Myositis with endomysial cell invasion indicates inclusion body myositis even if other criteria are not fulfilled.

The objective of this study was to investigate if patients with endomysial mononuclear cell infiltrates invading non-necrotic fibers have a disease course consistent with inclusion body myositis (IBM), irrespective of other histopathological and clinical characteristics. All patients with a muscle biopsy showing endomysial inflammation with invasion of non-necrotic muscle fibers during the period 1979-2006 in two tertiary neuromuscular referral centers were classified into three groups: 1) patients whose biopsies also showed rimmed vacuoles; 2) patients whose biopsies showed no vacuoles but fulfilled clinical criteria for IBM, and 3) patients whose biopsies showed no vacuoles, and also did not fulfill clinical criteria for IBM (unclassified patients). These groups were compared with regard to age, gender, clinical features, and disease course including response to immunosuppressive treatment. Eighty-one individuals (41 men) were included. Rimmed vacuoles were found in 49 patients (60.5%). Fourteen patients (17.3%) fulfilled clinical criteria for IBM and 18 patients (22.2%) were unclassified at presentation. At follow up (mean duration 9 years) three women remained unclassified (4%). There were no differences in disease course or effect of treatment between the three groups. Men had more often rimmed vacuoles than women (73% vs 48%; p = 0.018), and women more often than men were unclassified. Women tended to show more often temporary improvement if treated (p = 0.07), but none had sustained improvement. In conclusion, patients with a muscle biopsy showing endomysial cell infiltration with invasion of non-necrotic muscle fibers most probably have IBM, regardless of clinical and other pathological features. Women lack typical features more often than men.

Congenital posterior pole cataract and adult onset dilating cardiomyopathy: expanding the phenotype of αB-crystallinopathies.

Mutations in the αB-crystallin gene (CRYAB) have been reported in desmin-related myopathies, with or without cardiac involvement. Mutations in this gene have also been documented in large multi-generation families with autosomal dominant congenital posterior pole cataract (CPPC). In these congenital cataract families no cardiac or muscular phenotype was reported. This report describes a family with an unusual read-through mutation in CRYAB, leading to the elongation of the normal αB-crystallin protein with 19 amino acid residues. Affected family members combine a CPPC with an adult onset dilated cardiomyopathy (DCM), thereby expanding the αB-crystallinopathy phenotype. Repolarisation abnormalities preceded the onset of cardiomyopathy and were already present in childhood. No skeletal myopathy was observed. This report illustrates that congenital cataract can be a prelude to more severe disease even outside the context of inborn errors of metabolism. The identification of a CRYAB mutation in this family supports the notion that mutations in this gene are a rare cause of genetically determined DCM. The combined congenital cataract/cardiomyopathy phenotype adds to our understanding of the complex phenotypic spectrum of αB-crystallinopathies.

Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D.

BACKGROUND: Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects. METHODS: We collected the clinical details of all carriers of p.S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis. RESULTS: We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p.S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis. CONCLUSION: DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement.

Oral dexamethasone pulse therapy versus daily prednisolone in sub-acute onset myositis, a randomised clinical trial.

To determine if high-dose pulsed dexamethasone is more effective and safer than daily high-dose prednisolone in treatment-naive adult patients with inflammatory myopathies (sporadic inclusion body myositis excluded) we performed a multicenter, double-blind randomised controlled clinical trial with 18 months follow-up. Sixty-two patients were randomised into 28-day cycles of oral high-dose dexamethasone or daily high-dose prednisolone. Primary outcome measures included (1) seven point composite score of six clinically relevant outcomes and (2) (time-to) remission and (time-to) relapse. No difference between both treatment groups on the composite score was found. Side-effects occurred significantly less frequently in the dexamethasone group. Median time to relapse was 60 (2.9) weeks in the prednisolone and 44 (4.7) weeks in the dexamethasone group (log-rank test p=0.03). In conclusion, pulsed high-dose oral dexamethasone is not superior to daily prednisolone as first-line treatment of idiopathic inflammatory myopathies, but is a good alternative by causing substantially fewer side-effects.

