[Relapses in inflammatory myopathies]. / Miopatías inflamatorias con evolución recidivante.

Most studies about treatment of inflammatory myopathies consist of cross-sectional analyses that do not assess long-term efficacy. In the present study we describe the follow-up of seven patients with inflammatory myopathies, 5 polymyositis and 2 dermatomyositis. We describe their clinical features, follow-up, muscle enzyme levels, and treatment responses. We define the latter as treatment cycles, every one of which end when steroid doses need to be increased or a new immunosuppressive drug has to be added because of clinical worsening or sustained increases in muscle enzyme levels. Treatment can cause remission, partially control, or fail in achieving myositis improvement when it normalizes, stabilizes, or does not affect muscle enzymes or clinical features, respectively. We analyzed 20 cycles, in which remission was achieved in 14 cases, partial control in 5 instances, and treatment failure in one case. Remission occurred after an average of 139 ± 98 days, whereas partial control took place in 160 ± 100 days. Except in one case, all treatment cycles controlled or remitted the symptoms. However, in all patients the illness recurred with time.

Pilot study of interleukin-27 in pathogenesis of dermatomyositis and polymyositis: associated with interstitial lung diseases.

OBJECTIVE: To determine whether interleukin (IL)-27 is involved in dermatomyositis (DM) and polymyositis (PM). METHODS: Serum IL-27, IL-18 and interferon-γ (IFN-γ) levels in 37 DM and 15 PM were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum IL-27, IL-18 and IFN-γ levels were significantly higher in DM and PM patients than in healthy controls. Significant higher levels of IL-27 were found in high creatine kinase (CK) level group and in patients with interstitial lung disease (ILD). Level of IL-27 was correlated with global 100-mm visual analog scales (VASs) score in patients with PM. CONCLUSION: These data supports the hypothesis that IL-27 maybe involved in DM and PM pathogenesis.

Tyrosine kinases in inflammatory dermatologic disease.

Tyrosine kinases (TKs) are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific TKs have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of TKs are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight TK signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development.

Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases.

To clarify the pathogenic processes of thrombotic microangiopathies (TMAs) in patients with connective tissue disease (CTD), we analysed clinical characteristics and plasma ADAMTS13 levels in 127 patients with CTD-TMAs, including patients with systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis (RA), and 64 patients with acquired idiopathic thrombotic thrombocytopenic purpura (ai-TTP). Plasma levels of ADAMTS13 activity, antigen, and inhibitors were determined by enzyme immunoassays. IgG type anti-ADAMTS13 antibodies were also detected by immunoblots using purified ADAMTS13. ADAMTS13 activity was significantly decreased in CTD-TMAs, regardless of the underlying disease, but the frequency of severe deficiency (defined as <0.5% of normal) was lower in CTD-TMA patients than in ai-TTP patients (16.5% vs. 70.3%, p < 0.01). Severe deficiency of ADAMTS13 activity was predominantly detected in patients with RA- and SLE-TMAs, and was closely associated with the presence of anti-ADAMTS13 IgG antibodies. CTD-TMA patients with severe deficiency of ADAMTS13 activity appeared to have lower platelet counts and better therapeutic outcomes. At least two phenotypic TMAs occur in patients with CTDs: a minor population with deficient ADAMTS13 activity caused by neutralising autoantibodies, and a major population with normal or moderately reduced activity. Classifying CTD-TMAs by ADAMTS13 activity may be useful in predicting the clinical course and therapeutic outcomes, as patients with moderately reduced activity are likely to have more prominent renal impairment and poor prognoses.

Two cases with autoantibodies to small ubiquitin-like modifier activating enzyme: A potential unique subset of dermatomyositis-associated interstitial lung disease.

The presence of anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differential-associated gene 5 (MDA5) is strongly related to interstitial lung disease (ILD) in patients with dermatomyositis (DM). Several studies suggest a potential relationship between ILD and anti-small ubiquitin-like modifier activating enzyme (SAE) antibody in DM patients, but detailed clinical characteristics of anti-SAE-associated ILD still remain unknown. We have experienced 2 cases who were positive for anti-SAE antibody, who presented with ILD in the context of clinically amyopathic DM. These 2 patients had the following common ILD characteristics: an insidious course with preserved pulmonary function; a limited extent of pulmonary lesions with subpleural peripheral-dominant small ground glass opacity/consolidation on high-resolution computed tomography; and a favorable treatment response. These findings suggest that anti-SAE-associated ILD is unique in terms of clinical and imaging features and differs from ILD associated with anti-ARS or anti-MDA5 antibody.

