Publications by authors named "Katalin Dankó"

86 Publications

Heme-Induced Oxidation of Cysteine Groups of Myofilament Proteins Leads to Contractile Dysfunction of Permeabilized Human Skeletal Muscle Fibres.

Int J Mol Sci 2020 Oct 31;21(21). Epub 2020 Oct 31.

HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, H-4032 Debrecen, Hungary.

Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20-300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. A single heme exposure (20 µM) to muscle fibres decreased Ca-activated maximal (active) force (F) by about 50% and evoked an approximately 3-fold increase in Ca-independent (passive) force (F). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.
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http://dx.doi.org/10.3390/ijms21218172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663642PMC
October 2020

Anterior segment parameters associated with extramuscular manifestations in polymyositis and dermatomyositis.

Int J Ophthalmol 2020 18;13(9):1443-1450. Epub 2020 Sep 18.

Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.

Aim: To evaluate detailed anterior segment parameters of patients with idiopathic inflammatory myopathies (IIM), including polymyositis (PM), and dermatomyositis (DM), and to clarify the associations between these data and clinical variables of IIM.

Methods: Totally 57 PM, 41 DM patients and 62 controls were enrolled in this cross-sectional, observational, case-control study. All study participants underwent Pentacam evaluation. Laboratory investigations consisted of different antibody assays, while extramuscular clinical assessments included Raynaud's phenomenon, dysphagia, interstitial lung disease, arthritis/arthralgia, and weight loss. Objective signs and subjective symptoms of dry eye disease (DED) were also evaluated.

Results: All pachymetric parameters [center, apex, thinnest and maximal keratometry (K)] and corneal volume (CV) of both sides of PM patients proved to be significantly lower. Some pachymetric data were also noticed as significantly decreased compared to those of controls. Several significant differences were traced between anterior segment values and extramuscular manifestations of myositis, largely in case of arthritis/arthralgia and weight loss, whereas associations between anterior segment parameters and antibodies were weak. Objective clinical tests of DED were also significantly decreased in IIM patients.

Conclusion: The results suggest that all IIM patients have thinner corneas compared with those of controls, and decreased corneal parameters are significantly associated with the occurrence of some extramuscular manifestations. In addition, IIM patients tend to develop objective signs of DED.
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http://dx.doi.org/10.18240/ijo.2020.09.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459236PMC
September 2020

Eight pillars of oncorheumatology: Crossroads between malignancies and musculoskeletal diseases.

Autoimmun Rev 2020 Nov 14;19(11):102658. Epub 2020 Sep 14.

Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Oncorheumatology: RELATIONSHIP BETWEEN MALIGNANCIES AND MUSCULOSKELETAL DISEASES: Oncorheumatology is the meeting point of tumor formation and rheumatic musculoskeletal diseases (RMD). Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. Within the first group, secondary malignancies may be associated with rheumatic diseases. Mostly sustained inflammation is responsible for transition into cancer. Tumor-associated antigens (TAA) with adhesive properties are present on tumor cells. These molecules may also be expressed by inflammatory leukocytes and soluble TAA levels may be elevated in RMDs. There has been continuous debate with respect to the possible carcinogenicity of conventional and targeted antirheumatic drugs. Very recent data from registries suggest that neither biologics, nor JAK inhibitors increase cancer risk in arthritis patients. The issue of physiotherapy in rheumatic patients with recent or current cancer has also been controversial. Some modalities, primarily exercise, may be safely applied to patients with RMD and cancer. The second large topic includes paraneoplastic syndromes. Musculoskeletal paraneoplasias are triggered by tumor-derived mediators. These syndromes are sometimes slightly different from the classical RMDs. Various chemotherapies may also be associated with autoimmune side effects. Recently, these immune-related complications have also been observed in cancer patients treated with immune-checkpoint inhibitors. Sex hormone-deprivation therapies, such as aromatase inhibitors and anti-androgens are widely used for the treatment of breast and prostate cancer, respectively. These compounds may induce bone loss and lead to osteoporosis. Finally, primary and secondary malignancies of the musculoskeletal system may also interest rheumatologists. In this review, the clinical, practical aspects of these eight pillars of oncorheumatology will be discussed.
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http://dx.doi.org/10.1016/j.autrev.2020.102658DOI Listing
November 2020

A phase 2, double-blinded, placebo-controlled trial of toll-like receptor 7/8/9 antagonist, IMO-8400, in dermatomyositis.

