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F W Miller

Publications and source records attributed to F W Miller.

At least 55 records · Page 3Linked to original sources
PubMed1994

Predominant TCR-alpha beta variable and joining gene expression by muscle-infiltrating lymphocytes in the idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases in which autoreactive T cells are thought to play a pathogenetic role. We have determined the pattern of TCR-alpha beta gene expression by muscle-infiltrating lymphocytes within clinically and serologically defined groups of IIM patients. We utilized the PCR to study TCR V gene expression in muscle biopsies from nine polymyositis (PM) and eight dermatomyositis (DM) patients, all of whom had autoantibodies directed against histidyl-transfer RNA synthetase (anti-Jo-1 autoantibodies). While the TCR repertoire in DM patients was generally polyclonal, an oligoclonal profile characterized PM patients. Certain V gene families were predominantly expressed; V alpha 1 and V beta 6 gene families were detected in 82 and 91% of PM biopsies, respectively. TCR expression was characterized further by analyzing J gene usage from four PM patients expressing the V beta 6 gene. Sequence analysis of 40 independent recombinants (10 per patient) identified only seven V beta 6 clonotypes and restricted usage of the related J beta 2.1, -2.3, and -2.7 genes. These data, describing predominant TCR V and J gene usage by muscle-infiltrating lymphocytes in myositis patients, suggest that Ag-driven T cell responses may play a primary role in mediating some forms of the IIM.

Adult↗
PubMed1994

A broadened spectrum of juvenile myositis. Myositis-specific autoantibodies in children.

OBJECTIVE: Myositis-specific autoantibodies (MSA) define relatively homogeneous clinical and immunogenetic patient groups in adults with idiopathic inflammatory myopathies (IIM). This study explores the usefulness of MSA in defining groups of children with myositis. METHODS: Sera from 77 children with myositis and other connective tissue diseases were tested for MSA by immunoprecipitation and immunodiffusion. Clinical data were collected and analyzed. RESULTS: The MSA anti-PL-12 (alanyl-transfer RNA synthetase), anti-Jo-1 (histidyl-tRNA synthetase), anti-signal recognition particle, and anti-Mi-2 were each identified in the sera of 12 children with IIM. In these patients, the clinical manifestations, disease courses, and responses to therapy closely resembled those in adults with the same autoantibodies. CONCLUSION: These observations suggest that the clinical syndromes defined by particular MSA are similar in children and adults with IIM. By defining similar clinical syndromes in children who have MSA, this study provides a basis for future studies of MSA in the idiopathic inflammatory myopathies of childhood, which may be useful in predicting the clinical courses of a subset of these patients and improving their therapy.

Adolescent↗
PubMed1994

The alpha beta T-cell receptor repertoire in inclusion body myositis: diverse patterns of gene expression by muscle-infiltrating lymphocytes.

Inclusion body myositis (IBM) is one member of a group of disorders known as idiopathic inflammatory myopathies (IIM) in which autoreactive T cells directed against muscle are thought to play a primary role in disease pathogenesis. We have utilized the polymerase chain reaction to determine the pattern of alpha beta T-cell receptor (TCR) variable (V) gene expression in muscle biopsies from 13 IBM patients. In the majority of biopsies, we detected oligoclonal patterns of TCR V gene expression by muscle-infiltrating lymphocytes; an average of six out of the 22 TCR V alpha gene families surveyed and seven out of 24 TCR V beta gene families surveyed were detected per biopsy. While no TCR V alpha gene families were over-represented in our survey, TCR V beta 3 and V beta 6 gene usage was a prominent feature of IBM muscle biopsies. TCR gene expression was characterized further by analysing the junctional sequence composition of both V beta 3 and V beta 6 clones from muscle biopsies of the IBM patients. A large number of structurally diverse V beta 3 and V beta 6 clonotypes were identified from these patients demonstrating a polyclonal pattern of T cell infiltration. These data, while describing prominent TCR V beta 3 and V beta 6 gene detection, do not suggest that a common antigen-driven T-cell response promotes chronic inflammation in muscle of IBM patients.

