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1.
Arthritis Res Ther ; 22(1): 5, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915059

RESUMO

OBJECTIVE: To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. METHODS: Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. RESULTS: A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. CONCLUSION: While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31303436

RESUMO

OBJECTIVE: Juvenile idiopathic inflammatory myopathies (JIIM) are rare, chronic autoimmune muscle diseases of childhood, with the potential for significant morbidity. Data on long-term outcomes is limited. In this study we investigate correlations between clinical and demographic features with long-term outcomes in a referral population of adult patients with JIIM. METHODS: Forty-nine adults with JIIM were assessed at two referral centers between 1994 and 2016. Features of active disease and damage at a cross-sectional assessment were obtained. Regression modeling was used to examine factors associated with long-term outcomes, defined by the presence of calcinosis or a higher adjusted Myositis Damage Index (MDI) score. A multivariable model of MDI was constructed using factors that were statistically significant in bivariate models. RESULTS: At a median of 11.5 [IQR 4.5-18.9] years following diagnosis, median American College of Rheumatology (ACR) functional class was 2 [1.5-3.0], Health Assessment Questionnaire (HAQ) score was 0.4 out of 3.0 [0.0-1.0], and manual muscle testing (MMT) score was 229 out of 260 [212.6-256.8]. Median MDI score was 6.0 [3.5-8.9], with the most commonly damaged organ systems being cutaneous and musculoskeletal. Factors associated with an elevated MDI score were the presence of erythroderma and other cutaneous manifestations, disease duration, and ACR functional class. Calcinosis was present in 55% of patients. The strongest predictors of calcinosis were disease duration, periungual capillary changes, and younger age at diagnosis. CONCLUSION: In a tertiary referral population, long-term functional outcomes of JIIM are generally favorable, with HAQ scores indicative of mild disability. Although most patients had mild disease activity and virtually all had significant disease damage, severe or systemic damage was rare. Certain clinical features are associated with long-term damage and calcinosis.

3.
Ann Rheum Dis ; 78(7): 988-995, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31018961

RESUMO

OBJECTIVES: Anti-Ro52 autoantibodies are associated with more severe interstitial lung disease (ILD) in adult myositis patients with antiaminoacyl transfer (t)RNA synthetase autoantibodies. However, few studies have examined anti-Ro52 autoantibodies in juvenile myositis. The purpose of this study was to define the prevalence and clinical features associated with anti-Ro52 autoantibodies in a large cohort of patients with juvenile myositis. METHODS: We screened sera from 302 patients with juvenile dermatomyositis (JDM), 25 patients with juvenile polymyositis (JPM) and 44 patients with juvenile connective tissue disease-myositis overlap (JCTM) for anti-Ro52 autoantibodies by ELISA. Clinical characteristics were compared between myositis patients with and without anti-Ro52 autoantibodies. RESULTS: Anti-Ro52 autoantibodies were found in 14% patients with JDM, 12% with JPM and 18% with JCTM. Anti-Ro52 autoantibodies were more frequent in patients with antiaminoacyl tRNA synthetase (64%, p<0.001) and anti-MDA5 (31%, p<0.05) autoantibodies. After controlling for the presence of myositis-specific autoantibodies, anti-Ro52 autoantibodies were associated with the presence of ILD (36% vs 4%, p<0.001). Disease course was more frequently chronic, remission was less common, and an increased number of medications was received in anti-Ro52 positive patients. CONCLUSIONS: Anti-Ro52 autoantibodies are present in 14% of patients with juvenile myositis and are strongly associated with anti-MDA5 and antiaminoacyl tRNA synthetase autoantibodies. In all patients with juvenile myositis, those with anti-Ro52 autoantibodies were more likely to have ILD. Furthermore, patients with anti-Ro52 autoantibodies have more severe disease and a poorer prognosis.

4.
Methods Mol Biol ; 1855: 417-436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30426436

RESUMO

This report discusses recent methods of sample preparation and gel electrophoresis for 35S immunoprecipitation (IP) and IP western blotting. In both methods, IP is used to obtain purified proteins, and sodium dodecyl sulfate polyacrylamide gel electrophoresis is used to separate the proteins on a gel. In 35S IP, the proteins are radiolabeled and visualized on film by fluorography; in IP blotting, proteins are transferred onto nitrocellulose paper, and antibodies are used to detect specific proteins. A similar IP and SDS-PAGE method can be used for both procedures, but IP blotting has the potential advantages of improvement in sensitivity for low-abundance proteins and enhanced specificity for identification of proteins from a mixture. Some of the technical adaptations discussed here to facilitate IP blotting and avoid loss of beads or purified proteins may also be useful for 35S IP.