The unfolding clinical spectrum of POLG mutations.

BACKGROUND: Mutations in the DNA polymerase-gamma (POLG) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions. OBJECTIVE: To determine the spectrum of POLG mutations in our Dutch patient cohort, to evaluate the pathogenicity of novel mutations, and to establish genotype-phenotype correlations. RESULTS: The authors identified 64 predominantly recessive mutations in 37 patients from a total of 232 patients, consisting of 23 different mutations. The substitution p.A467T was most frequently observed (n = 23), but was as frequent in childhood cases as in adult cases. Five new pathogenic recessive mutations, p.Lys925ArgfsX42, p.R275X, p.G426S, p.A804T and p.R869Q were identified. The known dominant chronic progressive external ophthalmoplegia (CPEO) mutation p.R943H was for the first time associated with premature ovarian failure as well. In 19 patients the authors identified only a single recessive mutation, or a sequence variant with unclear clinical significance. The data substantiate earlier observations that in POLG patients a fatal status epilepticus and liver failure can be triggered by sodium valproate. It is therefore important to exclude POLG mutations before administering this treatment. CONCLUSION: The clinical features of the patient are the most important features to select putative POLG mutation carriers and not the presence of mtDNA deletions or OXPHOS (oxidative phosphorylation) activity. The authors conclude that POLG mutations are an important cause of heterogeneous mitochondrial pathology and that more accurate genotype-phenotype correlations allow a more rapid genetic diagnosis and improved prognosis for mutation carriers.

Association of the leukocyte immunoglobulin G (Fcgamma) receptor IIIa-158V/F polymorphism with inflammatory myopathies in Dutch patients.

Leukocytes are involved in the pathogenesis of idiopathic inflammatory myopathies (IIMs). Immunoglobulin G (IgG) receptors (FcgammaR) link the specificity of IgG to the effector functions of leukocytes. Several FcgammaR subclasses display functional polymorphisms that determine in part the vigour of the inflammatory response. FcgammaRIIIa genotypes were differentially distributed among 100 IIM patients compared with 514 healthy controls with a significant increase of the homozygous FcgammaRIIIa-V-158 genotype (3 x 2 contingency table, chi(2) = 6.3, P = 0.04). Odds ratios (ORs) increased at the addition of each FcgammaRIIIa-V-158 allele, in particular among patients with non-specific myositis and dermatomyositis {OR 2.1 [95% confidence interval (CI) 1.1-4.3] and 2.7 (95% CI 1.1-6.4) for FcgammaRIIIa-V/F158 and FcgammaRIIIa-V/V158 genotypes, respectively, using FcgammaRIIIa-F/F158 as a reference group}. These data suggest that the FcgammaRIIIa-V-158 allele may constitute a genetic risk marker for IIM.

Spontaneous recovery of dermatomyositis and unspecified myositis in three adult patients.

Dermatomyositis (DM), polymyositis and unspecified myositis are idiopathic inflammatory myopathies in which prednisone is usually started as soon as the diagnosis has been established. Therefore, little is known about the natural history of these diseases and spontaneous recovery may escape attention. Here, we present three patients who achieved remission without administration of immunosuppressants. In these three patients, treatment was not started because of spontaneously improving symptoms and signs during the diagnostic process. After 3-5 years, all patients are still free of muscle weakness. These case reports demonstrate that spontaneous long lasting remission can occur in a small proportion of patients with subacute onset idiopathic inflammatory myopathies. In some patients, immunosuppressive treatment with the risk of serious side effects can perhaps be omitted. However, close and frequent monitoring is required in these instances.

Long-term outcome in polymyositis and dermatomyositis.

