HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies

OBJECTIVE: To investigate possible associations of HLA polymorphisms with idiopathic inflammatory myopathy (IIM) in African Americans, and to compare this with HLA associations in European American IIM patients with IIM. METHODS: Molecular genetic analyses of HLA-A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM (n = 262) in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM (n = 571). RESULTS: In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti-Jo-1 autoantibodies shared the risk factor HLA-DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti-signal recognition particle (DQA1*0102) and anti-Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American-, anti-Mi-2-associated risk factor DRB1*0701 were found to share a 4-amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. CONCLUSION: These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene-environment interactions.     

The Myositis Autoantibody Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies

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

Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians: ethnogeographic influences in the genetics and clinical expression of myositis

OBJECTIVE: As part of a larger, worldwide study of the ethnogeography of myositis, we evaluated the clinical, serologic, and immunogenetic features of Mestizo (Mexican and Guatemalan) and North American Caucasian patients with idiopathic inflammatory myopathy (IIM). METHODS: Clinical manifestations, autoantibodies, HLA-DRB1 and DQA1 alleles, and immunoglobulin Gm/Km allotypes were compared between 138 Mestizos with IIM and 287 Caucasians with IIM, using the same classification criteria and standardized questionnaires. RESULTS: IIM in Mestizo patients was characterized by a higher proportion of dermatomyositis (69% of adult Mestizos versus 35% of adult Caucasians; P < 0.001) and anti-Mi-2 autoantibodies (30% versus 7% of adults, respectively, and 32% versus 4% of children, respectively; P < 0.01). Genetic risk factors also differed in these populations. Whereas Mestizos had no HLA risk factors for IIM, HLA-DRB1*0301, the linked allele DQA1*0501, and DRB1 alleles sharing the first hypervariable region motif (9)EYSTS(13) were major risk factors in Caucasian patients with IIM. Furthermore, different HLA-DRB1 and DQA1 alleles were associated with anti-Mi-2 autoantibodies (DRB1*04 and DQA1*03 in Mestizos and DRB1*07 and DQA1*02 in Caucasians). Immunoglobulin gamma-chain allotypes Gm(1), Gm(17) (odds ratio for both 11.3, P = 0.008), and Gm(21) (odds ratio 7.3, P = 0.005) and kappa-chain allotype Km(3) (odds ratio 7.3, P = 0.005) were risk factors for IIM in Mestizos; however, no Gm or Km allotypes were risk or protective factors in Caucasians. In addition, Gm and Km phenotypes were unique risk factors (Gm 1,3,17 5,13,21 and Gm 1,17 23 21 and Km 3,3) or protective factors (Km 1,1) for the development of myositis and anti-Mi-2 autoantibodies (Gm 1,2,3,17 23 5,13,21) in adult Mestizos. CONCLUSION: IIM in Mesoamerican Mestizos differs from IIM in North American Caucasians in the frequency of phenotypic features and in the immune-response genes predisposing to and protecting from myositis and anti-Mi-2 autoantibodies at 4 chromosomal loci. These and other data suggest the likelihood that the expression of IIM is modulated by different genes and environmental exposures around the world.     

Coexistencia de anticuerpos anti-histidil-tRNA-sintetasa y anti-partícula de reconocimiento de la señal en un paciente con polimiositis

Idiopathic inflammatory myopathies are a heterogeneous group of potentially treatable myopathies. They are classified, on the basis of clinical and histopathological features, into four subtypes: dermatomyositis, polymyositis, necrotizing autoimmune myositis and inclusion-body myositis. Myositis-associated antibodies and myositis-specific autoantibodies are frequently found in patients with idiopathic inflammatory myopathies, and are useful in the diagnosis and classification. Anti-histidyl transfer RNA synthetase antibody is the most widely prevalent and is highly specific for polymyositis. Signal recognition particle antibody is also a specific autoantibody for polymyositis, but it is infrequent and rarely found in patients having other myositis-specific autoantibodies.We present a man with polymyositis who had both antibodies in serum, which is considered an extremely rare clinical situation. Here we analyze the clinical course and findings, and examine the effect of the coexistence and possible interaction on prognosis.     

