Jessica E. Hoogendijk

119th ENMC international workshop: Trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands

Department of Neurology, University Medical Center, Heidelberg laan 100, Utrecht, CX 3584, The Netherlands Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA The Walton Centre for Neurology and Neurosurgery, Liverpool, UK Department of Rheumatology, King’s College Hospital, London, UK Rheumatology Unit, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden King’s Neurosciences Centre, King’s College Hospital, London, UK Institute of Rheumatology, Prague, Czech Republic Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands Department of Clinical Neurosciences, Guy’s, King’s and Thomas’ School of Medicine, London, UK

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.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.

Epidemiology of inclusion body myositis in the Netherlands: A nationwide study

Article abstract 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.

De-novo mutation in hereditary motor and sensory neuropathy type I

Isolated cases of hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1) have been thought to be most frequently autosomal recessive. We have found that a recently discovered duplication in chromosome 17, responsible for most cases of autosomal dominant HMSN I, is present as a de-novo mutation in 9 out of 10 sporadic patients. This finding has important implications for genetic counselling of isolated patients with HMSN I.

Two divergent types of nerve pathology in patients with different P0 mutations in Charcot-Marie-Tooth disease

In seven unrelated patients with a demyelinating motor and sensory neuropathy, we found mutations in exons 2 and 3 of the P sub 0 gene.Morphologic examination of sural nerve biopsy specimens showed a demyelinating process with onion bulb formation in all cases. In four patients, ultrastructural examination demonstrated uncompacted myelin in 23 to 68% of the myelinated fibers, which is in agreement with the widely accepted function of P0 as a homophilic adhesion molecule. Three patients showed normal compact myelin, but morphology was dominated by the abundant occurrence of focally folded myelin. The two divergent pathologic phenotypes exemplify that some mutations act differently on P0 protein formation or function than others, which is probably determined by site and nature of the mutation in the P0 gene. NEUROLOGY 1996;47: 761-765

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.

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

Abstract.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.

The unfolding clinical spectrum of POLG mutations

Background: Mutations in the DNA polymerase-γ (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.

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.

Genetic linkage of hereditary motor and sensory neuropathy type I (Charcot-Marie-Tooth disease) to markers of chromosomes 1 and 17

Hereditary motor and sensory neuropathy type 1 (HMSN I) is an autosomal dominant disorder genetically localized on chromosome 1 in a few families and on chromosome 17 in other families. We analyzed linkage between 6 markers of chromosome 1, 2 markers of chromosome 17, and the HMSN I locus using restriction fragment length polymorphisms and serotyping for the Duffy blood group in 5 families with HMSN I. Only in 1 of these families is linkage present between the disease locus and the loci for Duffy blood group and glucocerebrosidase (chromosome 1 markers). In the 4 other families the HMSN I locus is linked to the chromosome 17 markers pEW301 and pA10–41.