The association of sporadic inclusion body myositis and Sjögren's syndrome in carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype.

Sporadic inclusion body myositis (sIBM) usually occurs as an isolated condition, but it may occur in association with another autoimmune disorder such as Sjögren's syndrome. We reviewed sIBM cases with Sjögren's syndrome (sIBM/SS) from the Perth Inflammatory Myopathies Database to determine whether they are distinguishable from other sIBM cases. Six such cases were identified, representing 12% of all sIBM cases. Muscle biopsies confirmed the presence of an inflammatory myopathy with rimmed vacuoles and the characteristic muscle fibre inclusions of sIBM. Five of the six were females, contrasting with a 2:1 male preponderance in the rest of the sIBM cohort. The mean age-at-onset and the pattern of muscle weakness were similar in the two groups. Four out of five sIBM/SS patients treated with immune therapies had improvement in muscle strength lasting for 6-24 months, whereas only 27% of other sIBM patients improved. All 6 patients with sIBM/SS carried the HLA-DRB1*0301 allele, or its equivalent HLA-DR3 serological specificity, compared with 83% of other sIBM cases and all carried some or all of the major markers of the 8.1 MHC ancestral haplotype which is also associated with Sjögren's syndrome. Patients with sIBM/SS represent a subgroup of sIBM cases who are more likely to be female and carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype, and are more likely to respond to treatment. The association of sIBM and Sjögren's syndrome is likely to be due to a common genetic predisposition linked to the MHC and supports the notion that sIBM has an autoimmune basis.

Inflammatory myopathies: how to treat the difficult cases.

The initial approach to the treatment of patients with inflammatory myopathy is critical in determining the subsequent course and outcome. Prolonged administration of high doses of corticosteroids should be avoided and a second-line agent such as methotrexate or azathioprine should be introduced earlier rather than later. Intravenous immunoglobulin therapy has an important place if the myositis remains active, particularly in patients with dermatomyositis, and is the treatment of choice in patients with immunodeficiency who are not controlled by corticosteroids. In more resistant cases of polymyositis or dermatomyositis it may be necessary to use cyclophosphamide, cyclosporin or the promising newer immunosuppressive agents mycophenolate mofetil or tacrolimus to achieve disease control. The treatment of inclusion body myositis remains unsatisfactory but a trial of prednisolone and methotrexate is warranted in selected patients.

Patterns of muscle involvement in inclusion body myositis: clinical and magnetic resonance imaging study.

The differential patterns of muscle involvement in the upper and lower limbs in sporadic inclusion body myositis (sIBM) were examined in 18 patients using both quantitative and manual muscle testing as well as magnetic resonance imaging (MRI) in 9 patients. Weakness of the quadriceps femoris and the forearm flexors was present in most patients, but there was considerable variability in the patterns and severity of muscle involvement. MRI disclosed preferential patterns of muscle involvement within functional groups such as the quadriceps femoris, in which there was severe involvement of the vasti with relative sparing of the rectus femoris, and the triceps surae, in which selective involvement of the medial gastrocnemius was common. Involvement of flexor digitorum profundus on MRI was found in only one third of patients. The results emphasize the variability in the clinical phenotype and differential susceptibility of muscles to the disease process in sIBM.

Prevalence of sporadic inclusion body myositis in Western Australia.

A 10-year retrospective review was conducted to ascertain the prevalence of inclusion body myositis (IBM) in Western Australia. Seventeen patients with sporadic IBM aged 45-90 years were identified and the prevalence of IBM was calculated to be 9.3 x 10(-6). The prevalence was higher in men (10.9 x 10(-6)) than in women (7.7 x 10(-6)). The mean age of onset of IBM was 56.6 years, and the mean delay between onset of symptoms and diagnosis was 4.4 years. The age-adjusted prevalence over the age of 50 years was 35.3 x 10(-6). The results suggest a higher prevalence of IBM than has previously been reported.

Frequency of relapses in patients with polymyositis and dermatomyositis.