Clinical and Serological Features and Pregnancy Outcomes in Women with Polymyositis/Dermatomyositis: A Case-based Review

We encountered a 30-year-old woman who developed dermatomyositis during pregnancy and was positive for anti-Mi-2 antibodies. She was successfully treated with prednisolone and tacrolimus and delivered a healthy child. We reviewed the cases of idiopathic inflammatory myositis (IIM) that developed during pregnancy that were published after the year 2000 to elucidate the profile of myositis-specific antibodies (MSAs) in them and to evaluate their obstetric outcomes. In cases with IIM that developed during pregnancy, anti-Mi-2, anti-TIF1-g, anti-Jo-1, and anti-EJ antibodies was detected in one case each. The obstetric outcomes of the IIM-complicated pregnancies were poor, especially when complicated with active maternal myositis. Further studies focusing on the possible causal relationships between MSAs and cases with IIM that developed during pregnancy are needed. For better obstetric outcomes, appropriate suppression of the maternal disease activity using immunosuppressants and vigilance regarding the patient''s requirement of Caesarean section is important.     

HLA-D region genes associated with autoantibody responses to histidyl-transfer RNA synthetase (Jo-1) and other translation-related factors in myositis

Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class II specificities by Southern blotting with HLA-DR beta, DQ beta, and DQ alpha probes. The association of HLA-DR3 (DRw17) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLA-DRw8, an HLA-DRw52 haplotype on which the DR beta 3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DR5, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DR beta 1 first hypervariable region at amino acid positions 9-13. Thus, this DR beta 1 region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.     

Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases defined by chronic muscle inflammation and weakness associated with autoimmunity. We have performed low to high resolution molecular typing to assess the genetic variability of major histocompatibility complex loci (HLA-A, -B, -Cw, -DRB1, and -DQA1) in a large population of European American patients with IIM (n = 571) representing the major myositis autoantibody groups. We established that alleles of the 8.1 ancestral haplotype (8.1 AH) are important risk factors for the development of IIM in patients producing anti-synthetase/anti-Jo-1, -La, -PM/Scl, and -Ro autoantibodies. Moreover, a random forests classification analysis suggested that 8.1 AH-associated alleles B*0801 and DRB1*0301 are the principal HLA risk markers. In addition, we have identified several novel HLA susceptibility factors associated distinctively with particular myositis-specific (MSA) and myositis-associated autoantibody (MAA) groups of the IIM. IIM patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies have a unique HLA Class I risk allele, Cw*0304 (pcorr = 0.046), and lack the 8.1 AH markers associated with other anti-synthetase autoantibodies (for example, anti-Jo-1 and anti-PL-12). In addition, HLA-B*5001 and DQA1*0104 are novel potential risk factors among anti-signal recognition particle autoantibody-positive IIM patients (pcorr = 0.024 and p = 0.010, respectively). Among those patients with MAA, HLA DRB1*11 and DQA1*06 alleles were identified as risk factors for myositis patients with anti-Ku (pcorr = 0.041) and anti-La (pcorr = 0.023) autoantibodies, respectively. Amino acid sequence analysis of the HLA DRB1 third hypervariable region identified a consensus motif, 70D (hydrophilic)/71R (basic)/74A (hydrophobic), conferring protection among patients producing anti-synthetase/anti-Jo-1 and -PM/Scl autoantibodies. Together, these data demonstrate that HLA signatures, comprising both risk and protective alleles or motifs, distinguish IIM patients with different myositis autoantibodies and may have diagnostic and pathogenic implications. Variations in associated polymorphisms for these immune response genes may reflect divergent pathogenic mechanisms and/or responses to unique environmental triggers in different groups of subjects resulting in the heterogeneous syndromes of the IIM.     

Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance

PURPOSE OF REVIEW: Idiopathic inflammatory myopathy is characterized by the production of autoantibodies to various cellular constituents. These autoantibodies closely correlate with certain clinical conditions and prognosis of disease. This review examines recent progress in myositis-specific autoantibodies, particularly in their clinical significance and pathophysiological roles. RECENT FINDINGS: During the 1-year review period, novel myositis-specific autoantibodies were identified in clinically amyopathic dermatomyositis (anti-CADM-140 antibody) and malignancy-associated myositis (anti-p155 and anti-p155/p140 antibodies). These new autoantibodies are extremely important because it is thought that myositis-specific autoantibodies are negative in these subgroups, and may enable a new classification of idiopathic inflammatory myopathy. New clinical aspects of other myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-signal recognition particles and anti-Mi-2) are also described. The possibility was raised that the high expression of myositis-specific autoantigens in regenerating muscle cells and certain cancers may be involved in initiating and perpetuating the autoimmune response in myositis. SUMMARY: Myositis-specific autoantibodies are useful markers for clinical diagnosis, classification and predicting prognosis of idiopathic inflammatory myopathy. To understand the etiopathogenic mechanisms of the disease it is particularly important to elucidate the nature of target autoantigens recognized by these myositis-specific autoantibodies.     