Adult↗
PubMed1994

New perspectives on the idiopathic inflammatory myopathies of childhood.

The idiopathic inflammatory myopathies (IIMs) of childhood are a heterogenous group of rare diseases characterized by chronic skeletal muscle inflammation. Although juvenile dermatomyositis is the most common of these disorders, children may develop any of the other types of myositis that have been better studied in adults. These include not only the IIMs delineated by clinicopathologic features but also the serologic groups of myositis, recently defined by myositis-specific and myositis-associated autoantibodies. Differences in the frequencies of IIM groups between children and adults suggest differences in exposures to myositis-inducing environmental agents or differences in the frequencies of susceptibility genes between these two populations. Further investigation of the heterogeneity of the childhood IIMs and of the newly described clinicopathologic and autoantibody groups should improve our understanding and treatment of these disorders.

Autoantibodies↗
PubMed1994

Classification and prognosis of inflammatory muscle disease.

Although our understanding of the inflammatory myopathies is still evolving, it is becoming increasingly clear that these syndromes are composed of many separate and distinct disorders with widely divergent clinical signs, symptoms, laboratory abnormalities, and prognoses. Their classification remains controversial, but three approaches of dividing the myositis syndromes appear useful in helping to group disorders with similar features together. The three approaches divide these syndromes on the basis of clinical and histopathologic findings, by serology, and by exposures to known environmental agents. Studies of the prognosis of these disorders are limited by the rarity and heterogeneity of the myositis syndromes. Taken together, however, they suggest that a variety of demographic, clinical, and serologic features are associated with a poor outcome. These include older age at myositis onset, severe myositis, delay to diagnosis and therapy, significant cardiac, pulmonary or gastrointestinal involvement, and the presence of cancer, inclusion body myositis, or antisynthetase or anti-SRP auto-antibodies. It is hoped that our understanding of the classification and prognosis of the inflammatory myopathies will become more complete as we perceive more fully the interrelationships between the genetic and environmental risk factors necessary for the induction of myositis and develop more rational ways of dividing and treating these increasingly recognized syndromes.

Humans↗
PubMed1993

Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy.

PURPOSE: To identify factors associated with responses to treatment with prednisone, methotrexate, or azathioprine in patients with idiopathic inflammatory myopathy, and to compare the efficacy of these drugs. PATIENTS AND METHODS: Data were collected on 113 adult patients meeting criteria for definite idiopathic inflammatory myopathy in this retrospective cohort study. Patients were categorized as responding completely, partially, or not at all to each therapeutic trial based upon clinical and laboratory criteria. RESULTS: Clinical group, presence of certain myositis-specific autoantibodies, and time from disease onset to diagnosis influenced rates of complete clinical response to these therapeutic agents. Patients with inclusion body myositis responded comparatively poorly to prednisone and the other drugs: 43% had no clinical response to prednisone and none responded completely to any medication. Patients with autoantibodies to aminoacyl-tRNA synthetases or to signal recognition particle proteins were likely to respond partially, but not completely, to prednisone. No patient with a long delay to diagnosis (greater than 18 months) responded completely, compared with 34% of those with a short delay (less than 3 months). A patient's response to the first course of prednisone predicted subsequent responses to prednisone and to azathioprine better than response to methotrexate. Men responded to methotrexate better than women. Among certain subgroups of patients, responses to methotrexate were better than to either azathioprine or retreatment with prednisone. CONCLUSION: Determining the clinical group, autoantibody status, and time from disease onset to diagnosis of patients with myositis provides useful information in predicting clinical responses to therapy, and these factors should be considered in designing future therapeutic trials. Methotrexate therapy may be superior to either azathioprine or further steroid treatment alone in certain patients who do not respond completely to an initial adequate course of prednisone.

Adult↗
PubMed1993

Noninfectious environmental agents associated with myopathies.