The frequency of clinical and biochemical relapses was determined in a group of 50 patients with polymyositis (PM), dermatomyositis (DM), or overlap syndromes who were followed for periods of up to 13 years. Relapses occurred in 30 of the 50 patients (60%) during the period of follow-up. The annual relapse rate was not significantly different in the three groups of patients. Subclinical relapses occurred in each group but were less frequent in the DM than in the PM and overlap groups. Relapses could occur at any time but were more frequent during periods of stable maintenance therapy. There was no correlation between relapses and initial disease severity, delay to diagnosis and commencement of treatment, or any class I or II histocompatibility locus antigen.

Immunoglobulin therapy in inflammatory myopathies.

A prospective open label trial of add on therapy with intravenous immunoglobulin (i.v.Ig) was carried out in 16 patients with inflammatory myopathy who had continued to deteriorate or had relapsed on conventional therapy. The response was assessed using isometric myometry, functional scales, MRC grading, and serum creatine kinase concentrations with a three month run in period before commencement of i.v.Ig. Five of seven patients with isolated dermatomyositis or polymyositis and all four patients with an overlap syndrome responded to i.v.Ig with partial or complete remission of disease and normalisation of serum creatine kinase concentrations. None of five patients with inclusion body myositis showed any functional improvement although myometry scores improved in some muscles in one case. It is concluded that i.v.Ig is an effective therapeutic option in patients with drug resistant polymyositis or dermatomyositis. However, further controlled trials are required to confirm the efficacy of this form of treatment and to establish optimal doses and administration regimes.

Chronic sensory neuropathy with anti-Ro antibodies without clinical features of Sjögren's syndrome.

We present the clinical, electrophysiological and serological findings of a patient with a 13-year history of a chronic sensory neuropathy associated with anti-Ro (SS-A) antibodies, in whom there were no clinical or pathological features of Sjögren's syndrome. Given the possible therapeutic implications we suggest that anti-Ro antibodies be sought in any patient presenting with a chronic sensory neuropathy, even in the absence of clinical or pathological features of Sjögren's syndrome.

Treatment of inflammatory myopathies.

The treatment of the immune-mediated inflammatory myopathies remains largely empirical. Corticosteroids are usually effective in polymyositis and dermatomyositis but may need to be combined with methotrexate or azathioprine in some patients. Intravenous immunoglobulin (IVIg) is effective as add-on therapy in some patients not adequately controlled with steroids or immunosuppressive agents, but further controlled trials of IVIg are necessary to define the indications and optimal dose regimens. Cyclophosphamide, cyclosporin, or chlorambucil may be effective in patients with refractory polymyositis or dermatomyositis. Low-dose whole body or lymphoid irradiation is a last option in severely disabled patients resistant to all other treatments. As a small proportion of patients with inclusion body myositis respond to corticosteroid or immunosuppressive therapy, a 3-6-month trial of such therapy is justified in this condition. More specific immunotherapy for these disorders awaits identification of the target antigens and further clarification of the immunopathogenetic mechanisms.

Idiopathic inflammatory myopathies: optimum immunosuppressive treatment.

The idiopathic inflammatory myopathies include polymyositis and dermatomyositis, which tend to be responsive to drug therapy, and inclusion body myositis, which is often unresponsive or only partially responsive to drugs. Corticosteroids are considered the first line treatment of these disorders, and as well as being anti-inflammatory are immunosuppressive when used at dosages above prednisolone 20 mg/day or equivalent. In those patients who are refractory to corticosteroids, or are prone to develop complications from corticosteroids, second line drugs such as methotrexate, azathioprine or intravenous immunoglobulin should be introduced. These therapies tend to be slow acting, but response often occurs in 4 to 6 weeks and allows the dosage of corticosteroid to be reduced more rapidly. In those occasional patients with inflammatory myopathies that are refractory to corticosteroids and second line agents, one should consider adding in a third line agent such as cyclosporin, chlorambucil or cyclophosphamide. Although most clinicians would use these immunosuppressive drugs singly in combination with corticosteroids, multiple drug therapy should be considered in severe refractory cases.

