A Clinical Trial of Immunosuppressive Therapy for Myocarditis
Jay W. Mason, M.D., John B. O'Connell, M.D., Ahvie Herskowitz, M.D., Noel R. Rose, M.D., Ph.D., Bruce M. McManus, M.D., Ph.D., Margaret E. Billingham, M.D., Thomas E. Moon, Ph.D., for The Myocarditis Treatment Trial Investigators
Background Myocarditis is a serious disorder, and treatmentoptions are limited. This trial was designed to determine whetherimmunosuppressive therapy improves left ventricular functionin patients with myocarditis.
Methods We randomly assigned 111 patients with a histopathologicaldiagnosis of myocarditis and a left ventricular ejection fractionof less than 0.45 to receive conventional therapy alone or combinedwith a 24-week regimen of immunosuppressive therapy. Immunosuppressivetherapy consisted of prednisone with either cyclosporine orazathioprine. The primary outcome measure was a change in theleft ventricular ejection fraction at 28 weeks.
Results In the group as a whole, the mean (±SE) leftventricular ejection fraction improved from 0.25±0.01at base line to 0.34±0.02 at 28 weeks (P<0.001). Themean change in the left ventricular ejection fraction at 28weeks did not differ significantly between the group of patientswho received immunosuppressive therapy (a gain of 0.10; 95 percentconfidence interval, 0.07 to 0.12) and the control group (again of 0.07; 95 percent confidence interval, 0.03 to 0.12).A higher left ventricular ejection fraction at base line, lessintensive conventional drug therapy at base line, and a shorterduration of disease, but not the treatment assignment, werepositive independent predictors of the left ventricular ejectionfraction at week 28. There was no significant difference insurvival between the two groups (P = 0.96). The mortality ratefor the entire group was 20 percent at 1 year and 56 percentat 4.3 years. Features suggesting an effective inflammatoryresponse were associated with less severe initial disease.
Conclusions Our results do not support routine treatment ofmyocarditis with immunosuppressive drugs. Ventricular functionimproved regardless of whether patients received immunosuppressivetherapy, but long-term mortality was high.
Myocarditis is a precursor of dilated cardiomyopathy.1,2,3 Aberrantcellular and humoral immune responses have been proposed aspossible mechanisms in postviral myocarditis,4,5,6,7 and immunosuppressivetherapy has appeared to improve the course of the disease.8,9,10,11The efficacy of immunosuppression, however, has not been clearlyestablished.
The Myocarditis Treatment Trial12,13,14 was designed to evaluatethe efficacy of immunosuppression in patients with myocarditisand to identify immunologic markers of the severity of the diseaseand the response to therapy. In this report we describe theresults of the clinical trial and explore the relation betweenthe outcomes and the clinical, histologic, and immunologic characteristicsof the patients.
Methods
Enrollment and Randomization
The design and methods of the trial are fully described elsewhere.14Patients with an onset of heart failure during the two yearspreceding enrollment but without coronary artery disease oranother specific cause were enrolled at 31 centers in the UnitedStates, Canada, and Japan, as well as through an open-enrollmentprocess.14 Pathologists at the centers found histopathologicalevidence of myocarditis on endomyocardial biopsy in 214 of 2233patients (10 percent). Thirty of the 214 patients had left ventricularejection fractions greater than or equal to 0.45, as determinedby radionuclide gated blood-pool imaging, and 44 met one ormore medical criteria for exclusion14; an additional 29 patientsdeclined enrollment. The remaining 111 patients with histologicevidence of myocarditis and left ventricular ejection fractionsunder 0.45 were randomly assigned in equal proportions to oneof three treatment groups. One group received azathioprine andprednisone, another group received cyclosporine and prednisone,and the third group did not receive any immunosuppressive therapy.After the first 58 patients had been enrolled, random assignmentto the azathioprine–prednisone group was discontinuedin order to reduce the number of patients required for the trial.
At the time of the base-line endomyocardial biopsy, right-heartcatheterization was performed, and blood samples were obtainedfor chemical and immunologic studies. Echocardiography and anexercise stress test were performed within two weeks beforeor after the base-line biopsy.
