The Kaiser Study
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Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:1055-1060 1055 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.12.1055 on 1 December 1991. Downloaded from Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study William H Likosky, Bruce Fireman, Robert Elmore, Gary Eno, Kirby Gale, G Browne Goode, Katherine Ikeda, James Laster, Carter Mosher, Jack Rozance, Joel Richmon, Sidney Rosenberg, Antoine Samman, Robert Sternbach, Jay Whaley, Louis Fehrenbacher Abstract et al7 some work has suggested that The value of a short course of intensive the immunosuppressant cyclophosphamide immunosuppression with cyclophos- (CTX) alone or in conjunction with adreno- phamide in stabilising chronic pro- corticotropic hormone (ACTH) or prednisone gressive multiple sclerosis (MS) was may favourably modify the progression of examined in a randomised single- MS.""' Treatment with CTX has potential blinded, placebo-controlled clinical short- and long-term potential toxicities man- trial. Forty two patients, from the Kaiser dating more complete evaluation of efficacy Permanente Medical Care Program, before routine use in chronic progressive Northern California, were studied. MS. 19-21 Twenty two patients received a short This study was designed to test the utility course of cyclophosphamide in an out- of a short course of intensive immunosuppres- patient neurology clinic until their sion with CTX compared with a placebo of leucocyte counts fell below 4000/mm3, folic acid (FA) in stabilising chronic progres- Kaiser Permanente and 20 patients received folic acid. Level sive MS. We also tested whether such Medical Center, of disability, impairment of functional immunosuppression could be safely adminis- California, USA Departments of systems, and performance of social roles tered in outpatient neurology clinics. The Neurology were assessed before randomisation and physicians evaluating disease were blind to Santa Clara reassessed 12, 18, and 24 months after patients' treatment status. W H Likosky R Elmore therapy. In both the cyclophosphamide J Laster and folic acid groups, the mean level of Vallejo disability increased from the baseline G Eno examination to the 12 month follow up Methods K Gale examination (the primary endpoint) by The study was conducted at outpatient A Samman 0 5 on Kurtzke's Expanded Disability neurology clinics of the Kaiser Permanente San Francisco G B Goode Status Scale, indicating similar disease Medical Care Program in Northern California. This health maintenance organisation provides South San Francisco progression in the two groups. Although http://jnnp.bmj.com/ S Rosenberg immunosuppression therapy can be medical care for about two million health plan Martinez safely administered to MS patients in an members at 14 medical centres. Patients were K Ikeda outpatient clinic, evidence of substantial referred to the study by 19 neurologists at 13 of Sacramento benefits was not found. the centres. Seven neurologists and one C Mosher oncologist treated patients; seven neurologists J Rozance evaluated patients. Oakland Multiple sclerosis (MS) is a common cause of Patients who met the following criteria were J Richmon neurological disability. The majority of eligible for the study: 1) History, physical on October 3, 2021 by guest. Protected copyright. Walnut Creek patients experience a relatively benign course examination, and laboratory findings consis- R Sternbach with exacerbations and remissions. In a tent with MS and meeting the Schumacher Redwood City the disease criteria for the diagnosis of MS;22 2) Chronic J Whaley proportion of patients, however, Department of may enter a chronic progressive phase and progressive disease for one or more years as Medicine proceed to severe disability.' We examined established by clinical records and patient and Vallejo whether immunosuppression can stabilise this physician assessments. Chronic progressive L Fehrenbacher chronic progressive form of the disease. disease was defined as an estimated drop in the Kaiser Permanente The disease process of MS consists of the Kurtzke Expanded Disability Status Scale Medical Care Program, Oakland, breakdown of myelin in the central nervous (EDSS)2' and the Ambulation Index (AI)10 by California system accompanied by inflammation and one step over the previous year and a gradual Division of Research eventual scarring.2 A body of evidence pattern of disease progression with or without B Fireman implicates a disordered immune system in the superimposed acute exacerbations; 3) Gait Correspondence to Dr Likosky, Department of pathogenesis of MS.34 As a result, a number impairment but ability to walk retained; 4) Age Neurology, Kaiser of immune-system-altering agents have been at entry into study between 18 and 60 years; 5) Permanente Medical Center, disease or 900 Kiely Blvd, Santa Clara, used to treat the acute and chronic progressive Absence of debilitating chronic CA 95051, USA forms of the disease.5 recent immunosuppressive therapy. Informed Received 3 September 1990 