Journal of
J. Neurol. 214, 173--181 (1977)
Neurology © by Springer-Verlag 1977
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis F o l l o w up o f 110 Patients for 2 - - 6 Years* R. E. Gonsette**, L. Demonty, and P. Delmotte National Center for Multiple Sclerosis, Melsbroek, Belgium
Summary. 140 MS patients were treated with intensive I.V. cyclophosphamide i m m u n o t h e r a p y and 110 were followed over 2 4 years. Annual relapse rate incidence was calculated over a period of 2 years before and after treatment and repeated neurological scores were made during this period. The conclusions are that 62% of the patients were stabilized during 2 ~ 4 years and that clinical improvement of the neurological signs was observed in most of the cases. It is concluded that intensive immunosuppression is able to interfere with the pathological processes involved in the pathogenesis of disseminated sclerosis. Key words: Multiple sclerosis - Cyclophosphamide and Immunotherapy. Zusammenfassung. 140 Patienten mit multipler Sklerose wurden intensiv durch intraventSse Gaben von Cyklophosphamid behandelt. 110 konnten tiber einen Zeitraum von 2 - - 4 Jahren beobachtet werden. Die jlihrliche Rtickfallrate wurde tiber eine Zeitspanne von 2 Jahren vor und nach der Be.handlung errechnet, und es wurden mehrfach in diesen Perioden neurologische Untersuchungen durchgeffihrt. Es wird gefolgert, dab 62% der Patienten fiber einen Zeitraum von 2 ~ 4 Jahren stabilisiert wurden und dab bei den meisten dieser Ftille auch eine Besserung der neurologischen Symptome nachweisbar war. Die Autoren folgern, dab intensive Immunosuppression die pathologischen Vorgtinge bei der multiplen Sklerose zu beeinflussen vermag.
Introduction Even if an autoaggressive immunological reaction does not explain the whole pathogenesis of multiple sclerosis, it seems evident that immunological processes are involved at some stages of the disease.
* Supported by grant No. 76/2 from the Belgian Center for MS ** Address f o r offprint requests: Vanheylenstraat 16, B-1910 Melsbroek, Belgium
174
R.E. Gonsette et al.
T h i s p r o m p t e d m a n y a u t h o r s t o s t u d y t h e effect o f i m m u n o s u p p r e s s i o n o n d i s e a s e activity. It a p p e a r s f r o m t h e l i t e r a t u r e t h a t o n l y " i n t e n s i v e " i m m u n o t h e r a p y s e e m s a b l e to m o d i f y t h e c o u r s e o f t h e disease. T h e best results w e r e o b t a i n e d by a c o m b i n e d i m m u n o t h e r a p y i n c l u d i n g a n t i l y m p h o c y t e g l o b u l i n , thoracic duct drainage, steroids and/or cytotoxic drugs. T h e a i m o f this s t u d y w a s t o d e t e r m i n e w h e t h e r i n t e n s i v e i m m u n o s u p p r e s s i o n , p r o d u c e d in a s h o r t t i m e by c y c l o p h o s p h a m i d e , m i g h t i n f l u e n c e t h e natural history of MS.
Material and M e t h o d s 140 selected cases were drawn from a group of hospitalized MS patients according to the criteria set forth by Schumacher et al., and characterized by relative frequent relapses. Patients with an acute exacerbation within the previous days were not accepted in the trial. Cyclophosphamide was administered intravenously in order to reach immunosuppression in a short time (1--2 weeks). The total dose (1--12 g) was adapted to maintain a leucopenia of 2000 and a lymphopenia of 1000 during 2--3 weeks. Haematological examinations were repeated daily during treatment. No corticotherapy was instituted during of after immunosuppression untill the patients experienced new exacerbations after treatment. In the same way, no further immunosuppression was maintained after cyclophosphamide therapy. The side effects of immunotherapy are well known. Nausea, loss of hair and amenorrhea in female patients were most frequently encounfered. Infections were avoided as far as possible by keeping the patients away from infectious sources. Side effects (nausea) made a double blind study impossible. 110 patients were followed for 2--6 years and definition of success was assessed by an estimation of relapse rates and the evolution of disability. Relapses were identified by the appearance of new symptoms or any progression of preexisting neurological signs using patients as their own controls. Annual relapse rates were calculated over a period of 2 years, before and after treatment. We know from daily clinical experience that there is a tendency for the relapse rates to diminish with time when MS is progressing. However, according to McAlpine, annual relapse rates only slowly diminishes with time during the first 15 years of the disease. The age of the patients at the onset of the disease was under 30 years in 75%, with a mean of 26 years, and the age at treatment was under 40 years in 75% (Tables 1 and 2). In most of the cases, the duration of the disease before treatment was under 10 years (Table 3).