Increasing attention is being focused on environmental agents as possible factors in the etiology of certain connective tissue disorders. As our awareness in this area increases, the number and diversity of these agents is expanding yearly and now includes, in addition to infectious agents, a variety of foods and dietary supplements, drugs, occupational and other toxic exposures, biologics, and medical devices. Some of these agents have been associated with the development of muscle disease through mechanisms that involve alterations in the vascular supply to muscle, depletion of electrolytes, direct toxic effects on mitochondria or other metabolic processes, or activation of the immune system. Individual host susceptibility factors, including preexisting organ dysfunction and particular metabolizer or immunogenetic phenotypes, also appear to be important for development of the clinical syndromes identified as environmentally associated myopathies. Although data in this area are limited, they suggest that when susceptible individuals are exposed to selected agents, physiologic alterations occur that lead to myopathy. Physician awareness of chemicals implicated with myopathy and dissection of their pathogenetic mechanisms through human and animal studies may aid in the identification of additional toxic agents, minimize new cases in the future, and lead to a better understanding of the idiopathic myopathies.

Drug-Related Side Effects and Adverse Reactions↗
PubMed1993

The treatment of inclusion body myositis: a retrospective review and a randomized, prospective trial of immunosuppressive therapy.

We have sought to examine the response to immunosuppressive therapeutic intervention in inclusion body myositis (IBM) in a retrospective review of prior responses to therapy and in an open, randomized crossover trial. We collected information on the response to prior therapy on 25 patients, and for prospective therapy on 11 of these patients. All met criteria for a definite idiopathic inflammatory myopathy and had biopsy-proven IBM. Clinical and laboratory results were assessed by interviews of patients and by chart review in the retrospective trial. Manual muscle strength was assessed by a single trained observer; the patients' activities of daily living were assessed by questionnaire; and serum tests of muscle-associated enzymes were measured in the prospective trial. In the retrospective review, prednisone appeared to have been of some, albeit modest, clinical benefit in 10 of 25 (40%) patients. Other therapies, primarily azathioprine and methotrexate, also appeared to have halted the progression of weakness in 8 of 35 trials (23%). In the prospective study, combination therapy of oral azathioprine and methotrexate and a biweekly infusion of high-dose intravenous methotrexate with leucovorin rescue were given for 3 to 6 months in an open, crossover design. Both the oral and the intravenous regimens were clinically effective in some patients. There was clinical improvement in 3 trials, stabilization in 11 trials, and worsening in 5 trials, out of a total of 19 completed (22 intended) trials. The presence of active inflammation at entry into the prospective therapeutic protocol, either directly observed on muscle biopsy or indirectly indicated by serum creatine kinase level, may have been associated with clinical improvement. A complete laboratory response with normalization of creatine kinase and other muscle-associated enzymes did not, however, significantly predict clinical responsiveness in the prospective trial. In this first report, to our knowledge, of a prospective trial of immunosuppressive therapy for this disease, stabilization and even slight improvement of strength and functional abilities appeared to be achieved in some patients. We believe that prednisone and other immunosuppressive therapies were of modest benefit in about half of patients with inclusion body myositis, especially those with some evidence of active inflammation. Stabilization of an otherwise inexorably deteriorating course appears, therefore, to be an attainable goal in some patients with IBM.

Adult↗
PubMed1993

Reaction of anti-OJ autoantibodies with components of the multi-enzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase.

Autoantibodies to five aminoacyl-tRNA synthetases have been reported, and all have been associated with a syndrome of myositis and interstitial lung disease. Four of these synthetases exist free in the cytoplasm, but the fifth, isoleucyl-tRNA synthetase (recognized by anti-OJ autoantibodies), is a component of the multi-enzyme complex containing at least seven synthetases. In an effort to better understand the origins of these antibodies, we examined sera from 11 patients with anti-OJ autoantibodies for evidence of reaction with other components of the complex. All sera showed a characteristic pattern of 10 proteins bands by immunoprecipitation from HeLa cell extract. 10 of 11 sera significantly inhibited isoleucyl-tRNA synthetase enzyme activity. Serum and IgG from four patients also inhibited leucyl-tRNA synthetase activity, and serum and IgG from two inhibited lysyl-tRNA synthetase. Immunoblotting experiments supported reaction of the two sera with lysyl-tRNA synthetase, and revealed additional reactivity of three sera with a 160-kD component believed to be glutaminyl-tRNA synthetase. Despite reaction of some sera with additional synthetases, the immunoprecipitated tRNA appeared the same with all sera, and functioned as tRNA(ile). While reaction with more than one synthetase was seen with some anti-OJ sera, all synthetases targeted by anti-OJ sera were components of the complex, rather than unassociated synthetases. These findings suggest that an initial autoantibody response against isoleucyl-tRNA synthetase was followed by extension to involve other components of the synthetase complex. These observations may have implications for understanding the generation of antisynthetase autoantibodies.