No specific therapy has been shown to alter consent was obtained from all participating and in revised form 5 April 1991. the long-term prognosis for patients with the patients. Accepted 16 April 1991 disease.67 Following Aimard et al 8 and Girard Cyclophosphamide (400 to 500 mg) was 1056 Likosky, Fireman, Elmore, Eno, Gale, Goode, Ikeda, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.12.1055 on 1 December 1991. Downloaded from Table I Baseline characteristics of 22 patients treated with cyclophosphamide and 20 positive change scores indicated more severe patients treated withfolic acid impairment. Disease progression among patients in the CTXgroup FA group two groups was also examined using Mean (range) Mean (range) dichotomous indicators obtained from the Age, year 43 9 (31-58) 40Y8 (25-55) EDSS, the AI, each component ofthe FSS, the Per cent women 54-6 40-0 IS, and the ES. We categorised patients as Number years since onset of symptoms 9-2 (1-16) 11-5 (1-29) Age ofonset of illness, year 34-6 (22-52) 29 3 (19-42) "worse" if their follow up rating was at a level Expanded disability status scale (EDSS) 5-84 (3-8) 5-8 (2-7) of disability at least -0 units higher than their Ambulation index (Al) 4 3 (2-9) 4-3 (2-7) baseline rating; otherwise they were categor- CTX = cyclophosphamide. ised as "stable." FA = folic acid. Evaluating physicians were unaware of the treatment status of the patients they evaluated. Hair loss among CTX patients was brief and administered intravenously five days per week did not bias evaluation; their hair had regrown until the leucocyte count fell below 4000/mm'. by the time the one year examination took The intent was to achieve a leucocyte count in place. The senior author, blind to patient the range of 2500/mm'. On occasion CTX was treatment status, reviewed the ratings of the resumed to achieve that level of leucopenia. nine evaluating physicians to ensure that they Cyclophosphamide was administered by a consistently followed the criteria specified in neurologist in association with a chemothera- the protocol. pist or by a chemotherapist alone. Fluids were provided at the treatment centre and encouraged during the 24 Statistical methods following hours. The "benefit" ofCTX treatment Complete blood cell count, urine analysis, and at each follow up examination was estimated by the amount serum sodium results were monitored through- that the mean EDSS change in the CTX out the treatment period. Folic acid (1 mg) was group administered intravenously five times weekly exceeded that in the FA group. The null for two weeks. hypothesis-that EDSS change in the CTX group does not exceed that in the FA group- Assessment of disease progression was evaluated using a two sided t test. Multiple regression models were fitted to the data to Patients were evaluated four times: a baseline adjust comparisons of group means for examination was conducted before randomisa- differences between the groups tion and treatment, and follow up examinations (despite ran- domisation) in baseline EDSS, age, sex, and were conducted 12, 18, and 24 months later. duration of disease. The nonparametric Each time, the evaluating physician did a Wilcoxon test was also used to compare the neurological examination and rated on several distribution of EDSS scales the extent of the patient's disability. change scores in the These scales included the EDSS, the AI, and CTX group with that in the FA group. Also, Kurtzke's Functional Status Scale the logrank test was used to compare the two (FSS).2" groups with Also, at baseline and at 24 month follow respect to time until "failure," up, defined as a worsening ofat least one step on the patients were administered the Incapacity was Status (IS) and the Environmental Status (ES) EDSS, sustained at the subsequent exam- ination and not later reversed. Finally, the chi- http://jnnp.bmj.com/ inventories24 to further assess disability and performance of social roles. squared test was used to evaluate the difference between the groups at each follow up examina- The primary outcome measure was change tion in the proportion ofpatients whose EDSS in level of disability: the one year follow up EDSS minus the baseline change was < 1 level (indicating that their rating EDSS. condition was Changes in the EDSS from baseline to the 18 stable). and 24 month Similar methods were used to assess other examinations, similarly cal- indicators of treatment benefit, including culated, were also examined to determine on October 3, 2021 by guest. Protected copyright. change in the AI, the FSS, the ES, and the whether any treatment benefits observed at one IS. The primary endpoint was the EDSS change year were sustained at 18 and 24 months. at one We in the AI from baseline to each follow year. report nominal p values Change associated with a number of up session was also examined. To obtain additional hypo- thesis tests, recognising that even if CTX measures of change in the FSS, the and the IS, treatment has no benefits, we might ES from baseline to each follow up, we subtrac- find a few p values below 0 05.