J Am Acad Dermatol 2020 Aug 8. Epub 2020 Aug 8.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.07.122DOI Listing
August 2020

The risk of fracture and prevalence of osteoporosis is elevated in patients with idiopathic inflammatory myopathies: cross-sectional study from a single Hungarian center.

BMC Musculoskelet Disord 2020 Jul 2;21(1):426. Epub 2020 Jul 2.

Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Móricz Zsigmond út 22, Debrecen, H-4032, Hungary.

Background: The prevalence of osteoporosis and risk of fractures is elevated in rheumatoid arthritis (RA), but we have limited information about the bone mineral density (BMD) and fracture risk in patients with inflammatory myopathies. We intended to ascertain and compare fracture risk, bone mineral density and the prevalence of vertebral fractures in patients with inflammatory myositis and rheumatoid arthritis and to assess the effect of prevalent fractures on the quality of life and functional capacity.

Methods: Fifty-two patients with myositis and 43 patients with rheumatoid arthritis were included in the study. Fracture Risk was determined using FRAX® Calculation Tool developed by the University of Sheffield. Dual energy X-ray absorptiometry and bidirectional thoracolumbar radiographs were performed to assess BMD and vertebral fractures. Quality of life was measured with Short Form-36 (SF-36) and physical function assessment was performed using Health Assessment Questionnaire (HAQ).

Results: We found a significantly elevated fracture risk in RA as compared to myositis patients if the risk assessment was performed without the inclusion of the BMD results. If BMD results and glucocorticoid dose adjustment were taken into account, the differences in fracture risk were no longer significant. The prevalence of osteoporosis was found to be significantly higher in the myositis group (7% vs. 13.5%, p: 0.045), but the fracture prevalence was similar in the two groups (75% vs. 68%). The fracture rates were independently associated with age in the myositis group, and with lower BMD results in the RA patients. The number of prevalent fractures was significantly correlated to poorer physical function in both groups, and poorer health status in the myositis group, but not in the RA group.

Conclusions: Our findings suggest that inflammatory myopathies carry significantly elevated risks for osteoporosis and fractures. These higher risks are comparable to ones detected with RA in studies and strongly affect the physical function and quality of life of patients. Therefore further efforts are required to make the fracture risk assessment reliable and to facilitate the use of early preventive treatments.
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http://dx.doi.org/10.1186/s12891-020-03448-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333418PMC
July 2020

Oncorheumatology: relationship between malignancies and musculoskeletal diseases

Orv Hetil 2020 07;161(28):1151-1165

Klinikai Központ, Onkológiai Klinika,Debreceni Egyetem, Általános Orvostudományi Kar, Debrecen.

Oncorheumatology is the meeting point of tumour formation and rheumatic diseases. Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. In the first group, secondary malignancies associated with rheumatic diseases, role of tumour-associated antigens in rheumatology, the possible carcinogenicity of conventional and targeted antirheumatic drugs and physical therapy of rheumatic patients with recent or current cancer will be discussed. The second large topic includes paraneoplastic syndromes, autoimmune-rheumatic side effects of oncotherapies (chemotherapy and immunotherapy), effects of hormone-deprivation therapies on bone and primary and secondary malignancies of the musculoskeletal system. Orv Hetil. 2020; 161(28): 1151-1165.
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http://dx.doi.org/10.1556/650.2020.31800DOI Listing
July 2020

Identification of a novel autoantigen eukaryotic initiation factor 3 associated with polymyositis.

Rheumatology (Oxford) 2020 05;59(5):1026-1030

Pharmacy and Pharmacology, University of Bath, Bath.

Objectives: To describe the prevalence and clinical associations of autoantibodies to a novel autoantigen, eukaryotic initiation factor 3 (eIF3), detected in idiopathic inflammatory myositis.

Methods: Sera or plasma from 678 PM patients were analysed for autoantigen specificity by radio-labelled protein immunoprecipitation (IPP). Samples immunoprecipitating the same novel autoantigens were further analysed by indirect immunofluorescence and IPP using pre-depleted cell extracts. The autoantigen was identified through a combination of IPP and MALDI-TOF mass spectrometry, and confirmed using commercial antibodies and IPP-western blots. Additional samples from patients with DM (668), DM-overlap (80), PM-overlap (191), systemic sclerosis (150), systemic lupus erythematosus (200), Sjogren's syndrome (40), rheumatoid arthritis (50) and healthy controls (150) were serotyped by IPP as disease or healthy controls.

