Albert Selva-O'Callaghan

Usefulness of anti‐p155 autoantibody for diagnosing cancer‐associated dermatomyositis: A systematic review and meta‐analysis

OBJECTIVE Anti-p155 autoantibody, which was recently described in adult patients with dermatomyositis (DM), seems to be associated with cancer in this population. We performed a systematic review and meta-analysis to ascertain the accuracy of anti-p155 testing for the diagnosis of cancer-associated myositis. METHODS We searched relevant databases, with no restrictions on study design or language, for original studies that included adult patients with probable/definite DM or amyopathic DM who were evaluated for neoplasm and anti-p155 status. Pooled sensitivity and specificity were calculated using a bivariate model. We computed the diagnostic odds ratio (OR), likelihood ratios (LRs) for positive and negative test results, positive and negative predictive values, and the summary receiver operating characteristic (SROC) curve. Statistical heterogeneity between studies was assessed using the I(2) statistic, and 95% confidence intervals (95% CIs) were computed for the parameters studied. RESULTS Six studies including a total of 312 adult patients with DM were selected. The pooled sensitivity of anti-p155 for diagnosing cancer-associated DM was 78% (95% CI 45-94%), and specificity was 89% (95% CI 82-93%). The diagnostic OR was 27.26 (95% CI 6.59-112.82), and LRs for positive and negative test results were 6.79 (95% CI 4.11-11.23) and 0.25 (95% CI 0.08-0.76), respectively. Heterogeneity was substantial except with regard to the LR for a positive test result. The area under the SROC curve was 0.91 (95% CI 0.88-0.93). Taking the pooled prevalence of 17% as pretest probability, anti-p155 had a positive predictive value of 58% and a negative predictive value of 95%. CONCLUSION Our findings indicate that anti-p155 autoantibody determination is useful for diagnosing cancer-associated myositis and guiding disease management.

Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders

OBJECTIVE To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. CONCLUSION Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis.

A new myositis-specific autoantibody directed against melanoma differentiation-associated gene 5 (anti-MDA5) has been described in patients with dermatomyositis (DM). We report the clinical characteristics of patients with anti-MDA5 in a large Mediterranean cohort of DM patients from a single center, and analyze the feasibility of detecting this autoantibody in patient sera using new assays with commercially available recombinant MDA5. The study included 117 white adult patients with DM, 15 (13%) of them classified as clinically amyopathic dermatomyositis (CADM). Clinical manifestations were analyzed, with special focus on interstitial lung disease and its severity. Determination of anti-MDA5 antibodies was performed by a new ELISA and immunoblot technique. In sera, from 14 (12%) DM patients (8 CADM), MDA5 was recognized by ELISA, and confirmed by immunoblot. Eight of the 14 anti-MDA5-positive patients (57.14%) presented rapidly-progressive interstitial lung disease (RP-ILD) versus 3 of 103 anti-MDA5-negative patients (2.91%) (P < 0.05; OR: 44.4, 95% CI 9.3–212). The cumulative survival rate was significantly lower in anti-MDA5-positive patients than in the remainder of the series (P < 0.05). Patients with anti-MDA5-associated ILD presented significantly lower 70-month cumulative survival than antisynthetase-associated ILD patients. Among the cutaneous manifestations, only panniculitis was significantly associated with the presence of anti-MDA5 antibodies (P < 0.05; OR: 3.85, 95% CI 1.11–13.27). These findings support the reliability of using commercially available recombinant MDA5 for detecting anti-MDA5 antibodies and confirm the association of these antibodies with RP-ILD in a large series of Mediterranean patients with DM.

Conventional Cancer Screening versus PET/CT in Dermatomyositis/Polymyositis

OBJECTIVE To determine the value of whole-body [(18)F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for diagnosing occult malignant disease in patients with myositis compared with broad conventional cancer screening. METHODS We prospectively studied 55 consecutive patients with a recent diagnosis of myositis in 3 teaching hospitals over a 3-year period by whole-body FDG-PET/CT and compared the results with those of conventional cancer screening, which included thoracoabdominal CT, mammography, gynecologic examination, ultrasonography, and tumor marker analysis. Comparisons were made using predictive values and their 95% confidence intervals. RESULTS A total of 9 of 55 patients were diagnosed with paraneoplastic myositis. FDG uptake was positive in 7 patients (1 false-positive), negative in 44 patients (3 false-negative), and inconclusive in 4 patients. Positive and negative predictive values of FDG-PET/CT for the diagnosis of cancer were 85.7% and 93.8%, respectively. Conventional screening was cancer-positive in 9 patients (2 false-positive) and negative in the remaining 46 patients (2 false-negative). Positive and negative predictive values were 77.8% and 95.7%, respectively. The overall predictive value of broad conventional screening was the same as that of FDG-PET/CT (92.7 vs 92.7). CONCLUSION The performance of FDG-PET/CT, a single imaging study, for diagnosing occult malignant disease in patients with myositis was comparable to that of broad conventional screening, which includes multiple tests.