Assuntos
Western Blotting/métodos , Eletroforese em Gel de Poliacrilamida/métodos , Imunoprecipitação/métodos , Proteínas/análise , Animais , Colódio/química , Humanos , Proteínas/isolamento & purificação , Radioisótopos de Enxofre/análise
5.
Rheumatology (Oxford) ; 57(11): 1956-1963, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30016492

RESUMO

Objective: We examined features of clinically amyopathic JDM (CAJDM), in which patients have characteristic rashes with little to no evidence of muscle involvement, to determine whether this is a distinct phenotype from JDM. Methods: Demographic, clinical, laboratory and treatment data from 12 (9 hypomyopathic, 3 amyopathic) patients meeting modified Sontheimer criteria for CAJDM and from 60 matched JDM patients meeting Bohan and Peter criteria were examined. Differences were evaluated by Fisher's exact and Mann-Whitney tests, random forests and logistic regression analysis. Results: Nine (75%) CAJDM patients had anti-p155/140 (transcriptional intermediary factor 1), one (8.3%) anti-melanoma differentiation-associated gene 5 autoantibodies and two (16.7%) were myositis autoantibody negative. CAJDM patients were younger at diagnosis and frequently had mild disease at onset. CAJDM patients had less frequent myalgias, arthritis, contractures, calcinosis, dysphagia, abdominal pain and fatigue. The muscle, skeletal and overall clinical scores were lower in CAJDM. Serum muscle enzymes were less frequently increased in CAJDM, and peak values were lower. CAJDM patients received fewer medications compared with JDM patients. Only 50% of CAJDM patients received oral prednisone, but the maximum dose and treatment duration did not differ from JDM. At a median follow-up of 2.9 years, CAJDM patients had no documented functional disability, and none developed weakness, calcinosis, interstitial lung disease or lipodystrophy. Multivariable modelling revealed a lower skeletal score and less frequent myalgias as the most important factors in distinguishing CAJDM from JDM. Conclusion: CAJDM may be distinguished from JDM, in that they often have p155/140 (transcriptional intermediary factor 1) autoantibodies, have fewer systemic manifestations and receive less therapy.


Assuntos
Autoanticorpos/sangue , Dermatomiosite/diagnóstico , Fatores Etários , Criança , Pré-Escolar , Dermatomiosite/sangue , Dermatomiosite/imunologia , Diagnóstico Diferencial , Feminino , Humanos , Helicase IFIH1 Induzida por Interferon/imunologia , Masculino , Proteínas Nucleares/imunologia , Fatores de Transcrição/imunologia
6.
Semin Arthritis Rheum ; 48(3): 513-522, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29773230

RESUMO

OBJECTIVE: Few controlled studies are available to guide treatment decisions in juvenile dermatomyositis (JDM). This study evaluated therapies received, changes of treatment over time, and factors associated with medication choices in JDM. METHODS: We performed a retrospective analysis of the number and type of therapies and duration of treatment for 320 patients with JDM enrolled in a North American registry. Kaplan-Meier and logistic regression analysis were used to assess the association of demographic and clinical features and autoantibodies with medication usage. RESULTS: High-dose oral prednisone was the primary therapy given to 99% of patients. 1997 was determined to be a threshold year for increasing usage of medications other than prednisone. The median time to half the initial oral prednisone dose was shorter in patients diagnosed after vs. before 1997 (10 vs. 19 months, P < 0.01). Patients received intravenous methylprednisolone (IVMP), methotrexate, intravenous immunoglobulin, antimalarial drugs, and combination therapy more frequently when diagnosed after 1997. IVMP was frequently received by patients with severe illness onset, anti-p155/140 (anti-TIF1) and anti-MJ (anti-NXP2) autoantibodies. Treatment with methotrexate was associated with older age at diagnosis and anti-MJ autoantibodies, while antimalarial therapy was associated with anti-p155/140 autoantibodies and mild onset severity. CONCLUSION: Oral prednisone has been the mainstay of therapy in JDM, and prednisone was reduced faster in patients diagnosed after 1997 when there was also an increase in other medications. Specific medications received by patients with JDM correlated with year and age at diagnosis, myositis autoantibodies, onset severity, and illness features.


Assuntos
Antimaláricos/uso terapêutico , Dermatomiosite/tratamento farmacológico , Glucocorticoides/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Metilprednisolona/uso terapêutico , Prednisona/uso terapêutico , Adolescente , Fatores Etários , Idade de Início , Autoanticorpos/sangue , Criança , Pré-Escolar , Dermatomiosite/sangue , Quimioterapia Combinada , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
7.
Semin Arthritis Rheum ; 48(3): 504-512, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29703532