Therapy
Treatment in all three groups included a stepped regimen ofconventional drugs for heart failure, with each successive drugadded to the existing, tolerated regimen. The stepped regimenallowed the calculation of a score for the intensity of thetherapy.14 In the control group patients received only conventionaltherapy. In the azathioprine–prednisone group, patientsreceived 1 mg of azathioprine per kilogram of body weight twicedaily for 24 weeks. Prednisone was started at a dose of 1.25mg per kilogram per day, in divided doses, and was maintainedat that level for one week. The dose was then decreased by approximately0.08 mg per kilogram per week until the dose was 0.33 mg perkilogram per day at the end of week 12. This reduced dose wasmaintained through the end of week 20, after which it was reducedby 0.08 mg per kilogram per week until the end of week 24, whenthe drug was discontinued.
In the cyclosporine–prednisone group, cyclosporine wasstarted at a dose of 5 mg per kilogram given orally twice aday. The dose was adjusted to achieve a concentration of 200to 300 ng per milliliter at the end of week 1, as determinedby radioimmunoassay of whole blood at room temperature. Thedose was then tapered to achieve a blood level between 100 and200 ng per milliliter during weeks 2 through 4. From the endof week 4 to the end of week 24, the blood level was maintainedbetween 60 and 150 ng per milliliter. The initial dose of prednisonein this group was the same as that in the azathioprine–prednisonegroup. After one week, the dose was rapidly tapered to a levelof 0.15 mg per kilogram per day by the end of week 3. This dosewas maintained through week 23 and then halved for a week. Thedrug was discontinued at the end of week 24.
Endomyocardial Biopsy and Histopathological Studies
The majority of the biopsies were performed with the Stanfordtechnique15 and the Stanford–Scholten bioptome (ScholtenInstruments, Palo Alto, Calif.). At least four specimens wereobtained from each patient for light microscopical evaluationwith hematoxylin and eosin and Masson trichrome stains.
Pathologists at the participating centers were instructed inthe use of the Dallas criteria16,17 for the diagnosis of myocarditis.The pathologist at each center evaluated the biopsy specimensfrom candidates for the trial, and eligibility for randomizationwas determined on the basis of that evaluation. At a later date,the biopsy specimens were reviewed by a panel of seven pathologistsexperienced in the interpretation of histologic features ofendomyocardial-biopsy specimens and in the application of theDallas criteria.16,17 The final diagnosis was based on the consensusof the panel. Initial biopsy specimens were categorized as showingmyocarditis, borderline myocarditis, or no myocarditis. Whenmyocarditis was present, it was characterized as diffuse orfocal. Subsequent biopsy specimens were categorized as showingongoing, healing, healed, or recurrent myocarditis.
Immunologic Studies
Serum obtained at base line and follow-up was submitted to twolaboratories for the measurement of antibodies to cardiac andnoncardiac antigens by indirect immunofluorescence, as describedelsewhere.14,18,19 The technique we used to measure anti–cardiacIgG antibodies may not exclude anti–skeletal-muscle IgGantibodies in some cases. We use the term "general IgG antibodies"to refer to antibodies to skeletal and smooth muscle, nuclei,mitochondria, and parietal cells. Blood samples were submittedto a third laboratory for the measurement of cellular immunemarkers by a variety of techniques, including flow cytometryand assays of antibody-dependent cellular cytotoxicity and natural-killer-cellactivity.14
Follow-Up
At weeks 12, 28, and 52, the left ventricular ejection fractionwas determined by radionuclide ventriculography. Echocardiography,exercise testing, endomyocardial biopsies, and blood studieswere also performed. Between weeks 24 and 52, immunosuppressivetherapy was withheld while the regimen of conventional therapywas followed. After 52 weeks, each patient's vital status wasmonitored regularly until the end of the trial, but rigid controlof conventional therapy was suspended.
Statistical Analysis
Our primary objective was to compare the effects of immunosuppressivetherapy combined with conventional therapy and conventionaltherapy alone on the left ventricular ejection fraction betweenthe time of enrollment and week 28, according to an intention-to-treatstrategy. We estimated the sample size required for a two-tailedsignificance level of 0.05 and a power of 0.80. The two immunosuppressiongroups were combined for all analyses, since there were no differencesin their clinical characteristics or outcomes after random assignmentof the first 58 patients or after random assignment of all 111patients, and there was no evidence that the two immunosuppressiveregimens had different effects in subgroups of patients.