Table 1
Table 2
Age at the onset of MS Decades 10--20 20--30 30--40 40--50 Total
Number of patients
Age at treatment %
Decades
Number of patients
%
33 74 25 8
23 53 18 6
10--20 20--30 30~0 40--50 > 50
3 41 61 29 6
2 30 44 20 4
140
100%
140
100%
Total
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis Table 3
Table 4
Duration of disease before treatment
Follow up
Years
< 2 years 2--3 years 4--5 years 6--7 years > 7 years
0-- 5 5--10 10--15 15--20 Total
Number of patients
%
71 37 16 16
50 26 12 12
140
100%
Total
175
30 37 50 19 4 140
110 patients were followed for 2--6 years (Table 4) and 2 more patients with a fatal evolution within the 2 years period of observation after treatment were included. The course of the disease in 112 patients with a follow up over 2 years was a remittend form in most of the cases (100).
Results
The effect of c y c l o p h o s p h a m i d e t h e r a p y o n M S patients was estimated by c a l c u l a t i n g a n n u a l relapse rates over a period of 2 years before a n d after treatment. P a t i e n t s were distributed a c c o r d i n g to the d u r a t i o n of the disease before t r e a t m e n t a n d the results are given in Table 5. A n o t h e r a p p r e c i a t i o n of the effect of i m m u n o t h e r a p y is given by the s t a b i l i z a t i o n period of the disease after t r e a t m e n t (Table 6). D a i l y controls of the W.B.C. c o u n t a n d its differentiation indicated the effects of i m m u n o t h e r a p y o n the percentage of leucocytes a n d lymphocytes.
Table 5
Duration of disease before treatment
Number of patients (112)
Annual relapse rates Before treatment
After treatment
1--3 years 4--6 years 7--9 years 10 years 10 years
14 40 24 8 26
1.25 0.80 0.65 0.85 0.55
0.30 0.35 0.15 0.40 0.40
Table 6. Stabilization of disease after treatment
Stabilization in years
Number of patients
%
< 2 years 2--4 years > 4 years
36 68 6
(33%) (62%) (5%)
110
(100%)
Total
176
R.E. Gonsette et al.
Table 7. Lymphocyte transformation test (21 patients)
Increased Reduced Unaffected
5 4 11
Total
21
Table 8. Serum immunoglobulin levels (75 pa-
tients)
Ig A (mg%) Ig G (mg%) Ig M (mg%)
Before treatment
After treatment
197 941 177
211 962 178
Table 9. Annual relapse rates after 2 immunosuppressions (12 patients) Before treatment 0.85 After 1st treatment 0.45 After 2nd treatment 0.25 "Expected rate" after 2nd treatment 0.45
We observed that most of the patients could be distributed into 3 groups according to the evolution of leucopenia and lymphopenia. In the first group (57%), total W.B.C. count was depressed but the lymphocyte percentage remains unchanged. In the second group (7%), total W.B.C. count was not modified, but lymphocytes were selectively affected. In the third group (36%), both total W.B.C. and lymphocyte percentage diminished. However, no correlation could be detected between the 3 groups and the clinical evolution of the patients, even when the lymphocytes were selectively affected. Lymphocyte transformation test to phytohaemagglutinin was studied in 21 patients, but the results were not significant (Table 7). Serum immunoglobulin levels were measured in 75 patients, before and a few days after the end of the treatment but none of the three main immunoglobulin classes was influenced (Table 8). Since the aim of this investigation was to evaluate the influence of a single intensive immunosuppression on the course of the disease, we never proposed a second treatment to our patients. But some of them were so satisfied that they asked for a second treatment. The annual relapse rates after 2 treatments with cyclophosphamide on 12 patients are given in Table 9. In order to determine the "expected relapse rate" over a period of 2 years after the second treatment, we selected 35 patients with the same duration of the disease before the first treatment. In this group, the
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis
177
1500
1000 nr 63
C
500
I
70 ~
I
L
71
/Cyclophosph~mide
I
I
72
73
I
I
74
,
I
75
therapy
Fig. 1
annual relapse rate during the 3rd and 4th years after treatment, corresponding to the period of 2 years after the second treatment in twice treated patients, is 0.45. Another important issue is deterioration. In our experience, 60% of the patients experienced improvement in neurological signs and remained stable during 2--4 years. It is striking to observe that in the group with an evolution of 10 years or more before treatment an exacerbation occured after this period of stabilization in most of the patients with severe progressing signs and severe fixed disability. Figure 1 shows the usual evolution of scoring results for neurological signs after treatment. Discussion
The aim of this study was to determine whether a single intensive immunosuppression given over a short period, without any combined corticotherapy, might influence the course of MS. We selected cyclophosphamide because this cytotoxic drug is rather easy to handle. Moreover, during the last few years, small groups of patients were treated with cyclophosphamide (Table 10) and the results seemed encouraging with the exception of Drachman in acute phases and of Cendrowski in remittent forms. The number of patients treated in our trial is higher than the total amount published in the literature. This important material and a follow up for a prolonged period (1967--1975) made evaluation of these results more reliable. Annual relapse rates calculated over a period of 2 years before and after treatment seem to us a practical and valuable tool in evaluating the efficiency of a therapeutic trial in MS. In a group of 31 patients treated with basic proteins without any clinical influence on the progression of the disease, the annual relapse rates were not modified after treatment. The annual incidence, calculated according to the same criteria, was respectively 0.75 before and 0.70 after treatment.
