International consensus guidelines for trials of therapies in the idiopathic inflammatory myopathies
2005; Wiley; Volume: 52; Issue: 9 Linguagem: Inglês
10.1002/art.21291
ISSN1529-0131
AutoresChester V. Oddis, Lisa G. Rider, Ann M. Reed, Nicolino Ruperto, Hermine I. Brunner, Bhanu Koneru, Brian M. Feldman, Edward H. Giannini, Frederick W. Miller,
Tópico(s)Skin Diseases and Diabetes
ResumoPolymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM) are acquired inflammatory muscle disorders of unknown etiology that are currently classified under the rubric of idiopathic inflammatory myopathy (IIM). All forms of IIM are characterized clinically by muscle weakness and pathologically by chronic muscle inflammation, although systemic manifestations involving many organ systems are common. Clinical subgroups have been recognized for many years and include adult-onset and juvenile-onset forms of PM and DM, myositis associated with another connective tissue disorder or malignancy, and the more recently recognized entity termed inclusion body myositis (1, 2). The presence of characteristic cutaneous features such as Gottron's papules and sign or the classic heliotrope rash distinguish DM from PM, and skin lesions may dominate the clinical presentation in some instances. Although the IIMs are rare diseases with an estimated incidence of 10 cases per million per year (3), they are associated with substantial morbidity and mortality. Currently available treatment of IIM is unsatisfactory. Corticosteroids are the only agents approved by the US Food and Drug Administration (FDA) for myositis. However, anecdotal reports and reports of case series do support the use of other immunosuppressive agents such as methotrexate and azathioprine in the treatment of myositis. Because of the rarity and heterogeneity of IIM, there is a paucity of controlled prospective clinical trials, and most published studies are from single referral centers reporting retrospectively on small numbers of patients followed up for relatively brief periods of time. Furthermore, accurate assessment of the effects of therapeutic interventions in IIM has been hampered by unreliable and insensitive outcome measures, as well as the challenge of distinguishing active and reversible disease from irreversible damage to muscle and other organs. Although previously published trials have utilized predefined outcome measures, no uniform criteria have been used to guide the conduct of these trials. As a result, different inclusion and exclusion criteria, trial duration, frequency of assessments, concomitant therapies, safety monitoring procedures, outcome measures, definitions of responses and disease flares, and stratifications of patients at outcome analysis have been used in almost all trials. Thus, it has been difficult to compare results from any two myositis trials even when the same agent is being studied, resulting in the current uncertainty regarding the safety and efficacy of most agents. In an effort to standardize the conduct and reporting of clinical studies in all forms of adult and juvenile IIM, and to coordinate and facilitate future clinical trials, an international multidisciplinary group, the International Myositis Assessment and Clinical Studies Group (IMACS), was founded in 2000. The IMACS consortium consists of more than 100 adult and pediatric specialists—including rheumatologists, neurologists, dermatologists, rehabilitation medicine physicians, statisticians, nurses, and others—with expertise in myositis. The coordination of studies of juvenile and adult-onset disease has been emphasized because of recent National Institutes of Health and FDA encouragement of parallel investigations in children and adults (4). IMACS has achieved a number of milestones toward its goals, which include the following: development of consensus on core set outcome measures to comprehensively describe myositis disease activity (5) (that are similar to those of another international group [6]); development of preliminary definitions of improvement, which reflect clinically meaningful change in the core set measures, for use as clinical trial end points, (7); and development and validation of new tools to assess myositis disease activity and damage (7, 8). Another goal of IMACS is to develop multidisciplinary, international consensus on the conduct of multicenter international trials of therapies for adult and juvenile IIM. This report describes the current IMACS consensus guidelines for the design and conduct of clinical trials in adult and pediatric patients with myositis. Given the limited number of controlled trials that have been conducted and the variability in expert opinion in the field, however, it is not the purpose of this report to propose a dogmatic approach to such issues. Rather, guidelines that are more structured