Myositis specific autoantibodies

Recent studies have continued to examine the clinical associations of the group of autoantibodies that occurs predominantly in patients who have myositis (antibodies to aminoacyl-tRNA synthetases, to signal recognition particle [SRP], and to the nuclear helicase Mi-2). The anti-synthetase syndrome has been further studied, and the value of tacrolimus in treatment of the associated interstitial lung disease has been noted. The low frequency of myositis specific autoantibodies in non-myositis neuromuscular disorders has been more clearly demonstrated. The clinical associations of anti-Mi-2 and anti-SRP were further studied, and patients with antibodies without myositis were reported. Evidence suggested that ultraviolet light exposure may influence the expression of dermatomyositis and anti-Mi-2. A new classification for myositis using overlap clinical features and autoantibodies was proposed. A new autoantibody, anti-caDM-140, was described, associated with clinically amyopathic dermatomyositis and interstitial lung disease. The possibility was raised that increased antigen expression in regenerating muscle may help to perpetuate the disease. These antibodies continue to be the subject of active investigation.     

Real world utilization of the myositis autoantibody panel

Objective

Myositis autoantibody panel results can offer diagnostic and prognostic information in patients with concern for idiopathic inflammatory myopathy (IIM). However, there has been widespread utilization of myositis autoantibody testing clinically, often in situations where concern for an IIM is unclear. We sought to determine ordering practices and factors predicting positive results on ordered myositis antibody panels.

Methods

We included all patients in the Duke University Health System who had a “myositis antibody panel” ordered from October 2014 through December 2016. Retrospective chart review was performed evaluating antibody positivity, provider specialty, ordering location, demographics, medical history, review of systems (ROS), physical examination (PE), and laboratory values. Fisher’s exact and t test tests and backward multivariable regression analysis were performed for statistical analysis.

Results

There were 642 unique tests obtained with 114 positive autoantibodies (17.7%) over the 26-month period. Myositis-specific autoantibodies (MSAs) were the most common and anti-Mi-2 was the most frequent (40% of MSAs). Pulmonology providers ordered the majority of tests (383; 59.6%). Adult Rheumatology had the highest antibody positivity rate (34.3%, p=0.0001) among specialties with at least 10 panels ordered. In backward multivariable regression analysis, factors independently associated with a positive myositis antibody panel were chronic corticosteroid use (OR: 2.10, 95% CI: 1.30–3.38) and sclerodermoid skin changes (OR: 6.89; 95% CI: 2.02–23.47).

Conclusion

The positivity rate of myositis antibody panel testing in this real-world clinical setting was 18%. Anti-Mi-2 antibody was the most frequent autoantibody present. Specific factors associated with positive results can be utilized to identify patients at higher risk for IIM.

Key Points

? Only eighteen percent of all myositis antibody panel tests ordered returned positive.

? Anti-Mi-2 antibody was the most frequent autoantibody in our cohort.

? Specific factors associated with positive results can help identify patients at higher risk for IIM, particularly for non-rheumatologists.

     

Myositis specific autoantibodies

Recent studies have continued to examine the clinical associations of the group of autoantibodies that occurs predominantly in patients who have myositis (antibodies to aminoacyl-tRNA synthetases, to signal recognition particle [SRP], and to the nuclear helicase Mi-2). The antisynthetase syndrome has been further studied, and the value of tacrolimus in treatment of the associated interstitial lung disease has been noted. The low frequency of myositis specific autoantibodies in non-myositis neuromuscular disorders has been more clearly demonstrated. The clinical associations of anti-Mi-2 and anti-SRP were further studied, and patients with antibodies without myositis were reported. Evidence suggested that ultraviolet light exposure may influence the expression of dermatomyositis and anti-Mi-2. A new classification for myositis using overlap clinical features and autoantibodies was proposed. A new autoantibody, anti-caDM-140, was described, associated with clinically amyopathic dermatomyositis and interstitial lung disease. The possibility was raised that increased antigen expression in regenerating muscle may help to perpetuate the disease. These antibodies continue to be the subject of active investigation.     

