Original Article
Controlled Trial of Plasma Exchange and Leukapheresis in Polymyositis and Dermatomyositis
N Engl J Med 1992; 326:1380-1384May 21, 1992
- Abstract
- Abstract
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 5×109 to 10×109 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<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. (N Engl J Med 1992;326:1380–4.)
Media in This Article
Figure 1
Mean Changes in the ADL Scores, Scores for Manual Muscle Testing (MMT), Serum Creatine Kinase Levels, and Peripheral-Blood Lymphocyte Counts in the Three Study Groups.Table 1
Demographic and Clinical Characteristics of the Patients with Myositis, According to Treatment.*Article Activity
- Article
Polymyositis and dermatomyositis are the most common forms of a group of systemic inflammatory diseases affecting muscle, collectively known as the idiopathic inflammatory myopathies. Patients with these disorders are identified by the presence of proximal muscle weakness; elevations in serum levels of creatine kinase and other muscle-associated enzymes; characteristic electromyographic abnormalities; chronic mononuclear-cell infiltration, with evidence of the degeneration and regeneration of myocytes on muscle biopsy; and in patients with dermatomyositis, distinctive rashes on the hands and face.1 They may also have cardiac, pulmonary, and gastrointestinal dysfunction that results in substantial morbidity and mortality.2 , 3 The causes of these diseases are unknown, but they are thought to be the result of environmental agents that act on genetically susceptible hosts to induce immune activation and subsequent tissue damage.2
Activated T and B lymphocytes and immunoglobulin and complement deposits are found in the muscles of patients with polymyositis or dermatomyositis, and activated lymphocytes and autoantibodies are frequently present in the peripheral circulation.2 , 4 Since leukapheresis can remove lymphocytes and plasmapheresis can remove lymphokines and immunoglobulins from the peripheral circulation, physicians have attempted to treat corticosteroid-resistant polymyositis or dermatomyositis with apheresis. Although several uncontrolled trials have suggested that plasma exchange and leukapheresis improve the clinical course of patients with polymyositis or dermatomyositis, uncertainties persist about the possibility of placebo responses, the effects of concomitant cytotoxic therapy, and the heterogeneity and small sizes of the treatment groups.5 6 7 8 9 10 To test the efficacy of the relatively costly therapeutic approaches of plasma exchange and leukapheresis in polymyositis and dermatomyositis, we conducted a double-blind, sham-controlled trial in 39 patients.
Methods
Patients
Patients were eligible for the study if they had the following: definite polymyositis or dermatomyositis meeting the criteria of Bollan and Peter,1 including a muscle-biopsy specimen obtained at some point that showed the changes typical of idiopathic inflammatory myopathy; an incomplete response to high-dose prednisone therapy (≥1 mg per kilogram of body weight per day for at least one month), the need for a prednisone dose of at least 0.25 mg per kilogram per day, or the occurrence of unacceptable side effects during the administration of the dose of corticosteroid needed to control disease; the ability to maintain a stable condition while receiving a constant dose of corticosteroids for more than two weeks without other agents for the treatment of myositis just before the initiation of apheresis; weakness of at least two muscle groups of 3 or less (as measured by a standard six-point evaluation scale in which a score of 5 represents normal strength11), that resulted in a functional deficit in at least one area, according to an analysis that assessed the ability to perform activities of daily living (ADL); and clinical evidence of active myositis requiring further therapy as judged by the treating physician. In addition, the patients had to have been older than 16 years at the onset of myositis, and they had to be able to provide informed consent.
Patients were excluded if they had inclusion-body myositis, a pathologically separate category of idiopathic inflammatory myopathy that is more resistant to therapy,12 a history of cancer, an active acute or chronic infection requiring therapy, a critical illness requiring intensive care, or a potentially life-threatening problem, including coronary artery disease and arrhythmias.
