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.

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.

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.

Clinical trials of a stromelysin inhibitor. Osteoarthritis, matrix metalloproteinase inhibition, cartilage loss, surrogate markers, and clinical implications.

Long-term trials with BAY 12-9566, a stromelysin inhibitor, have been initiated in osteoarthritis. Validation of the long-term, clinical relevance of early markers has to be tested in these and other trials. Detection of the slowing of cartilage loss (as gauged by measures of joint space narrowing and by other techniques, such as MRI) remains to be proven, but now may be possible in intervention trials.

A possible role for oxygen inactivation in the regulation of amidophosphoribosyltransferase activity in mammalian cells.

Human and other mammalian forms of ATase, including the Chinese hamster enzyme, are oxygen-sensitive enzymes and human ATase, like the enzyme from B. subtilis, is an iron-sulfur protein. When protein synthesis is inhibited in cultured Chinese hamster cells, ATase activity is lost in an oxygen-dependent reaction. The hypothesis is developed that the sensitivity of ATase to oxygen inactivation controls the rate of degradation of this enzyme in mammalian cells, similar to the mechanism which has been demonstrated for regulation of ATase degradation in B. subtilis.

Office evaluation and treatment of Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon, an episodic vascular disorder induced by cold temperatures or stress and characterized by white, blue, and red discoloration of the fingers and toes, may affect up to 20% of the general population. KEY POINTS: Raynaud's phenomenon may exist independently (primary) or in association with an underlying disease (secondary), most commonly systemic sclerosis. The pathophysiologic features include vasospasm, endothelial cell changes, vessel obstructive features, and hemorrheologic factors. Raynaud's phenomenon is the initial manifestation of disease in 70% of patients with systemic sclerosis, in whom it may be present for many years before the development of the connective tissue disease. Patients with primary Raynaud's phenomenon need only conservative management and should be reassured that digital ischemia and loss of tissue occur extremely rarely. Pharmacologic agents that have been studied include vasodilators, platelet inhibitors, serotonin antagonists, and fibrinolytics. CONCLUSIONS: For prognostic and therapeutic reasons, it is important to determine if Raynaud's phenomenon is associated with an underlying condition and if the patient may develop a connective tissue disease.

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.

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.

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.

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.

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

OBJECTIVE: To assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis. METHODS: Thirty 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. RESULTS: Of 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). CONCLUSION: Combination 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.