Autoantibodies: Pathogenic or epiphenomenon

Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune diseases. There are distinct subgroups, including antisynthetase syndrome, dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and sporadic inclusion body myositis. In patients with IIM, autoantibodies are present in up to 80% of the patients. These autoantibodies are often characterized as myositis-specific autoantibodies (MSA) or myositis-associated autoantibodies (MAA). The recognition of the importance of autoantibodies, especially MSA, is increasing in recent years. In this chapter, we provide an overview of the MSAs, including some new autoantibodies of interest as they target mainly muscle-specific autoantigen, in clinical classification, the measurement of the disease activity, and a possible role in the pathogenesis in the patients with IIM.     

Myositis-specific and myositis-associated autoantibodies in Indian patients with inflammatory myositis

We aimed to study the prevalence and clinical associations of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) in a large cohort of Indian patients with idiopathic inflammatory myositis (IIM). Clinical details and serum samples were collected from patients with IIM (satisfying Bohan and Peter Criteria, 1975) and CTD-associated myositis. Sera were analysed for antibodies against SRP, Mi2, Jo1, PL7, PL12, EJ, OJ, Ro52, Ku, Pm-Scl 75 and PM-Scl 100, using immunoblot assay. The cohort comprised 124 patients with IIM (M:F = 1:3.6). Fifty-five of them had dermatomyositis (DM), 22 had juvenile dermatomyositis (JDM), 25 had polymyositis (PM) and 22 had connective tissue disease-associated myositis (CTD myositis). Mean disease duration was 10.9 months. ANA was positive in 84 (68.9 %), and MSAs in 61 (49.2 %) patients. Among MSAs, autoantibodies to Mi2, synthetase (Jo1, PL7, PL12, EJ) and SRP were present in 26 (20.9 %), 29 (23.4 %) and 6 (4.8 %) patients, respectively. Prevalence of MAAs was as follows: antibodies to Ro52 in 45 (36.3 %), Ku and PM-Scl 75 in 13 (10.5 %) and PM-Scl 100 in 5 (4 %) patients. Anti-Mi2 antibodies were positively associated with DM (21/55, 38.2 %; p < 0.0001) and pharyngeal weakness (13/34, 38.2 %; p = 0.004) and negatively associated with ILD (0/28; p = 0.001). ILD and mechanics’ hands were significantly more in patients with anti-synthetase antibodies (16/28, 57 % and 14/22, 63.6 %; p < 0.0001). Four of six patients with anti-SRP antibody showed poor response to multiple drugs. Higher prevalence of anti-Mi2 is probably related to higher proportion of patients with DM. Absence of ILD in patients with anti-Mi2 antibody suggests that it may protect against ILD. In Indian population also, anti-synthetase antibodies are associated with ILD, and anti-SRP antibodies with poor response to treatment.     

Serum BAFF in Indian patients with IIM: a retrospective study reveals novel clinico-phenotypic associations in children and adults

We studied the serum levels of B cell survival factors BAFF and APRIL in patients with idiopathic inflammatory myositis (IIM) and their relation with clinical and autoantibodies. Seventy-five patients (51 females and 24 males) with IIM (Bohan and Peter’s criteria 1975) and 25 healthy adults were analyzed for BAFF, APRIL and IL-17 by ELISA, and myositis-specific and associated antibodies (MSA and MAA) using line immunoblot assay. Of the 75 patients, 59 were adults, 42 had Dermatomyositis (DM), and 17 had Polymyositis. Median disease duration was 5 (3–12) months. BAFF levels were higher in IIM than healthy controls [p?=?0.001], and in children with jDM than adults [p?=?0.026]. BAFF levels were higher in adults with arthritis [p?=?0.018], weight loss [p?=?0.007], and PAH [p?=?0.004]. Among the various MSAs, lowest levels were seen in those with anti-SRP [p?=?0.043]. Median follow-up duration was 145 patient years. Twelve patients relapsed, while nine were in drug-free remission. BAFF were similar between these groups. Serum APRIL levels were elevated in limited number of patients with myositis, and the levels did not differ amongst the clinico-serologic phenotypes. IL-17 levels were higher in individuals positive for anti-SRP [p?=?0.028]. Serum BAFF levels are elevated in IIM, more so in children. BAFF levels may be useful as biomarker for PAH and arthritis. Anti-SRP positivity is associated with elevated IL-17 levels suggesting role in pathogenesis.     