Approximately 175 patients were evaluated at the National Institutes of Health (NIH) over a six-year period. All patients who met the entry criteria were invited to participate in the apheresis study, and all accepted. Thus, a total of 42 patients, 11 men and 31 women, were enrolled in the trial. Two patients, one man and one woman whose conditions did not improve during the study, were subsequently excluded from the analysis because later muscle biopsies showed them to have inclusion-body myositis. Another patient withdrew from the study after the first week of therapy for personal reasons, leaving 39 patients with definite polymyositis or dermatomyositis who could be evaluated.1 Of these, 19 had polymyositis, 16 had dermatomyositis, and 4 had overlap syndromes meeting the criteria for both polymyositis or dermatomyositis and another connective-tissue disease.13 Twenty-nine of the patients had previously not responded to at least one adequate trial of cytotoxic therapy, and many patients had not responded to more than one such trial.
Assessment
The patients were admitted to the Warren Grant Magnuson Clinical Center at the NIH for the duration of the study. Each patient underwent a base-line physical examination and laboratory screening tests, including measurements of serum electrolytes, serum creatine kinase, and other muscle-associated enzymes; a general chemical survey, thyroid-function tests, a complete blood count, urinalysis, autoantibody analyses,14 , 15 chest radiography, electromyography, and a muscle biopsy.
Outcome measures used in the study were changes in strength and functional levels. Standard manual muscle testing of 16 muscle groups was performed with the use of a six-point scale (with 0 the lowest score and 5 the highest) to assess the strength of each muscle group; the maximal total score was 80.11 The muscle groups tested were the right and left gluteus medius, gluteus maximus, iliopsoas, quadriceps femoris, deltoid, trapezius, and biceps brachialis, as well as the neck flexor and extensor muscles. Each patient was evaluated throughout the study by the same registered physical therapist, who was unaware of the patient's treatment assignment and was not involved in the care of the patient. Functional assessment of ADL was determined with the Convery Assessment scale,16 an instrument whose validity has been established in patients with rheumatoid arthritis. To adapt the scale to measure function in patients with polymyositis or dermatomyositis, we deleted four questions concerning feeding, grooming, wheelchair use, and perineal care and added a question on the patient's ability to reach for things located above eye level. Each of 13 ADL areas was graded on a weighted four-component scale in which a score of 0 indicated that the patient was totally dependent, a score of 2 that the patient needed another person's assistance, a score of 4 that the patient needed assistive devices to be independent, and a score of 7 that the patient was totally independent; the maximal possible score was 91. The patient's condition was classified as having improved (or deteriorated) if there was a net increment (or decrement) of at least one grade of strength in at least two muscle groups and a net increment (or decrement) of at least one functional grade in at least one involved area of function over the course of the study. The condition of all other patients was classified as remaining unchanged.
Apheresis
Patients were randomly assigned to receive one of three apheresis procedures: plasma exchange, leukapheresis, or sham apheresis. During plasma exchange, 1 to 1 1/2 volumes of plasma (40 to 50 ml per kilogram) were removed per session and replaced with an equivalent amount of a solution of 5 percent albumin in saline containing 80 percent colloid and 20 percent crystalloid. During leukapheresis, 6 liters of whole blood was processed per procedure, with the goal of removing of 5×109 to 10×109 lymphocytes per session. During sham apheresis, 5 to 6 liters of whole blood was processed through the cell separator per session, but the separated cellular and plasma fractions were recombined and infused into the patient without removing or exchanging any components.
Apheresis was performed three times per week for four consecutive weeks with one of three continuous-flow cell separators, the CS-3000 (Fenwal Laboratories, Deerfield, Ill.) or the model 2997 or TPE devices (Cobe Laboratories, Lakewood, Colo.). Acid citrate dextrose (NIH formula A) was used as the anticoagulant. To prevent the patient from determining which apheresis procedure was being performed, the cell-separator device and attached tubing and component bags were shielded from view, therapy was not discussed with the patient by the apheresis personnel, and evaluators were not present during apheresis and were unaware of the patient's form of treatment. The dose of prednisone was kept constant for each patient, and no immunosuppressive drugs or rehabilitation therapy was given during the study. Although all patients were hospitalized during the month of the study, they were encouraged to perform their usual daily activities as if they were at home.