178 Table
R. E. Gonsette et al. 10. Immunosuppression with cyclophosphamide in MS
Year
Authors
Number of cases
Follow up
Results
1966 1967 1969 1973 1975 1975
Aimard et al. Girard et al. Millac et al. Cendrowski Drachman et al. Hommes et al.
1 30 8 23 6 32
1 year 2 years 1 year 1.5 years exacerbations 1--3 years
stabilization 50% stabilized 33% stabilized none none >50% stabilized
Total
100
Our results indicate that intensive immunosuppression with cyclophosphamide influences the natural history of MS in 62% of the patients. The beneficial effect of this therapy is characterized by an improvement of neurological signs during the first 3---4 weeks after treatment, and a significant reduction in relapses which were less severe and easier to control with corticotherapy than those which had occured before treatment. Unfortunately, the success or the failure of this therapy cannot be predicted accurately. H o m m e s et al. suggested that a high percentage of I g G in the C S F might indicate sensitivity of MS patients for immunosuppression. Favorable effects have been observed more frequently in patients with a short evolution before treatment. However, a period of 2--3 years seems necessary to appreciate the natural course of the disease and the individual relapse rate. Immunosuppression seems totally ineffective after an evolution of 10 years or more. Cyclophosphamide immunotherapy had a beneficial effect on the forms characterized by frequent relapses and rapidly progressing signs. However, it was not possible to influence the dramatic and rapid downhill course in 2 acute cases, confirming the findings of D r a c h m a n et al. It was a failure in patients with heavy neurological deficits such as tetraparesis due to brain stem lesions. I m p r o v e m e n t was reached in 4 of 6 cases with slowly progressive forms and remained present in the period of 1 to 2 years after treatment. This is in agreement with the observations of H o m m e s et al. F r o m our results, it seems evident that a brief but "intensive" immunosuppression can interfere with the pathological processes involved in the pathogenesis of MS. This suggests that these pathological processes are based on immune reactions. However, the beneficial effect of immunosuppression does not exclude a viral aetiology since we know from Camenga et al. that immune response may induce pathology in experimental virus encephalitides. It seems also evident that this interference is limited in time, acting during 2 years in most of the cases. After this period, the disease progresses again. The problem is therefore to maintain the stabilization of MS disease when obtained by immunotherapy. One way is to induce a second immunosuppression after 2 years. Our experience in 12 patients indicates that in 50% of these cases, a remission was
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis
179
again obtained and that the annual relapse rate in this group was reduced from 0.45 to 0.25. One patient had 3 cyclophosphamide treatments in 6 years without any apparent discomfort. But we are rather reluctant to repeat strong immunosuppression on the same patient since the long term effects of this therapy are not yet clear. A second way is to maintain a mild immunosuppression with daily oral doses of cyclophosphamide. According to m a n y authors, mild immunosuppression, when administered alone, is ineffective. However, we know from H o m m e s et al. that "strong" immunosuppression obtained by oral administration of high doses of cyclophosphamide may improve chronic progressive forms of MS and may stop the progression of the disease for 1--2 years. For this reason, we now intend to start maintained oral immunotherapy directly after the intensive I.V. immunosuppression, in order to obtain a more prolonged stabilization of MS disease. There is a real hope that the association of both forms of immunotherapy will be more effective than each form when administered separately.