BACKGROUND: Although polymyositis and dermatomyositis are regarded as treatable disorders, prognosis is not well known, as in the literature long-term outcome and prognostic factors vary widely. AIM: To analyse the prognostic outcome factors in polymyositis and adult dermatomyositis. METHODS: We determined mortality, clinical outcome (muscle strength, disability, persistent use of drugs and quality of life) and disease course and analysed prognostic outcome factors. RESULTS: Disease-related death occurred in at least 10% of the patients, mainly because of associated cancer and pulmonary complications. Re-examination of 110 patients after a median follow-up of 5 years showed that 20% remained in remission and were off drugs, whereas 80% had a polycyclic or chronic continuous course. The cumulative risk of incident connective tissue disorder in patients with myositis was significantly increased. 65% of the patients had normal strength at follow-up, 34% had no or slight disability, and 16% had normal physical sickness impact profile scores. Muscle weakness was associated with higher age (odds ratio (OR) 3.6; 95% confidence interval (CI) 1.3 to 10.3). Disability was associated with male sex (OR 3.1; 95% CI 1.2 to 7.9). 41% of the patients with a favourable clinical outcome were still using drugs. Jo-1 antibodies predicted the persistent use of drugs (OR 4.4, 95% CI 1.3 to 15.0). CONCLUSIONS: Dermatomyositis and polymyositis are serious diseases with a disease-related mortality of at least 10%. In the long term, myositis has a major effect on perceived disability and quality of life, despite the regained muscle strength.

Late onset axonal Charcot-Marie-Tooth phenotype caused by a novel myelin protein zero mutation.

A late onset axonal Charcot-Marie-Tooth phenotype is described, resulting from a novel mutation in the myelin protein zero (MPZ) gene. Comparative computer modelling of the three dimensional structure of the MPZ protein predicts that this mutation does not cause a significant structural change. The primary axonal disease process in these patients points to a function of MPZ in maintenance of the myelinated axons, apart from securing stability of the myelin layer.

[The practice guideline 'Dermatomyositis, polymyositis and sporadic inclusion body myositis']. / Richtlijn 'dermatomyositis, polymyositis en sporadische "inclusion body"-myositis'.

This guideline presents recommendations for the diagnosis and treatment of dermatomyositis, polymyositis and sporadic inclusion body myositis (sIBM) according to the best available evidence. Characteristic skin abnormalities can be sufficient for the diagnosis of dermatomyositis. In case of doubt, a skin biopsy is advisable. A muscle biopsy is indicated when other examinations are inconclusive and the musculature is involved. The working group considers screening for cancer to be required in adults with dermatomyositis and presents recommendations for the way that this should be done. At least one-third of all patients with polymyositis has, or will develop, an associated inflammatory connective tissue disease. If a patient with a connective tissue disease develops symmetrical, proximal muscle weakness in the course of weeks or months, this may be assumed to be due to polymyositis. In the absence ofpre-existing connective tissue disease, demonstration of a mononuclear cell infiltrate in muscle tissue is a prerequisite for the diagnosis ofpolymyositis. The histopathology of muscle tissue is used as the gold standard for the diagnosis of sIBM. The practice guideline presents criteria for the concept 'activity' of myositis. Disease activity serves as a guideline for the treatment of polymyositis and dermatomyositis. The treatment of choice for dermatomyositis and polymyositis is high-dose prednisone. Physical activity does not have a negative effect on the course of these diseases. The long-term prognosis ofdermatomyositis and polymyositis is not well known. The clinical course of sIBM is slowly progressive.

Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis.