The primary analysis was an analysis of covariance with a linearmodel, which assessed the effect of treatment after adjustmentfor the left ventricular ejection fraction and other characteristicsat base line. For the 10 patients who died, the 4 patients whounderwent cardiac transplantation, and the 1 patient in whomtreatment failed14 before the evaluation of left ventricularejection fraction at 28 weeks, the most recently determinedvalues for the ejection fraction were used in the analysis.A similar analysis was performed for the change in the ejectionfraction at week 52. The effects of treatment on secondary measuresof ventricular function (echocardiographic determination ofthe left ventricular internal diameter at end diastole and pulmonary-capillarywedge pressure) were analyzed in a similar way.
A second objective of the trial was to examine immune-activationmeasures as possible markers of the severity of disease andas predictors of the response to therapy. Each of five indexesof disease severity (left ventricular ejection fraction, leftventricular internal diameter at end diastole, pulmonary-capillarywedge pressure, conventional-therapy score, and duration ofsymptoms at the time of enrollment) was assessed as the dependentvariable in a separate linear- or logistic-regression model,with backward elimination, that initially included only theimmunologic markers. We report the results of these analysesboth before and after other correlates of the severity of disease(pulmonary-artery mean pressure, cardiac index, heart rate,and New York Heart Association class) were added to the modelsas independent variables.
Other secondary objectives of the trial were to compare survivalin the treatment groups and to evaluate changes over time inendomyocardial-biopsy specimens, the intensity of conventionaltherapy, and immunologic markers. All patients were includedin the survival analyses, and those who died or underwent cardiactransplantation were considered to have reached a mortalityend point. Survival at one year was evaluated by censoring datafor all patients who survived for a longer period. Cox proportional-hazardsregression models were used to compare survival in the groupsafter adjustment for the effects of other patient characteristics.Survival probabilities were estimated with the Kaplan–Meiermethod. Means and proportions were compared with standard statisticaltests for continuous and categorical data. SAS software20 wasused for all analyses.
Results
Clinical Characteristics
There were no significant differences in clinical characteristicsbetween the treatment groups (Table 1). The mean (±SD)left ventricular ejection fraction for the overall group ofpatients was 0.24±0.10, and most of the patients werein New York Heart Association class II or III.
Table 1. Initial Demographic, Clinical, Histopathological, and Immunologic Characteristics of 111 patients with Myocarditis.
Changes in Left Ventricular Function
We analyzed changes after therapy in three indexes of left ventricularfunction: left ventricular ejection fraction, left ventricularinternal diameter at end diastole, and pulmonary-capillary wedgepressure. There was no difference between the two groups inthe mean left ventricular ejection fraction at base line, week28, or week 52 (Figure 1A and Figure 1B). The primary analysisof changes in left ventricular ejection fraction after therapy(with data from 89 patients at week 28 and with data from 84patients at week 52) also showed no significant differences(Figure 1A and Figure 1B). The left ventricular ejection fractionimproved in both treatment groups during the course of the trial.The mean (±SE) base-line left ventricular ejection fractionwas 0.24±0.01 in the immunosuppression group (54 patients),with a mean increase at 28 weeks of 0.10 (95 percent confidenceinterval, 0.07 to 0.12), and it was 0.26±0.01 in thecontrol group (35 patients), with a mean increase of 0.07 (95percent confidence interval, 0.03 to 0.12). The increase inthe mean left ventricular ejection fraction achieved by week28 was maintained in the group as a whole and actually increasedfurther (P = 0.03) through week 52.
Figure 1. Mean (±SE) Left Ventricular Ejection Fraction (LVEF) in the immunosuppression and Control Groups at Base Line, Week 28, and Week 52.
Panel a shows the mean values for all available studies at each time, with the numbers of patients indicated at the bottom of the panel. There was no difference between the two groups in the mean LVEF at base line, week 28, or week 52 ( P = 0.97, P = 0.95, and P = 0.45, respectively). Panel B shows the mean values for the 78 patients in whom data were available at all three times. Again, there was no significant difference between the groups (P = 0.51, P = 0.60, and P = 0.50, respectively).