Results: IPP revealed a novel pattern in three PM patients (0.44%) that was not found in disease-specific or healthy control sera. Indirect immunofluorescence demonstrated a fine cytoplasmic speckled pattern for all positive patients. Mass spectrometry analysis of the protein complex identified the target autoantigen as eIF3, a cytoplasmic complex with a role in the initiation of translation. Findings were confirmed by IPP-Western blotting. The three anti-eIF3-positive patients had no history of malignancy or interstitial lung disease, and had a favourable response to treatment.

Conclusion: We report a novel autoantibody in 0.44% of PM patients directed against a cytoplasmic complex of proteins identified as eIF3. Although our findings need further confirmation, anti-eIF3 appears to correlate with a good prognosis and a favourable response to treatment.
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http://dx.doi.org/10.1093/rheumatology/kez406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188460PMC
May 2020

Retrospective Analysis of Cancer-Associated Myositis Patients over the Past 3 Decades in a Hungarian Myositis Cohort.

Pathol Oncol Res 2020 Jul 23;26(3):1749-1755. Epub 2019 Oct 23.

Faculty of Medicine, Department of Medicine, Division of Clinical Immunology, University of Debrecen, Debrecen, Hungary.

Association between cancer and myositis has been extensively reported and malignancy is a potentially life-threating complication in myositis. In this retrospective study authors give an overview of Hungarian cancer-associated myositis (CAM) patients treated at a single centre managing 450 myositis patients. All patients were diagnosed according to Bohan and Peter. Statistical analysis of disease onset, age, sex, muscle, skin and extramuscular symptoms, muscle enzymes, presence of antibodies, treatment and prognosis was performed. 43 patients could be considered as having CAM. 83.72% had cancer within one year of diagnosis of myositis. Most common localizations were ductal carcinoma of breast and adenocarcinoma of lung. Significant differences were observed between CAM and the non-CAM control patients: DM:PM ratio was 2.31:1 vs. 0.87:1, respectively (p = 0.029), age at diagnosis was 56.60 ± 12.79 vs. 38.88 ± 10.88 years, respectively (p < 0.001). Tumour-treatment was the following: surgical removal in 55.81%, chemotherapy in 51.1%, radiotherapy in 39.53%, hormone treatment in 18.6%, combination therapy in 51.16% of patients. Muscle enzyme levels of patients undergoing surgery were significantly reduced after intervention. 36 patients died (83.72%); 25 DM (83.33%) and 11 PM patients (84.62%); 5 years survival was 15.4% for PM and 27.5% for DM. This study demonstrates that DM, distal muscle weakness, asymmetric Raynaud's phenomenon, older age, ANA-negativity are risk factors for developing malignancy and polymyositis patients have less chance of long-lasting survival. It is very important to think about cancer and follow every single myositis patient in the clinical routine because survival rate of CAM is very poor.
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http://dx.doi.org/10.1007/s12253-019-00756-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297838PMC
July 2020

Dysregulated expression profile of myomiRs in the skeletal muscle of patients with polymyositis.

EJIFCC 2019 Jun 24;30(2):237-245. Epub 2019 Jun 24.

Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary.

MicroRNA (miRNA) research has intensively developed over the past decade. Characterization of dysregulated miRNA expression profiles could give a better understanding of the development of pathological conditions and clinical disorders, such as autoimmune diseases with polygenic etiology, including idiopathic inflammatory myopathies (IIMs). IIMs are a group of rare autoimmune disorders characterized by skeletal weakness and inflammation. Polymyositis (PM) is one of the conditions of autoimmune myopathies with proximal skeletal muscle weakness. A novel group of miRNAs, known as myomiRs are described as striated muscle-specific or muscle-enriched miRNAs. They are involved in myoblast proliferation/differentiation as well as muscle regeneration. To determine the role of myomiRs in the development and progression of PM, we performed an initial skeletal muscle miRNA profiling using microarray technique at diagnosis. The aim of the study was to examine myomiRs expression profile in patients with PM in order to remark the association between the dysregulated myomiRs' expression and the development of the disease. As a results of microarray investigation, most of the myomiRs showed altered expression patterns in the muscle samples of PM patients compared to controls. These results suggest that myomiRs, especially miR-1, miR-133a, miR-208b, miR-486, and miR-499 function in a network, and are associated with the development of PM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599196PMC
June 2019

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.