in some aspects of trial design where consensus has been achieved, but less structured in other areas where data-driven evidence is lacking, are provided. In an effort to develop a consensus approach for the conduct of adult and juvenile myositis clinical trials, the design and features of 26 prospective treatment trials in IIM were reviewed (9-34). These included 14 trials of adult PM and DM, 5 of adult IBM, 5 prospective series of patients with juvenile DM, and 2 studies that combined adult PM, DM, and IBM patients. It was concluded that there is a clear lack of consistency in the design and conduct of clinical trials in adult and juvenile IIM, necessitating consensus among clinical investigators. The process to develop consensus for the design of adult and juvenile myositis clinical trials is described immediately below, with further detail provided in Appendix A. Several IMACS investigators outlined general topics regarding myositis clinical trial design issues that required consensus. An initial survey was then sent by e-mail to IMACS investigators (who included rheumatologists, neurologists, dermatologists, and physiatrists), and 41 adult and 29 pediatric specialists responded. Comments were reviewed and responses collated from both the adult and pediatric respondents to establish areas of both consensus (defined as agreement by at least two-thirds of the respondents) and lack of consensus. A second, focused survey, concentrating on major areas for which consensus was not achieved from the first survey, was sent by e-mail to the initial respondents and 7 additional investigators. Thirty-six adult and 31 pediatric specialists returned the second survey. The clinical trial design issues on which consensus was not achieved were then discussed at the third IMACS outcomes workshop, utilizing consensus-building approaches including nominal group and Delphi techniques (35). IMACS members who participated in the surveys and workshops are listed in Appendix B. Adult and pediatric working groups, each comprising 15 myositis experts, discussed these items, with ≥70% agreement required for consensus at this workshop. Both the adult and the pediatric specialists discussed issues of general applicability jointly, while issues that pertained exclusively to either group were discussed separately. Both adult and pediatric specialists agreed that the Bohan and Peter criteria (36, 37) should be utilized for the enrollment of adult and juvenile PM and DM patients into clinical trials and that probable or definite DM as defined by these criteria would be required. In accordance with these criteria, a diagnosis of probable or definite PM and DM requires that all other forms of myopathy, including infectious, metabolic, dystrophic, endocrine, and inclusion body myopathies, be excluded by appropriate clinical, laboratory, genetic, or pathologic techniques (36-38). There was some difference of opinion between the adult and pediatric specialists regarding the specifics of the required criteria, as discussed below. Dermatomyositis. Consensus was reached by both adult and pediatric specialists that the presence of Gottron's papules or heliotrope rash alone was sufficient to distinguish DM from PM; pediatric specialists also believed Gottron's sign was sufficient to distinguish juvenile DM from juvenile PM. It was decided that other criteria are necessary to enroll either adult DM or juvenile DM patients into a clinical trial. Pediatric specialists agreed that the criteria for probable juvenile DM were adequate and a muscle biopsy prior to entry was not necessary. Adult specialists did not come to consensus that a pathognomonic DM rash plus 2 other elements of the Bohan and Peter criteria were sufficient for enrollment of adult DM patients into a clinical trial, and adult specialists would leave this decision up to the investigators in individual clinical trials. Polymyositis. Adult and pediatric specialists agreed that an abnormal muscle biopsy result consistent with PM was necessary to enroll adult and juvenile PM patients into a clinical trial, due to concern about inadvertent inclusion of patients with non–immune-mediated myopathies (i.e., atypical dystrophies or toxic myopathies). Thus, patients without the pathognomonic rash of DM can be enrolled in a myositis trial and be considered to meet probable criteria only if one element of the criteria that are met is an abnormal muscle biopsy result consistent with PM. Other forms of myositis. It was the consensus that malignancy-associated myositis and myositis associated with another connective tissue disease (CTD) should be studied in separate clinical trials, but the definition of an associated CTD and the inclusion of such patients in a trial would be left to the trial's principal investigators so as not to exclude potentially