Intensive immunosuppression in patients with disseminated sclerosis. I. Clinical response.

(1) There is evidence that the symptoms of multiple sclerosis (MS) are at least partly the consequence of an auto-aggressive immunological reaction. For this reason, we undertook a small (fourteen patients) trial of the remedial effects of intensive immunosuppression: the combined administration of corticosteroid, Imuran (azathioprine) and antilymphocyte globulin (ALG). (2) When the trial started the patients were 19–58 years old (eleven under 40) and their disease was of 1–33 years duration (ten had the disease for 3 years or less, and twelve had active disease at the outset). (3) Taking day 0 as the first day of treatment, prednisone (150 mg/day) was started on day 0 and tapered rapidly to 20 mg/day by day 7. In an attempt to annul the immunogenicity of ALG as a foreign protein all patients received intravenous infusions of aggregate-free normal horse IgG on days 1 and 4 at dosages of 60 mg/kg and 30 mg/kg respectively. Imuran (3 mg/kg) was started on day 0 and continued at this level throughout the study. (4) Intravenous ALG/500 mg was given on day 7, and on the weekdays of the following 3 weeks. During this intensive immunosuppression the patients were maintained in semi-isolation using barrier nursing techniques. (5) Patients were kept in hospital for 1 week after the end of ALG treatment, and then discharged on a maintenance dose of prednisone (20 mg/day) and Imuran (3 mg/day). Patients were asked to attend Outpatients at 3-monthly intervals to evaluate their progress. At the end of a year immunosuppressive drugs were tapered in preparation for complete withdrawal. (6) Undesirable side effects, classified under the agents probably responsible for them, were as follows. ALG. Minor phlebitic episodes responding to warm soaks, and in one patient evidence of anaphylaxis relieved by hydrocortisone, antihistamine and reduction of ALG. A second patient developed signs of serum sickness which disappeared when ALG was stopped and the steroid dosage temporarily increased. . Some hair loss, but no patient became anaemic or leukopaenic, and liver function tests revealed no abnormality. . This was responsible for the most distressing side effects; mild to moderate moon facies and weight gain in eleven out of fourteen patients. Six patients were dyspeptic, and one developed duodenal ulceration with occult bleeding. One patient with a long history of ACTH treatment developed osteoporosis and a spontaneous compression fracture. Infection was not a cause of anxiety. (7) The clinical appraisal was based on a 4-point scalar evaluation of sensory and motor modalities, balance, speech and vision. The final ratings were agreed by three assessors. (8) Most patients reported improvement during the first 2–3 weeks' treatment, especially during the first few days of ALG therapy, though the degree and nature of the improvement varied greatly. In a few patients symptoms of many years' standing improved. (9) As most patients had MS of the intermittently active type, special attention was paid to relapse rates before, during and after treatment. Relapses were signalized by the appearance of any new sign or symptom or progression for more than 10 days of a pre-existing complaint. (10) In two patients who relapsed at 6 and 9 months respectively, the relapses were less severe than those which had occurred before treatment and were easier to control. (11) Using patients as their own controls, there was found to be a significant reduction in relapse rate compared with the number predicted on the basis of their experience before treatment. (12) Some patients underwent relapses a few weeks or months after significant drug reductions; for this reason some patients required continued immunosuppressive treatment, though all drugs have been withdrawn from three patients. (13) Intensive immunosuppression, well tolerated by patients, is a feasible and clinically acceptable procedure, and its results, taken in conjunction with those of Brendel in Munich, justify further investigation of its use for the treatment of MS. (14) Detailed immunological findings are the subject of two succeeding papers.