Ann Rheum Dis 2019 07 28;78(7):996-1002. Epub 2019 May 28.

Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.

Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.

Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.

Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10 and HLA-DRB1*03:01, p=3.25×10), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10) and position 9 of HLA-B (p=7.03×10). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.

Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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http://dx.doi.org/10.1136/annrheumdis-2019-215046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585280PMC
July 2019

Effect of Genetic and Laboratory Findings on Clinical Course of Antisynthetase Syndrome in a Hungarian Cohort.

Biomed Res Int 2018 25;2018:6416378. Epub 2018 Oct 25.

University of Debrecen, Faculty of Medicine, Division of Clinical Immunology, Móricz Zs. krt. 22, 4032 Debrecen, Hungary.

The aim of this study was to determine the clinical, serological, and genetic features of anti-Jo-1 positive antisynthetase patients followed by a Hungarian single centre to identify prognostic markers, which can predict disease phenotypes and disease progression. It was a retrospective study using clinical database of 49 anti-Jo-1 positive patients. 100% of patients exhibited myositis, 73% interstitial lung disease, 88% arthritis, 65% Raynaud's phenomenon, 43% fever, 33% mechanic's hand, and 12% dysphagia. We could detect significant correlation between anti-Jo-1 titer and the CK and CRP levels at disease onset and during disease course. HLA DRB1⁎03 positivity was present in 68.96% of patients, where the CK level at diagnosis was significantly lower compared to the HLA DRB1⁎03 negative patients. HLA DQA1⁎0501-DQB1⁎0201 haplotype was found in 58.62% of patients, but no significant correlation was found regarding any clinical or laboratory features. Higher CRP, ESR level, RF positivity, and the presence of fever or vasculitic skin lesions at the time of diagnosis indicated a higher steroid demand and the administration of higher number of immunosuppressants during the follow-up within anti-Jo-1 positive patients. The organ involvement of the disease was not different in HLA-DRB1⁎0301 positive or negative patients who were positive to the anti-Jo-1 antibody; however, initial CK level was lower in HLA-DRB1⁎0301 positive patients. Distinct laboratory and clinical parameters at diagnosis could be considered as prognostic markers.
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http://dx.doi.org/10.1155/2018/6416378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222225PMC
March 2019

Corneal Involvement of Patients with Polymyositis and Dermatomyositis.

Ocul Immunol Inflamm 2020 16;28(1):58-66. Epub 2018 Nov 16.

Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

: To evaluate corneal parameters in patients with polymyositis (PM) and dermatomyositis (DM) and compare them with those of healthy controls.: A total of 43 PM and 32 DM patients and 93 controls were enrolled in this cross-sectional, observational, case-control study. Corneal parameters were evaluated by Pentacam. Objective clinical tests of dry eye disease (DED) were also performed.: All pachymetric measurements and corneal volumes (CVs) proved to be significantly lower both in PM and DM patients. The values of DM patients were closer to control values than those of the PM patients. For tear break-up time and Schirmer-I test values significant differences were observed between patients and controls, with values decreased both in PM and DM patients.: PM patients rather than DM patients tend to develop thinner and low-volume corneas as compared to controls. Additionally, a high prevalence of DED among both PM and DM patients was also detected.
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http://dx.doi.org/10.1080/09273948.2018.1547407DOI Listing
December 2020

EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a methodology report.

RMD Open 2017 14;3(2):e000507. Epub 2017 Nov 14.

Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.

Objective: To describe the methodology used to develop new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs) and their major subgroups.

Methods: An international, multidisciplinary group of myositis experts produced a set of 93 potentially relevant variables to be tested for inclusion in the criteria. Rheumatology, dermatology, neurology and paediatric clinics worldwide collected data on 976 IIM cases (74% adults, 26% children) and 624 non-IIM comparator cases with mimicking conditions (82% adults, 18% children). The participating clinicians classified each case as IIM or non-IIM. Generally, the classification of any given patient was based on few variables, leaving remaining variables unmeasured. We investigated the strength of the association between all variables and between these and the disease status as determined by the physician. We considered three approaches: (1) a probability-score approach, (2) a sum-of-items approach criteria and (3) a classification-tree approach.

Results: The approaches yielded several candidate models that were scrutinised with respect to statistical performance and clinical relevance. The probability-score approach showed superior statistical performance and clinical practicability and was therefore preferred over the others. We developed a classification tree for subclassification of patients with IIM. A calculator for electronic devices, such as computers and smartphones, facilitates the use of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria.