A multivariate covariance analysis showed that therapy had nosignificant effect on the change in the left ventricular ejectionfraction at week 28 (P = 0.30). As expected, the initial valuefor the left ventricular ejection fraction was strongly associatedwith the subsequent value. After adjustment for base-line leftventricular function, several variables predicted the left ventricularejection fraction at week 28. Patients receiving less intensiveconventional therapy at the time of enrollment had higher leftventricular ejection fractions at week 28 than those receivingmore intensive conventional therapy (P = 0.04). Patients withdisease of one month's duration or less at the time of enrollmentalso had a greater improvement in the left ventricular ejectionfraction than those with a longer duration of disease (P = 0.007).A similar multivariate analysis showed that therapy had no significantindependent effect on the left ventricular ejection fractionat week 52.
Like the left ventricular ejection fraction, the pulmonary-capillarywedge pressure was improved at week 28, and the extent of thechange did not differ significantly between the two groups (P= 0.25). The mean (±SD) left ventricular internal diameterat end diastole was higher in the immunosuppression group thanin the control group at week 28 (64±2 mm vs. 59±2mm, P = 0.05).
We investigated the possibility that more intensive conventionaltherapy for heart failure during the course of the trial accountedfor the observed improvement in the left ventricular ejectionfraction. However, we found that a decrease in the intensityof conventional therapy at week 28, in comparison with the base-lineintensity, was correlated with a higher left ventricular ejectionfraction, and an increase in the intensity of conventional therapywas correlated with a lower left ventricular ejection fraction.
Survival
Figure 2 compares actuarial survival in the two groups. Therewere 34 deaths and 10 cardiac transplantations among the 111patients. The immunosuppression and control groups did not differsignificantly in survival at one year (P = 0.62) or throughoutthe period of follow-up (P = 0.96) (Table 2). The base-lineleft ventricular ejection fraction was positively associatedwith the duration of survival (P<0.001), and the intensityof conventional therapy at base line was negatively associatedwith survival (P = 0.003).
Table 2. Multivariate Cox Model for Mortality among 109 Patients with Myocarditis.
Adverse Drug Effects
An increase in the creatinine level by at least 0.5 mg per deciliterduring therapy was more common in the cyclosporine–prednisonegroup (46 percent of the patients) than in the control group(9 percent) or the azathioprine–prednisone group (16 percent)(P<0.001), but no patients were withdrawn because of renaldysfunction. The incidence of new hypertension (14 percent)or severe infection (6 percent) did not differ significantlyamong the three groups.
Endomyocardial-Biopsy Findings
Base-line histopathological findings in endomyocardial-biopsyspecimens are summarized in Table 1. At the time of enrollment,all 111 patients were considered to have histopathological evidenceof myocarditis. Sixty-four percent of the biopsy specimens fromthe 107 patients in whom adequate slides were available forreview were later judged by the Pathology Panel to meet theDallas criteria16 for myocarditis or borderline myocarditis.In most cases, disagreement with the diagnosis of myocarditisby a pathologist at a participating center resulted from thepanel's judgment that myocyte necrosis was not clearly present.Sixty biopsy specimens obtained at week 28 were available forreview by the Pathology Panel. Only two specimens showed ongoingevidence of myocarditis, and in one of the two the diagnosiswas borderline myocarditis. At week 52, 45 biopsy specimenswere available. Four specimens showed evidence of myocarditis:borderline in one, ongoing in one, and recurrent in two.
Immune Activation, Disease Severity, and Outcome
Selected indexes of immune activation are listed in Table 1.The treatment groups were similar with respect to most of theseindicators. Associations between these indexes and objectivemeasures of the severity of disease are shown in Table 3. Severalassociations suggest that disease at the time of enrollmentin the trial was less severe in patients who had a more robustinflammatory response. A higher level of cardiac IgG antibodieswas associated with a higher left ventricular ejection fractionand a smaller left ventricular size. A higher level of generalIgG antibodies was associated with a lower pulmonary-capillarywedge pressure. A higher level of anti–skeletal-muscleIgG antibodies was associated with a shorter duration of disease.A higher white-cell count was correlated with a smaller leftventricular internal diameter at end diastole. A higher levelof natural killer cells and macrophages (Leu-11b+ cells) wasassociated with a longer exercise time and less intensive conventionaldrug therapy for heart failure. However, a lower level of helperT cells (Leu-3a+ cells) was also associated with less intensiveconventional therapy. Six of the eight associations were stillsignificant after adjusting for clinical characteristics. Therewas no systematic change in the immunologic variables duringfollow-up.