Conclusions Based on our experience with 140 patients, I.V. intensive cyclophosphamide immunosuppression does not exacerbate disseminated sclerosis. We observed no fatality and side effects were trivial or easy to control. Decrease of relapse rate and improvement of neurological signs were observed and 62% of the patients were stabilized during 2---4 years. Relapses, when occuring after treatment, were less severe and easier to control with corticotherapy. I m m u n o t h e r a p y thus seems able to influence the natural history of MS during the first 10 years of the duration of the disease. On the contrary, no effect was obtained after a duration of 10 years or more. In the same way, severe chronic neurological deficits (tetraparesis e.g.) were not influenced by cyclophosphamide treatment. The remaining problem is how to maintain this stabilization of the disease after 2 years. Maintained oral immunotherapy started immediately after intensive I.V. immunosuppression will perhaps be able to extend the remission period.
References Aimard, G., Girard, P. F., Raveau, J.: "Scl~rose en plaques et proc~ssus d'auto-immunisation. Traitement par les anti-mitotiques." Lyon Med. 6, 345 (1966) Brendel, W., Seifert, J., Lob, G.: "Effect of 'maximum immune suppression' with thoracic duct drainage, ALG, Azathioprine and Cortisone in some neurological disorders." Proc. Roy. Soc. Med. 65, 531 (1972) Camenga, D. L., Nathanson, N.: "An immunopathologic component in experimental togavirus encephalitis." J. Neuropath. & Exper. Neurol. 34, 492 (1975) Castaigne, P., Lhermitte, F., Schuller, E., Rouques, C., Loridan, M.: "Etude 61eetrophor6tique des prot6ines du liquide c6phalo-rachidien au cours de la scl6rose en plaques: II. Influence des chimioth6rapies immunosuppressives." Rev. Europ. Etudes Clin. & Biol. 16, 703 (1971)
180
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Cendrowski, W. S.: "Multiple sclerosis: Pilot therapeutic trial of immunosuppressants." Arch. Suisses de Neuroi., Neurochir. & Psych. 105, 241 (1969) Cendrowski, W. S.: "Therapeutic trial of Imuran (Azathioprine) in multiple sclerosis." Acta Neurol. Scand. 47, 254 (1971) Cendrowski, W. S.: "Immunosuppression in multiple sclerosis: Therapeutic trial of Azathioprine/Imuran'. Multiple Sclerosis. Progress in research, 1972, 168 Cendrowski, W. S.: "Combined therapeutic trial in multiple sclerosis: hydrocortisone hemisuccinate with cyclophosphamide or cytosine arabinoside". Acta Neurol. Belg. 73, 209 (1973) Cendrowski, W. S., Riekkinen, P. J., Rinne, U. K.: "Immunosuppressive therapy in neurological diseases." Ann. Clin. Research 6, 323 (1974) Danielczyk, W.: ,,Immunosuppressiva bei der multiplen Sklerose. Vorl~iufige Erfahrungen mit Proresid." Wiener Mediz. Wochenschr. 44, 934 (1968) Danielzcyk, W.: ,,Erfahrungen mit Zytostatika bei der multiplen Sklerose." Wiener Mediz. Wochensehr. 40, 697 (1970) Dau, P. C., Peterson, R. D. A.: "Transformation of lymphocytes from patients with multiple sclerosis." Arch. Neurol. 23, 32 (1970) Davis, L. E., Hersh, E. M., Curtis, J. E., Lynch, R. E., Ziegler, D. K., Neumann, J. W., Chin, T. D. Y.: "Immune status of patients with multiple sclerosis. Analysis of primary and established immune responses in 24 patients." Neurol. 22, 989 (1972) Drachman, D. A., Paterson, P. Y., Schmidt, R. T., Spehlmann, R. F.: "Cyclophosphamide in exacerbations of multiple sclerosis. Therapeutic trial and a strategy for pilot drug studies." J. Neurol., Neurosurg. & Psych. 38, 592 (1975) Fasanaro, G., Gentile, A., Stella, L.: "Prospettive per una terapia immunologica della sclerosi multipla." Acta Neurol. (Napoli) 27, 367 (1972) Frick, E., Angstwurm, H., Sp[ith, G.: ,,Immunosuppressive Therapie der multiplen Sklerose. 1. Vorliiufige Mitteilung der Behandlungsergebnisse mit Azathioprin und Antilymphozytenglobulin." Mtinich Med. Wschr. 221 (1971) Girard, P. F., Aimard, G., Pellet, H.: "Les immuno-d6presseurs. Th6rapeutique immunod6pressive en neurologie." Pr. M6dic. 75, 967 (1967) Gonsette, R. E., Demonty, L., Delmotte, P.: "Failure of basic protein therapy in multiple sclerosis." To be published Hommes, O. R., Prick, J. :I. G., Lamers, K. J. B.: "Treatment of the chronic progressive form of multiple sclerosis with a combination of cyclophosphamide and prednisone." Clin. Neurol. Neurosurg. 59 (1975) Hommes, O. R.: "De behandeling van multiple sclerose door middel van immunosuppressie. Een kritische bespreking van de resultaten." Ned. T. Geneesk. 120, 424 (1976) Lance, E. M., Kremer, M., Abbosh, J., Jones, V. E., Knight, S., Medawar, P. B.: "Intensive immunosuppression in patients with dissiminated sclerosis. I. Clinical response." Clin. Exp. Immunol. 