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P H Plotz

Publications and source records attributed to P H Plotz.

At least 55 records · Page 3Linked to original sources
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

The role of autoantibodies in autoimmune disease.

In autoimmune diseases, autoantibodies may be the actual pathogenetic agents of the disease, the secondary consequences of tissue damage, or the harmless footprints of an etiologic agent. Establishing a pathogenetic role for autoantibodies requires that they meet stringent criteria. It appears that the location of the presumptive target antigen most critically influences the pathogenetic potential of autoantibodies. Autoantibodies directed against cell surface targets, such as hormone receptors, are clearly pathogenetic; those directed against extracellular targets, such as circulating molecules or extracellular matrix, may or may not cause any damage. Those apparently directed against intracellular targets are usually not pathogenetic unless it can be clearly demonstrated (a) that the antigen is released from within the cell so that it can bind onto a cell surface receptor or other extracellular location, such as proteinase 3; (b) that the antigen moves to an aberrant site on the cell surface, such as, perhaps, the small ribonucleoprotein antigen Ro; or (c) that a cross-reactive molecule, the actual target, such as the membrane ribosomal P-like protein, is at an accessible location.

Antigens, Surface↗
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

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↗
PubMed1990

The role of an autoantigen, histidyl-tRNA synthetase, in the induction and maintenance of autoimmunity.

Patients with systemic autoimmune diseases make specific autoantibodies that are directed against self structures. According to one view, these autoantibodies arise as a result of an immune response to foreign antigens such as infectious agents that share, by molecular mimicry, common structures with host proteins. An alternative view is that the target autoantigen itself initiates, selects, and sustains autoantibody synthesis. We show here that anti-Jo-1 autoantibodies directed against histidyl-tRNA synthetase in the human autoimmune muscle disease polymyositis undergo, in addition to spectrotype broadening and class switching, the sine qua non of an immune response to the target antigen--affinity maturation to that antigen. We demonstrate further that these autoantibodies, unlike anti-synthetase antibodies induced in mice immunized with heterologous antigen, bind only nonlinear epitopes on the native human synthetase that remain exposed when the enzyme is complexed to tRNA(His). These data suggest that the native target autoantigen itself has played a direct role in selecting and sustaining the autoantibody response and sharply restrict the time and the way in which a molecular mimic might act to provoke autoantibodies.

Animals↗
PubMed1990

Lymphocyte activation markers in idiopathic myositis: changes with disease activity and differences among clinical and autoantibody subgroups.

We studied the immunologic correlates of disease activity and differences among subgroups of patients with idiopathic inflammatory myopathy by analysing phenotypic and activation marker expression on peripheral blood mononuclear cells (PBMC). Compared with controls, myositis patients with clinically active disease (n = 51) had significantly lower proportions of CD8+ cells and higher proportions of PBMC that expressed DR, CD3- DR, CD14- DR, interleukin-2 receptors, and the late T cell activation markers CD26 and TLiSA1. TLiSA1 expression, a marker for cytotoxic differentiation, correlated significantly with both clinical activity indices and serum levels of muscle-associated enzymes. In serial studies of seven patients, the proportion of PBMC expressing MHC class II antigen and late T cell activation markers decreased as myositis disease activity decreased, independent of type of therapy. Among the clinical subgroups, polymyositis (n = 21) and inclusion body myositis (n = 11) were virtually indistinguishable; dermatomyositis patients (n = 19) showed decreased proportions of CD3+DR+ and TLiSA1+ cells, and increased proportions of CD20+ and CD20+DR+ cells compared with the other two groups. Patients with autoantibodies to histidyl-tRNA synthetase (Jo-1 antigen, n = 11) had significantly lower proportions of CD3+ and CD4+ cells, lower CD4/CD8 ratios, and higher proportions of CD+ cells expressing CD20, compared with patients without anti-Jo-1 antibodies. These findings support the concept that activated lymphocytes, especially cells undergoing anamnestic responses and cytotoxic differentiation, are important in the pathogenesis of idiopathic myositis. Moreover, taken together with other studies, these data suggest that groups of patients segregated by clinical or autoantibody status have different mechanisms of systemic immune activation and immunopathology.

Adult↗
PubMed1990

Origin and regulation of a disease-specific autoantibody response. Antigenic epitopes, spectrotype stability, and isotype restriction of anti-Jo-1 autoantibodies.

Anti-Jo-1 antibodies (AJoA), which bind to and inhibit the activity of histidyl-transfer RNA synthetase (HRS), are found in a genetically and clinically distinct subset of myositis patients. This specificity suggests that understanding the antigenic epitopes and immunoregulation governing the production of AJoA may result in clues to disease pathogenesis. Limited digestion of human HRS by V8 protease resulted in four major antigenic polypeptides of 35, 34, 21, and 20 kD; digestion with subtilisin gave four fragments of the same sizes and two additional major antigenic polypeptides of 28 and 17 kD. Sera from 12 AJoA positive patients reacted indistinguishably with these proteolytic fragments by Western blotting, and AJoA elution studies suggested a common epitope(s) on all six. Isoelectric focusing showed a different polyclonal pattern of AJoA in each patient, although serial analyses in individual patients revealed stable AJoA spectrotypes over years of observation. Enzyme-linked immunosorbent assays showed that the AJoA response was mainly restricted to the IgG1 heavy chain isotype. The levels of IgG1 AJoA varied in proportion to disease activity over time but were independent of total IgG1 levels, and three patients became AJoA negative as their myositis remitted after treatment. These findings suggest that AJoA are induced by an antigen-driven mechanism, bind to a common epitope or epitopes on HRS, and are modulated by an immune response closely linked to that which is responsible for myositis in these patients.