Conclusions: The new EULAR/ACR classification criteria provide a patient's probability of having IIM for use in clinical and research settings. The probability is based on a score obtained by summing the weights associated with a set of criteria items.
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http://dx.doi.org/10.1136/rmdopen-2017-000507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687535PMC
November 2017

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

Arthritis Rheumatol 2017 12 27;69(12):2271-2282. Epub 2017 Oct 27.

National Institute of Environmental Health Sciences, NIH, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1002/art.40320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846474PMC
December 2017

Long-term treatment of refractory myasthenia gravis with subcutaneous immunoglobulin.

Ther Adv Neurol Disord 2017 Nov 26;10(11):363-366. Epub 2017 Jul 26.

Department of Neurology, University of Debrecen, Clinical Center, Faculty of Medicine, 4032 Debrecen, Móricz Zs. krt. 22, Hungary.

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http://dx.doi.org/10.1177/1756285617722437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642010PMC
November 2017

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

Ann Rheum Dis 2017 12 27;76(12):1955-1964. Epub 2017 Oct 27.

US Department of Health and Human Services, Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA.

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.
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http://dx.doi.org/10.1136/annrheumdis-2017-211468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736307PMC
December 2017

2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects.

Rheumatology (Oxford) 2017 11;56(11):1884-1893

Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

Objective: The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM.

Methods: Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data.

Results: Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference.

Conclusion: Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis.
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http://dx.doi.org/10.1093/rheumatology/kex226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850656PMC
November 2017

The EuroMyositis registry: an international collaborative tool to facilitate myositis research.

Ann Rheum Dis 2018 Jan 30;77(1):30-39. Epub 2017 Aug 30.

Department of Rheumatology, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK.

Aims: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data.

Methods: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtypes, extramuscular involvement, environmental exposures and medications were investigated.

Results: Of 3067 IIM cases, 69% were female. The most common IIM subtype was dermatomyositis (DM) (31%). Smoking was more frequent in connective tissue disease overlap cases (45%, OR 1.44, 95% CI 1.09 to 1.90, p=0.012). Smoking was associated with interstitial lung disease (ILD) (OR 1.32, 95% CI 1.06 to 1.65, p=0.013), dysphagia (OR 1.43, 95% CI 1.16 to 1.77, p=0.001), malignancy ever (OR 1.78, 95% CI 1.36 to 2.33, p<0.001) and cardiac involvement (OR 2.40, 95% CI 1.60 to 3.60, p<0.001).Dysphagia occurred in 39% and cardiac involvement in 9%; either occurrence was associated with higher Health Assessment Questionnaire (HAQ) scores (adjusted OR 1.79, 95% CI 1.43 to 2.23, p<0.001). HAQ scores were also higher in inclusion body myositis cases (adjusted OR 3.85, 95% CI 2.52 to 5.90, p<0.001). Malignancy (ever) occurred in 13%, most commonly in DM (20%, OR 2.06, 95% CI 1.65 to 2.57, p<0.001).ILD occurred in 30%, most frequently in antisynthetase syndrome (71%, OR 10.7, 95% CI 8.6 to 13.4, p<0.001). Rash characteristics differed between adult-onset and juvenile-onset DM cases ('V' sign: 56% DM vs 16% juvenile-DM, OR 0.16, 95% CI 0.07 to 0.36, p<0.001). Glucocorticoids were used in 98% of cases, methotrexate in 71% and azathioprine in 51%.

Conclusion: This large multicentre cohort demonstrates the importance of extramuscular involvement in patients with IIM, its association with smoking and its influence on disease severity. Our findings emphasise that IIM is a multisystem inflammatory disease and will help inform prognosis and clinical management of patients.
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http://dx.doi.org/10.1136/annrheumdis-2017-211868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754739PMC
January 2018

[Clinical features and therapeutic response of our anti-SRP positive patients with myositis].

Orv Hetil 2017 Sep;158(35):1382-1389

Belgyógyászati Intézet, Klinikai Immunológia Tanszék, Debreceni Egyetem Klinikai Központ Debrecen.

Introduction: Idiopathic inflammatory myopathies are a group of clinically heterogeneous diseases, which have been classified by myositis specific antibodies recently. The anti-SRP positive subset of this group is characterized by more severe clinical prognosis than other myositis specific antibody positive types.