RESUMO

OBJECTIVE: Cigarette smoking is associated with immune-mediated disorders. We explored the contribution of smoking to polymyositis (PM) and dermatomyositis (DM) phenotypes and attempted to determine whether cigarette smoking effects differ by race and genotype. METHODS: Associations of tobacco smoking with disease features, autoantibodies, HLA types, and race were evaluated using multiple logistic regressions in 465 patients. RESULTS: Caucasian ever-smokers (n = 140) were more likely to have PM (adjusted OR = 2.24, 95% CI: 1.41\x963.57), anti-synthetase (adjusted OR = 1.93, 95% CI: 1.12\x963.34) and anti-Jo-1 autoantibodies (adjusted OR = 1.94, 95% CI: 1.08\x963.46) and less likely to have anti-p155/140 autoantibodies (adjusted OR = 0.36, 95% CI: 0.14\x960.92). In Caucasians, ever-smokers had a greater interstitial lung disease (ILD) frequency than never-smokers, while in African-Americans this relationship was inverted, but neither trend reached statistical significance. Pack-years of cigarette smoking showed significant positive associations with PM (adjusted OR = 1.02, 95% CI: 1.002\x961.04) and ILD (adjusted OR = 1.02, 95% CI: 1.001\x961.03) and was inversely associated with anti-p155/140 autoantibodies (adjusted OR = 0.93, 95% CI: 0.87\x960.99) in Caucasians. Caucasian heavy smokers (=20 pack-years) were more likely to have PM (adjusted OR = 2.52, 95% CI: 1.25\x965.09), ILD (adjusted OR = 2.48, 95% CI: 1.23\x965.00) and anti-Jo-1 autoantibodies (adjusted OR = 2.65, 95% CI: 1.16\x966.08) than never-smokers. In Caucasians, compared to never-smokers without HLA-DRB1*03:01 allele, ever-smokers with HLA-DRB1*03:01 allele had the highest odds of PM, ILD, ASA, and anti-Jo-1 autoantibodies. Risks for those with only one of these two factors were intermediate. An inverse pattern was observed regarding anti-p155/140 autoantibodies. CONCLUSION: Tobacco smoking was associated with clinical and autoantibody phenotypes in Caucasians. Our findings also suggest possible interactions among HLA-DRB1*03:01 and smoking on the risk of PM and ILD, as well as, anti-synthetase, anti-Jo-1, and anti-p155/140 autoantibodies in Caucasians.


Assuntos
Autoanticorpos/sangue , Fumar Cigarros/sangue , Dermatomiosite/diagnóstico , Polimiosite/diagnóstico , Adulto , Dermatomiosite/sangue , Dermatomiosite/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimiosite/sangue , Polimiosite/complicações
8.
Ann Rheum Dis ; 77(5): 714-719, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29363513

RESUMO

OBJECTIVES: Autoantibodies recognising cytosolic 5'-nucleotidase 1A (NT5C1A) are found in adult patients with myositis and other autoimmune diseases. They are especially prevalent in adults with inclusion body myositis (IBM), in which they are associated with more severe weakness and higher mortality. This study was undertaken to define the prevalence and clinical features associated with anti-NT5C1A autoantibodies in juvenile myositis. METHODS: We screened sera from 380 patients with juvenile myositis, 30 patients with juvenile idiopathic arthritis (JIA) and 92 healthy control children for anti-NT5C1A autoantibodies. Clinical characteristics were compared between patients with myositis with and without anti-NT5C1A autoantibodies. RESULTS: Anti-NT5C1A autoantibodies were present in 102 of 380 (27%) patients with juvenile myositis and in 11 of 92 (12%) healthy control children (P=0.002) and 27% of children with JIA (P=0.05 vs controls). Sera of 83 of 307 (27%) patients with juvenile dermatomyositis and 16 of 46 (35%) patients with juvenile overlap myositis were anti-NT5C1A autoantibody-positive (P<0.01 vs healthy controls for each), but sera of only 3 of 27 (11%) patients with juvenile polymyositis were anti-NT5C1A-positive. Patients with juvenile myositis with and without anti-NT5C1A autoantibodies had similar clinical phenotypes. However, patients with anti-NT5C1A autoantibody-positive myositis had greater pulmonary symptoms at diagnosis (P=0.005), more frequent hospitalisations (P=0.01) and required a larger number of medications (P<0.001). CONCLUSION: Anti-NT5C1A autoantibodies are present in more than one-quarter of children with juvenile myositis and JIA compared with only 12% of healthy children, suggesting they are myositis-associated in children. As in adults with IBM, patients with juvenile myositis with anti-NT5C1A autoantibodies have more severe disease.


Assuntos
5'-Nucleotidase/imunologia , Autoanticorpos/sangue , Dermatomiosite/sangue , Polimiosite/sangue , Índice de Gravidade de Doença , Artrite Juvenil/sangue , Artrite Juvenil/imunologia , Autoanticorpos/imunologia , Criança , Dermatomiosite/imunologia , Feminino , Humanos , Masculino , Fenótipo , Polimiosite/imunologia
9.
Medicine (Baltimore) ; 96(3): e5694, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28099331