eligible patients for study. IBM, defined according to the criteria for possible or definite IBM described by Griggs et al (2), should be studied separately from other myositis subgroups given the fact that it has distinguishing clinicopathologic characteristics and responses to treatment that differ from those of PM or DM. Subjects who develop myositis in association with an environmental exposure recognized as a probable risk factor for disease should also be studied separately. Consensus was achieved that clinical trials of refractory disease in adult and pediatric patients should include patients with muscle weakness of predetermined severity so response to the therapeutic agent can be adequately quantitated. Although patients who have chronic muscle weakness due to damage but do not have active disease will need to be excluded, the method of excluding such patients is not yet validated and will be decided by the investigators organizing the trial. Current approaches that appear promising (if available to investigators) include muscle biopsy, magnetic resonance imaging of muscle, and the use of the Myositis Disease Activity Assessment Tool and Myositis Damage Index (39, 40). Refractory disease was defined as disease with inadequate response to first-line agents such as corticosteroids and methotrexate (or another conventional immunosuppressive agent). It was agreed that, in order to assess corticosteroid treatment failure, adult patients had to have received 60 mg/day for at least 2 months, and pediatric patients had to have received 2.0 mg/kg/day prednisone for at least 2.5 months. It was further agreed that methotrexate treatment failure in pediatric patients could be defined as inadequate response to 25 mg/m2/week given parenterally for at least 3 months, but consensus regarding a definition of methotrexate failure in adult patients was not achieved. For other agents, the treatment regimen prior to trial entry was not agreed upon and should be decided by the team of investigators designing the trial. Patients with myositis-related organ dysfunction (e.g., cardiac, pulmonary, gastrointestinal, or cutaneous involvement) can be included in trials if the therapeutic agent under study is not toxic to the affected organ system. The inclusion of patients with non–myositis-related systemic illnesses is also reasonable if the organ system involved does not preclude adequate assessment of the myositis and is not adversely affected by the agent being studied. Inclusion of patients with hepatic disease, however, is problematic due to the difficulty of assessing transaminase (aspartate aminotransferase, alanine aminotransferase), aldolase, and lactate dehydrogenase elevations, which may be due to either hepatitis or myositis. There was consensus that additional inclusion criteria would be trial-specific and determined based on the therapeutic agent being studied. Examples of such criteria are a specified level of functional disability, inadequate response to other therapeutic agents, unacceptable corticosteroid toxicity, and persistence of cutaneous or other extramuscular manifestations. In trials involving patients with new-onset disease, adult specialists agreed that these patients should meet definite Bohan and Peter criteria and pediatric specialists agreed on probable Bohan and Peter criteria. The initial treatment regimen prior to trial entry was not agreed upon but should be decided by the team of clinical investigators designing the trial. Both adult and pediatric specialists agreed that concomitant corticosteroid treatment should be allowed in a clinical trial, but that tapering should take place according to a standardized dosage reduction regimen. At this time, there is no agreed-upon regimen for corticosteroid dosage reduction, and this should be determined by the investigator and may vary based on the agent being studied and the design of the trial. If methotrexate or another immunosuppressive agent is to be continued during a trial, the dosage should generally be held constant. Pediatric specialists agreed that methotrexate at a dosage of up to 30 mg/m2/week (maximum 50 mg/week) could be allowed as concomitant therapy in a myositis clinical trial. However, if methotrexate or another immunosuppressive agent is to be discontinued before a patient is enrolled in a trial, a pre-enrollment washout period of at least 1 month for methotrexate and 2–3 months for other immunosuppressive agents was suggested. The group reached consensus that it was appropriate to continue concomitant physical and occupational therapy in trials as long as these interventions were kept constant. It was agreed to exclude complementary and alternative medicines that may have potential effects on muscle, such as creatine, coenzyme Q, adrenal extracts, niacin, and anabolic/male steroids. The