Effects of immunosuppressive treatment on microsomal prostaglandin E synthase 1 and cyclooxygenases expression in muscle tissue of patients with polymyositis or dermatomyositis.

OBJECTIVES: To investigate the expression of microsomal prostaglandin E (PGE) synthase 1 (mPGES-1) and cyclooxygenase (COX) in muscle biopsies from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. METHODS: mPGES-1 and COX expression was evaluated by immunohistochemistry in muscle tissue from healthy individuals and from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. The number of inflammatory cell infiltrates, T lymphocytes and macrophages was estimated before and after treatment. To localise the mPGES-1 expression double immunofluorescence was performed with antibodies against mPGES-1, CD3, CD68, CD163 and a fibroblast marker. A functional index was used to assess muscle function. RESULTS: In patients with myositis, mPGES-1, COX-2 and COX-1 expression was significantly higher compared to healthy individuals and associated with inflammatory cells. Double immunofluorescence demonstrated a predominant expression of mPGES-1 in macrophages. Conventional immunosuppressive treatment resulted in improved but still lower muscle function than normal. A decreased number of CD68-positive macrophages and reduced COX-2 expression in muscle tissue was also seen. By contrast, following the same treatment no significant changes were observed in muscle tissue regarding number of infiltrates, T lymphocytes, CD163-positive macrophages or mPGES-1 protein levels. CONCLUSIONS: Increased expression of mPGES-1, COX-1 and COX-2 at protein level was observed in muscle tissue from patients with myositis compared to healthy individuals. Conventional immunosuppressive treatment led to a significant downregulation of COX-2 in myositis muscle tissue. However, the expression of mPGES-1 and COX-1 remained unchanged indicating a role of these enzymes in the chronicity of these diseases.

Risk factors associated with calcinosis of juvenile dermatomyositis.

OBJECTIVE: To identify risk factors associated with calcinosis in children and adolescents with juvenile dermatomyositis. METHODS: A review was carried out of the medical records of 54 patients with juvenile dermatomyositis. Data were collected on demographic characteristics, clinical features: muscle strength (stages I to V of the Medical Research Council scale), pulmonary involvement (restrictive pulmonary disease with presence or absence of anti-Jo1 antibodies), gastrointestinal problems (gastroesophageal reflux) and/or heart disease (pericarditis and/or myocarditis); laboratory tests: elevated muscle enzyme levels in serum (creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase and/or lactate dehydrogenase); and on the treatments given: corticoid therapy in isolation or associated with hydroxychloroquine and/or immunosuppressants. The patients were divided into two groups, depending on presence or absence of calcinosis and data were evaluated by both univariate and multivariate analyses. RESULTS: Calcinosis was identified in 23 (43%) patients, and in six (26%) patients it had emerged prior to diagnosis while in 17 (74%) it was post diagnosis. The univariate analysis revealed that cardiac (p = 0.01) and pulmonary (p = 0.02) involvement and the need for one or more immunosuppressor (methotrexate, cyclosporine A and/or pulse therapy with intravenous cyclophosphamide) to treat juvenile dermatomyositis (p = 0.03) were all associated with an increased incidence of calcinosis. The multivariate analysis then demonstrated that only cardiac involvement (OR = 15.56; 95%CI 1.59-152.2) and the use of one or more immunosuppressor (OR = 4.01; 95%CI 1.08-14.87) were independently associated with the presence of calcinosis. CONCLUSIONS: Calcinosis was a frequent development among these juvenile dermatomyositis cases, generally emerging as the disease progressed. Calcinosis was associated with the more severe cases that also had cardiac involvement and where immunosuppressors had to be included in the treatment.

A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase.

Chromatin structure plays a crucial regulatory role in the control of gene expression. In eukaryotic nuclei, enzymatic complexes can alter this structure by both targeted covalent modification and ATP-dependent chromatin remodeling. Modification of histone amino termini by acetyltransferases and deacetylases correlates with transcriptional activation and repression [1-3], cell growth [4], and tumorigenesis [5]. Chromatin-remodeling enzymes of the Snf2 superfamily use ATP hydrolysis to restructure nucleosomes and chromatin, events which correlate with activation of transcription [6,7]. We purified a multi-subunit complex from Xenopus laevis eggs which contains six putative subunits including the known deacetylase subunits Rpd3 and RbAp48/p46 [8] as well as substoichiometric quantities of the deacetylase-associated protein Sin3 [9-13]. In addition, we identified one of the other components of the complex to be Mi-2, a Snf2 superfamily member previously identified as an autoantigen in the human connective tissue disease dermatomyositis [14,15]. We found that nucleosome-stimulated ATPase activity precisely copurified with both histone deacetylase activity and the deacetylase enzyme complex. This association of a histone deacetylase with a Snf2 superfamily ATPase suggests a functional link between these two disparate classes of chromatin regulators.

