Frederick W. Miller

Treatment of refractory myositis: a randomized crossover study of two new cytotoxic regimens.

OBJECTIVEnTo assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis.nnnMETHODSnThirty patients with refractory myositis, of whom 25 had an inadequate or no response to previous cytotoxic therapy, were randomized to begin either a combination of weekly oral methotrexate and daily azathioprine (MTX/AZA) or intravenous methotrexate with leucovorin rescue (I.V. MTX) every 2 weeks for 6 months. Crossover to the alternate therapy occurred according to defined rules; evaluations of muscle strength and functional abilities were performed at the beginning, and after 3 and 6 months, of each treatment.nnnRESULTSnOf the 15 patients initially randomized to oral MTX/AZA, 8 improved with oral therapy and 1 improved with I.V. MTX during the crossover period. Of the 15 patients initially randomized to I.V. MTX therapy, 3 improved with the I.V. therapy and 4 with the oral combination during the crossover period. Although the study lacked the power to directly compare both treatments, intention-to-treat analysis showed a trend in favor of those patients who first received oral combination therapy (P = 0.025). There were 0.09 adverse events per patient-month with oral combination therapy and 0.16 per patient-month with I.V. therapy (P = 0.09).nnnCONCLUSIONnCombination oral MTX/AZA may benefit patients with treatment-resistant myositis, including those who previously had inadequate responses to either MTX or AZA alone. I.V. MTX with leucovorin rescue may also benefit some patients with refractory myositis.

Familial autoimmunity in pedigrees of idiopathic inflammatory myopathy patients suggests common genetic risk factors for many autoimmune diseases

OBJECTIVEnTo test the hypothesis that many autoimmune diseases share common genetic risk factors and to define the frequency and distribution of autoimmune diseases in relatives of patients with very rare disorders, the idiopathic inflammatory myopathies (IIM).nnnMETHODSnWe evaluated, in a prospective case-control study, consecutive patients with IIM who were referred to our center and ascertained without regard to family history or known risk factors for autoimmunity, and all available family members. We used a standardized assessment to determine the presence and type of autoimmune disease in each subject. A matched comparison group of control subjects without autoimmune disease who were referred to our center and their families were similarly assessed.nnnRESULTSnAutoimmune diseases were significantly increased in prevalence (21.9%) in the 151 first-degree relatives of the 21 IIM probands compared with the prevalence (4.9%) in the 143 relatives of the 21 control probands (odds ratio [OR] by regression analysis 7.9, 95% confidence interval [95% CI] 2.9-21.9, P < 0.001). Women had more autoimmune disease than men (OR by regression analysis 4.6, 95% CI 2.3-9.0) and the odds ratio for autoimmune disease increased 0.02 per year of age. These disorders tended to follow the frequency distribution of autoimmune diseases in the general population. Genetic modeling studies showed that a non-Mendelian polygenic inheritance pattern for autoimmune disease was most consistent with these data.nnnCONCLUSIONnAutoimmune diseases are significantly increased in frequency in first-degree relatives of IIM patients, affect more women than men, increase with age, and are distributed in a pattern similar to that in the general population. Many autoimmune disorders share genes that together act as polygenic risk factors for autoimmunity.

Clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy

OBJECTIVEnTo describe the clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy (IIM) and to compare these with the features of sporadic IIM.nnnMETHODSnClinical signs and symptoms, autoantibodies, HLA-DRB1 and DQA1 alleles, and GM/KM phenotypes were compared among 36 affected and 28 unaffected members of 16 unrelated families in which 2 or more blood relatives developed an IIM. In addition, findings in patients with familial IIM were compared with those in 181 patients with sporadic IIM. The families included 3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with other siblings or relatives with polymyositis or dermatomyositis, and 2 families with inclusion body myositis.nnnRESULTSnThe clinical features of familial IIM were similar to those of sporadic IIM, although the frequency of myositis-specific autoantibodies was lower in familial than in sporadic IIM. DRB1*0301 was a common genetic risk factor for familial and sporadic IIM, but contributed less to the genetic risk of familial IIM (etiologic fraction 0.35 versus 0.51 in sporadic IIM). Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor unique to familial IIM (57% versus 24% of controls; odds ratio 4.2, corrected P = 0.002).nnnCONCLUSIONnThese findings emphasize that 1) familial muscle weakness is not always due to inherited metabolic defects or dystrophies, but may be the result of the development of IIM in several members of the same family, and 2) multiple genetic factors are likely important in the etiology and disease expression of familial IIM, as is also the case for sporadic myositis, but DQA1 homozygosity is a distinct risk factor for familial IIM.

Genetic risk and protective factors for idiopathic inflammatory myopathy in Koreans and American Whites: A tale of two loci

OBJECTIVEnTo better understand genetic contributions to autoimmunity, immunogenetic markers were studied in two racially discrete and geographically isolated populations of patients with idiopathic inflammatory myopathy (IIM).nnnMETHODSnClinical characteristics, as well as clinical and autoantibody subsets, were defined in 151 American white patients and 50 Korean patients with IIM. HLA-DRB1 and DQA1 genotyping was performed on patients and racially matched controls by standard molecular techniques. Gm allotypes and phenotypes were determined by the hemagglutination-inhibition method.nnnRESULTSnHLA-DRB1*0301, the linked allele DQA1*0501, and DRB1 alleles sharing the first hypervariable region motif 9EYSTS13 were major genetic risk factors for the development of myositis in whites (corrected P [Pcorr] < 0.0004, odds ratio [OR] 11.2, 4.5, and 3.1, respectively, for each factor versus controls). Although both the white and Korean patients had a similar distribution of clinical characteristics, autoantibody profiles, and clinical groups, no HLA-DRB1 nor DQA1 allele or motif was found to be a risk factor for IIM in the Korean patients. However, DRB1*14 was a protective factor in Korean patients without myositis-specific autoantibodies (Pcorr = 0.004, OR 0.046). In addition, although no Gm phenotype or allotype was identified as a risk factor in whites, Gm 21 was a protective factor for the development of IIM in Koreans (Pcorr = 0.024, OR 0.3).nnnCONCLUSIONnAlthough myositis patients in the US and Korea share similar clinical and serologic features, the immune response genes predisposing to and protecting from myositis in each of these ethnic groups differ at two chromosomal loci. These data suggest that multiple genetic loci should be studied to identify risk and protective factors for some autoimmune diseases in various ethnic populations.

Signal Recognition Particle Autoantibodies

Publisher Summary nThis chapter discusses the pathogenetic role, methods of detection, and clinical associations of signal recognition particle autoantibodies. Human autoantibodies to the signal recognition particle (anti-SRP) were first described in a polymyositis patient. Anti-SRP antibodies primarily target and bind to SRP54, the 54 kd protein of this ribonucleoprotein complex that is involved in facilitating the translocation of nascent polypeptides from the polysome to the endoplasmic reticulum. Characterized by a diffuse cytoplasmic staining pattern after indirect immunofluorescence on HEp-2 cells, anti-SRP are confirmed by immunoprecipitation of the characteristic six SRP proteins and 7SL RNA. The chapter shows that for all myositis-specific autoantibodies, anti-SRP delineate a relatively homogenous group of patients with similar clinical features, immunogenetics, and responses to therapy. Patients in the U.S. with the ‘anti-SRP syndrome” tend to be black females with an acute onset of severe polymyositis in the fall of the year, with a high incidence of cardiac involvement, resistance to corticosteroid, and progressive muscle weakness and atrophy.