21, l (1975) Lhermitte, F., Mart eau, R., de Saxe, H.: "Traitement de la scl6rose en plaques par le s6rum anti-lymphocytaire." Inserm 1974, rapport No. 4, 281 Mac Alpine, D., Lumsden, C. E., Acheson, E. D.: "Multiple sclerosis. A reappraisal." 1972, 2nd Ed., 644 p Mac Fadyen, D. J., Reeve, C. E., Bratty, P. J. A., Thomas, J. W.: "Failure of antilymphocytic globulin therapy in chronic progressive multiple sclerosis." Neurol. 23, 592 (1973) Mackay, I. R., Carnegie, P. R., Coates, A. S.: "Immunopathological comparisons between experimental autoimmune encephalomyelitis and multiple sclerosis." Clin. Exp. Immunol. 15, 471 (1973) Marteau, R.: "Traitement de la scl6rose en plaques. (Notions r6eentes)." Rev. M6die. Liege 27, 543 (1972) Millac, P., Miller, H.: "Cyclophosphamide in multiple sclerosis." Lancet 196911, 783 Neumann, J. W., Ziegler, D. K.: "Therapeutic trial of immunosuppressive agents in multiple sclerosis." Neurol. 22, 1268 (1972) Oger, J., Sabouraud, O., Chatel, M., Menault, F.: "Consid6rations sur une exp6rience de traitement ~tvis6e immuno-suppressive dans la scl6rose en plaques. Apropos de 47 malades trait6s pendant 2 ans Y2~t 7 ans." Inserm, 1974, rapport No. 4, 273
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis
181
Ring, J., Lob, G., Angstwurm, H., Brass, B., Backmund, H., Seifert, J., Coulin, K., Frick, E., Mertin, J., Brendel, W.: "Intensive immunosuppression in the treatment of multiple sclerosis." Lancet 1974 II, 1093 Schumacher, G. A.: "Critique of experimental trials of therapy in multiple sclerosis." Neurol. 24, 1010 (1974) Seland, T. P., McPherson, T. A., Grace, M., Lamoureux, G., Blain, J. G.: "Evaluation of antithymocyte globulin in acute relapses of multiple sclerosis." Neurol. 24, 34 (1974) Sigwald, J., Mazalton, A., Raymondeaud, C., Piot, C., Jacquillat, C.: "Etude critique du traitement de la selrrose en plaques par le Chlorambucil et la cortieothrrapie intrarachidienne. A p r o p o s de 100 cas suivis pendant une prriode comprise entre 2 et 9 arts." Revue Neurol.128, 72 (1973) Silberberg, D., Lisak, R., Zweiman, B.: "Multiple sclerosis unaffected by Azathioprine in pilot study." Arch. Neurol. 28, 210 (1973) Springers, A., Tschabitscher, H.: ,,Vorl~ufiger Bericht Uber Therapieversuche mit Azathioprin bei Multipler Sklerose." Wien. Z. Nervenheilk., suppl. II, 218 (1969) Swinburn, W. R., Liversedge, L. A.: "Long-term treatment of multiple sclerosis with Azathioprine." J. Neurol. 36, 124 (1973) Trouillas, P., Chazot, G., Aimard, G., Devic, M.: "Traitement de la sclrrose en plaques par le srrum antilymphoeytaire intra-rachidien. Bases th~oriques. Faeilit~s d'utilisation." Revue Neurol. 123, 65 (1970) Tucker, W. G., Kapphahn, K. H.: "A preliminary evaluation of Azathioprine (Imuran) in the treatment of multiple sclerosis." Henry Ford Hosp. Med. J. 17, 89 (1969) Received September 15, 1976
J. Neurol. 214, 173--181 (1977)
Neurology © by Springer-Verlag 1977
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis F o l l o w up o f 110 Patients for 2 - - 6 Years* R. E. Gonsette**, L. Demonty, and P. Delmotte National Center for Multiple Sclerosis, Melsbroek, Belgium
Summary. 140 MS patients were treated with intensive I.V. cyclophosphamide i m m u n o t h e r a p y and 110 were followed over 2 4 years. Annual relapse rate incidence was calculated over a period of 2 years before and after treatment and repeated neurological scores were made during this period. The conclusions are that 62% of the patients were stabilized during 2 ~ 4 years and that clinical improvement of the neurological signs was observed in most of the cases. It is concluded that intensive immunosuppression is able to interfere with the pathological processes involved in the pathogenesis of disseminated sclerosis. Key words: Multiple sclerosis - Cyclophosphamide and Immunotherapy. Zusammenfassung. 140 Patienten mit multipler Sklerose wurden intensiv durch intraventSse Gaben von Cyklophosphamid behandelt. 110 konnten tiber einen Zeitraum von 2 - - 4 Jahren beobachtet werden. Die jlihrliche Rtickfallrate wurde tiber eine Zeitspanne von 2 Jahren vor und nach der Be.handlung errechnet, und es wurden mehrfach in diesen Perioden neurologische Untersuchungen durchgeffihrt. Es wird gefolgert, dab 62% der Patienten fiber einen Zeitraum von 2 ~ 4 Jahren stabilisiert wurden und dab bei den meisten dieser Ftille auch eine Besserung der neurologischen Symptome nachweisbar war. Die Autoren folgern, dab intensive Immunosuppression die pathologischen Vorgtinge bei der multiplen Sklerose zu beeinflussen vermag.