Aim: Our goal was to compare 16 anti-SRP positive patients in the Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen with 16 antibody negative ones.

Method: Muscle strength validated in both groups by the manual muscle test proved to be significantly decreased both before and after therapy (χ = 0.006 and 0.019) in the anti-SRP positive group.

Results: Muscle-specific inflammatory laboratory parameters showed significant difference only in case of LDH-levels after therapy. Both groups showed good clinical response to first line steroid treatment, yet the significantly higher rate of second line administration suggests worse therapeutic response of the antibody positive group.

Conclusion: Based on these facts we determined poor clinical prognosis and therapeutic response of the anti-SRP positive group. Orv Hetil. 2017; 158(35): 1382-1389.
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http://dx.doi.org/10.1556/650.2017.30827DOI Listing
September 2017

Pharmacological management of dermatomyositis.

Expert Rev Clin Pharmacol 2017 Oct 17;10(10):1109-1118. Epub 2017 Jul 17.

a Division of Clinical Immunology, Faculty of Medicine , University of Debrecen , Debrecen , Hungary.

Introduction: Dermatomyositis is a rare heterogeneous systemic autoimmune disease with multiple organ involvement which can result in significant disability and mortality. Despite the lack of placebo-controlled trials, glucocorticoids are considered to be the mainstay of initial management. Treatment strategies are mainly based on uncontrolled studies, evidence based guidelines for treatments do not exist. Areas covered: This review provides an overview of the currently available pharmacological treatments in the field of dermatomyositis including conventional immunosuppressants, biologics and topical agents. The role of antibodies in different treatment responses of dermatomyositis related clinicoserological syndromes is also discussed. A PubMed search was performed in order to find relevant literature for this review. Expert commentary: Early recognition and intervention is essential to ameliorate disease outcome. Determination of antibodies provide a useful key in diagnosis, clinical manifestations, malignancy, prognosis, and treatment response and may lead to wider acceptance of personalized medicine. Corticosteroids with adjunctive steroid-sparing immunosuppressive therapies are recommended to treat disease activity, prevent mortality, and reduce long-term disability. Combinations of second-line therapies or newer third-line therapies are used in severe, refractory, or corticosteroid-dependent diseases. Further research is required to assess the role of new therapies.
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http://dx.doi.org/10.1080/17512433.2017.1353910DOI Listing
October 2017

2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

Ann Rheum Dis 2017 May;76(5):792-801

Charles University, Prague, Czech Republic.

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.
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http://dx.doi.org/10.1136/annrheumdis-2017-211400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496443PMC
May 2017

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

Arthritis Rheumatol 2017 05 6;69(5):898-910. Epub 2017 Apr 6.

Charles University, Prague, Czech Republic.

Objective: To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM).

Methods: Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus.

Results: Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001).

Conclusion: The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.
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http://dx.doi.org/10.1002/art.40064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407906PMC
May 2017

Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum.

Arthritis Rheumatol 2017 05 4;69(5):1090-1099. Epub 2017 Apr 4.

Central Manchester University Hospitals NHS Foundation Trust, University of Manchester, Manchester, UK.

Objective: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune-related genes using the Immunochip.

Methods: A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA.

Results: The HLA region was confirmed as the most strongly associated region in IBM (P = 3.58 × 10 ). HLA imputation identified 3 independent associations (with HLA-DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA-DRB1 molecule. No association with anti-cytosolic 5'-nucleotidase 1A-positive status was found independent of HLA-DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non-HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant.

Conclusion: This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide-binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5.
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http://dx.doi.org/10.1002/art.40045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516174PMC
May 2017

Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study.

Autoimmun Rev 2016 Oct 1;15(10):983-93. Epub 2016 Aug 1.

Department of Research, Inova Diagnostics, San Diego, CA, USA. Electronic address:

In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria.
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http://dx.doi.org/10.1016/j.autrev.2016.07.023DOI Listing
October 2016

[New insights of myositis-specific and -associated autoantibodies in juvenile and adult type myositis].

Orv Hetil 2016 Jul;157(30):1179-84

Általános Orvostudományi Kar, Klinikai Központ, Belgyógyászati Intézet, Klinikai Immunológia Tanszék, Debreceni Egyetem Debrecen.