Apolipoprotein E epsilon 4 in inclusion body myositis.

The genetic predisposition to inclusion body myositis (IBM) is probably multifactorial. The deposition of the beta-amyloid protein is a characteristic histological feature of both IBM and Alzheimer's disease (AD). The epsilon 4 allele of apolipoprotein E (APO E) has been strongly associated with familial and late-onset AD. We therefore compared the APO E allele frequencies in a group of 14 patients with IBM with those in a group of patients with other inflammatory muscle diseases and in the general population. The frequency of the epsilon 4 allele in IBM was increased (0.29) compared with that in patients with other inflammatory muscle diseases (0.15) and the general population (0.13) (p < 0.05). These data suggest that APO E genotype may be one of the factors involved in determining the predisposition to the development of IBM.

HLA associations with inclusion body myositis.

Inclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8+ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class III region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class I, DR and complement loci along with the C4 and CYP21 RFLP. Ten of the DR3+ subjects had a 6.4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class II and III regions, of the extended haplotype marked by B8/C4A*Q0/C4B1/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11% of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B18/C4A3/C4BW*0/BfF1/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.

Fibromyalgia syndrome: assessment of the severity of the condition 2 years after diagnosis.

OBJECTIVE: To review the outcome of patients with fibromyalgia syndrome (FMS) diagnosed and treated with minimal intervention in community rheumatology practice. METHODS: Forty-four ambulant patients with FMS, first seen in a 2-month period and treated with a simple management program, were identified and reviewed 2 years after diagnosis. A variety of clinical and psychological features were assessed using standard techniques. RESULTS: Forty-seven percent no longer fulfilled Smythe or ACR criteria for FMS. Remission was objectively identified in 24.2% of assessed patients. Significant differences in objective clinical signs, in symptoms, and in self-described disability were found between patients with and without FMS. Regular physical exercise, rather than drug or specific physical therapies, correlated highly with low FMS activity scores. Analysis of mood and coping strategies at the 2-year review showed low correlations with current FMS activity. CONCLUSION: Community FMS has a better prognosis than the literature suggests. Simple intervention may be associated with good outcome in a significant number of patients with FMS.

Treatment of inflammatory myopathies.

Although there have been considerable advances in our understanding of the immunopathogenesis of the different forms of autoimmune inflammatory myopathy, the treatment of these conditions remains largely empirical, being based upon the use of immunosuppressive and immunomodulatory therapies which, for the most part, are non-selective in their actions. Corticosteroids are usually effective in adult and childhood cases of polymyositis and dermatomyositis, but are only rarely helpful in inclusion body myositis, which is usually also unresponsive to other forms of immunosuppressive therapy. Alternate-day corticosteroid therapy has a role in patients with mild disease and as a means of minimizing the side-effects of steroids. This may also be achieved by the early introduction of a second-line agent such as methotrexate or azathioprine, which will allow more rapid steroid withdrawal and may also improve the chances of inducing a remission in more severe cases. In patients who fail to respond adequately to oral corticosteroids, or who relapse after an initial response, intravenous immunoglobulin therapy or pulse therapy with intravenous methylprednisolone are promising approaches which appeal as safer alternatives to cytotoxic drugs. However these forms of treatment will require further evaluation in prospective clinical trials. The same applies to cyclosporin, which has a more selective action on T cells, and which has been reported to be effective in resistant cases of adult and juvenile polymyositis and dermatomyositis. In the longer term, the development of more specific forms of immunotherapy for these myopathies, aimed at blocking autoantigen presentation or its interaction with T cells, awaits the identification of the target antigens and T cells which initiate the autoimmune process.

Scleromyxedema and inflammatory myopathy: a clinicopathologic study of three patients.

