anti-signal recognition particle and anti-polymyositis-scleroderma autoantibodies, but not with anti-MDA5 autoantibodies.Case presentationA 14-year-old male presented with weakness, second-degree heart block, arthritis, and hematologic cytopenias. Imaging and biopsies confirmed the diagnosis of juvenile idiopathic inflammatory myopathy, and he had high titer anti-MDA5 autoantibodies. There were no cutaneous or pulmonary abnormalities. While on prednisone and methotrexate, the patient’s heart block improved from second- to first-degree and the cytopenias resolved. Persistent myositis prompted the addition of intravenous immunoglobulin. Seven months into the disease course, the arthritis and myositis are in remission and the patient is no longer taking corticosteroids.ConclusionsWe report a novel case of a patient with juvenile idiopathic myositis who lacked the typical cutaneous and pulmonary findings associated with anti-MDA5 positivity, but who had cardiac conduction defects. This report broadens the clinical spectrum of anti-MDA5-associated inflammatory myopathy.

Clinical Characteristics of Juvenile Idiopathic Inflammatory Myopathy and Comparison With Adult Patients: Analysis From a Multicentric Cohort in Spain.

This study reviewed the medical records of patients from the REMICAM cohort, a multicentric longitudinal study carried out in patients with IIM, followed up between 1980 and 2014 in 12 hospitals in Madrid, Spain. Patients with definite or probable JPM, JDM, adult DM, and adult PM according to the modified Bohan and Peter criteria were selected. We compared the characteristics between JDM and JPM, and between JIIM and adult IIM. Eighty-six juvenile patients (75 JDMs and 11 JPMs) and 283 adult patients (133 DMs and 150 PMs) were included. Compared with patients with JDM, patients with JPM were older at diagnosis, had more fever and arthritis, and were less frequently treated with disease-modifying antirheumatic drugs (these differences were not statistically significant). Compared with patients with adult DM, those with JDM presented more frequently with calcinosis (33.8% vs 6.9%, p < 0.0001) and had less severe infections (4.3% vs 23.4%, p < 0.0001), malignancies (1.3% vs 25.6%, p < 0.0001), and mortality (3.5% vs 33%, p < 0.0001). Patients with JDM were treated less frequently with azathioprine (10.8% vs 44.7%, p < 0.0001). Our findings confirm that JIIMs are a heterogeneous group of diseases with relevant differences compared with adult IIMs.

Monitoring disease activity and damage in adult and juvenile idiopathic inflammatory myopathy.

We have reviewed the literature to identify significant advances related to disease activity and damage in the idiopathic inflammatory myopathies (IIMs) from January 2019 to July 2020. New observations in the field from 2019 to 2020 have resulted in a better understanding of the clinical association and pathogenic origins of IIM. The use of patient-reported outcome measures and perspectives, identifying biomarkers and making better use of autoantibody testing are summarized. Basic sciences have led to an improved understanding of the role of NETosis in calcinosis, and of interferon type 1, in IIM. Preliminary insights are offered into Covid-19 in the setting of IIM, and the use of potential tools for monitoring disease remotely, which may assume larger importance for optimal disease management during a global pandemic. The wider exploration of newer imaging modalities and the use of nailfold capillaroscopy is a further step in better management of the condition. The summarized research in IIM is a step forward in being able to further define, and to distinguish disease activity from damage, in order to potentially aid future clinical diagnosis and management in this challenging disease.

Risk factors associated with Pneumocystis jirovecii pneumonia in juvenile myositis in North America.

Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM. An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP-) from similar geographic regions who enrolled in National Institutes of Health natural history studies. PJP+ patients were more often of Asian ancestry than PJP- patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP- patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications. PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.

Clinical practice guidance for juvenile dermatomyositis (JDM) 2018-Update

Juvenile dermatomyositis is the most common type of juvenile idiopathic inflammatory myopathy mainly affecting the skin and proximal muscles. We have published the Japanese version of ‘Clinical practice guidance for juvenile dermatomyositis (JDM) 2018 ‘consisting of a review of articles in the field and evidence-informed consensus-based experts’ opinion on the treatment strategy in collaboration with The Pediatric Rheumatology Association of Japan and The Japan College of Rheumatology under the financial support by ‘Research on rare and intractable diseases, Health and Labor Sciences Research Grants’. This article is a digest version of the Japanese guidance.

Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.

JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

A Path to Prediction of Outcomes in Juvenile Idiopathic Inflammatory Myopathy.