Do Muscle Enzyme Changes Forecast Liver Injury in Polymyositis/Dermatomyositis Patients Treated with Methylprednisolone and Methotrexate?

BACKGROUND: Long-term use of hormones and immunosuppressive agents is necessary for treating polymyositis (PM)/dermatomyositis (DM) but may cause liver damage. At what point do the costs of treatment outweigh the benefits, and how will the breakeven point be determined? METHODS: Serum muscle enzyme changes in 93 PM/DM patients were analyzed over the course of hormone and immunosuppressive agent treatment. From the analysis, a forecasting method was developed to help anticipate possible drug-induced liver injury. RESULTS: Before treatment, CK levels were frequently elevated and showed correlation with ALT,AST,LDH and CK-MB levels (r=0.682, 0.766, 0.739 and 0.784, respectively). After treatment, all muscle enzyme levels were decreased except ALT (p>0.05). ALT level was positively correlated with CK level (r=0.681) in those patients whose CK level remained abnormal after treatment. Linear regression analysis yielded an equation(CK Level=12.66*ALT Level-136.23) that could predict potential liver damage. CONCLUSIONS: CK level was the most sensitive index of PM/DM and was highly correlated with other serum muscle enzyme levels. An equation capable of predicting potential liver damage according to the correlation of CK and ALT was produced.

Cytosolic 5'-Nucleotidase 1A As a Target of Circulating Autoantibodies in Autoimmune Diseases.

OBJECTIVE: Prior investigations demonstrated that autoantibodies recognizing cytosolic 5'-nucleotidase 1A (NT5C1A) are found in 33-76% of patients with inclusion body myositis (IBM) but are observed only rarely in patients with polymyositis (PM). Thus, anti-NT5C1A may help distinguish IBM from PM. Although 4-21% of patients with dermatomyositis (DM) were shown to be anti-NT5C1A antibody positive, the clinical features of anti-NT5C1A-positive patients with DM have not been described. Furthermore, the prevalence of anti-NT5C1A antibodies in other rheumatic conditions has not been reported. This study was undertaken to define the prevalence and clinical features of anti-NT5C1A-positive patients with DM, PM, IBM, or other systemic autoimmune diseases. METHODS: We screened for anti-NT5C1A autoantibodies in patients with IBM, DM, PM, Sjögren's syndrome (SS), or systemic lupus erythematosus (SLE) and in healthy volunteers. Clinical characteristics were compared between patients who were anti-NT5C1A positive and those who were anti-NT5C1A negative. RESULTS: Anti-NT5C1A autoantibodies were detected in 71 (61%) of 117 patients with IBM, 2 (5%) of 42 patients with PM, 2 (5%) of 42 healthy volunteers, 24 (15%) of 159 patients with DM, 10 (23%) of 44 patients with SS, and 13 (14%) of 96 patients with SLE. No anti-NT5C1A antibody-positive patients with SS or SLE had muscle involvement. Anti-NT5C1A-positive patients with IBM had a lower prevalence of rimmed vacuoles (62% versus 83% of antibody-negative patients; P = 0.02). No differences in the clinical characteristics of antibody-positive and antibody-negative patients with DM, SS, or SLE were observed. CONCLUSION: Anti-NT5C1A is a common target of circulating autoantibodies, especially in IBM but also in several different autoimmune diseases. In SLE and SS, anti-NT5C1A autoreactivity is not associated with muscle disease.

Can tissue transglutaminase be a marker of idiopathic inflammatory myopathies?

In the normal striated muscle, tissue transglutaminase (TG2) content is vestigial. However, this protein's presence has been reported to occur in myoblasts and myotubes during the fetal period. Its increased expression has been also found in the muscle tissue in the course of sporadic inclusion body myositis, as well as in polymyositis (PM) and dermatomyositis (DM), which are considered to be diseases of immunological origin. Based on in vitro studies, a substantial TG2 role in the infiltration of some T cell subsets into inflamed tissues has been suggested lately. In this study, the immunohistochemical reactions in the guinea pig experimental myositis specimens and in the ones from PM/DM patients were compared. The guinea pig tissue specimens were taken from muscles affected by experimental myositis induced by intramuscular injections of: 1/sera from 30 neoplasm patients with no metastases; 2/sera from 10 healthy people; 3/sera from 2 DM patients; 4/neuropeptides (SP, NPY or VIP) and from 5/the muscles affected by the reversed passive Arthus reaction (RPAR). The immunostaining for TG2 revealed substantial presence of this protein in single, damaged muscle fibers and a weak reaction in regenerating fibers appearing in PM/DM patients' specimens. From among experimental myositis specimens, a very intensive reaction appeared only in the damaged and regenerating muscle fibers present in the slides from guinea pig muscles injected with DM patients' sera. Such results suggest some presence of a specific factor(s) (the one(s) responsible for TG2 expression in the damaged muscle fibers) in DM patients' sera. The results suggest that transglutaminase can be a marker of inflammatory myopathies. A probable correlation between TG2 expression in muscles and organismal immunological factors, including the complement activation status, requires additional studies.