Amino Acyl-tRNA Synthetases↗
PubMed1990

Idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies are a heterogeneous group of uncommon diseases. The incidence rate of IIM is approximately 5 cases per million population, but there appears to be an increase in the rate over the last two decades, particularly in black females. This may be a true increase or due to renewed interest and awareness of the disease and improvement in our ability to diagnose mild disease. There has also been progress in decreasing the mortality rate in IIM perhaps secondary to better treatment and/or the diagnosis of mild disease. The discovery of anti-Jo-1 antibodies has renewed the investigation of a possible viral etiology of IIM. Studies of quantitative slot blot hybridization with coxsackievirus probes and RNA from IIM muscle biopsies and in situ hybridization of biopsies with a Theiler's virus probe have revealed a few positive hybridizations in each study. Although there are some fundamental problems with these studies, these intriguing results bear confirmation. These results continue to implicate picornaviruses as the primary suspects in the pathogenesis of IIM. HIV has now been associated with a number of rheumatologic syndromes, including a polymyositis that is indistinguishable from IIM, and we can expect additional changes in the epidemiology of this family of disorders in coming years. Study of these patients may provide insight into the etiopathogenesis of IIM.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders.

Idiopathic inflammatory myopathy, a category encompassing polymyositis, dermatomyositis, and a number of other disorders, is very uncommon, but has been the focus of intense study in the Arthritis and Rheumatism Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases for the past several years. We describe the clinical picture, stressing the need for biopsy to ensure correct diagnosis. It is especially important to recognize the treatment-resistant variant, inclusion body myositis. The extraskeletal manifestations, particularly the cardiopulmonary, oropharyngeal, gastrointestinal, and endocrine involvement, are described. The cardiopulmonary involvement, especially interstitial lung disease, arrhythmias, and cardiac failure, may dominate the clinical picture. The known causes are varied, and include drugs, toxins, and some infectious agents, however, in most cases a cause cannot yet be identified. Circumstantial evidence suggests that picornaviruses may initiate some cases in humans, and a very similar disease in mice caused by a picornavirus is actively under study. Studies of autoantibodies and cellular immune function support a central role for disordered immunity in the pathogenesis. The myositis-specific autoantibodies, especially those directed at certain enzymes important in protein synthesis (the aminoacyl-transfer RNA synthetases), are found in a clinically distinct subset of patients. Although most patients respond initially to corticosteroids, cytotoxic drugs are sometimes added when steroid toxicity or refractoriness develops. We describe several newer therapies under study for such cases and outline future directions in research.

Animals↗
PubMed1989

The failure of intravenous cyclophosphamide therapy in refractory idiopathic inflammatory myopathy.

Eleven patients with idiopathic inflammatory myopathy refractory to treatment with corticosteroids and other immunosuppressive agents were treated with monthly intravenous cyclophosphamide (0.75-1.357 g/m2). Six patients completed a full course of 7 infusions at which point only one patient met predefined criteria for improvement in both strength and function. Five had modest improvement in strength but did not meet the criteria for improvement. All patients have subsequently required treatment with other medications. Major complications observed during therapy included serious infections in 2 patients (streptococcal endocarditis and disseminated Mycobacterium avium intracellulare) and death in one patient in which the contribution of cyclophosphamide cannot be excluded. We conclude that intravenous cyclophosphamide as used in our study cannot be recommended for the treatment of patients with refractory inflammatory myopathy.

Adult↗
PubMed1988

The natural history of encephalomyocarditis virus-induced myositis and myocarditis in mice. Viral persistence demonstrated by in situ hybridization.

Picornaviruses can initiate chronic inflammation that persists after the virus can no longer be cultured from inflamed tissues. In an attempt to understand this transition we have sought evidence for viral persistence by methods that detect viral genome independent of whether or not whole competent virus is present. In mice infected with a myotropic variant of encephalomyocarditis virus, EMC-221A, virus can be cultured in high yield at 1 wk and in low yield at 2 wk from skeletal muscle, heart, and brain; a small number of plaque-forming units could be cultured from brain at 4 wk. By contrast, in situ hybridization detected viral nucleic acid at least a week or two thereafter, often in single cells. In the skeletal muscle, inflammation disappeared by 3 wk, but in heart it remained for the full 12 wk of observation. In the brain, microglial nodules, sometimes with associated viral nucleic acid, were present for a long period. Application of this technique allows a more accurate assessment of the role of viral persistence in the pathogenesis of virus-initiated but apparently autoimmune inflammation.

Animals↗
PubMed1988

Stimulation and partial stabilization of human histidyl-tRNA synthetase by hemoglobin.

Histidyl-tRNA synthetase, an enzyme against which antibodies are directed in some patients with polymyositis, has been purified 5000-fold from HeLa cells, but was extremely labile to dilution or on storage at -80 degrees C. In order to facilitate study of the biochemical and immunological properties of the enzyme, a stabilizer was sought. Hemoglobin at 2 mg/ml was found to stimulate the enzyme and also partially preserved the activity of the enzyme stored at a low concentration (less than 10 micrograms/ml). Hematin, but not the globin protein, could substitute for hemoglobin in stimulating the enzyme.

Amino Acyl-tRNA Synthetases↗