Table 3. Multivariate Analysis of Associations between the Severity of Initial Disease and Markers of Immune Activation.
The effects of these immunologic variables on outcome were alsoevaluated. After adjustment for the treatment-group assignmentand the base-line values for the continuous outcome measures,the immunologic variables were added to the separate multivariatemodels previously developed for each measure of cardiac performance(left ventricular ejection fraction, left ventricular internaldiameter at end diastole, and pulmonary-capillary wedge pressure)and survival. None of the variables were significantly associatedwith the measures of cardiac performance in the group of patientsas a whole. A higher peripheral-blood CD2+ T-lymphocyte count(Leu-5b+ cells) was associated with a higher risk of death (Table 2).
Discussion
Immunosuppression did not have a beneficial effect on the primaryend point, a change in the left ventricular ejection fractionat 28 weeks, and actually had a statistically significant, thoughclinically mild, negative influence on the left ventricularinternal diameter at end diastole. Immunosuppression also didnot improve survival. We conclude that immunosuppressive therapyis not beneficial in most patients with histologically confirmedmyocarditis.
We cannot be dogmatic, however, in advising the withholdingof immunosuppressive therapy in all patients with myocarditis,for several reasons. Numerous viruses can cause myocarditis,and they vary in their prevalence, virulence, and responsivenessto immunosuppressive therapy, both geographically and temporally.Our definition of myocarditis included a left ventricular ejectionfraction that was less than 0.45, a duration of illness of lessthan two years, and an endomyocardial biopsy that was indicativeof myocarditis, according to an experienced pathologist. Theremay be other ways to identify myocarditis. Of course, our findingsdo not apply to patients with other forms of histologicallyconfirmed myocarditis that we did not study, including giant-cellmyocarditis, peripartum myocarditis, hypersensitivity myocarditis,and cardiac sarcoidosis. Thus, the patients we studied may notbe representative of all patients with myocarditis. Finally,the immunosuppressive therapies that we used — the drugs,dosages, and duration of their administration — cannotbe considered representative of all immunosuppressive strategies.
As we have noted elsewhere,14,21 there was a low incidence ofhistologic evidence of myocarditis (10 percent) in the 2233patients undergoing biopsy specifically to rule out this diagnosis.Thus, the assumption should never be made that a patient presentingwith clinical findings consistent with myocarditis has microscopicalevidence of the disease. Although an endomyocardial biopsy isrequired for histologic confirmation of the diagnosis, the needfor a routine biopsy when myocarditis is suspected is mitigatedby the facts that histologic evidence of myocarditis is foundinfrequently and there is no therapy for the condition. Thepatients who had negative biopsy results in our study may havehad idiopathic dilated cardiomyopathy or a form of myocarditisthat was not detected by endomyocardial biopsy. Our findingsare not applicable to patients thought to have myocarditis withouthistologic evidence of it.
A multivariate analysis identified a better base-line left ventricularejection fraction, less intensive conventional therapy at baseline, and a shorter duration of disease as independent predictorsof improvement in the left ventricular ejection fraction. Theseresults and the multivariate predictors of mortality that weidentified (Table 2) were not surprising. The left ventricularejection fraction is a well-known predictor of survival, andmore intensive therapy for heart failure would be expected inpatients with more severe disease and a poorer prognosis.