Angiotensin-converting enzyme insertion/deletion gene polymorphism is associated with dermatomyositis.

BACKGROUND AND OBJECTIVE: The cornerstone of dermatomyositis (DM) pathogenesis involves vascular disturbance that leads to hypoxia, capillary necrosis and muscle perifascicular atrophy. Hence, the hypothesis is that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism could be associated with susceptibility to DM. METHOD: A single centre, case control study that genotyped ACE gene in 88 DM and 99 healthy individuals. The ACE gene polymorphism was determined by melting curve analysis of real-time polymerase chain reaction products using SYBR Green. RESULTS: The DM and the control subjects had a comparable mean age, gender frequency and ethnicity. The frequency of the D allele was higher in DM than in the control individuals (63.6% vs 55.6%, respectively). The DM had more ACE D/D and less ACE I/D genotype when compared to the control individuals, whereas the ACE I/I genotype distribution was similar in both case and control groups. Moreover, after sex-age-adjusted analysis, the ACE D/D genotype was strongly associated with DM disease (odds ratio (OR) 2.44, 95% confidence interval (CI): 1.17-4.37), in contrast to ACE I/D genotype (OR 0.51, 95% CI: 0.28-0.93). CONCLUSIONS: Homozygous ACE D/D was associated significantly with the DM risk. Further investigations are required to clarify and to confirm the association of these genes with DM susceptibility.

Muscle adenylate deaminase deficiency. Report of six new cases.

We describe six adult patients (five men and one woman) out of 364 whose muscle biopsy specimens disclosed muscle adenylate deaminase deficiency. Two men had an associated dermatomyositis and another man had an associated progressive systemic sclerosis. Although the patients were different clinically, all complained of muscular weakness or poor exercise tolerance. The occurrence of muscle adenylate deaminase deficiency in both sexes suggests a possible autosomal mode of inheritance.

Antimyosin scintigraphy compared with magnetic resonance imaging in inflammatory myopathies.

OBJECTIVE: To compare indium In 111 altumomab pentetate-labeled antimyosin scintigraphy with magnetic resonance imaging (MRI) in the diagnosis and follow-up of patients with myositis. DESIGN AND METHODS: Sixteen patients with polymyositis and 1 patient with dermatomyositis, all verified with biopsy samples, were examined during diagnostic evaluation with antimyosin antibody scintigraphy and low-field MRI of the thighs and calves using T1- and T2-weighted sequences. Both examinations were repeated 6 to 22 months after therapeutic intervention with antiinflammatory drugs. The performance of the 2 methods for the assessment of the severity of muscle inflammation was evaluated using comparison with clinical examination and the serum creatine kinase level. RESULTS: At diagnosis all patients had increased uptake of antimyosin antibody in the thighs and/or calves. In T2-weighted MRI images, increased signal intensity changes reflecting intramuscular edema and inflammation were seen in all patients in at least 1 muscle group in the thighs or calves. After anti-inflammatory drug therapy, the mean uptake of antibody and the mean signal intensity changes in T2-weighted MRI had decreased. However, in T1-weighted MRI the signal intensity changes reflecting intramuscular fatty degeneration were more pronounced in the follow-up study. The level of serum creatine kinase had decreased markedly by the second examination except in 1 patient who also had more accumulation of antibody in the calves after than before treatment. The clinical condition improved in 8 patients and remained unchanged in 9 patients. CONCLUSIONS: Antimyosin scintigraphy and T2-weighted MRI are feasible tools for the detection and follow-up of lesions in patients with myositis. Scintigraphy findings correlate with serum creatine kinase activity and seem to reflect disease activity better than T2-weighted MRI changes, whereas secondary degenerative intramuscular lesions are only detectable using T1-weighted MRI.

Aberrant expression of cyclin-dependent kinase 5 in inclusion body myositis.