Humans have an innate desire to observe and subsequently dissect an event into component pieces in an effort to better characterize the event. We then examine these pieces individually and in combinations using this information to determine the outcome of future similar events and the likelihood of their recurrence. Practically, this attempt to foretell an occurrence and predict its outcomes is evident in multiple disciplines ranging from meteorology to sociologic studies. In this manuscript we share the historical and present-day tools to predict course and outcome in juvenile idiopathic inflammatory myopathy including clinical features, testing, and biomarkers. Further we discuss considerations for building more complex predictive models of outcome especially in diseases such as juvenile idiopathic inflammatory myopathy where patients numbers are low. Many of the barriers to developing risk prediction models for juvenile idiopathic inflammatory myopathy outcomes have improved with many remaining challenges being addressed.

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features.

AimJuvenile idiopathic inflammatory myopathies have been recently reclassified into clinico‐serological subgroups. Myopathological correlates of the subgroups are incompletely understood.MethodsWe studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b‐9 complement analysis.ResultsAutoantibody data were available for 90/101 cases with 18/90 cases positive for anti‐TIF1γ, 15/90 anti‐NXP2, 11/90 anti‐MDA5, 5/90 anti‐Mi2 and 6/90 anti‐PmScl. JDM biopsy severity scores were consistently low in the anti‐MDA5 group, high in the anti‐Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage‐rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b‐9‐deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b‐9 deposition.ConclusionWe have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes.

Efficacy of ultrasound elastography in detecting active myositis in children: can it replace MRI?

Juvenile idiopathic inflammatory myopathy is a rare yet potentially debilitating condition. MRI is used both for diagnosis and to assess response to treatment. No study has evaluated the performance of US elastography in the diagnosis of this condition in children. To assess the performance of compression-strain US elastography in detecting active myositis in children with clinically confirmed juvenile idiopathic inflammatory myopathy and to compare its efficacy to MRI. Children with juvenile idiopathic inflammatory myopathy underwent non-contrast MR imaging as well as compression-strain US elastography of the quadriceps muscles. Imaging findings from both modalities were compared to each other as well as to the clinical determination of active disease based on physical examination and laboratory data. Active myositis on MR was defined as increased muscle signal on T2-weighted images. Elastography images were defined as normal or abnormal based on a previously published numerical scale of muscle elastography in normal children. Muscle echogenicity was graded as normal or abnormal based on gray-scale sonographic images. Twenty-one studies were conducted in 18 pediatric patients (15 female, 3 male; age range 3-19years). Active myositis was present on MRI in ten cases. There was a significant association between abnormal MRI and clinically active disease (P = 0.012). US elastography was abnormal in 4 of 10 cases with abnormal MRI and in 4 of 11 cases with normal MRI. There was no association between abnormal elastography and either MRI (P > 0.999) or clinically active disease (P > 0.999). Muscle echogenicity was normal in 11 patients; all 11 had normal elastography. Of the ten patients with increased muscle echogenicity, eight had abnormal elastography. There was a significant association between muscle echogenicity and US elastography (P < 0.001). The positive and negative predictive values for elastography in the determination of active myositis were 75% and 31%, respectively, with a sensitivity of 40% and specificity of 67%. Compression-strain US elastography does not accurately detect active myositis in children with juvenile idiopathic inflammatory myopathy and cannot replace MRI as the imaging standard for detecting myositis in these children. The association between abnormal US elastography and increased muscle echogenicity suggests that elastography is capable of detecting muscle derangement in patients with myositis; however further studies are required to determine the clinical significance of these findings.

Ovarian reserve in adult patients with childhood-onset lupus: a possible deleterious effect of methotrexate?

Objectives: To assess ovarian reserve markers and anti-corpus luteum antibodies (anti-CoL) in adult patients with childhood-onset systemic lupus erythematosus (c-SLE).Method: Fifty-seven adult c-SLE female patients and 21 healthy controls were evaluated for anti-CoL. Ovarian reserve was assessed by: follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol, anti-Müllerian hormone (AMH), and antral follicle count (AFC). Demographic data, menstrual abnormalities, disease activity, damage, and treatment were also analysed.Results: The median current age was similar in adult c-SLE patients and controls (27.7 vs. 27.7 years, p = 0.414). The medians of AMH (1.1 vs. 1.5 ng/mL, p = 0.037) and AFC (6 vs. 16, p < 0.001) were significantly reduced in SLE patients compared to controls without significant menstrual abnormalities. Anti-CoL were solely observed in c-SLE patients (16% vs. 0%, p = 0.103) and were not associated with demographic data, ovarian reserve parameters, disease activity/damage, and treatment. Further evaluation of c-SLE patients treated with cyclophosphamide revealed a higher median of FSH levels compared to c-SLE patients not treated with cyclophosphamide and controls (8.8 vs. 5.7 vs. 5.6 IU/L, p = 0.032) and lower median AMH (0.4 vs. 1.5 vs. 1.5 ng/mL, p = 0.004) and AFC (4.0 vs. 6.5 vs. 16 IU/L, p = 0.001) levels. Nineteen patients treated exclusively with methotrexate demonstrated a negative correlation between the cumulative dose and AMH levels (p = 0.027, r = –0.507).Conclusions: The present study demonstrated for the first time that a high cumulative methotrexate dose is a possible cause of subclinical ovarian dysfunction in adult c-SLE patients. Further studies are required to confirm this deleterious effect in other rheumatic diseases, particularly juvenile idiopathic arthritis and idiopathic inflammatory myopathy.