use of placebos in clinical trials is controversial, and may be an even more contentious issue for pediatric studies. However, it is important to note that, depending on the design of a trial, "placebo" does not necessarily mean "no therapy"; it may refer to the use of placebo in addition to background therapy maintained at a constant dosage, which is often viewed as more acceptable by physicians enrolling patients in a clinical trial. In fact, adult and pediatric specialists did not find it acceptable for patients with refractory myositis to be receiving no background therapy while enrolled in a trial. Nevertheless, the use of a placebo for a limited period of time in both adult and pediatric myositis trials was deemed acceptable. The median allowable time according to adult specialists was 8 weeks, while pediatricians agreed that a median of 6 weeks for placebo administration was more appropriate for trials involving children with IIM. The design of placebo-controlled trials should take these time points into consideration so that patients with evidence of deterioration or lack of response to therapy may receive appropriate and timely treatment for their active disease. The duration of a clinical trial includes the time in which the experimental agent(s) is administered as well as a period of appropriate followup, determined based on the agent being studied, safety factors, or other design-specific issues such as the phase of the trial. It was the consensus of the adult specialists that a duration of 6 months was the minimum time acceptable for therapeutic trials in PM and DM. However, depending on the experimental agent(s) being studied, the duration could certainly exceed 6 months. Pediatric specialists similarly agreed on a minimum mean trial duration of 5 months for both phase I and phase II designs (i.e., exploratory studies to assess safety, efficacy, and dosing of an agent), but suggested that phase III trials be longer, with a mean recommended duration of 9 months. There was consensus among both adult and pediatric specialists that the frequency of assessment should be monthly for both safety and toxicity monitoring in trials of adult and juvenile DM and PM. The use of novel trial designs, such as randomized withdrawal or randomized placebo phase designs (41), and the study of biologic agents with more rapid response rates could allow for the shorter-duration placebo use noted above without compromising assessment of the primary end points in myositis trials (42). Some phase I studies, particularly first-time-into-human or single-dose safety studies, may be conducted over shorter time frames. However, it should be noted that if a trial demonstrates a positive result but a randomized control is included for only 6 or 8 weeks, questions may remain regarding the efficacy of long-term use of the product (i.e., beyond the 6- or 8-week period tested). The study of long-term efficacy is of considerable practical significance: for example, immunogenicity to certain biologic products might mitigate their efficacy over time. Products for use in rheumatoid arthritis are ordinarily studied in controlled trials of 6–12 months (4). A variety of the study designs noted above may be used to ascertain evidence of long-term efficacy. The National Cancer Institute has defined the Common Toxicity Criteria (http://ctep.cancer.gov/reporting/ctc.html) to standardize assessments of adverse events in clinical trials, and consensus was reached to utilize this system for assessing and grading adverse events in adult and pediatric IIM patients enrolled in trials. It was decided that, after completion of the dosing regimen in a myositis trial, certain parameters (to be determined according to the agent being studied and the design of the trial) should continue to be monitored during the posttreatment period. Adult and pediatric specialists agreed that these parameters should be assessed at ∼3-month intervals for a minimum of 6–9 months, but the guidelines for subsequent followup will depend on the toxicity of the agent studied during the initial treatment phase. As discussed above, IBM is viewed as a clinically distinct myositis subgroup and, due to its insidious onset, generally slow progression, and the difficulty in assessing its response to treatment, adult specialists suggested a mean treatment duration of at least 12 months in IBM clinical trials. Similarly, outcome efficacy measures can be spaced further apart and should be assessed at 2-month intervals. The IMACS core set disease activity measures and preliminary definitions of improvement (5, 7, 8) should be used in trials of adult and juvenile DM and PM. These should include the highest-ranking definition (termed A1 for adult disease and P1 for pediatric disease) as a measure of improvement, i.e., that 3 of any 6 core set