Adult↗
PubMed1992

Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis.

BACKGROUND: The therapeutic options for patients with polymyositis or dermatomyositis that is resistant to corticosteroids are limited, unproved, and often toxic. Uncontrolled trials concluded that both plasma exchange and leukapheresis are beneficial, but despite the considerable use of these approaches, proof of their efficacy is lacking. METHODS: Thirty-nine patients with definite polymyositis or dermatomyositis were randomly assigned to receive plasma exchange (replacement of one volume of plasma with 5 percent albumin in saline), leukapheresis (removal of 5 x 10(9) to 10 x 10(9) lymphocytes), or sham apheresis in a double-blind manner, with 12 treatments given over a one-month period. Muscle strength, functional capacity, and serum levels of muscle-associated enzymes were measured before and after the 12 procedures. RESULTS: In each group 3 of 13 patients had improvements in strength and functional capacity. The condition of 3 patients treated with leukapheresis and 1 treated with plasma exchange deteriorated, and it was unchanged in the other 26 patients. Adverse effects of apheresis included the need for a central venous catheter (9 patients), major vasovagal episodes (3 patients), and severe citrate reactions (2 patients). Despite the occurrence of significant reductions in the serum levels of muscle enzymes with plasma exchange (P less than 0.001) and significant decreases in lymphocyte counts with leukapheresis (P = 0.002), there were no significant differences among the three treatment groups in the final muscle strength or functional capacity of the patients. CONCLUSIONS: As treatments for corticosteroid-resistant polymyositis or dermatomyositis, leukapheresis and plasma exchange are no more effective than sham apheresis.

Activities of Daily Living↗
PubMed1992

Viruses in idiopathic inflammatory myopathies: absence of candidate viral genomes in muscle.

There is indirect evidence that various viruses have aetiological roles in the idiopathic inflammatory myopathies. By means of a sensitive and specific method based on the polymerase chain reaction (PCR), we sought direct evidence for the presence in affected muscle of nucleic acid sequences from Coxsackie virus, mumps virus, encephalomyocarditis virus, adenovirus, human T-lymphotropic virus types I and II, and human immunodeficiency virus. RNA was extracted from muscle biopsy samples obtained from 44 patients with idiopathic inflammatory myopathies a mean of 45 (range 0-216) months after disease onset. All the subjects were older than 16 years at disease onset. The integrity of the mRNA extracted was confirmed by the successful PCR amplification of insulin receptor mRNA in all samples. The PCR method was able to detect between 1 and 20 molecules of added viral nucleic acid for the picornaviruses sought. No detectable virus sequences were found, however, in any of the patients' muscle samples or in samples from 13 controls. We tested for retroviral DNA in 22 samples (17 patients, 5 controls) that met our criterion for adequate DNA extraction (detectable beta-actin DNA by PCR); again no virus sequences were found. Persistence in muscle of these or closely related viruses is unlikely to be a continuing stimulus for disease in the idiopathic inflammatory myopathies.

Adenoviruses, Human↗
PubMed1992

Antibodies to glycyl-transfer RNA synthetase in patients with myositis and interstitial lung disease.