The Myositis Autoantibody Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies

The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, “shawl-sign” rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and “mechanic’s hands,” and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high frequencies of black race, severe onset, distal weakness, falling episodes, Raynaud phenomenon, cardiac involvement, high CK levels, chronic disease course, frequent hospitalization, and wheelchair use. Characteristic features of the anti-Mi-2 subgroup included Hispanic ethnicity, classic dermatomyositis and malar rashes, high CK levels, and very low mortality. Finally, the most common features of patients without any currently defined MSA or myositis-associated autoantibodies included linear extensor erythema, arthralgia, and a monocyclic disease course. Several demographic and clinical features were shared between juvenile and adult idiopathic inflammatory myopathy subgroups, but with several important differences. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct autoantibody phenotypes defined by varying clinical and demographic characteristics, laboratory features, and outcomes.

Genetic association study of NF-κB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy

Objective. Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM.Methods. Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-κB-related genes. Data were stratified by IIM subgroup/serotype.Results. A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D′ = 1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08.Conclusion. An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-κB genes therefore do not independently confer susceptibility in IIM.

Update on the Assessment of Children with Juvenile Idiopathic Inflammatory Myopathy

The availability of validated measurement tools to assess children with juvenile idiopathic inflammatory myopathies is critical to clinical care and to ongoing research into new therapeutic modalities and approaches. Recent work has led to the development of tools for assessment of muscle strength and physical function, skin disease, global disease activity and damage, extramuscular disease, and quality of life. Ongoing work is attempting to integrate these assessments into core sets and definitions of improvement and flare. Future work will refine these assessments and definitions and--where there are multiple choices--determine which tools constitute an optimal assessment.

An update on the immunogenetics of idiopathic inflammatory myopathies: major histocompatibility complex and beyond

To update the reader on immunogenetic advances in idiopathic inflammatory myopathy (IIM) over the past 18 months. In Caucasian IIM, despite a shared association with the human leukocyte antigen (HLA) 8.1 ancestral haplotype (HLA-DRB1*03-DQA1*05-DQB1*02), anti-Jo-1 and anti-PM-Scl antibody-positive cases have differing IIM clinical phenotypes. A study of the HLA-DPB1 region has shown that DPB1*0101 is associated with anti-Jo-1 positivity but not with anti-PM-Scl. IIM single nucleotide polymorphism studies have demonstrated associations in the protein tyrosine phosphatase, nonreceptor type 22, tumour necrosis factor alpha and interleukin-1 genes. The GM 13 allotype has been confirmed as a risk factor in Caucasian IIM. In inclusion body myositis, the HLA 8.1 ancestral haplotype may not only influence disease susceptibility but also disease expression. A follow-up study including a meta-analysis of the apolipoprotein E gene in inclusion body myositis suggests that this gene does not confer risk of disease. Although a substantial part of the genetic risk for developing adult and juvenile IIM lies within the major histocompatibility complex, recent research suggests that genetic regions outside of the major histocompatibility complex are also potentially involved in conferring IIM disease susceptibility, although with more modest effect sizes. An ongoing and internationally coordinated IIM genome-wide association scan may provide further insights into IIM immunogenetics.