RESUMO

The general aim of this study was to evaluate the disease spectrum in patients presenting with a pure polymyositis (pPM) phenotype. Specific objectives were to characterize clinical features, autoantibodies (aAbs), and membrane attack complex (MAC) in muscle biopsies of patients with treatment-responsive, statin-exposed necrotizing autoimmune myositis (NAM). Patients from the Centre hospitalier de l'Université de Montréal autoimmune myositis (AIM) Cohort with a pPM phenotype, response to immunosuppression, and follow-up ≥3 years were included. Of 17 consecutive patients with pPM, 14 patients had a NAM, of whom 12 were previously exposed to atorvastatin (mean 38.8 months). These 12 patients were therefore suspected of atorvastatin-induced AIM (atorAIM) and selected for study. All had aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and none had overlap aAbs, aAbs to signal recognition particle, or cancer. Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram [EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). At diagnosis, 10/12 (83%) patients had stage 3 myopathy (mean CK elevation: 7247 U/L). The presenting mode was stage 1 in 6 patients (50%) (mean CK elevation: 1540 U/L), all of whom progressed to stage 3 (mean delay: 37 months) despite atorvastatin discontinuation. MAC deposition was observed in all muscle biopsies (isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, or mixed pattern). Oral corticosteroids alone failed to normalize CKs and induce remission. Ten patients (83%) received intravenous immune globulin (IVIG) as part of an induction regimen. Of 10 patients with ≥1 year remission on stable maintenance therapy, IVIG was needed in 50%, either with methotrexate (MTX) monotherapy or combination immunosuppression. In the remaining patients, MTX monotherapy or combination therapy maintained remission without IVIG. AtorAIM emerged as the dominant entity in patients with a pPM phenotype and treatment-responsive myopathy. Isolated CK elevation was the mode of presentation of atorAIM. The new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Statin-induced AIM should be included in the differential diagnosis of asymptomatic hyperCKemia. Three patterns of MAC deposition, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy.


Assuntos
Atorvastatina/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Polimiosite/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Quimioterapia de Indução , Estudos Longitudinais , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Polimiosite/tratamento farmacológico , Polimiosite/metabolismo , Polimiosite/patologia
10.
Arthritis Care Res (Hoboken) ; 69(7): 1088-1094, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28129483

RESUMO

OBJECTIVE: Autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are associated with statin exposure, the HLA allele DRB1*11:01, and necrotizing muscle biopsies in adult myositis patients. The aim of this study was to characterize the features of juvenile anti-HMGCR-positive myositis patients. METHODS: The sera of 440 juvenile myositis patients were screened for anti-HMGCR autoantibodies. Demographic and clinical features, responses to therapy, and HLA alleles were assessed. The features of anti-HMGCR-positive patients were compared to those of previously described adult patients with this autoantibody and to children with other myositis-specific autoantibodies (MSAs). RESULTS: Five of 440 patients (1.1%) were anti-HMGCR-positive; none had taken statin medications. Three patients had rashes characteristic of juvenile dermatomyositis and 2 patients had immune-mediated necrotizing myopathies. The median highest creatine kinase (CK) level of anti-HMGCR-positive subjects was 17,000 IU/liter. All patients had severe proximal muscle weakness, distal weakness, muscle atrophy, joint contractures, and arthralgias, which were all more prevalent in HMGCR-positive subjects compared to MSA-negative patients or those with other MSAs. Anti-HMGCR-positive patients had only partial responses to multiple immunosuppressive medications, and their disease often took a chronic course. The DRB1*07:01 allele was present in all 5 patients, compared to 26.25% of healthy controls (corrected P = 0.01); none of the 5 juvenile patients had DRB1*11:01. CONCLUSION: Compared to children with other MSAs, muscle disease appears to be more severe in those with anti-HMGCR autoantibodies. Like adults, children with anti-HMGCR autoantibodies have severe weakness and high CK levels. In contrast to adults, in anti-HMGCR-positive children, there is a strong association with HLA-DRB1*07:01.


Assuntos
Acil Coenzima A/sangue , Autoanticorpos/sangue , Miosite/sangue , Miosite/diagnóstico , Proteínas do Tecido Nervoso/sangue , Proteínas de Ligação a RNA/sangue , Índice de Gravidade de Doença , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino
11.
Pediatr Rheumatol Online J ; 14(1): 64, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27894310

RESUMO

BACKGROUND: Dystrophic calcifications may occur in patients with J uvenile Idiopathic Inflammatory Myopathy (JIIM) as well as other connective tissue and metabolic diseases, but a reliable method of measuring the volume of these calcifications has not been established. The purpose of this study is to determine the feasibility of low dose, limited slice, Computed Tomography (CT) to measure objectively in-situ calcification volumes in patients with JIIM over time. METHODS: Ten JIIM patients (eight JDM, two Overlap) with calcifications were prospectively recruited over a 2-year period to undergo two limited, low dose, four-slice CT scans. Calculation of the volume of calcifications used a CT post processing workstation. Additional patient data included: Disease Activity Scores (DAS), Childhood Myositis Assessment Scale (CMAS), myositis specific antibodies (MSA), and the TNFα-308 promoter region A/G polymorphism. Statistical analysis utilized the Pearson correlation coefficient, the paired t-test and descriptive statistics. RESULTS: Ten JIIM, mean age 14.54 ± 4.54 years, had a duration of untreated disease of 8.68 ± 5.65 months  MSA status: U1RNP (1), PM-Scl (1), Ro (1, 4 indeterminate), p155/140 (2), MJ (3), Mi-2 indeterminate (1), negative (3). 4/8 JDM (50%) were TNF-α-308 A+. Overall, the calcification volumes tended to decrease from the first to the second CT study by 0.5 cm3 (from 2.79 ± 1.98 cm3 to 2.29 ± 2.25 cm3). The average effective radiation dose was 0.007 ± 0.002, 0.010 ± 0.005, and 0.245 mSv for the upper extremity, lower extremity and chest, respectively (compared to a standard chest x-ray-- 0.02mSV effective dosage). CONCLUSION: We conclude: 1) the limited low dose CT technique provides objective data about volume of the calcifications in JIIM; 2) measuring the volume of calcifications in an extremity is associated with minimal radiation exposure; 3) This method may be useful to evaluate the efficacy of therapies for JIIM dystrophic calcification.


