Home Page - About the Arthritis Center -Hopkins Rheumatology - Myositis Center - Vasculitis Center - Scleroderma Center
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| Lisa Christopher-Stine, M.D.
Treatments Pathogenesis | |||||||||||||||||||||||
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Abstract 720 Preliminary Definitions in Improvement for Adult Myositis Objective: Recently, a core set of outcome measures for adult myositis has been developed. The authors, therefore, sought to develop a responder index, which combines the core measures for use in clinical trials. Specifically, they wanted to determine a preliminary definition of improvement (DOI). Methods: Experts in the field of adult myositis rated 113 paper patient profiles, based on data from 4 NIH clinical trials, as "clinically improved" or "not improved." Nominal group technique was used to reach consensus - defined here as 70% or greater agreement. Consensus was achieved in 102 of the 113 cases. The six core set measures of disease status used were: Physician Global activity; Patient Global Activity; Muscle Strength; Physical Function; Muscle Enzymes, and Extra-muscular Activity. These consensus patient profiles were next used to test the DOIs for sensitivity, specificity, positive and negative predictive values, and rate of false positives and false negatives. Thirteen candidate DOI's that had greater than or equal to 80% sensitivity and specificity in the adult paper patient profile dataset were presented to a working group of 15 myositis experts then ranked their top choices for validity and ease of use. Results: The three DOIs that received top ranking were as follows: (1) MD Global Improvement >30% and Manual Muscle Test (MMT) improved 0-15%, OR MMT improved >15% and MD Global improved >10%, no more than 2 worse by >25%; (2) 3 of any 6 core set measures improved >20%, no more than 2 worse by >25%, which cannot be MMT; (3) MMT improved by >15%, OR MD global improved >30% and MMT improved 0-15%, no more than 2 worse by >25%. Editorial Comments: To date, there have been no standardized definitions of improvement for myositis clinical trials. Although the method to reach a consensus is somewhat cumbersome, these preliminary DOIs represent the first concerted attempt to provide standardized measures by which future myositis clinical trials can be evaluated and eventually compared to one another. Abstract 723 Major Organ Involvement and Long Term Survival in 136 Patients with Amyopathic Dermatomyositis, Dermatomyositis, and Polymyositis: An 18-Year Experience Objective: This study aimed to compare long- term prognosis and major organ involvement among three groups of myositis patients: those with amyopathic dermatomyositis (ADM), dermatomyositis (DM) and polymyositis (PM). Methods: Medical records of all patients evaluated in the authors' medical institute over the past 18 years diagnosed with polymyositis or dermatomyositis by Bohan and Peter criteria were reviewed. The cases that met the definition of amyopathic dermatomyositis as described by Sontheimer were reclassified as such. Results: 136 cases were identified (15 ADM; 70 DM; 51 PM). Interstitial pneumonia was observed in 60%, 56%, and 51% of ADM, DM, and PM cases respectively. Malignancy developed in 20%, 27%, and 8% of patients with ADM, DM, and PM respectively. Patients with IP had a statistically lower incidence of malignancy than those without IP (12% vs. 28%, p< .05). Cardiac failure was observed in 13% of ADM cases, 7% of DM cases, and 12% if PM cases. Five- year survival rate, as determined by Kaplan-Meier survival analysis was 56% for ADM, 71% for DM, and 81% for PM. The authors also conducted a sub-analysis in which ADM and DM cases were combined, showing that survival in the combined DM group was significantly lower than that of PM (p<0.05). Editorial Comments: This abstract reminds clinicians that internal organ involvement may be a feature of amyopathic dermatomyositis. Additionally, long-term survival was similar among dermatomyositis patients with or without clinical muscle involvement. The small numbers of ADM patients, however, may not provide the adequate statistical power needed for a direct comparison. Additionally, cardiac failure, generally not appreciated as a common prognostic factor in the idiopathic inflammatory myopathies, ranked third among all prognostic risk factors assessed. These authors found that DM overall had a lower five-year survival than PM patients, in contrast to the current literature. This may be secondary to a higher incidence of malignancy in this group. Finally, as others have suggested, patients in this study with interstitial pneumonia (IP) developed malignancy less often than those without IP. Abstract 724 Development of Consensus Criteria on the Conduct and Clinical trials in Adult and Juvenile Idiopathic Inflammatory Myopathy (IIM) Objective: Because there is currently a lack of uniformity in the design and conduct of clinical trials in adult and juvenile idiopathic inflammatory myopathies, the authors sought to develop consensus criteria which will help to standardize myositis clinical trials. Methods: Several IMACS members helped to develop key questions important to myositis