OBJECTIVE: To investigate abnormal protein expression in inclusion body myositis (IBM). BACKGROUND: In IBM, ectopic deposition of beta-amyloid protein as well as several other proteins in some muscle fibers occurs. Some, but not all, of these proteins are also expressed in myofibrillar myopathy (MFM). The authors recently reported aberrant expressions of several cyclin-dependent kinases (CDKs)-enzymes regulating the cell replication cycle-in MFM. They therefore tested the notion that aberrant expression of CDKs also occurs in IBM. Among CDKs, CDK1, CDK2, and CDK5 have been demonstrated to phosphorylate tau, which is a component of inclusions in IBM. CDK5 appears in a stage of myogenesis when CDK1 and CDK2 are downregulated. METHODS: Cryostat sections of muscle specimens from 10 patients with sporadic IBM were immunostained for CDK1, CDK2, and CDK5. Fourteen patients with polymyositis and eight individuals with dermatomyositis served as disease control subjects. RESULTS: In IBM, numerous CDK5-positive inclusions were present in vacuolated fibers. CDK5 expression was not observed in any disease control subject. Regenerating fibers expressed CDK1 and CDK2 in all diseases. CONCLUSION: The results suggest that cyclin-dependent kinases (CDK)5, but no other CDKs, is involved in the formation of inclusions in IBM.

Elevated serum levels of manganese superoxide dismutase in polymyositis and dermatomyositis.

We studied serum concentrations of manganese superoxide dismutase (Mn SOD) and copper-zinc superoxide dismutase (Cu/Zn SOD) in 22 patients with polymyositis and dermatomyositis (PM/DM), 87 patients with four types of muscular dystrophy, 20 patients with amyotrophic lateral sclerosis, and 15 patients with collagen vascular diseases (CVD). Serum levels of Mn SOD were increased only in the patients with PM/DM and CVD, and the elevation was more prominent in those with PM/DM. Levels of Cu/Zn SOD were slightly elevated in some patients with PM/DM and Duchenne muscular dystrophy. In patients with PM/DM, the change in Mn SOD levels corresponded to disease activity as closely as or more closely than those of creatine kinase. The results indicate that serum Mn SOD may be a useful clinical marker for PM/DM.

Expression of matrix metalloproteinases in the muscle of patients with inflammatory myopathies.

OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) in the pathogenesis of inflammatory myopathies and the amyloid formation in sporadic inclusion body myositis (s-IBM). BACKGROUND: MMPs comprise a family of calcium-dependent zinc endoproteinases induced by cytokines and secreted by inflammatory cells. They enhance T-cell migration or adhesion and degrade components of the extracellular matrix proteins. Some MMPs also have been implicated in the formation of beta-amyloid. METHODS: We examined the expression of MMPs with single and double immunocytochemistry using antibodies against MMP-2, MMP-3, MMP-7, MMP-9, major histocompatibility complex (MHC) class I, CD8+ cells, macrophage, and beta-amyloid precursor protein (beta-APP) on serial muscle biopsy sections from patients with s-IBM, polymyositis (PM), dermatomyositis (DM), and disease control specimens. The enzyme activity of MMPs was measured by gelatin substrate zymography. RESULTS: Only the gelatinases, MMP-9 and MMP-2, were expressed in the muscle. In s-IBM and PM, but not the control specimens, MMP-9 and MMP-2 immunostained the non-necrotic and MHC class-I-expressing muscle fibers, and MMP-9, but not MMP-2, immunostained the autoinvasive CD8+ cytotoxic T cells. Zymography in muscle homogenates confirmed the increased MMP-2 and MMP-9 enzymatic activity. MMP-2, but not MMP-9, immunostained the rimmed vacuoles in s-IBM and colocalized with beta-APP, suggesting a possible involvement with the amyloid deposits. CONCLUSIONS: Because collagen IV is prominent on the muscle membrane, the overexpression of matrix metalloproteinases (MMPs) 2 and 9 on the non-necrotic muscle fibers in polymyositis (PM) and sporadic inclusion body myositis (s-IBM) may facilitate lymphocyte adhesion and enhance T-cell-mediated cytotoxicity by degrading extracellular matrix proteins. The findings may have practical implications in considering therapeutic trials with MMP inhibitors in patients with PM and s-IBM.

Dermatomyositis without creatine kinase elevation. A poor prognostic sign.

Serum muscle enzyme levels are usually elevated in patients with untreated polymyositis and dermatomyositis. Creatine kinase is the muscle enzyme most often used to diagnose inflammatory myopathies. Seven patients with dermatomyositis and normal creatine kinase levels are described. Five of the seven patients had either an associated malignancy or severe interstitial lung disease. The one-year survival of the six patients followed for that length of time was 33 percent. A lack of creatine kinase elevation in patients with dermatomyositis is a poor prognostic sign.