Introduction Even if an autoaggressive immunological reaction does not explain the whole pathogenesis of multiple sclerosis, it seems evident that immunological processes are involved at some stages of the disease.
* Supported by grant No. 76/2 from the Belgian Center for MS ** Address f o r offprint requests: Vanheylenstraat 16, B-1910 Melsbroek, Belgium
174
R.E. Gonsette et al.
T h i s p r o m p t e d m a n y a u t h o r s t o s t u d y t h e effect o f i m m u n o s u p p r e s s i o n o n d i s e a s e activity. It a p p e a r s f r o m t h e l i t e r a t u r e t h a t o n l y " i n t e n s i v e " i m m u n o t h e r a p y s e e m s a b l e to m o d i f y t h e c o u r s e o f t h e disease. T h e best results w e r e o b t a i n e d by a c o m b i n e d i m m u n o t h e r a p y i n c l u d i n g a n t i l y m p h o c y t e g l o b u l i n , thoracic duct drainage, steroids and/or cytotoxic drugs. T h e a i m o f this s t u d y w a s t o d e t e r m i n e w h e t h e r i n t e n s i v e i m m u n o s u p p r e s s i o n , p r o d u c e d in a s h o r t t i m e by c y c l o p h o s p h a m i d e , m i g h t i n f l u e n c e t h e natural history of MS.
Material and M e t h o d s 140 selected cases were drawn from a group of hospitalized MS patients according to the criteria set forth by Schumacher et al., and characterized by relative frequent relapses. Patients with an acute exacerbation within the previous days were not accepted in the trial. Cyclophosphamide was administered intravenously in order to reach immunosuppression in a short time (1--2 weeks). The total dose (1--12 g) was adapted to maintain a leucopenia of 2000 and a lymphopenia of 1000 during 2--3 weeks. Haematological examinations were repeated daily during treatment. No corticotherapy was instituted during of after immunosuppression untill the patients experienced new exacerbations after treatment. In the same way, no further immunosuppression was maintained after cyclophosphamide therapy. The side effects of immunotherapy are well known. Nausea, loss of hair and amenorrhea in female patients were most frequently encounfered. Infections were avoided as far as possible by keeping the patients away from infectious sources. Side effects (nausea) made a double blind study impossible. 110 patients were followed for 2--6 years and definition of success was assessed by an estimation of relapse rates and the evolution of disability. Relapses were identified by the appearance of new symptoms or any progression of preexisting neurological signs using patients as their own controls. Annual relapse rates were calculated over a period of 2 years, before and after treatment. We know from daily clinical experience that there is a tendency for the relapse rates to diminish with time when MS is progressing. However, according to McAlpine, annual relapse rates only slowly diminishes with time during the first 15 years of the disease. The age of the patients at the onset of the disease was under 30 years in 75%, with a mean of 26 years, and the age at treatment was under 40 years in 75% (Tables 1 and 2). In most of the cases, the duration of the disease before treatment was under 10 years (Table 3).
Table 1
Table 2
Age at the onset of MS Decades 10--20 20--30 30--40 40--50 Total
Number of patients
Age at treatment %
Decades
Number of patients
%
33 74 25 8
23 53 18 6
10--20 20--30 30~0 40--50 > 50
3 41 61 29 6
2 30 44 20 4
140
100%
140
100%
Total
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis Table 3
Table 4
Duration of disease before treatment
Follow up
Years
< 2 years 2--3 years 4--5 years 6--7 years > 7 years
0-- 5 5--10 10--15 15--20 Total
Number of patients
%
71 37 16 16
50 26 12 12
140
100%
Total
175
30 37 50 19 4 140
110 patients were followed for 2--6 years (Table 4) and 2 more patients with a fatal evolution within the 2 years period of observation after treatment were included. The course of the disease in 112 patients with a follow up over 2 years was a remittend form in most of the cases (100).