BACKGROUND: Idiopathic inflammatory myopathies are chronic skeletal diseases with significant mortality and morbidity despite treatment by corticosteroids. Immunosuppressive agents and immunomodulatory therapy are used to improve disease control and reduce the long-term side effects of corticosteroids. While these treatments are used commonly in routine clinical practice, the optimal therapeutic regimen remains unclear. OBJECTIVES: To systematically review the evidence for the effectiveness of immunosuppressants and immunomodulatory treatments for dermatomyositis and polymyositis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2002 and updated in November 2003) and MEDLINE (January 1966 to December 2002). We checked bibliographies of identified trials and wrote to disease experts. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials including patients with probable or definite dermatomyositis and polymyositis as defined by the criteria of Bohan and Peter or definite, probable or mild/early by the criteria of Dalakas. Patients with inclusion body myositis should have been excluded by muscle biopsies. Any immunosuppressant or immunomodulatory treatment including corticosteroids, azathioprine, methotrexate, ciclosporin, chlorambucil, cyclophosphamide, intravenous immunoglobulin, interferon and plasma exchange was considered. Primary outcome was assessment of muscle strength after at least six months. Other outcomes were: change in disability, number of relapses and time to relapse, number of patients in remission and time-to-remission, cumulative corticosteroid dose and serious adverse effects. DATA COLLECTION AND ANALYSIS: Two authors (EC and JH) independently selected trials for inclusion in the review. Four authors independently assessed each study. Methodological criteria and the results of each study were recorded on data extraction forms. MAIN RESULTS: Seven potentially relevant randomised controlled trials were identified. One trial was excluded. Three studies compared immunosuppressant with placebo control, one trial compared one immunosuppressant (methotrexate) with another (azathioprine), another trial compared ciclosporin A with methotrexate and the final trial compared intramuscular methotrexate with oral methotrexate plus azathioprine. The study comparing intravenous immunoglobulin with placebo concluded that the former was superior. Two randomised placebo-controlled trials assessing plasma exchange, leukapheresis and azathioprine produced negative results. The fourth study compared azathioprine with methotrexate and found azathioprine and methotrexate equally effective but methotrexate had a better side effect profile. The fifth study comparing ciclosporin A with methotrexate and the sixth study comparing intramuscular methotrexate with oral methotrexate plus azathioprine found no statistically significant differences between the treatment groups. Immunosuppressants are associated with significant side effects. AUTHORS' CONCLUSIONS: This systematic review highlights the lack of high quality randomised controlled trials that assess the efficacy and toxicity of immunosuppressants in inflammatory myositis.

Follow up of patients with signs and symptoms of polyneuropathy not confirmed by electrophysiological studies.

The outcome and final diagnoses of patients with symptoms and/or signs suggestive of polyneuropathy, but with normal electrophysiological studies, were investigated. All patients who presented at the outpatient clinic between 1993 and 1998 with signs and symptoms suggestive of polyneuropathy, but in whom electrophysiological studies were normal, were included. We retrospectively collected data from the medical records and then interviewed the patients and used the Sickness Impact Profile scale to investigate functional status at least 2 years after presentation. We included 74 patients, of whom 39 had neurological signs at neurological examination at the first visit. A final diagnosis was made in 24 of the 39 patients with neurological signs, and in three of the 35 patients without neurological signs but with symptoms. One (3%) of the 35 patients without neurological signs at the first visit had a poor outcome versus 15 (39%) of the 39 patients with neurological signs. In 11 (41%) of the 27 patients in the group with a final diagnosis the outcome was poor versus 5 (11%) of 47 patients without a final diagnosis. In 11 patients we concluded that they probably had small fibre neuropathy. Patients presenting with symptoms of polyneuropathy but who have neither neurological signs of polyneuropathy nor electrophysiological studies confirming a polyneuropathy have a good outcome at least 2 years after presentation. Further investigations are not indicated, except for patients fulfilling the criteria of small fibre neuropathy. In patients with neurological signs, as the outcome depends on the diagnosis and an explanation for these signs is often found, repeated investigations in this group are mandatory.

Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis.

Whether autoimmune mechanisms play a role in the pathogenesis of inclusion body myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52 patients, including 17 with autoimmune disorders (AIDs), showed that patients were more likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral haplotype than healthy control subjects, irrespective of the presence of AIDs. Patients lacked the apparently protective HLA-DR53 antigen. The results provide further support for an autoimmune basis in IBM.