Assuntos
Calcinose/diagnóstico por imagem , Miosite/diagnóstico por imagem , Adolescente , Calcinose/patologia , Criança , Estudos de Viabilidade , Feminino , Humanos , Masculino , Miosite/patologia , Projetos Piloto , Doses de Radiação , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
12.
Arthritis Rheumatol ; 68(3): 761-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26474155

RESUMO

OBJECTIVE: To identify early factors associated with disease course in patients with juvenile idiopathic inflammatory myopathies (IIMs). METHODS: Univariable and multivariable multinomial logistic regression analyses were performed in a large juvenile IIM registry (n = 365) and included demographic characteristics, early clinical features, serum muscle enzyme levels, myositis autoantibodies, environmental exposures, and immunogenetic polymorphisms. RESULTS: Multivariable associations with chronic or polycyclic courses compared to a monocyclic course included myositis-specific autoantibodies (multinomial odds ratio [OR] 4.2 and 2.8, respectively), myositis-associated autoantibodies (multinomial OR 4.8 and 3.5), and a documented infection within 6 months of illness onset (multinomial OR 2.5 and 4.7). A higher overall clinical symptom score at diagnosis was associated with chronic or monocyclic courses compared to a polycyclic course. Furthermore, severe illness onset was associated with a chronic course compared to monocyclic or polycyclic courses (multinomial OR 2.1 and 2.6, respectively), while anti-p155/140 autoantibodies were associated with chronic or polycyclic courses compared to a monocyclic course (multinomial OR 3.9 and 2.3, respectively). Additional univariable associations of a chronic course compared to a monocyclic course included photosensitivity, V-sign or shawl sign rashes, and cuticular overgrowth (OR 2.2-3.2). The mean ultraviolet index and highest ultraviolet index in the month before diagnosis were associated with a chronic course compared to a polycyclic course in boys (OR 1.5 and 1.3), while residing in the Northwest was less frequently associated with a chronic course (OR 0.2). CONCLUSION: Our findings indicate that myositis autoantibodies, in particular anti-p155/140, and a number of early clinical features and environmental exposures are associated with a chronic course in patients with juvenile IIM. These findings suggest that early factors, which are associated with poorer outcomes in juvenile IIM, can be identified.


Assuntos
Miosite/fisiopatologia , Autoanticorpos/análise , Criança , Doença Crônica , Exposição Ambiental , Feminino , Humanos , Modelos Logísticos , Masculino , Miosite/genética , Miosite/imunologia , Polimorfismo Genético , Sistema de Registros
13.
Methods Mol Biol ; 1312: 327-42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26044015

RESUMO

Combining the procedures of immunoprecipitation and immunoblotting can help overcome some of the limitations of each separate procedure. Immunoblotting can identify immunoprecipitated proteins more specifically and with higher sensitivity than nonspecific protein stains or autoradiography. Immunoprecipitation can enrich proteins of interest to improve sensitivity for detection when compared with immunoblotting of whole cell extracts. Recently, immunoprecipitation-blotting helped us characterize a new autoantibody, anti-p155, and to test for the presence of the autoantibody in patient sera to study its clinical associations. The procedure for immunoprecipitation-blotting, with specific reference to this autoantibody test ("reverse" immunoprecipitation-blotting), is reported here in detail.


Assuntos
Western Blotting/métodos , Imunoprecipitação/métodos , Proteínas/análise , Proteínas/isolamento & purificação , Anticorpos Monoclonais/imunologia , Eletroforese em Gel de Poliacrilamida , Humanos , Limite de Detecção , Proteínas/química , Proteínas/imunologia , Sefarose/química , Proteína Estafilocócica A/análise , Proteína Estafilocócica A/química , Proteína Estafilocócica A/imunologia , Proteína Estafilocócica A/isolamento & purificação
14.
Medicine (Baltimore) ; 93(24): 383-94, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25500708