clinical trials conduct and design. An electronic survey was established to record the opinions international and national myositis experts. A Delphi approach established consensus as 2/3 agreement. Adult and pediatric specialists, including rheumatologists, neurologists, dermatologists, and physiatrists responded, and a follow-up survey addressed issues in which consensus was not achieved. A final resolution of these issues was completed at the 2002 IMACS workshop, where 15-member adult and pediatric myositis expert groups attempted to achieve resolution, defined as greater than or equal to 70% agreement using nominal group techniques. Results: Both adult and pediatric groups were able to reach consensus on most issues of trial design, but there were many differences between the adult and pediatric groups. Specifically, a muscle biopsy consistent with PM or DM was necessary for enrollment into adult myositis trials, but was not necessary for pediatric enrollment. Efficacy and safety outcomes assessment were recommended monthly with a minimum trial duration of 6 months for adults and 5 months for patients with JDM. The use of placebo was acceptable, but the recommended time frame varied: 8 weeks median for adult trials; 6 weeks for pediatrics. Additional areas of consensus similar in adult and clinical trials included the use of concomitant methotrexate and corticosteroids, but a standard corticosteroid taper was suggested. Additionally, inclusion of patients with non-myositis related systemic illnesses would be determined based on the safety of the investigational therapy being studied. Editorial Comments: Consensus was reached on several issues, and the differences between adult and pediatric trials were defined; however, definitions for complete clinical response (CCR) and remission require further refinement. | |||||||||||||||||||||||
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Abstract 730 The Natural Course of Statin-Induced Myopathy Objective: Myalgias are a common side effect of HMG Co-A reductase Inhibitors ("statins"), with reported rates of 2-11%. Frank myositis is rare, with an estimated rate of 0.5%. This study addressed the time course, severity, and long-term complications of patients who have experienced statin-related myopathy. Methods: A chart review of patients meeting the definition of statin myopathy was conducted. Patient charts were screened if they had an ICD-9 code of myositis; myopathy due to drugs; inflammatory myopathy; progressive or toxic myopathy; or adverse drug reaction to a cholesterol-lowering agent. A standardized chart review form was used to gather information on onset and duration of symptoms, drug name and dose, presence of muscle weakness, CPK, therapy, and outcome. Those patients with elevated CPK due to myocardial infarction or existing muscle disease were excluded. Results: 217 Medical records were reviewed. Thirty patients taking a statin medication presented with muscle complaints: 27 (90%) with myalgia and 11 (36.7%) with weakness.: 7 proximal and 3 diffuse weakness. The mean duration of therapy prior to statin therapy was 2.7 months. Fifteen (75%) of 20 tested had an elevated CPK. Discontinuation of the statin was observed in 26/30 patients.
Editorial Comments: Although not an inflammatory myopathy, statin-induced myopathies are often confused with idiopathic inflammatory myopathies in their clinical presentation. Indeed, a subset of patients who have been exposed to statin drugs may go on to develop a true inflammatory myopathy. This study suggests a generally good long-term outcome in satin-related myopathies. It is somewhat limited by its design as a retrospective chart review. Further study is needed to explore any predictive patient demographic characteristics as well as the mechanisms by which some patients develop persistent myopathies, both inflammatory and non-inflammatory, after stain exposure. Abstract 1081 Treatment of Antisynthetase Associated Interstitial Lung Disease with Tacrolimus in Patients with Idiopathic Inflammatory Myopathy Objective: This was a retrospective review of 13 patients with anti-aminoacyl tRNA -synthetase- associated ILD and inflammatory myopathy in the University of Pittsburgh myositis cohort treated with tacrolimus between 1992-2003. This review was undertaken to assess the efficacy of tacrolimus for treatment of interstitial lung disease (ILD) in patients with the anti-synthetase syndrome. Methods: Pulmonary response parameters included FVC, FEV-1, and DLCO. Manual muscle testing (MMT), serum CK, and a reduction in daily steroid dose were used to assess improvement in myositis. Random coefficient modeling using polynomials of time as a linear, quadratic, and cubic variable were constructed to assess clinical response to tacrolimus over time. Results: Of the 98 patients with the anti-synthetase syndrome in the Pittsburgh cohort, fifteen had been treated with tacrolimus over the past decade. Fourteen had the Anti-Jo-1 (Anti HRS) antibody, and one had the anti-PL-12 autoantibody. Fourteen patients had probable or definite myositis as defined by Peter and Bohan. One patient had pure ILD. Two patients received tacrolimus for less than two months duration due to