Cancer-Associated Myositis and Anti-p155 Autoantibody in a Series of 85 Patients With Idiopathic Inflammatory Myopathy

A new autoantibody against a 155-kDa protein has been described in patients with myositis. We conducted a study to determine the occurrence and types of cancer occurring in a cohort of patients with polymyositis (PM) or dermatomyositis (DM) and analyzed the value of this autoantibody as a serologic marker of cancer-associated myositis (CAM). Serum samples from all patients were examined by protein immunoprecipitation assays with HeLa cells to determine the presence of a 155-kDa protein band. HLA-DRB1 and DQA1 typing was performed by polymerase chain reaction-reverse sequence specific oligonucleotide. Statistical analyses were carried out with the Mann Whitney U and Fisher exact tests. Associations were determined using odds ratios (ORs) with 95% confidence intervals (CI). Eighty-five patients with myositis (20 PM and 65 DM) were included. CAM was detected in 16 patients (19%), 14 with DM. The shawl sign rash was significantly more frequent in patients with CAM than in those without (p < 0.01). Adenocarcinoma was the most frequent type of cancer (87.5%). Anti-p155 autoantibody was found in 1 of the 20 (5%) patients with PM and in 15 of the 65 (23%) patients with DM. A relationship between anti-p155 and CAM was found in DM patients (OR, 23; 95% CI, 5.23-101.2). The HLA-DQA1*0102 allele was not found in any of the anti-p155-positive patients. The prevalence of CAM in our cohort was 19%. Autoantibody against p155 was highly related to CAM and could be a reliable marker of cancer in patients with DM. Abbreviations CAM = cancer-associated myositis, CI = confidence interval, DM = dermatomyositis, OR = odds ratio, PM = polymyositis.

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

Objectives The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. Results The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10−8). Nine regions were associated at a significance level of p<2.25×10−5, including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. Conclusions This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.

Nailfold capillary microscopy in adults with inflammatory myopathy.

OBJECTIVES To study the presence and characteristics of nailfold capillary changes in a cohort of adult patients with inflammatory myopathies, determine correlations with disease activity and severity, and investigate any relationship between capillary findings and the immunological or clinical characteristics of the groups. METHODS Fifty-three consecutive adult patients followed in our outpatient clinic were evaluated using a Wild M3 stereomicroscope with an Intralux 5000 Volpi cold light lamp. A semiquantitative rating scale was used to score capillaroscopy changes. Disease activity and severity were assessed with the Myositis Disease Activity Assessment Tool and Myositis Damage Index, respectively. Associations between capillaroscopy findings and other factors were calculated with the chi(2) and Mann-Whitney U tests. Serum autoantibody profile was determined in all patients. RESULTS Twenty-three patients (43%) showed relevant capillaroscopy changes. No significant association was observed between the number of capillaroscopy alterations and the clinical or immunological groups, or disease duration. Disease activity and severity were both significantly associated with a larger number of capillaroscopy findings (P < 0.05). The combination of microhemorrhages and capillary enlargement was significantly more frequent in patients with dermatomyositis (OR, 8.9; 95% CI, 1.8-45.2), and a characteristic capillaroscopy pattern was associated with paraneoplastic myositis (OR, 14.7; 95% CI, 2.0-106.4). Interstitial lung disease significantly correlated with higher capillary score (OR, 3.7; 95% CI, 1.1-13.0). CONCLUSIONS Nailfold microcirculation as determined by semiquantitative simple capillaroscopy appears to provide useful information in patients with idiopathic inflammatory myopathy, contributing to an early diagnosis and identifying patients with a poor prognosis.

CELIAC DISEASE AND ANTIBODIES ASSOCIATED WITH CELIAC DISEASE IN PATIENTS WITH INFLAMMATORY MYOPATHY

Celiac disease is usually associated with autoimmune disorders and has occasionally been reported in patients with inflammatory myopathies. Our aim was to determine the presence of celiac disease and antibodies associated with celiac disease in patients with inflammatory myopathies and to investigate their relationship. Serum antigliadin, anti–tissue transglutaminase, and antiendomysial antibodies were determined in 51 patients with inflammatory myopathies. HLA‐DQ2 and ‐DQ8 alleles were studied to assess their complementary diagnostic value. Jejunal biopsy was performed in patients with moderate to high levels of antigliadin antibodies. Patients with jejunal histology consistent with celiac disease initiated a gluten‐free diet. Seventeen patients (31%) were positive for antigliadin antibodies, which were significantly more frequent in patients with inclusion‐body myositis than dermatomyositis (P < 0.001). Positive status to HLA‐DQ2 and/or ‐DQ8 did not differ between antigliadin‐positive (75% and 12.5%) or ‐negative (60% and 15%) patients. Three of five jejunal biopsies were diagnostic for celiac disease with histological normalization after a gluten‐free diet. Thus, celiac disease is more prevalent in patients with inflammatory myopathies than in the general population. Positive status to HLA‐DQ2 allele, which is known to be more frequent in patients with inflammatory myopathies, could explain the high prevalence of antigliadin antibodies in this population. The diagnostic value of HLA‐DQ2 or ‐DQ8 haplotypes to detect celiac disease in patients with inflammatory myopathy is limited. Muscle Nerve, 2006

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.

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.