Myositis, which means inflammation of the muscles, is a general term used for inflammatory myopathies. Myositis is a rare idiopathic autoimmune disease. It is believed that environmental factors such as virus, bacteria, parasites, direct injuries, drugs side effect can trigger the immune system of genetically susceptible individuals to act against muscle tissues. There are several types of myositis with the same systemic symptoms such as muscle weakness, fatigue, muscle pain and inflammation. These include dermatomyositis, juvenile dermatomyositis, inclusion-body myositis, polymyositis, orbital myositis and myositis ossificans. Juvenile and adult dermatomyositis are chronic, immune-mediated inflammatory myopathies characterized by progressive proximal muscle weakness and typical skin symptoms. The aim of the authors was to compare the symptoms, laboratory and serological findings and disease course in children and adult patients with idiopathic inflammatory myopathy. Early diagnosis and aggressive immunosuppressive treatment improve the mortality of these patients. Myositis-specific autoantibodies have predictive and prognostic values regarding the associated overlap disease, response to treatment and disease course. The authors intend to lighten the clinical and pathogenetic significance of the new target autoantigens. Orv. Hetil., 2016, 157(29), 1179-1184.
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http://dx.doi.org/10.1556/650.2016.30404DOI Listing
July 2016

[The shades of anti-Jo1 positive antisynthetase syndrome in a Hungarian cohort].

Orv Hetil 2016 Apr;157(15):575-83

Klinikai Immunológiai Tanszék, Debreceni Egyetem, Klinikai Központ Debrecen, Móricz Zs. út 22., 4032.

Introduction: In idiopathic inflammatory myopathies, the presence of anti-Jo-1 antibody defines a distinct clinical phenotype (myositis, arthritis, interstitial lung disease, Raynaud's phenomenon fever, mechanic's hands), called antisynthetase syndrome.

Aim: To determine the demographic data as well as clinical, laboratory and terapeutical features of anti-Jo1 positive patients, followed by the department of the authors.

Method: The medical records of 49 consecutive anti-Jo1 patients were reviewed.

Results: Demographic and clinical results were very similar to those published by other centers. Significant correlation was found between the anti-Jo-1 titer and the creatine kinase and C-reactive protein levels. Distinct laboratory results measured at the time of diagnosis of the disease (C-reactive protein, antigen A associated with Sjogren's syndrome, positive rheumatoid factor), and the presence of certain clinical symptoms (fever, vasculitic skin) may indicate a worse prognosis within the antisyntetase positive patient group.

Conclusion: In the cases above more agressive immunosuppressive therapy may be required.
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http://dx.doi.org/10.1556/650.2016.30400DOI Listing
April 2016

[Clinical features of patients with juvenile and adult dermatomyositis].

Orv Hetil 2015 Sep;156(37):1491-6

Belgyógyászati Intézet, Klinikai Immunológiai Tanszék, Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Debrecen.

Introduction: Juvenile and adult dermatomysitis are chronic, immune-mediated inflammatory myopathies characterized by progressive proximal muscle weakness and typical skin symptoms.

Aim: To compare the symptoms, laboratory and serological findings, treatment and disease course in children and adults suffering from dermatomyositis.

Method: In this retrospective study, juvenile and adult dermatomyositis groups were formed. There were 27 patients with juvenile dermatomyositis (mean age, 8.7 years; mean follow-up time: 104.6 months) and 30 adult patients (mean age, 50.3; mean follow-up time: 58.1 months).

Results: In patients with juvenile dermatomyositis, treatment with intravenous immunoglobulin and cyclosporine A were more frequent as compared to adult patients. Acute onset of the disease was more frequent in adult patients than in those with juvenile disease. In children symptoms of the disease developed gradually.

Conclusions: The findings confirm previously published data showing that there are differences between juvenile and adult patients with dermatomyositis. The authors recommend to follow the patients regularly after reaching remission to avoid bad patient compliance and decrease the number and severity of relapses.
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http://dx.doi.org/10.1556/650.2015.30214DOI Listing
September 2015

Late onset dysferlinopathy mimicking treatment resistant polymyositis.

Joint Bone Spine 2016 May 21;83(3):355-6. Epub 2015 Oct 21.

Division of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.

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http://dx.doi.org/10.1016/j.jbspin.2015.03.017DOI Listing
May 2016

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.

Ann Rheum Dis 2016 Aug 11;75(8):1558-66. Epub 2015 Sep 11.

Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1136/annrheumdis-2015-208119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300750PMC
August 2016