Results
The effect of c y c l o p h o s p h a m i d e t h e r a p y o n M S patients was estimated by c a l c u l a t i n g a n n u a l relapse rates over a period of 2 years before a n d after treatment. P a t i e n t s were distributed a c c o r d i n g to the d u r a t i o n of the disease before t r e a t m e n t a n d the results are given in Table 5. A n o t h e r a p p r e c i a t i o n of the effect of i m m u n o t h e r a p y is given by the s t a b i l i z a t i o n period of the disease after t r e a t m e n t (Table 6). D a i l y controls of the W.B.C. c o u n t a n d its differentiation indicated the effects of i m m u n o t h e r a p y o n the percentage of leucocytes a n d lymphocytes.
Table 5
Duration of disease before treatment
Number of patients (112)
Annual relapse rates Before treatment
After treatment
1--3 years 4--6 years 7--9 years 10 years 10 years
14 40 24 8 26
1.25 0.80 0.65 0.85 0.55
0.30 0.35 0.15 0.40 0.40
Table 6. Stabilization of disease after treatment
Stabilization in years
Number of patients
%
< 2 years 2--4 years > 4 years
36 68 6
(33%) (62%) (5%)
110
(100%)
Total
176
R.E. Gonsette et al.
Table 7. Lymphocyte transformation test (21 patients)
Increased Reduced Unaffected
5 4 11
Total
21
Table 8. Serum immunoglobulin levels (75 pa-
tients)
Ig A (mg%) Ig G (mg%) Ig M (mg%)
Before treatment
After treatment
197 941 177
211 962 178
Table 9. Annual relapse rates after 2 immunosuppressions (12 patients) Before treatment 0.85 After 1st treatment 0.45 After 2nd treatment 0.25 "Expected rate" after 2nd treatment 0.45
We observed that most of the patients could be distributed into 3 groups according to the evolution of leucopenia and lymphopenia. In the first group (57%), total W.B.C. count was depressed but the lymphocyte percentage remains unchanged. In the second group (7%), total W.B.C. count was not modified, but lymphocytes were selectively affected. In the third group (36%), both total W.B.C. and lymphocyte percentage diminished. However, no correlation could be detected between the 3 groups and the clinical evolution of the patients, even when the lymphocytes were selectively affected. Lymphocyte transformation test to phytohaemagglutinin was studied in 21 patients, but the results were not significant (Table 7). Serum immunoglobulin levels were measured in 75 patients, before and a few days after the end of the treatment but none of the three main immunoglobulin classes was influenced (Table 8). Since the aim of this investigation was to evaluate the influence of a single intensive immunosuppression on the course of the disease, we never proposed a second treatment to our patients. But some of them were so satisfied that they asked for a second treatment. The annual relapse rates after 2 treatments with cyclophosphamide on 12 patients are given in Table 9. In order to determine the "expected relapse rate" over a period of 2 years after the second treatment, we selected 35 patients with the same duration of the disease before the first treatment. In this group, the
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis
177
1500
1000 nr 63
C
500
I
70 ~
I
L
71
/Cyclophosph~mide
I
I
72
73
I
I
74
,
I
75
therapy
Fig. 1
annual relapse rate during the 3rd and 4th years after treatment, corresponding to the period of 2 years after the second treatment in twice treated patients, is 0.45. Another important issue is deterioration. In our experience, 60% of the patients experienced improvement in neurological signs and remained stable during 2--4 years. It is striking to observe that in the group with an evolution of 10 years or more before treatment an exacerbation occured after this period of stabilization in most of the patients with severe progressing signs and severe fixed disability. Figure 1 shows the usual evolution of scoring results for neurological signs after treatment. Discussion
The aim of this study was to determine whether a single intensive immunosuppression given over a short period, without any combined corticotherapy, might influence the course of MS. We selected cyclophosphamide because this cytotoxic drug is rather easy to handle. Moreover, during the last few years, small groups of patients were treated with cyclophosphamide (Table 10) and the results seemed encouraging with the exception of Drachman in acute phases and of Cendrowski in remittent forms. The number of patients treated in our trial is higher than the total amount published in the literature. This important material and a follow up for a prolonged period (1967--1975) made evaluation of these results more reliable. Annual relapse rates calculated over a period of 2 years before and after treatment seem to us a practical and valuable tool in evaluating the efficiency of a therapeutic trial in MS. In a group of 31 patients treated with basic proteins without any clinical influence on the progression of the disease, the annual relapse rates were not modified after treatment. The annual incidence, calculated according to the same criteria, was respectively 0.75 before and 0.70 after treatment.