RESUMO

Autoimmune myositis encompasses various myositis-overlap syndromes, each being identified by the presence of serum marker autoantibodies. We describe a novel myositis-overlap syndrome in 4 patients characterized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes. The clinical phenotype was characterized by prominent myositis in association with erosive, anti-CCP, and rheumatoid factor-positive arthritis, trigeminal neuralgia, mild interstitial lung disease, Raynaud phenomenon, and weight loss. The myositis was typically chronic, relapsing, and refractory to corticosteroids alone, but remitted with the addition of a second immunomodulating drug. There was no clinical or laboratory evidence for liver disease. The prognosis was good with 100% long-term survival (mean follow-up 19.5 yr).By indirect immunofluorescence on HEp-2 cells, sera from all 4 patients displayed a high titer of antinuclear autoantibodies (ANA) with a distinct punctate peripheral (rim) fluorescent pattern of the nuclear envelope characteristic of nuclear pore complexes. Reactivity with nuclear pore complexes was confirmed by immunoelectron microscopy. In a cohort of 100 French Canadian patients with autoimmune myositis, the nuclear pore complex fluorescent ANA pattern was restricted to these 4 patients (4%). It was not observed in sera from 393 adult patients with systemic sclerosis (n = 112), mixed connective tissue disease (n = 35), systemic lupus (n = 94), rheumatoid arthritis (n = 45), or other rheumatic diseases (n = 107), nor was it observed in 62 normal adults.Autoantibodies to nuclear pore complexes were predominantly of IgG isotype. No other IgG autoantibody markers for defined connective tissue diseases or overlap syndromes were present, indicating a selective and highly focused immune response. In 3 patients, anti-nuclear pore complex autoantibody titers varied in parallel with myositis activity, suggesting a pathogenic link to pathophysiology. The nuclear pore complex proteins, that is, nucleoporins (nup), recognized by these sera were heterogeneous and included Nup358/RanBP2 (n = 2 patients), Nup90 (n = 1), Nup62 (n = 1), and gp210 (n = 1). Taken together the data suggest that nup autoantigens themselves drive the anti-nup autoimmune response. Immunogenetically, the 4 patients shared the DQA1*0501 allele associated with an increased risk for autoimmune myositis.In conclusion, we report an apparent novel subset of autoimmune myositis in our population of French Canadian patients with connective tissue diseases. This syndrome is recognized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes that react with nups, consistent with an "anti-nup syndrome."


Assuntos
Anticorpos Antinucleares/imunologia , Doenças Autoimunes/imunologia , Miosite/imunologia , Poro Nuclear/imunologia , Adulto , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Miosite/diagnóstico , Miosite/tratamento farmacológico , Prognóstico , Síndrome
15.
Medicine (Baltimore) ; 93(24): 318-32, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25500701

RESUMO

Dermatomyositis (DM) is a major clinical subset of autoimmune myositis (AIM). The characteristic DM rash (Gottron papules, heliotrope rash) and perifascicular atrophy at skeletal muscle biopsy are regarded as specific features for this diagnosis. However, new concepts are challenging the current definition of DM. A modified Bohan and Peter classification of AIM was proposed in which the core concept was the inclusion of the diagnostic significance of overlap connective tissue disease features. In this clinical classification, a DM rash in association with myositis in the absence of overlap features indicates a diagnosis of pure DM. However, overlap features in association with myositis allow a diagnosis of overlap myositis (OM), irrespective of the presence or absence of the DM rash. Perifascicular atrophy may be present in both pure DM and OM. Recently, the presence of perifascicular atrophy in myositis without a DM rash was proposed as diagnostic of a novel entity, adermatopathic DM. We conducted the present study to evaluate these new concepts to further differentiate pure DM from OM.Using the modified Bohan and Peter classification, we performed a follow-up study of a longitudinal cohort of 100 consecutive adult French Canadian patients with AIM, including 44 patients with a DM phenotype, defined as a DM rash, and/or DM-type calcinosis, and/or the presence of perifascicular atrophy on muscle biopsy. A detailed evaluation was performed for overlap features, the extent and natural history of the DM rash, adermatopathic DM, DM-specific and overlap autoantibodies by protein A immunoprecipitation on coded serum samples, and associations with cancer and survival.Two distinct subsets were identified in patients with a DM phenotype: pure DM (n = 24) and OM with DM features, or OMDM (n = 20). In pure DM, the DM rash was a dominant finding. It was the first disease manifestation, was always present at the time of myositis diagnosis, and was associated with a high cutaneous score and chronicity. Concurrent heliotrope rash and Gottron papules (positive predictive value [PPV] 91%), as well as the V-sign and/or shawl sign (PPV 100%), were diagnostic of pure DM. Anti-Mi-2, anti-MJ, and anti-p155 autoantibodies were present in 50% of pure DM patients and were restricted to this subset (PPV 100%). Cancer was present in 21% of pure DM patients. The 15-year survival was excellent (92%).In contrast, in patients with OMDM, the first manifestation was proximal muscle weakness or other skeletal muscle-related complaints. The DM rash appeared at diagnosis or at follow-up, was associated with a low cutaneous extent score and was transient. Adermatopathic DM, which was absent in pure DM, was highly predictive (PPV 100%) of OMDM. Overlap autoantibodies (including anti-Jo-1, anti-PL-7, anti-PM-Scl, anti-U1RNP, and/or anti-U5-RNP) were found in 70% of OMDM patients. OMDM was not associated with cancer, but the 15-year survival was significantly decreased (65%).Perifascicular atrophy occurred as commonly in OMDM (n = 6/20, 30%) as in pure DM (n = 4/24, 17%) patients. These 6 OMDM patients had adermatopathic DM at myositis diagnosis, and only 1 of them developed a DM rash at follow-up, emphasizing the lack of specificity of perifascicular atrophy for pure DM.In conclusion, using the modified Bohan and Peter classification of AIM allowed identification of OMDM, a new clinical subset of OM. Furthermore, identification of OMDM allowed recognition of pure DM as a new entity that was distinct from OMDM or from OM without DM features. However, the absolute specificity of a DM rash and perifascicular muscle atrophy for the diagnosis of pure DM was lost. The distinctive clinical manifestations and autoantibody profiles presented are proposed as diagnostic criteria to differentiate pure DM from OMDM.