measures improve by ≥20%, with no more than 2 worsening by ≥25% (measures that worsen cannot include manual muscle strength). We recommend that investigators designing clinical trials in myositis utilize this published definition of improvement as the primary outcome measure (7). Secondary measures of improvement could also include any of the other IMACS preliminary definitions of improvement, as well as individual core set measures of activity, or other measures as determined by the investigators in a given study. Criteria for disease worsening in a clinical trial, to be used as the basis for designating treatment as unsuccessful and offering alternative therapies, were preliminarily defined at the IMACS workshop. These include 1) worsening of the patient's global condition, as assessed by the physician, by ≥2 cm on a 10-cm visual analog scale (VAS) and worsening of findings of manual muscle testing by ≥20%, or 2) worsening of global extramuscular organ disease activity (a composite of constitutional, cutaneous, skeletal, gastrointestinal, pulmonary, and cardiac activity) by ≥2 cm on a 10-cm VAS, or 3) worsening of any 3 of 6 IMACS core set activity measures by ≥30%. It was also noted that significant worsening in cardiac, pulmonary, or gastrointestinal organs should be considered as alternate criteria for worsening and could also lead to withdrawal of patients from the trial or designation of treatment as unsuccessful. Both adult and pediatric specialists agreed that further work is needed to define and validate the degree of worsening and criteria to define myositis disease flares. Although, the criteria for altering therapy noted above were accepted by the IMACS workshop participants, they were not consensus driven to the same degree as were the other guidelines shown in Table 1. Complete clinical response and clinical remission were defined in a manner similar to that used for juvenile idiopathic arthritis (JIA) (4, 43). As in the case of JIA, these criteria do not entail imaging or biopsy evaluation due to the difficulty of obtaining these in multicenter international trials (43). Complete clinical response and clinical remission were defined, respectively, as lack of evidence of active myositis while still receiving drug therapy and lack of evidence of active myositis while not receiving any drug therapy, for a 6-month continuous period. In order to define complete clinical response and remission in IIM patients, one must apply the current construct of myositis disease activity to these definitions. There was consensus that lack of evidence of myositis disease activity is defined as assessed by global and extramuscular assessments, stable muscle strength and function, and normal muscle enzyme levels. Similarly, stable muscle strength and function were defined as equivalent to <15% change in the semiquantitative scoring of the measures of these domains over at least a 6-month period. It is possible that certain patients meeting these definitions may continue to develop weakness due to damage or ongoing disease activity. Additional imaging or biopsy evaluations in a proportion of subjects participating in a trial would be helpful in confirming an absence of disease activity. These clinical, consensus-derived definitions require prospective validation. Assuming that there would be no compromise to the statistical analysis of the data in a clinical trial, participating adult and pediatric specialists agreed that patients should be stratified for exploratory outcome analysis. Post hoc stratification factors may include IIM clinical subgroup, duration of disease, degree and nature of muscle weakness or physical dysfunction at the time of enrollment, and extramuscular organ involvement, such as interstitial lung disease and pharyngeal weakness. For adult myositis, autoantibodies and muscle histopathology were considered important factors, and for juvenile myositis, cutaneous or gastrointestinal ulceration and calcinosis were frequently mentioned as important post hoc stratification factors to consider. As outlined in Table 2, there are a number of important unresolved issues related to the design of clinical trials in adult and pediatric patients with inflammatory myopathy, which require further discussion. These areas will need to be addressed in future analyses utilizing data-driven mechanisms and other consensus-building approaches. The lack of consensus on the conduct and reporting of clinical trials in the IIMs has hampered therapeutic advancement in the myositis syndromes and makes it difficult to compare studies. Utilizing standardized outcome assessments, efforts in other rheumatic diseases such as systemic sclerosis and rheumatoid arthritis have resulted in consensus approaches to trial design issues (4, 44). A group of international myositis experts, termed