The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients

AbstractObjectiveTo examine single‐nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase N22 gene (PTPN22) and to study the relationship between PTPN22 and the HLA region in patients with idiopathic inflammatory myopathies (IIMs).MethodsPTPN22 SNPs were assessed in a large, cross‐sectional, case–control study from the UK involving patients with adult or juvenile IIM, comprising patients with polymyositis (PM) (n = 114), dermatomyositis (DM) (n = 102), myositis associated with another connective tissue disease (myositis–CTD overlap syndrome) (n = 64), or juvenile DM (n = 101), in comparison with 748 control subjects. Seventeen PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis‐specific/myositis‐associated autoantibodies (MSAs/MAAs) was performed by radioimmunoprecipitation.ResultsA significant association was noted between the R620W variant (rs2476601) and IIM (corrected P [Pcorr] = 0.0009 versus controls), and specifically with the clinical subgroup of PM (Pcorr = 0.003 versus controls). A weaker association was noted with juvenile DM (Pcorr = 0.009 versus controls). No significant associations were noted after stratification by serologic subgroups. The association with the R620W variant was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM.ConclusionThe R620W variant is a significant risk factor for IIM, independent of the HLA 8.1 haplotype. Unlike that in the HLA region, risk is not increased in individuals possessing MSAs/MAAs. These results are further evidence that the PTPN22 gene confers autoimmune susceptibility.

The Cutaneous Assessment Tool: development and reliability in juvenile idiopathic inflammatory myopathy

Clinical care and therapeutic trials in idiopathic inflammatory myopathies (IIM) require accurate and consistent assessment of cutaneous involvement. The Cutaneous Assessment Tool (CAT) was designed to measure skin activity and damage in IIM. We describe the development and inter-rater reliability of the CAT, and the frequency of lesions endorsed in a large population of juvenile IIM patients. The CAT includes 10 activity, 4 damage and 7 combined lesions. Thirty-two photographic slides depicting IIM skin lesions were assessed by 11 raters. One hundred and twenty-three children were assessed by 11 paediatric rheumatologists at 10 centres. Inter-rater reliability was assessed using simple agreements and intra-class correlation coefficients (ICC). Simple agreements in recognizing lesions as present or absent were generally high (0.5-1.0). ICCs for CAT lesions were moderate (0.4-0.75) in both slides and real patients. ICCs for the CAT activity and damage scores were 0.71 and 0.81, respectively. CAT activity scores ranged from 0 to 44 (median 7, potential range 0-96) and CAT damage scores ranged from 0 to 13 (median 1, potential range 0-22). The most common cutaneous lesions endorsed were periungual capillary loop changes (63%), Gottron's papules/sign (53%), heliotrope rash (49%) and malar/facial erythema (49%). Total CAT activity and damage scores have moderate to good reliability. Assessors generally agree on the presence of a variety of cutaneous lesions. The CAT is a promising, semi-quantitative tool to comprehensively assess skin disease activity and damage in IIM.

Muscle metabolites, detected in urine by proton spectroscopy, correlate with disease damage in juvenile idiopathic inflammatory myopathies

To assess for novel markers of muscle damage using urinary muscle metabolites by 1H magnetic resonance spectroscopy in patients with juvenile idiopathic inflammatory myopathy (IIM). Creatine (Cr), choline (Cho), betaine (Bet), glycine (Gly), trimethylamine oxide (TMAO), and several other metabolites were measured in first morning void urine samples from 45 patients with juvenile IIM and from 35 healthy age-matched controls, and correlated with measures of myositis disease activity and damage. Urinary metabolite to age-adjusted creatinine (Cn) ratios were examined. Age-adjusted initial Cr:Cn, Cho:Cn, Bet:Cn, Gly:Cn, and TMAO:Cn ratios were higher in patients with juvenile IIM than controls (P < 0.01). Cr:Cn ratios showed significant correlations with physician-assessed global disease damage (Spearman rs = 0.37; P = 0.01), Steinbrocker functional class (rs = 0.35; P = 0.02), serum Cr (rs = 0.72; P = 0.001), and lactate dehydrogenase (rs = 0.34; P = 0.03) levels. Cho:Cn (rs = 0.3; P = 0.05), Gly:Cn (rs = 0.33; P = 0.03), and TMAO:Cn (rs = 0.36; P = 0.02) ratios showed a significant correlation with serum aldolase levels. Cho:Cn ratios also showed a significant correlation with aspartate aminotransferase levels (rs = 0.35; P = 0.02). A linear regression model was used to evaluate the factors influencing urinary Cr:Cn ratios in the 43 patients with data sets available at the initial visit. The regression model explained 73% of the variation in Cr:Cn ratios. The most significant factor was the physician-assessed global disease damage (R2 = 0.50, P = 0.015). Urinary Cr:Cn, Cho:Cn, Bet:Cn, Gly:Cn, and TMAO:Cn ratios are elevated in juvenile IIM and Cr:Cn correlates strongly with global disease damage. The Cr:Cn ratio may have potential utility as a marker of myositis disease damage.