Polymyositis: an overdiagnosed entity.

BACKGROUND: According to widely used criteria (Bohan and Peter criteria, 1975), dermatomyositis (DM) is differentiated from polymyositis (PM) only by skin changes. More recent criteria also include histopathologic characteristics enabling the distinction between PM and DM and the differentiation of sporadic inclusion body myositis (s-IBM) from PM. The authors investigated the applicability of diagnostic features for diagnosing PM and DM. METHODS: The authors performed a retrospective follow-up study of 165 patients with 1) a previous diagnosis of myositis; 2) subacute onset of symmetric, proximal weakness; and 3) an evaluation between 1977 and 1998 excluding other neuromuscular disorders. RESULTS: The diagnoses at initial evaluation based on clinical, laboratory, and histopathologic criteria were PM, 9 (5%); DM, 59 (36%; 54 isolated, 3 with associated connective tissue disease [CTD], 2 with associated malignancy); unspecified myositis (perimysial/perivascular infiltrates, no PM or DM), 65 (39%; 38 isolated myositis, 26 with associated CTD, 1 with malignancy); and possible myositis (necrotizing myopathy, no inflammatory infiltrates), 32 (19%; 29 isolated myositis, 3 with associated CTD). At follow-up evaluation, five of the nine patients with PM had typical s-IBM features. None of the remaining four patients complied with the assumed typical signs of PM. Ten of the 38 patients with isolated unspecified myositis had been diagnosed with a CTD. CONCLUSIONS: Polymyositis is an overdiagnosed entity. At evaluation, more than half the patients with autoimmune myositis cannot be specifically diagnosed with polymyositis or dermatomyositis. A quarter of patients with isolated unspecified myositis subsequently developed connective tissue disease.

Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy.

OBJECTIVE: To evaluate the clinical features, muscle pathology and response to treatment in patients with a necrotising myopathy, without mononuclear cell infiltrates. BACKGROUND: Mononuclear cell infiltrates in the muscle biopsy specimen are the diagnostic hallmark of the immune-mediated idiopathic inflammatory myopathies (IIM). In patients with the typical clinical features of IIM, absence of these infiltrates in the muscle biopsy specimen casts doubt on the diagnosis and leads to uncertainty about therapeutical strategies. METHODS: A detailed description is given of the clinical, laboratory, and histopathological features of eight patients suspected of having an idiopathic inflammatory myopathy, in whom mononuclear cell infiltrates in their muscle biopsy specimens were lacking. RESULTS: Eight patients (five men, three women, age range 40-69 years) had severe, symmetrical proximal weakness with a subacute onset. There were no skin abnormalities suggesting dermatomyositis. Serum creatine kinase activity was more than 10 times elevated. Repeated muscle biopsy specimens, taken from a symptomatic muscle prior to immunosuppressive treatment showed widespread necrosis, regeneration, and atrophy of muscle fibres, but no mononuclear cell infiltrates. Known causes of necrotising myopathy were excluded. Three patients had a malignancy. Adequately dosed and sustained immunosuppressive treatment eventually resulted in normal or near normal muscle strength in seven patients. One patient showed marked improvement. CONCLUSION: Occasionally, patients who clinically present as an idiopathic inflammatory myopathy may lack mononuclear cell infiltrates in their muscle biopsy specimens. This subacute-onset progressive necrotising myopathy should not deter the clinician from timely and appropriate treatment as we consider this myopathy to be steroid-responsive with a possible immune-mediated pathogenesis.

Evidence for heterogeneity of T cell expansion in polymyositis and inclusion body myositis.