Laboratory abnormalities and autoantibodies

Laboratory tests in inflammatory myopathies (IIM) are of great help in the diagnosis of these diseases. Two main groups can be defined, one of them quantifies the muscle enzymes that reflect muscle inflammation and the other one detects the presence of autoantibodies which reflect the autoimmune process in these diseases. The most important muscle enzyme is creatine kinase and other enzymes to take into consideration are aspartate and alanine aminotransferase, aldolase and lactic dehydrogenase. In the autoantibodies group, antinuclear antibodies are the most important, since they occur in approximately 50-80% of patients with IIM and help define the distinct disease sub-groups. They are divided into myositis specific antibodies (MSA) and myositis associated antibodies (MAA). The most important MSA are anti-Jo-1 antibody which occur in patients with Polymyositis and anti-Mi-2 antibody that occur in patients with Dermatomyositis.     

The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis

OBJECTIVES: There is a known association between myositis and cancer. The risk is greater in dermatomyositis (DM) than polymyositis (PM), although reliable methods to predict cancer risk in specific patients with myositis are not presently available. This study was undertaken to determine whether risk of developing cancer in myositis can be predicted by antibody profiling. METHODS: A cross-sectional study of UK Caucasian adults with PM (n = 109), DM (n = 103) and connective tissue disease overlap (myositis/CTD-overlap, n = 70). Patients were tested for a comprehensive range of myositis-specific/associated autoantibodies. Sensitivity and specificity analyses were performed for the optimal identification of cancer risk. RESULTS: Sixteen patients had cancer-associated myositis (CAM) (15 DM, 1 myositis/CTD-overlap). CAM patients were older at disease onset, and patients without myositis-specific/associated autoantibodies on "routine" laboratory testing (negative for anti-Jo-1, anti-PM-Scl, anti-U1-RNP, anti-U3-RNP, anti-Ku antibodies) had a significantly increased risk of CAM. Possession of the antibody against 155 kDa and 140 kDa protein specificities (anti-155/140 antibody) represented a significant risk factor for CAM, and was found exclusively in DM. A positive anti-155/140 antibody result proved highly specific, moderately sensitive, with high negative predictive value for CAM. A "negative routine myositis antibody panel" result was highly sensitive, with high negative predictive value for CAM. The combination of these two approaches was 94% sensitive, detecting 15 of 16 CAM, with 100% sensitivity and negative predictive value in DM. CONCLUSIONS: These results may help clinicians predict which patients with myositis are at greater risk of developing cancer, thus identifying those requiring aggressive diagnostic evaluation and intensive cancer surveillance at myositis onset and follow-up.     

High Frequencies and co-existing of myositis-specific autoantibodies in patients with idiopathic inflammatory myopathies overlapped to rheumatoid arthritis

A small proportion of patients with rheumatoid arthritis (RA) develop idiopathic inflammatory myopathies (IIM); however, the clinical and immunological characteristics of these patients have not been elucidated. In the present study, we evaluate the frequency of autoantibodies and the accompanying clinical features in patients with IIM overlapped to RA (IIM-RA) and in patients with IIM without RA. Twelve patients with IIM-RA were selected from 142 patients with IIM who were admitted to our hospital. Clinical and laboratory data, including autoantibody test results, were collected from patient medical records. Myositis-specific antibodies (MSAs) were analyzed by immunoprecipitation. Clinically, patients with IIM-RA were more likely to be male, to have polymyositis, and to be older at the time of IIM onset than patients with IIM without RA. Patients with IIM-RA had been treated for 2–25?years prior to the onset of IIM with more than two disease-modifying antirheumatic drugs (DMARDs). Patients with IIM-RA had a high frequency (75.0%) of positivity for MSAs, including anti-Jo-1, anti-PL-7, anti-PL-12, or anti-signal recognition particle (SRP) antibodies; anti-Jo-1 antibody was detected in 4 patients (33.3%). In addition, 2 out of 12 patients with IIM-RA were concurrently positive for two different MSAs, anti-Jo-1, and anti-PL-7 antibodies. In 3 other patients with IIM-RA, anti-Jo-1 antibody, or anti-PL-7 antibody was detected in serum samples collected 6–18?months prior to development of myositis. High frequency and coexistence of MSAs were detected in patients with IIM-RA. MSAs detected in patients with RA even without symptoms of myositis may indicate possible future development of myositis.     