Assuntos
Dermatomiosite/diagnóstico , Miosite/diagnóstico , Adolescente , Adulto , Idoso , Atrofia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Dermatomiosite/patologia , Diagnóstico Diferencial , Exantema/diagnóstico , Exantema/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/patologia , Pele/patologia , Adulto Jovem
16.
Arthritis Care Res (Hoboken) ; 66(5): 732-40, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24151254

RESUMO

OBJECTIVE: Because juvenile idiopathic inflammatory myopathies (IIMs) are potentially life-threatening systemic autoimmune diseases, we examined risk factors for juvenile IIM mortality. METHODS: Mortality status was available for 405 patients (329 with juvenile dermatomyositis [DM], 30 with juvenile polymyositis [PM], and 46 with juvenile connective tissue disease-associated myositis [CTM]) enrolled in nationwide protocols. Standardized mortality ratios (SMRs) were calculated using US population statistics. Cox regression analysis was used to assess univariable associations with mortality, and random survival forest (RSF) classification and Cox regression analysis were used for multivariable associations. RESULTS: Of 17 deaths (4.2% overall mortality), 8 (2.4%) were in juvenile DM patients. Death was related to the pulmonary system (primarily interstitial lung disease [ILD]) in 7 patients, gastrointestinal system in 3, and multisystem in 3, and of unknown etiology in 4 patients. The SMR for juvenile IIMs overall was 14.4 (95% confidence interval [95% CI] 12.2-16.5) and was 8.3 (95% CI 6.4-10.3) for juvenile DM. The top mortality risk factors in the univariable analysis included clinical subgroup (juvenile CTM, juvenile PM), antisynthetase autoantibodies, older age at diagnosis, ILD, and Raynaud's phenomenon at diagnosis. In multivariable analyses, clinical subgroup, illness severity at onset, age at diagnosis, weight loss, and delay to diagnosis were the most important predictors from RSF; clinical subgroup and illness severity at onset were confirmed by multivariable Cox regression analysis. CONCLUSION: Overall mortality was higher in juvenile IIM patients, and several early illness features were identified as risk factors. Clinical subgroup, antisynthetase autoantibodies, older age at diagnosis, and ILD are also recognized as mortality risk factors in adult myositis.


Assuntos
Miosite/diagnóstico , Miosite/mortalidade , Adolescente , Adulto , Criança , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Masculino , Fatores de Risco , Adulto Jovem
17.
Int J Rheum Dis ; 16(6): 674-80, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24330273

RESUMO

AIM: Prolidase deficiency is a rare autosomal recessive disease in which one of the last steps of collagen metabolism, cleavage of proline-containing dipeptides, is impaired. Only about 93 patients have been reported with about 10% also having systemic lupus erythematosus (SLE). METHODS: We studied a large extended Amish pedigree with four prolidase deficiency patients and three heterozygous individuals for lupus-associated autoimmunity. Eight unaffected Amish children served as normal controls. Prolidase genetics and enzyme activity were confirmed. Antinuclear antibodies (ANA) were determined using indirect immunofluorescence and antibodies against extractable nuclear antigens were determined by various methods, including double immunodiffusion, immunoprecipitation and multiplex bead assay. Serum C1q levels were determined by enzyme-linked immunosorbent assay. RESULTS: Two of the four homozygous prolidase deficiency subjects had a positive ANA. One had anti-double-stranded DNA, while another had precipitating anti-Ro. By the simultaneous microbead assay, three of the four had anti-Sm and anti-chromatin. One of the three heterozygous subjects had a positive ANA and immunoprecipitation of a 75 000 molecular weight protein. The unaffected controls had normal prolidase activity and were negative for autoantibodies. CONCLUSIONS: Prolidase deficiency may be associated with the loss of immune tolerance to lupus-associated autoantigens even without clinical SLE.