Vbeta usage of muscle-infiltrating T lymphocytes in polymyositis (PM) and sporadic inclusion body myositis (s-IBM) was correlated with clinical and histopathological features. Immunohistochemical analysis was combined with complementarity-determining region 3 (CDR3) length analysis in nine muscle biopsies of eight PM patients and six biopsies of five s-IBM patients. Vbeta usage was heterogeneous in seven patients. Four of these patients had definite PM with endomysial located T cell infiltrates, but T cells specifically surrounding and invading individual non-necrotic fibers were not found. In two s-IBM patients, Vbeta 2 usage was increased. In one of them, a repeat biopsy showed a heterogeneous Vbeta usage. We conclude that clonal expansion of muscle-infiltrating T cells could only be detected in part of the patients. Explanations may be that clonal expansion does not take place in all disease phases and that PM is a heterogeneous disease with respect to pathogenesis.

[Three patients with divergent presentations of idiopathic inflammatory myopathy]. / Drie patiënten met uiteenlopende presntaties van idiopathische inflammatoire myopathie.

The group of idiopathic inflammatory myopathies encompasses polymyositis, dermatomyositis and inclusion body myositis. These diseases share the following features: progressive muscle weakness, an increase in serum creatine kinase activity and the presence of mononuclear cell infiltrates in the muscle biopsy. Polymyositis, dermatomyositis and inclusion body myositis are differentiated on the basis of the distribution of muscle weakness, and specific histopathological features. Many specialties may see these patients as the clinical presentation can vary widely and may be atypical, requiring further diagnostic procedures. A 40-year-old man with a heliotrope rash and periorbital oedema, but no muscle involvement, was diagnosed with dermatomyositis sine myositis. He was successfully treated with corticosteroids but died later of cardiac failure. A 72-year-old man with a pulmonary malignancy subsequently developed the clinical features of dermatomyositis. Steroid therapy diminished the complaints but he died of pulmonary embolism. A 54-year-old woman with the clinical features of inclusion body myositis did not have rimmed vacuoles in her muscle biopsy specimen and was initially erroneously diagnosed with polymyositis, for which she was treated with corticosteroids, but without beneficial effect.

Rimmed vacuoles and the added value of SMI-31 staining in diagnosing sporadic inclusion body myositis.

Problems in diagnosing sporadic inclusion body myositis may arise if all clinical features fit a diagnosis of polymyositis, but the muscle biopsy shows some rimmed vacuoles. Recently, immunohistochemistry with an antibody directed against phosphorylated neurofilament (SMI-31) has been advocated as a diagnostic test for sporadic inclusion body myositis. The aims of the present study were to define a quantitative criterion to differentiate sporadic inclusion body myositis from polymyositis based on the detection of rimmed vacuoles in the haematoxylin-eosin staining and to evaluate the additional diagnostic value of the SMI-31 staining. Based on clinical criteria and creatine kinase levels in patients with endomysial infiltrates, 18 patients complied with the diagnosis of sporadic inclusion body myositis, and 17 with the diagnosis of polymyositis. A blinded observer counted the abnormal fibres in haematoxylin-eosin-stained sections and in SMI-31-stained sections. The optimal cut-off in the haematoxylin-eosin test was 0.3% vacuolated fibres. Adding the SMI-31 staining significantly increased the positive predictive value from 87 to 100%, but increased the negative predictive value only to small extent. We conclude that (1) patients with clinical and laboratory features of polymyositis, including response to treatment, may show rimmed vacuoles in their muscle biopsy and that (2) adding the SMI-31 stain can be helpful in differentiating patients who respond to treatment from patients who do not.

Epidemiology of inclusion body myositis in the Netherlands: a nationwide study.

Epidemiologic data on inclusion body myositis (IBM) are scarce, and possibly biased, because they are derived from larger neuromuscular centers. The present nationwide collaborative cross-sectional study, which culminated on July 1, 1999, resulted in identification of 76 patients with IBM and the establishment of a prevalence of 4.9 patients with IBM per million inhabitants in the Netherlands. Several discrepancies suggest that this may be an underestimation. The most frequently identified pitfall in diagnosing IBM was an erroneous diagnosis of polymyositis or motor neuron disease.