Scleromyxedema (lichen myxedematosus) is a rare cutaneous manifestation in patients with idiopathic inflammatory myopathy. The clinical and histological findings in three patients with this association are presented. Two patients had a severe inflammatory polymyopathy which responded incompletely to corticosteroid therapy, while in the third, who developed esophageal carcinoma, the myopathy was relatively mild and the skin changes were the dominant feature. The occurrence of scleromyxedema in patients with inflammatory myopathy appears to carry a poor prognosis.

Genetic markers in rheumatoid arthritis relationship to toxicity from D-penicillamine.

In a 3-centre study involving 144 patients with rheumatoid arthritis (RA), a relationship between side effects from D-penicillamine and HLA antigens, allotypic markers of the IgG heavy chain (Gm) and allotypes of complement components Bf, C4A and C4B was sought. There was a significant association between proteinuria induced by D-penicillamine and the antigens DR3 and B8. However, the presence of DR2 seemed to protect against the development of proteinuria. Thrombocytopenia from D-penicillamine was significantly associated with HLA-A1 and DR4; 15 of 23 patients who possessed both antigens developed thrombocytopenia (p less than 0.001 uncorrected, approximate relative risk (RR) = 5.5). A null complement allele located at the C4B locus (C4BQO) was also associated with thrombocytopenia from D-penicillamine (p less than 0.005, RR = 17.3). Our study confirms the findings from other series which indicate that there is a genetic predisposition for the development of proteinuria from D-penicillamine in RA and suggests that this may also be the case in D-penicillamine induced thrombocytopenia.

Genetic studies in familial fibrosing alveolitis. Possible linkage with immunoglobulin allotypes (Gm).

A family containing 12 subjects spanning three generations and including six cases with clinical evidence of definite or probable fibrosing alveolitis has been investigated. Histologic confirmation was available for three cases. The subjects were between 15 and 54 years of age at diagnosis. Although the size of the sample is small, the mode of inheritance of fibrosing alveolitis within this family appeared to be dominant with incomplete penetrance. HLA typing showed that at least one of the affected siblings did not share any HLA haplotypes with other affected siblings in the third generation. This makes it unlikely that a disease gene would be in association with HLA genes on chromosome 6. In contrast, all affected siblings, as well as two as yet unaffected siblings, carried the immunoglobulin haplotype Gm 1. These studies indicate that familial fibrosing alveolitis in this family may be inherited by a dominantly inherited gene located on chromosome 14 close to the loci encoding for Gm.

Thyrogastric autoimmunity and MHC associated alleles at the C4 locus in patients with type 1 (insulin-dependent) diabetes.

HLA antigens, complement allotypes, insulin antibodies and thyrogastric autoantibodies were determined in 69 patients with Type 1 (insulin-dependent) diabetes defined by a tendency to ketosis, non-obesity and insulin requirement within 2 years of diagnosis. Analysis of HLA and C4 allotypes suggested that Type 1 diabetes was associated with only certain DR3- and DR4-containing supratypes. Low antibody response to insulin was associated with all HLA-DR3, being present in 89% of those with DR3 compared with 48% of those without. Thyrogastric autoantibodies were associated with a null allele at the C4A locus, usually with HLA-B8-C4AQO-C4B1-BfS-DR3. These results indicate that, unlike Type 1 diabetes, low insulin antibody response was associated with all HLA-DR3. Thyrogastric autoantibodies, on the other hand, were associated with a null allele at the C4A locus. It is probable that while interaction between certain HLA-DR3 and DR4-containing supratypes is important in conferring susceptibility to Type 1 diabetes, other manifestations of autoimmunity are associated with supratypes containing C4AQ0, and in particular the diabetogenic supratype HLA-B8-C4AQ0-C4B1-BfS-DR3.

Guillain-Barré syndrome and pemphigus foliaceus associated with D-penicillamine therapy.

The Guillain-Barré syndrome and pemphigus foliaceus occurred simultaneously in a patient on long-term treatment with D-penicillamine. It is proposed that both conditions may have developed as a result of a disturbance of immunoregulation caused by D-penicillamine.