Autoantibodies in polymyositis.

A group of autoantibodies have been identified that are found almost exclusively in patients with polymyositis and dermatomyositis (myositis-specific antibodies). Most have been associated with characteristic clinical subgroups. Five of the myositis-specific antibodies are directed at aminoacyl-tRNA synthetases and have been associated with a similar clinical syndrome marked by myositis, interstitial lung disease, arthritis, and Raynaud's phenomenon (antisynthetase syndrome). Myositis-specific antibodies can help with patient diagnosis, subgroup classification, and possible prognosis. Their role in the pathogenesis of myositis remains to be defined, but their production is genetically influenced and appears to be linked to fundamental etiologic factors.     

Immunoglobulin gene polymorphisms are susceptibility factors in clinical and autoantibody subgroups of the idiopathic inflammatory myopathies

OBJECTIVE: To investigate possible associations of GM and KM markers with adult and juvenile forms of the idiopathic inflammatory myopathies (IIMs) in Caucasian and African American patients. METHODS: We performed serologic analyses of polymorphic determinants associated with immunoglobulin gamma heavy chains (GM) and kappa light chains (KM) in large populations of Caucasian patients (n= 514 [297 adults and 217 children]) and African American patients (n=123 [73 adults and 50 children]) with IIM representing the major clinical and autoantibody groups. RESULTS: For Caucasian patients with dermatomyositis (DM), the Gm 3 23 5,13 phenotype was a risk factor in both adults (odds ratio [OR] 2.2, corrected P [Pcorr]=0.020) and children (OR 2.2, Pcorr=0.0013). Of interest, the GM 13 allotype was a risk factor for juvenile DM in both Caucasian subjects (OR 3.9, Pcorr<0.0001) and African American subjects (OR 4.8, Pcorr=0.033). However, the Gm 1,3,17 5,13,21 phenotype was a risk factor for juvenile DM in Caucasian subjects but not African American subjects. Among the IIM autoantibody groups, Gm 3 23 5,13 was a risk factor in Caucasian adults with anti-Jo-1 autoantibodies (OR 3.4, Pcorr=0.0031), while the GM 3 allotype was protective in adults with anti-threonyl-transfer RNA synthetase or anti-U RNP autoantibodies (OR 0.1, Pcorr=0.047 and OR 0.2, Pcorr=0.034, respectively). In contrast, GM 6 was a risk factor in African American adults with anti-signal recognition particle autoantibodies (OR 7.5, Pcorr=0.041). CONCLUSION: These data suggest that polymorphic alleles of GM and KM loci are differentially associated with IIM subgroups defined by age, ethnicity, clinical features, and autoantibody status, and expand the list of immune response genes that are possibly important in the pathogenesis of myositis.     

A broadened spectrum of juvenile myositis. myositis-specific autoantibodies in children

Objective. Myositis-specific autoantibodies (MSA) define relatively homogenous clinical and immunogenetic patient groups in adults with idiopathic inflammatory myopathies (IIM). This study explores the usefulness of MSA in defining groups of children with myositis. Methods. Sera from 77 children with myositis and other connective tissue diseases were tested for MSA by immunoprecipitation and immunodiffusion. Clinical data were collected and analyzed. Results. The MSA anti-PL-12 (alanyl-transfer RNA synthetase), anti-Jo-1 (histidyl-tRNA synthetase), anti-signal recognition particle, and anti-Mi-2 were each identified in the sera of 12 children with IIM. In these patients, the clinical manifestations, disease courses, and responses to therapy closely resembled those in adults with the same autoantibodies. Conclusion. These observations suggest that the clinical syndromes defined by particular MSA are similar in children and adults with IIM. By defining similar clinical syndromes in children who have MSA, this study provides a basis for future studies of MSA in the idiopathic inflammatory myopathies of childhood, which may be useful in predicting the clinical courses of a subset of these patients and improving their therapy.