178 Table
R. E. Gonsette et al. 10. Immunosuppression with cyclophosphamide in MS
Year
Authors
Number of cases
Follow up
Results
1966 1967 1969 1973 1975 1975
Aimard et al. Girard et al. Millac et al. Cendrowski Drachman et al. Hommes et al.
1 30 8 23 6 32
1 year 2 years 1 year 1.5 years exacerbations 1--3 years
stabilization 50% stabilized 33% stabilized none none >50% stabilized
Total
100
Our results indicate that intensive immunosuppression with cyclophosphamide influences the natural history of MS in 62% of the patients. The beneficial effect of this therapy is characterized by an improvement of neurological signs during the first 3---4 weeks after treatment, and a significant reduction in relapses which were less severe and easier to control with corticotherapy than those which had occured before treatment. Unfortunately, the success or the failure of this therapy cannot be predicted accurately. H o m m e s et al. suggested that a high percentage of I g G in the C S F might indicate sensitivity of MS patients for immunosuppression. Favorable effects have been observed more frequently in patients with a short evolution before treatment. However, a period of 2--3 years seems necessary to appreciate the natural course of the disease and the individual relapse rate. Immunosuppression seems totally ineffective after an evolution of 10 years or more. Cyclophosphamide immunotherapy had a beneficial effect on the forms characterized by frequent relapses and rapidly progressing signs. However, it was not possible to influence the dramatic and rapid downhill course in 2 acute cases, confirming the findings of D r a c h m a n et al. It was a failure in patients with heavy neurological deficits such as tetraparesis due to brain stem lesions. I m p r o v e m e n t was reached in 4 of 6 cases with slowly progressive forms and remained present in the period of 1 to 2 years after treatment. This is in agreement with the observations of H o m m e s et al. F r o m our results, it seems evident that a brief but "intensive" immunosuppression can interfere with the pathological processes involved in the pathogenesis of MS. This suggests that these pathological processes are based on immune reactions. However, the beneficial effect of immunosuppression does not exclude a viral aetiology since we know from Camenga et al. that immune response may induce pathology in experimental virus encephalitides. It seems also evident that this interference is limited in time, acting during 2 years in most of the cases. After this period, the disease progresses again. The problem is therefore to maintain the stabilization of MS disease when obtained by immunotherapy. One way is to induce a second immunosuppression after 2 years. Our experience in 12 patients indicates that in 50% of these cases, a remission was
Intensive Immunosuppression with Cyclophosphamide in Multiple Sclerosis
179
again obtained and that the annual relapse rate in this group was reduced from 0.45 to 0.25. One patient had 3 cyclophosphamide treatments in 6 years without any apparent discomfort. But we are rather reluctant to repeat strong immunosuppression on the same patient since the long term effects of this therapy are not yet clear. A second way is to maintain a mild immunosuppression with daily oral doses of cyclophosphamide. According to m a n y authors, mild immunosuppression, when administered alone, is ineffective. However, we know from H o m m e s et al. that "strong" immunosuppression obtained by oral administration of high doses of cyclophosphamide may improve chronic progressive forms of MS and may stop the progression of the disease for 1--2 years. For this reason, we now intend to start maintained oral immunotherapy directly after the intensive I.V. immunosuppression, in order to obtain a more prolonged stabilization of MS disease. There is a real hope that the association of both forms of immunotherapy will be more effective than each form when administered separately.
Conclusions Based on our experience with 140 patients, I.V. intensive cyclophosphamide immunosuppression does not exacerbate disseminated sclerosis. We observed no fatality and side effects were trivial or easy to control. Decrease of relapse rate and improvement of neurological signs were observed and 62% of the patients were stabilized during 2---4 years. Relapses, when occuring after treatment, were less severe and easier to control with corticotherapy. I m m u n o t h e r a p y thus seems able to influence the natural history of MS during the first 10 years of the duration of the disease. On the contrary, no effect was obtained after a duration of 10 years or more. In the same way, severe chronic neurological deficits (tetraparesis e.g.) were not influenced by cyclophosphamide treatment. The remaining problem is how to maintain this stabilization of the disease after 2 years. Maintained oral immunotherapy started immediately after intensive I.V. immunosuppression will perhaps be able to extend the remission period.
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