Statistical Analysis
The primary analysis of the results involved changes in the variables from base line to the end of the study among the three treatment groups, as assessed by one-way analysis of variance. Two-way analysis of variance was also performed to analyze these differences with adjustment for possible prognostic factors among the groups, such as sex, race, clinical group, and autoantibody status. The common logarithm of the value for serum creatine kinase levels was analyzed, since the initial plots of the values showed a highly non-gaussian distribution. Because of the possibility that clinical groups might have been ordered with respect to their effects on outcome, we used Jonckheere's nonparametric analysis of variance test for trend to test for this possibility.17 All reported P values are two-sided.
Results
There were no significant differences at randomization in the demographic or clinical characteristics of the patients. The mean ages, sex ratios, severity and duration of disease, clinical groups, serologic subgroups, corticosteroid doses, and proportions of patients who had previously received cytotoxic therapy were similar in each of the treatment groups (Table 1Table 1
Demographic and Clinical Characteristics of the Patients with Myositis, According to Treatment.*). In addition, there were no significant differences at randomization in muscle strength (measured by manual muscle testing), functional capacity (assessed on the basis of the ADL scale), or serum creatine kinase levels among the three groups. Increasingly severe disease developed in one patient in the plasma-exchange group during the study, and he was withdrawn from the study after six sessions. Three patients in each group had an improvement in their condition, three patients had a deterioration in their condition during leukapheresis, and the condition of all the rest of the patients was classified as unchanged (Table 2Table 2
Responses of the Patients with Myositis, According to Treatment.). In all but one of the nine patients whose condition improved, it did so within two weeks of starting apheresis.An overall analysis of the changes in muscle strength and functional capacity from base line to the end of the study revealed that there were no significant differences among the three treatment groups or within each group. Serum concentrations of creatine kinase (Fig. 1Figure 1
Mean Changes in the ADL Scores, Scores for Manual Muscle Testing (MMT), Serum Creatine Kinase Levels, and Peripheral-Blood Lymphocyte Counts in the Three Study Groups.), aldolase, and immunoglobulins (data not shown) decreased significantly during the plasma-exchange sessions, reflecting their physical removal during the exchange. The decreases in serum creatine kinase values during the protocol in both the leukapheresis and plasma-exchange groups were significantly greater than that seen in the sham-apheresis group (P = 0.03 and P<0.001, respectively). There was, however, no correlation between the degree of the decrease in creatine kinase or immunoglobulin levels and clinical improvement. Peripheral-blood lymphocyte counts, but not total leukocyte counts, declined significantly during leukapheresis, from a mean of 3290 per cubic millimeter to a mean of 1280 per cubic millimeter (P = 0.002). The mean (±SD) number of lymphocytes removed during leukapheresis was 6.12±2.95×109 per procedure (range, 0.47×109 to 15.0×109). There was no correlation between the number of lymphocytes removed and the response to leukapheresis in the trial. There was no statistical evidence that the different clinical groups responded differently on any of the three arms of the protocol nor that the treatments resulted in ordered effects on the outcome.Adverse effects of apheresis were encountered during the study. Nine patients (23 percent) required placement of a central venous catheter to maintain venous access; three patients (8 percent) had major vasovagal episodes; two patients (5 percent) had clinically important citrate reactions; and one patient (3 percent) receiving sham treatments required a two-unit transfusion of red cells for an apheresis-related decline in hematocrit from 0.35 to 0.25. In addition, acute transient respiratory distress developed during plasma exchange in one patient, and multidermatomal herpes zoster developed at the end of a course of plasma exchange in another patient.
Of the nine patients whose condition improved during the study, only three (two who had received leukapheresis and one who had received plasma exchange) were able to have their dose of prednisone tapered during the following year without the need for new therapeutic agents for polymyositis or dermatomyositis. Most of the other patients had an increase in disease activity within three months of completing the study and required additional therapies. Despite aggressive therapy, nine patients (23 percent) subsequently died of complications of their disease and one died of complications of cytotoxic therapy, during a mean follow-up of 3.2 years.
Discussion
The results of this study indicate that, as compared with a sham procedure, neither aggressive leukapheresis nor plasma exchange, given as 12 treatments over a one-month period, had beneficial effects on muscle strength or functional capacity in patients with active polymyositis or dermatomyositis. Although there were decreases in the serum levels of muscle-associated enzymes in patients receiving plasma exchange or leukapheresis, this did not result in substantial clinical improvement in the patients and may have been the result of the physical removal and dilution of these enzymes rather than of any immune regulatory effect. The few instances of clinical improvement, which occurred in all three apheresis groups, may have been the result of bed rest, a placebo effect, or other factors and were very short-lived in most instances.