IMACS, has organized in an attempt to develop standards for the conduct of studies in the inflammatory myopathies. The results presented here represent the first international, multidisciplinary effort to standardize the conduct of myositis clinical trials. Even though these efforts are preliminary, they represent a starting point for investigators interested in studying patients with myositis, utilizing a unified and systematic approach. All contributors to this consensus report, however, recognize the necessity to prospectively assess these guidelines and to refine them as trials are completed and rigorously analyzed. The newly developed IMACS Clinical Studies Data Repository (http://www.dir.niehs.nih.gov/imacs/) will serve as a central location for such data and their analyses in the future. Therapy for IIM traditionally includes corticosteroids and other immunosuppressive agents that have been studied using various designs. Investigations of these and other novel biologic or immunosuppressive treatments in myositis are necessary, and we propose these guidelines in order to efficiently and effectively evaluate therapeutic agents in large multicenter trials. The goal of IMACS has been to encourage dialogue among members of all subspecialties that manage and study patients with inflammatory myopathy and to initiate well-designed and innovative collaborative trials. The previously published IMACS initiatives, along with the guidelines set forth in this consensus document, lay the groundwork for such collaborations. While these proposed guidelines are based on the best judgments of the IMACS participants, we appreciate that the specific circumstances of a particular trial may necessitate an altered approach. In summary, the first consensus guidelines for trials of disease-modifying interventions in IIM have been developed in an attempt to standardize these efforts for international multispecialty protocols in adults and children. These guidelines will be updated periodically as additional information becomes available. All contributors recognize the need for enhanced coordination among all specialists caring for patients with myositis, the prospective validation of these guidelines, and attention to the unresolved issues of trial design discussed herein. We are grateful to other members of IMACS for their helpful contributions and useful discussions throughout this project. The valuable comments of Drs. Jeffrey Siegel, Gregory Dennis, and Elizabeth Adams on the manuscript are gratefully acknowledged. We also thank the following for their assistance and support, without which these workshops could not have been held: Linda Stover (The Myositis Association), and Dr. Laura James-Newton, Beverly Sellers-Robinson, Gail Kestner, and Dr. Ken Olden (National Institute of Environmental Health Sciences). We gratefully acknowledge members of the FDA's Rheumatology Working Group for valuable discussions throughout the process and especially thank Dr. Suzanne Serrate-Sztein, LaWanna Branch, and personnel of the National Institute of Arthritis and Musculoskeletal and Skin Diseases for their support. We are grateful to the sponsors of these workshops: the National Institute of Environmental Health Sciences, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, The NIH Office of Rare Diseases, the National Institute of Neurological Diseases and Stroke, the UK Myositis Support Group, and The Myositis Association. The IMACS coordinating committee outlined the general topics regarding myositis clinical trial design issues noted in Table 1. A survey in questionnaire format (survey 1), which incorporated all of these issues, was sent by e-mail to all IMACS investigators. Responses were received from 41 adult and 29 pediatric specialists (rheumatologists, neurologists, dermatologists, and physiatrists). In an introductory letter, IMACS members were informed of the reason for the survey (to develop consensus on clinical trial design issues as a first step toward multicenter international trials of therapies for IIMs). For each of the key issues identified in Table 1, IMACS investigators were provided background summary information from the 26 prospective IIM studies published to date to help them in answering the survey questions. They were informed that a second e-mail survey focusing on the major areas of disagreement from the first survey would follow, that subsequent discussions at the IMACS outcomes workshops would utilize consensus-building approaches including nominal group and Delphi techniques, and that the results of the consensus process would be published. The responses to the questions in survey 1 were collated to establish both areas of consensus (defined as at least two-thirds agreement obtained utilizing a Delphi approach) and areas of controversy. Comments were reviewed and the