Assuntos
Anticorpos Antinucleares/sangue , Autoantígenos/imunologia , Autoimunidade , Lúpus Eritematoso Sistêmico/imunologia , Deficiência de Prolidase/imunologia , Tolerância a Antígenos Próprios , Amish/genética , Antígenos Nucleares/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C1q/análise , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Linhagem , Fenótipo , Deficiência de Prolidase/sangue , Deficiência de Prolidase/etnologia , Deficiência de Prolidase/genética , Estados Unidos/epidemiologia
18.
Arthritis Care Res (Hoboken) ; 65(12): 1969-75, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23925923

RESUMO

OBJECTIVE: To differentiate juvenile polymyositis (PM) and muscular dystrophy, both of which may present with chronic muscle weakness and inflammation. METHODS: We studied 39 patients with probable or definite juvenile PM and 9 patients with muscular dystrophies who were initially misdiagnosed as having juvenile PM. Differences in demographic, clinical, and laboratory results; outcomes; and treatment responses were evaluated by Fisher's exact and rank sum tests. Random forests classification analysis and logistic regression were performed to examine significant differences in multivariable models. RESULTS: Clinical features and serum muscle enzyme levels were similar between juvenile PM and dystrophy patients, except 89% of dystrophy patients had muscle atrophy compared with 46% of juvenile PM patients. Dystrophy patients had a longer delay to diagnosis (median 12 versus 4 months) and were less frequently hospitalized than juvenile PM patients (22% versus 74%). No dystrophy patients, but 54% of juvenile PM patients, had a myositis autoantibody. Dystrophy patients more frequently had myopathic features on muscle biopsy, including diffuse variation of myofiber size, fiber hypertrophy, and myofiber fibrosis (44-100% versus 8-53%). Juvenile PM patients more frequently had complex repetitive discharges on electromyography and a complete response to treatment with prednisone or other immunosuppressive agents than dystrophy patients (44% versus 0%). Random forests analysis revealed that the most important features in distinguishing juvenile PM from dystrophies were myositis autoantibodies, clinical muscle atrophy, and myofiber size variation on biopsy. Logistic regression confirmed muscle atrophy, myofiber fibrosis, and hospitalization as significant predictors. CONCLUSION: Muscular dystrophy can present similarly to juvenile PM. Selected clinical and laboratory features are helpful in combination in distinguishing these conditions.


Assuntos
Diagnóstico Diferencial , Distrofias Musculares/diagnóstico , Polimiosite/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Distrofias Musculares/sangue , Distrofias Musculares/fisiopatologia , Polimiosite/sangue , Polimiosite/fisiopatologia
19.
Medicine (Baltimore) ; 92(4): 223-43, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23877355

RESUMO

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.


Assuntos
Autoanticorpos/genética , Miosite/genética , Miosite/imunologia , Adolescente , Adulto , Anticorpos Antinucleares/análise , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Modelos Logísticos , Masculino , Modelos Estatísticos , Análise Multivariada , Fenótipo
20.
Arthritis Rheum ; 65(7): 1934-41, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23658122

RESUMO

OBJECTIVE: Genetic and environmental factors may contribute to the etiology of the juvenile idiopathic inflammatory myopathies (IIMs), which are systemic autoimmune diseases that are characterized by muscle and skin inflammation. We undertook this study to investigate the association between ultraviolet radiation (UVR) exposure and the clinical and autoantibody expression of juvenile IIM. METHODS: The relationship between UVR exposure in the month before symptom onset and the prevalence of juvenile dermatomyositis (DM), compared to juvenile polymyositis (PM), was assessed in 298 juvenile IIM patients. Among the patients with juvenile DM, the association between UVR exposure and presence of myositis autoantibodies was assessed. Regression models were stratified by sex and race. The association between the regional UV index in US geoclimatic zones and the clinical and autoantibody subgroups was examined by weighted least squares regression analysis. RESULTS: Among girls in this population, the odds of having juvenile DM, compared to juvenile PM, increased per unit increase in the patients' highest UV index in the month before symptom onset (odds ratio [OR] 1.18, 95% confidence interval 1.00-1.40). Moreover, both the mean and highest UV indices were associated with increasing odds of having anti-p155/140 autoantibodies, with the strongest odds in white males (ORs of 1.30 and 1.23, respectively). No association was observed between the UV index and presence of anti-MJ autoantibodies or lack of any myositis autoantibodies. Across all 9 US geoclimatic regions, the mean UV index was associated with increasing odds of having juvenile DM and anti-p155/140 autoantibodies, but decreasing odds of having anti-MJ autoantibodies. CONCLUSION: Short-term UVR exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis. Further research examining the mechanisms of action of UVR in the pathogenesis of juvenile IIM is suggested from these findings.


Assuntos
Autoanticorpos/imunologia , Dermatomiosite/imunologia , Raios Ultravioleta/efeitos adversos , Adolescente , Dermatomiosite/etnologia , Dermatomiosite/etiologia , Feminino , Humanos , Masculino , Polimiosite/etnologia , Polimiosite/etiologia , Polimiosite/imunologia , Fatores Desencadeantes , Análise de Regressão , Fatores Sexuais
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