end-stage fibrosis and drug intolerance respectively; they were not included in the analysis. Of the remaining 13 patients, 62% were female; 38% were male. The mean duration of ILD prior to beginning tacrolimus was 4.7 months. Ten of 13 had failed corticosteroids or other immunosuppressive drugs prior to beginning tacrolimus. Patients were treated for an average of 52 months (range 6-120 months), and the pulmonary and myositis responses were measured up to 3 years after beginning tacrolimus. Significant improvement was measured in all pulmonary parameters. Patients had a significant decrease in CK level over time and maintained or improved muscle strength over time. Corticosteroid dose was reduced after tacrolimus was initiated. Side effects included hypertension, renal insufficiency, tremors, and mild electrolyte disturbances. Editorial Comments: This study suggests that tacrolimus may be a promising agent for both the myopathic and pulmonary complications of the anti-synthetase syndrome. The study design is limited, as it is a retrospective review. A randomized prospective clinical trail utilizing tacrolimus versus corticosteroids or other immunosuppressive agents for the treatment of anti-synthetase syndrome-related ILD should be considered in the future to confirm whether these study findings hold true. | |||||||||||||||||||||||
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Abstract 1082 Revelation of a Neo-epitope at the Granzyme B Cleavage site of Histidyl-tRNA Synthetase: Implications for Immunogenicity in Myositis Objective: The authors have previously described that HRS is cleaved by Granzyme B and that autoantibody binding to HRS abolishes this cleavage. This current study was performed in order to gain further insight into the nature of the association with granzyme B cleavage sites with autoantigen status by further defining the B cell epitope in HRS and its relation to the Granzyme B cleavage site. Methods: Wild-type or N-terminal GST-tagged [35S] methionine-labeled Jo-1 (HRS) were incubated in the presence or absence of Granzyme B and immunoprecipitated with 7 patient sera of patients with known anti-Jo-1 antibodies. To further elucidate the dominant epitope, an immunoblot-based peptide competition assay was performed. Results: Intact endogenous HRS is inefficiently cleaved in native cell lysates, and immunoprecipitation is enhanced by prior boiling in SDS, indicating that the immunodominant epitope is not exposed under normal physiologic circumstances. Editorial Comments: The Granzyme B cleavage site appears to be obscured under homeostatic conditions. Autoantibodies to HRS prevent Granzyme B cleavage. Possible mechanisms include direct steric effects at the cleavage site, or perhaps autoantibodies bind at a site distant from the cleavage site, allowing Granzyme B binding but not cleavage. Whether this site is critical in generating the dominant T cell epitope that potentially drives this process remains a topic of future investigation. Abstract 1084 Striking Neovascularization and Dendritic Cells in Close Proximity in endothelial Cells are Found in Myositis Objective: The role of neovascularization in the pathogenesis in myositis is thought to play a role in facilitation of inflammatory cells access into the mileu as well as the maturation of monocytes into dendritic cells. This study assesses the status of endothelial cells and dendritic cells in fifteen patients: five patients with polymyositis, five with dermatomyositis, and five normal controls. Methods: Markers for endothelial cells and dendritic cells were assessed in the study patients using immunohistochemistry and immunofluorescence. Results: Using expression of the integrin V B3, a marker for blood vessels undergoing angiogenesis, Nagaraju and colleagues found significantly greater neovascularization in myositis (PM + DM) compared to normal controls. (Mean number of blood vessels in five high power fields per sample + S.E.: 43 + 7 vs. 7+ 3.4;p<0.001). There was no difference in neovascularization between the dermatomyositis and polymyositis subsets. Additionally, dendritic cells (DC-LAMP positive) were seen in close proximity to endothelial cells (CD 146 positive) in myositis but not in control tissues. A surprising finding was the number of new blood vessels in both dermatomyositis and polymyositis subjects, as previous work has shown a decrease in capillaries in DM compared to PM. Editorial Comments: The finding of dendritic cells in close proximity to endothelial cells in myositis tissue biopsies suggests that transmigration of dendritic cells through the endothelial cells may provide access to lymphatic vessels to generate an autoimmune response. The finding of professional antigen presenting cells at sites of neovascularization lends credence to a mechanism by which antigens are presented and transported to the lymph nodes where they can be presented, generating an autoimmune response. The authors further suggest that blocking angiogenesis may help prevent the generation of the autoimmune response in myositis. This has implications for the development of future immunosuppressive therapeutic agents. | |||||||||||||||||||||||
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