Features consistent with a stronger immune response were associatedwith less severe initial disease. Table 3 shows the resultsof multivariate analyses of the association of immunologic variableswith six measures of the initial severity of disease. Increasednatural-killer-cell activity and a higher white-cell count areconsistent with a more effective inflammatory response. Thoughwe did not measure antiviral antibodies specifically, the increasedIgG antibody levels that we observed may also be indicativeof an inflammatory response. These observations suggest thatin patients with myocarditis, a prominent immunologic responsemay be a benefit rather than a principal cause of the disease.Although the presence of cardiotropic virus and a virus-specificimmune response was not assessed in this study, enterovirusesare thought to be associated with most cases of myocarditisin humans. In the earliest phase of viral myocarditis, the virusreplicates in cardiac tissue and elicits a cellular response(predominantly natural killer cells and macrophages) and a humoralimmune response.3 If this response is adequate, the virus islargely or completely eliminated from the heart, and recoveryis possible. If the initial immune response is insufficient,however, the virus is not eliminated, and either direct myocardialdamage continues22 or an autoimmune process may develop. Inthe latter case, a chronic, destructive immune reaction, mediatedprimarily by T lymphocytes and characterized by various manifestationsof autoimmunity and myocytolytic activity, may ensue and causefurther myocyte injury.4,23,24 Allosensitized T lymphocyteshave recently been shown to cause both reversible and irreversiblemyocyte dysfunction through direct contact between cells.25These findings are consistent with our observation that higherlevels of helper T cells were associated with more severe initialdisease, as indicated by the need for more intensive conventionaltherapy of heart failure, and that higher levels of circulatingCD2+ T cells were associated with a greater risk of death.
Thus, our data support the interpretation that an early, appropriateinflammatory response has a beneficial effect in patients withmyocarditis. In some patients, however, heightened T-cell activitymay be deleterious. This interpretation does not preclude thepossibility that appropriately timed immunosuppressive treatmentwould be helpful in some patients with myocarditis, if it preventedor ameliorated the harmful T-cell response.23,25
Although the results of this trial do not suggest new optionsfor treatment, they do suggest that a distinct subgroup of patientswith myocarditis, identified on the basis of serologic and cellularindicators of heightened immune activity, has less severe disease.However, the rate of mortality (which we defined as death orthe need for cardiac transplantation) reached 56 percent atfour years. Myocarditis is often a devastating illness thatevolves into a chronic, progressive disease with a prognosissimilar to that of idiopathic dilated cardiomyopathy.26 Thus,although some patients have an appropriate, early immune response,many have a response that is inadequate to prevent permanentcardiac injury.
Supported by grants from the National Heart, Lung, and BloodInstitute (RO-1-HL34744) and the National Center for ResearchResources (M01-RR00064).
* The centers and investigators participating in the MyocarditisTreatment Trial are listed in the Appendix.
Source Information
From the Division of Cardiology, University of Utah, Salt Lake City (J.W.M.); the Department of Medicine, University of Mississippi, Jackson (J.B.O.); the Division of Cardiology (A.H.) and the Department of Molecular Microbiology and Immunology (N.R.R.), Johns Hopkins University, Baltimore; the Department of Pathology, University of British Columbia, Vancouver (B.M.M.); the Department of Pathology, Stanford University, Stanford, Calif. (M.E.B.); and the Department of Family and Community Medicine, University of Arizona, Tucson (T.E.M.).
Address reprint requests to Dr. Mason at the Cardiology Division, University of Utah Medical Center, 50 N. Medical Dr., Salt Lake City, UT 84132.