Power calculations that address the likelihood of a Type II error in this study can be based on the sizes of the three treatment groups (13 patients in each group) and the observed variability of the changes, from the beginning to the end of the protocol, in muscle strength (measured by manual muscle testing) and functional capacity (assessed with an ADL scale). This study had approximately an 80 percent chance of detecting a minimal (16 percent) improvement in muscle strength in one or both of the active treatment groups and an 80 percent chance of detecting a minimal (10 to 11 percent) improvement in functional capacity in one or both of these treatment groups.
The results of this study differ from outcomes reported in uncontrolled studies of apheresis in patients with polymyositis or dermatomyositis5 6 7 , 9 and from controlled trials of the effect of apheresis on patients with other rheumatic diseases. The controlled trials documented slight and often short-lived, but statistically significant, improvements in patients with rheumatoid arthritis that was treated by leukapheresis,18 leukoplasmapheresis,19 , 20 or plasma exchange.21 Some controlled studies of plasma exchange in patients with rheumatoid arthritis and systemic lupus erythematosus, however, have not demonstrated its effectiveness in these diseases.22 , 23 Given the current expense of plasma exchange (estimated as ranging from $918 to $1,220 per procedure) and leukapheresis (estimated as ranging from $440 to $900 per procedure), it is important to determine the clinical situations in which these procedures are beneficial and those in which apheresis is not an effective therapy.
Although we may have failed to detect any beneficial responses because of the specific schedule of procedures that we studied, the small numbers of patients in each group, the type of patients that we treated, or other factors, we believe that our study improves on previous efforts in several respects. It was a randomized, double-blinded, sham-controlled trial of apheresis in polymyositis or dermatomyositis. We removed the confounding factor of concomitant cytotoxic therapy for myositis during apheresis. Finally, clinical response was defined by the same functional criteria in all patients and was determined by the same blinded examiner before and after apheresis. Although the number of patients in this study was small, it was large enough to detect significant differences in lymphocyte counts, immunoglobulin levels, and creatine kinase levels among the three groups, and it represents one of the largest prospective studies of any therapy to date for this uncommon autoimmune disease.
Recent data suggest that certain clinical and serologic groups of patients with myositis may have different therapeutic responses and prognoses2 , 3 and that dissimilar pathophysiologic mechanisms may be at work in the various subgroups.24 , 25 Although the number of patients in each of our study groups was too small to allow conclusive statistical analysis, there were no obvious associations, trends, or differences among the clinical or serologic groups with respect to the response to treatment.
Polymyositis and dermatomyositis are rare but increasingly recognized26 systemic autoimmune diseases that result in substantial morbidity and mortality.3 Despite the paucity of therapeutic approaches for patients with corticosteroid-resistant myositis, on the basis of the results of this study, we cannot recommend either plasma exchange or leukapheresis as a treatment for such patients.
We are indebted to Drs. John Klippel, Ronald Wilder, Alfred Steinberg, Howard Austin, James Balow, and Lori A. Love for clinical assistance; to Dr. Ira Targoff for autoantibody analyses; to Ms. Regina Dowling and the dedicated personnel in the NIH Apheresis Clinic; to Ms. Bonnie Thornton and other personnel in the NIH Rehabilitation Medicine Department; to Ms. Peg Wilt, Sue Burgess, and the other members of the 9E clinical staff for assistance in patient care; and to the many patients and their referring physicians without whom this study could not have been accomplished.
Source Information
From the National Institute of Arthritis and Musculoskeletal and Skin Diseases (F.W.M., M.E.C., R.L.L., D.D.F., P.H.P.), the Departments of Transfusion Medicine (S.F.L.) and Rehabilitation Medicine (J.E.H.), the Clinical Center (R.W.), and the National Institute of Neurological Diseases and Stroke (M.D.), National Institutes of Health, Bethesda, Md. Address reprint requests to Dr. Plotz at the Arthritis and Rheumatism Branch, NIAMS, Clinical Center, NIH 10, 9N228, Bethesda, MD 20892.
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