OBJECTIVE: We have previously described anti-EJ antibodies, and provided evidence that these antibodies react with glycyl-transfer RNA (gly-tRNA) synthetase. The aim of the present study was to identify patients with anti-EJ antibodies and describe the clinical associations of the antibody, in particular, whether it is associated with the syndrome of myositis and interstitial lung disease (ILD) that has been previously associated with autoantibodies to the aminoacyl-tRNA synthetases for histidine, threonine, and alanine. METHODS: Sera from patients with suspected or proven polymyositis or dermatomyositis (DM), sera with anticytoplasmic patterns, and control sera were tested for anti-EJ antibodies by immunoprecipitation (IPP). Positive sera and controls were tested for the ability to inhibit gly-tRNA synthetase by preincubation of the enzyme source with the serum. RESULTS: Anti-EJ antibodies were demonstrated in the sera of 5 patients, by IPP of characteristic tRNAs and protein. Original serum EJ and each of the new sera significantly inhibited the enzymatic activity of gly-tRNA synthetase but not histidyl-tRNA synthetase. All 5 of the new patients had inflammatory myopathy, a typical DM rash, and ILD. One, who had an overlap syndrome with systemic lupus erythematosus, had anti-EJ at least 4 months before the development of clinical myositis. Arthritis and Raynaud's phenomenon, other features associated with antisynthetases, were also seen. CONCLUSION: Anti-EJ is associated with the syndrome of myositis and lung disease that is seen in association with other antisynthetases. The finding of specific inhibition of gly-tRNA synthetase by all anti-EJ-positive sera strongly supports the identification of EJ antigen as gly-tRNA synthetase.

Adult↗
PubMed1991

Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti-Jo-1 and anti-signal recognition particle autoantibodies.

In idiopathic inflammatory myopathy (IIM; or, polymyositis/dermatomyositis), the myositis-specific autoantibodies anti-Jo-1 and anti-signal recognition particle (anti-SRP), appear to define clinically and immunogenetically distinct groups of patients. We show here that the month during which the onset of weakness occurs is not random in patients with anti-Jo-1 auto-antibodies (average month April, P less than 0.02) and in those with anti-SRP autoantibodies (average month November, P less than 0.02); both groups of patients also experience rapid onset of disease. By contrast, patients classified into the traditional categories of polymyositis and dermatomyositis do not have recognizable seasonal patterns and do not differ in the rate of onset of disease. These findings suggest that searches for seasonal patterns in the onset of autoimmune disorders characterized by disease-specific autoantibodies may provide useful clues to etiology.

Adult↗
PubMed1991

Thyroid stimulating and thyrotrophin binding-inhibitory immunoglobulin activity in patients with systemic lupus erythematosus having thyroid function abnormalities.

In order to determine whether thyroid function abnormalities seen in patients with systemic lupus erythematosus (SLE) are associated with autoantibodies directed against the TSH receptor, 28 patients with SLE who demonstrated abnormal thyroid function tests were evaluated for the presence of anti-TSH receptor antibodies. Anti-TSH receptor antibody activity was evaluated by assessing cAMP production in vitro in FRTL-5 (rat thyroid) cells (TSI) and the ability of the subjects' IgG to block the binding of thyrotrophin to its receptor in vitro (TBII). Complete thyroid function tests, including TRH testing, also were performed. Ten of the 28 patients demonstrated TSI activity, ranging from 133% to 183% of control. Five patients also had evidence of TBII activity, ranging from 22% to 90% inhibition (of control TSH binding levels), with 2 patients having evidence of both types of antibodies. Neither the TSI nor TBII activity in these patients was associated with the abnormal thyroid function tests. However, there were significantly more patients with TBII activity who had elevated TSH levels (3 of 4 vs 1 of 24, p less than 0.05), suggesting a potential physiologic response to TSH receptor blockade. These results indicate that patients with SLE and thyroid function abnormalities can demonstrate TBII and TSI activity in their serum. However, these antibodies do not necessarily correlate with specific abnormalities of thyroid function.