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Appendix
The centers and investigators participating in the MyocarditisTreatment Trial are listed below, with the number of patientsrandomized at each center given in parentheses (15 further patientswere received in open enrollment). For each center, the firstperson listed was the principal investigator. Loyola UniversityMedical Center, Maywood, Ill.(12): M.R. Costanzo and K. Grady;Winthrop University Hospital, Mineola, N.Y.(10): N.E. Kantrowitz,S.M. Zeldis, S. Kane, M.E. Coglianese, C. Tomeo, and K. Bacon;Toronto Hospital, Toronto(8): P.R. McLaughlin, P. Liu, andB. Ross; Massachusetts General Hospital, Boston(7): I.F. Palacios,W. Dec, B. Block, and D. Cocca-Spoffard; Baylor College of Medicine,Houston(6): J.B. Young, C. Leon, R. Casta, and C. Kingry; St.Luke's Episcopal Hospital, Houston(6): N.E. Strickman and M.Harlan; University of Cincinnati, Cincinnati (5): N. Fowler,P. Engel, and N. Nunn; University of Michigan, Ann Arbor(5):S.K. Das, P. Suhy, E. Kline, and A.J. Gilles; Harbor–UCLAMedical Center, Torrance(4): W. J. French and A. Skinner; OhioState University College of Medicine, Columbus (4): D.V. Unverferth,R. Starling, P. Newton, and M. Wooding-Scott; Pennsylvania Hospital,Philadelphia(4): W.J. Untereker, D. Poll, K. Hoffman, and J.Frank; University of Utah, Salt Lake City(4): J.W. Mason, J.B.O'Connell, R. Fowles, K. Millar, L. Freedman, and S. Lyver;Brooke Army Medical Center, Fort Sam Houston, Tex.(3): R. Lathamand R. Peeples; Minneapolis Heart Institute Foundation, Minneapolis(3): I.F. Goldenberg, D. Hunn, and P. Anderson; New York MedicalCollege, Valhalla(3): M.B. Weiss and N. Truelieb; Oregon HealthSciences University, Portland(3): J. Hosenpud, R. Conner, andL.J. Brown; University of Tennessee, Memphis(2): K.B. Ramanathan,C. Pounders, M. Mills, and K. Kantor; Beth Israel Hospital,Boston(1): W.H. Abelmann, A. Flaherty, and K. Thorp; Beth IsraelMedical Center, New York (1): J. Strain, P. Virzi, A. Grayeski,and A. Kelly; Cleveland Clinic Foundation, Cleveland(1): R.E.Hobbs and D. Pelegrin; Mount Sinai Medical Center, New York(1): M. Cohen and L. Hawkins; University Hospital, London, Ont.,Canada (1): W.J. Kostuk and R. Kennedy; University of Connecticut,Farmington(1): W.D. Hager, J. Dougherty, A. Riba, S. Larkin,and L. Kearney; University of Ottawa Heart Institute, Ottawa,Ont. (1): R.A. Davies and K. Drouin; Kyoto University, Kyoto,Japan(0): A. Matsumori; Montefiore Hospital, New York(0):R.M. Grose and B. Levine; Presbyterian University Hospital,Pittsburgh(0): B.F. Uretsky, S. Murali, and A. Betschart; St.Louis University Medical Center, St. Louis (0): G.A. Williams,L. Miller, and S. Wittry; Tulsa Heart Institute, Tulsa, Okla.(0): A.D. Hagan and J. Durham; University of California, SanDiego(0): R. Shabetai and R. Cremo; and University of NebraskaMedical Center, Omaha (0): B.M. McManus, T. Sears, and W. Arteaga.
Clinical Coordinating Center (University of Utah): J.W. Masonand J.B. O'Connell; Data Coordinating Center (University ofArizona): T. Moon, E. Hahn, V. Hartz, A. Rico, and N. Jenrow;Core Immunology Laboratory (Johns Hopkins University): N.R.Rose, A. Herskowitz, C.L. Burek, P. Jones, and M. Vladut-Talor;CoreImmunology Laboratory (University of Nebraska Medical Center):B.M. McManus, J. Wilson-McManus, B. Switzer, and K. Guy; PathologyPanel: M.E. Billingham (chair), H.T. Aretz, W.B. Edwards, S.Factor, J. Fallon, M.E. Hammond, B.M. McManus, and F. Schoen;Safety Monitoring Committee: G.S. Francis (chair), H. Burchell,B.H. Brundage, S. Goldstein, R. Luepker, and P. Miller.
Cyclosporine and Methotrexate for Severe Rheumatoid Arthritis
Schlesinger N., Huppert A., Hoch S., Malleson P., Steinberg A. D., Rosh J. R., Birnbaum A. H., van de Rijn M., Kamel O. W., Storb R., Thomas E. D., Tugwell P., Yocum D., Pincus T., Wells G.
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Full Text
N Engl J Med 1995;
333:1567-1569, Dec 7, 1995.
Correspondence
Immunosuppressive Therapy for Myocarditis
Cunnion R. E., Parrillo J. E., Maisch B., Camerini F., Schultheiss H.-P., Cooper L. T., Shabetai R., Mason J. W., O'Connell J. B., McManus B. M.
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N Engl J Med 1995;
333:1713-1714, Dec 21, 1995.
Correspondence
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