results were analyzed separately for the adult specialist respondents (by CVO) and the pediatric specialists respondents (by LGR). Unresolved clinical trial design issues were discussed by the designers of survey 1 and a second, shorter and more focused, survey (survey 2) was sent by e-mail to survey 1 responders and 7 additional investigators. Thirty-six adult and 31 pediatric specialists returned surveys, which were again analyzed separately using the same guidelines as for the first survey. A final resolution of the controversial clinical trial design issues was completed at the second IMACS workshop (in 2002). Here, adult and pediatric working groups, each comprising 15 myositis experts, discussed the controversial items using a nominal group technique and voted in an attempt to achieve resolution. The working groups consisted of IMACS members (all of whom completed surveys 1 and 2), and they were informed of the composite analyses of both surveys completed by their IMACS peers, since not all survey respondents attended the workshop. Consensus at this workshop was defined as ≥70% agreement. Some of the controversial issues were discussed jointly by both the adult and pediatric specialists, while other, more specialty-specific, topics were discussed separately. A consensus document outlining the guidelines for clinical trials in adult and juvenile myositis, which is the subject of this report, was developed. Members of the International Myositis Assessment and Clinical Studies Group, in addition to the authors of this article, are as follows: Sulaiman M. Al-Mayouf, MD (Riyadh, Saudi Arabia), Dana Ascherman, MD (Pittsburgh, PA), Brenda Banwell, MD (Toronto, Ontario, Canada), Richard Barohn, MD (Kansas City, KS), Claudia Borges, MD (Sao Paulo, Brazil), Walter Bradley, MD (Miami, FL), Ruben Burgos-Vargas, MD (Mexico City, Mexico), Jeffrey Callen, MD (Louisville, KY), Hanna Chwalinska-Sadowska, MD (Warsaw, Poland), Leslie Crofford, MD (Lexington, KY), Mary Cronin, MD (Milwaukee, WI), Katalin Danko, MD (Debrecen, Hungary), Joyce Davidson, MBChB (Liverpool, UK), Sheila Knupp Feitosa de Oliveira, MD (Rio de Janeiro, Brazil), Richard Finkel, MD (Philadelphia, PA), Ignacio Garcia de la Torre, MD (Guadalajara, Mexico), Leonardo Guzman, MD (Santiago, Chile), Kamran Hameed, FCPS (Bethesda, MD), Michael Harris-Love, DHSc, MPT (Bethesda, MA), Jeanne Hicks, MD (Bethesda, MD), Adam Huber, MD (Halifax, Nova Scotia, Canada), Hans-Iko Huppertz, MD (Bremen, Germany), Lisa Imundo, MD (New York, NY), David Isenberg, MD (London, UK), Joseph Jorizzo, MD (Winston-Salem, NC), Lawrence Kagen, MD (New York, NY), John Kissel, MD (Columbus, OH), Ashok Kumar, MD (New Delhi, India), Nancy Kuntz, MD (Rochester, MN), Teruyuki Kurihara, MD (Tokyo, Japan), Abraham Garcia Kutzbach, MD (Guatemala City, Guatemala), David Lacomis, MD (Pittsburgh, PA), Bianca Lang, MD (Halifax, Nova Scotia, Canada), Todd Levine, MD (Phoenix, AZ), Carol Lindsley, MD (Kansas City, KS), Hanns Lochmüller, MD (Munich, Germany), Daniel Lovell, MD (Cincinnati, OH), Ingrid Lundberg, MD, PhD (Stockholm, Sweden), Peter Malleson, MB, MRCP (Vancouver, British Columbia, Canada), Suely Kazue Nagahashi Marie, MD (Sao Paulo, Brazil), Alberto Martini, MD (Genoa, Italy), Frank Mastalgia, MD (Perth, Western Australia, Australia), Thomas Medsger, MD (Pittsburgh, PA), Pawel Mielnik, MD (Warsaw, Poland), Hans Muller-Felber, MD (Munich, Germany), Kevin Murray, MBBS (London, UK), Lauren Pachman, MD (Chicago, IL), Murray H. Passo, MD (Cincinnati, OH), Alan Pestronk, MD (St. Louis, MO), Clarissa Pilkington, MD (London, UK), Paul Plotz, MD (Bethesda, MD), Dieter Pongratz, MD (Munich, Germany), Lynn Punaro, MD (Dallas, TX), Angelo Ravelli, MD (Genoa, Italy), Robert Rennebohm, MD (Columbus, OH), Barry Russman, MD (Portland, OR), Seward Rutkove, MD (Boston, MA), Clive Ryder, MBSMB (Birmingham, UK), Anna M. Romicka, MD (Warsaw, Poland), Mario Salazar-Paramo, MD (Guadalajara, Mexico), Adriana Maluf Elias Sallum, MD (Sao Paulo, Brazil), Leslie Schrieber, MD (St. Leonard's, New South Wales, Australia), Albert Selva-O'Callaghan, MD (Barcelona, Spain), Jacques Serratrice, MD (Marseille, France), David D. Sherry, MD (Philadelphia, PA), Clovis Artur Almeida Silva, MD (Sao Paulo, Brazil), Yeong Wook Song, MD (Seoul, Korea), Kumar Sivakumar, MD (Phoenix, AZ), Richard Sontheimer, MD (Iowa City, IA), Robert Sundel, MD (Boston, MA), Ira Targoff, MD (Oklahoma City, OK), Lori Tucker, MD (Vancouver, British Columbia, Canada), Jiri Vencovsky, MD, PhD (Prague, Czech Republic), Maria Angela do Amaral Gurgel Vianna, MD (Sao Paulo, Brazil), Maria Villalba, MD (Rockville, MD), Carol Wallace, MD (Seattle, WA), Victoria Werth, MD (Philadelphia, PA), Robert Wortmann, MD (Tulsa, OK), Steven Ytterberg, MD (Rochester, MN).
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