Antibodies, Antinuclear↗
PubMed1991

Humoral immunity and immunogenetics in the idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare but increasingly recognized syndromes characterized by chronic muscle inflammation of unknown cause. The finding of other autoimmune diseases in association with IIM, the inflammatory pathology, the response to immunosuppressive therapy, and the frequent occurrence of autoantibodies all support the notion that the IIMs are autoimmune diseases. IIM patients are unique in their immune targeting of a group of autoantigens involved in protein synthesis. Recent studies of the autoantibodies that bind these autoantigens (the myositis-specific autoantibodies) suggest that they arise by mechanisms that closely resemble standard immune responses. There is increasing interest in and efforts directed toward dividing the rheumatic diseases into more uniform groups for purposes of better defining etiology and pathogenesis. This approach has been useful in the analysis of the IIMs in which new approaches, subsetting patients by autoantibodies, have produced more homogeneous groupings. Recent data on predisposing immunogenetic factors in different clinical and serologic subsets of IIM patients also suggest that these disorders result from environmental agents acting on groups of genetically restricted individuals to induce immunologic activation and subsequent tissue pathology. This review summarizes these findings about the origins of the myositis-specific autoantibodies and their epidemiologic, clinical, prognostic, and immunogenetic associations.

Antibody Formation↗
PubMed1991

A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups.

The IIM are a heterogeneous group of systemic rheumatic diseases which share the common features of chronic muscle weakness and mononuclear cell infiltrates in muscle. A number of classification schemes have been proposed for them, but none takes into consideration the marked immunologic, clinical, and genetic heterogeneity of the various clinical groups. We compared the usefulness of myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-SRP, anti-Mi-2 and anti-MAS) to the standard clinical categories (polymyositis, dermatomyositis, overlap myositis, cancer-associated myositis, and inclusion body myositis) in predicting clinical signs and symptoms, HLA types, and prognosis in 212 adult IIM patients. Although patients with inclusion body myositis (n = 26) differed in having significantly more asymmetric and distal weakness, falling, and atrophy than other patients, there were few other significant differences among the other clinical groups. In contrast, autoantibody status defined distinct sets of patients and each patient had only 1 myositis-specific autoantibody. Patients with anti-amino-acyl-tRNA synthetase autoantibodies (n = 47), compared to those without these antibodies, had significantly more frequent arthritis, fever, interstitial lung disease, and "mechanic's hands"; HLA-DRw52; higher mean prednisone dose at survey, higher proportion of patients receiving cytotoxic drugs, and higher death rates. Those with anti-signal recognition particle antibodies (n = 7) had increased palpitations; myalgias; DR5, DRw52; severe, refractory disease; and higher death rates. Patients with anti-Mi-2 antibodies (n = 10) had increased "V-sign" and "shawl-sign" rashes, and cuticular overgrowth; DR7 and DRw53; and a good response to therapy. The 2 patients with anti-MAS antibodies were the only ones with alcoholic rhabdomyolysis preceding myositis; both had insulin-dependent diabetes mellitus, and both had HLA-B60, -C3, -DR4, and -DRw53. These findings suggest that myositis-specific autoantibody status is a more useful guide than clinical group in assessing patients with myositis, and that specific associations of immunogenetics, immune responses, and clinical manifestations occur in IIM. Thus the myositis-specific autoantibodies aid in interpreting the diverse symptoms and signs of myositis patients and in predicting their clinical course and prognosis. We propose, therefore, that an adjunct classification of the IIM, based on the myositis-specific autoantibody status, be incorporated into future studies of their epidemiology, etiology, and therapy.

Adult↗
PubMed1991

Magnetic resonance imaging in the idiopathic inflammatory myopathies.

We examined the usefulness of magnetic resonance imaging (MRI) in detecting active muscle disease in 40 patients with idiopathic inflammatory myopathies (IIM). Ten patients without evidence of an inflammatory neuromuscular disease were also studied. The fat-suppressive (STIR) image signal intensity correlated with clinical disease activity and, in most cases, with the presence of inflammation on muscle biopsy. Increased STIR signal intensity paralleled disease activity in 3 patients followed serially. MRI provided a detailed anatomic view of the extent of muscle changes in these diseases. Because of inherent limitations of other measures of disease in these disorders, MRI may prove to be a useful complimentary test for assessing disease activity and guiding therapeutic decisions and biopsy in the idiopathic inflammatory myopathies.

Adult↗