A.R. MASSARO,   A. CARNEVALE,  G. SCIVOLETTO,  M. COLOSIMO**,   C. RUMI*,   A. LAUDISIO,   P. TONALI

Institute of Neurology and

*Institute of Internal Medicine of the "Sacro Cuore" University Medical School;

**USI MRI-Unit / "Cristo Re" Hospital; 

Roma, Italy

Introduction

This study is an additional two-year follow-up of the previous two-year pilot study which was presented at the ECTRIMS meeting of St. Gallen in 1991^1,2. In that pilot study a clearly different evolution of the disease in two relapsing-remitting MS patient groups treated with alpha-2A-interferon (a-ifn) was reported (c²: p <0.001). The first group was formed by subjects younger than 40, and the second older than 40 (Table 1). At that time a beneficial effect of a-ifn in relapsing-remitting MS patients older than 40 years was suggested. As the disease usually follows a slower and rather progressive course in that age period³, the possible interference of this factor was also considered, admitting only patients who had at least two relapses in the previous two years.

Table I.  Results of the two year pilot study  (1991)^1,2.

Another important point was the absence of serious side effects or hazard for the patients. Two explanations for the possible age-dependent different response to a-ifn were suggested. The first was that MS may change its immunopathological pattern through the years⁴. The second was that the increased permeability of the BBB, due to age-related changes⁵, may allow an easier passage of the a-ifn in the CNS compartment, making it possible for a lower dosage to be effective on the level of the CNS, which is the supposed target organ.

Patients and methods

Reported here is an additional two-year follow-up study on those 14 patients older than 40 who did not present any exacerbation or any increase of the Kurtzke’s EDSS at the end of that pilot study. Seven of those patients decided to continue the treatment, while the remaining seven stopped. Their decision was not influenced by the neurologist.

Furthermore, those two patients (15 and 16 of the table II) who failed to show a positive result in the pilot study were also followed-up, and added to the non treated patient group, making a total of five patients.

Table II. Follow-up quadriennale dell'EDSS di Kurtzke in pazienti SM trattati con interferone a-2A. Sono evidenziati in neretto i pazienti che hanno continuato il trattamento sino a 4 anni. Gli asterischi (***) evidenziano i pazienti peggiorati alla valutazione finale.

The treatment schedule was slightly modified: 3 MIU IM every three days, without any interruption, while previously the same dosage was administered every other day, for a month, at alternative months. This was done to avoid the recurrence of fatigue and/or fever that some patients experienced at the beginning of every bimonthly treatment.

All patients continued to be evaluated by clinical parameters (Kurtzke’s scales included), cerebral and cervical MRI, also with gadolinium-DTPA, lymphocyte subsets, and routine laboratory tests. The MRI evaluation was done at the end of the four-year period, therefore the patients received a total of four MRI: immediately before the onset of treatment, after one year, after two years, and after four years. MRI evaluation was also done at every clinical relapse. Due to the lack of a computerized program for evaluating the areas of altered intensity signal in the white matter, the comparison was done only visually by two independent neuroradiologists and the neurologist. The inter-examiners agreement was highly satisfactory. In spite of the care used in maintaining constant positioning techniques, scanning standards, and gadolinium dosage (0.2 mmol per kg of body weight), this method of comparison might not be completely precise.

Results

The results are as follows: None of the treated patients presented any major side effects, nor alterations in the routine tests. Of the 7 treated patients, only one relapsed during the additional observation period, with an increase at the EDSS at the final biennial evaluation. Of the 9 untreated patients, only 2 remained stable with no relapses nor increase at the EDSS; the others experienced relapses, with worsening of the final EDSS scores (table II). Patients’ annual exacerbation rate, which was 1.03 at the pre-trial evaluation and 0.06 after the first two-year treatment, was 0.07 for the treated group after the additional two years; while it was 0.52 for the untreated patient group. Kurtzke’s EDSS mean score was 5.35 at the pre-trial evaluation and 5.41 in the group of seven patients who continued the treatment, and 6.05 in the remaining untreated nine.

Table IIIa. Mean annual  exacerbation rate.

Table IIIb. Kurtzke's EDSS mean scores.

Even after 4 years the MRI evaluation presented a complete overlapping with the clinical situation: only patients who worsened presented new lesions and/or gadolinium enhancement. This finding is particularly important because MRI changes are known to be more frequent and dynamic than clinical manifestations, as a consequence of new asymptomatic lesions.

The lymphocyte subsets continued to present wide variations, but even after the change in the treatment schedule a clear trend was not seen.

Conclusions

From these data we can conclude that:

Long-term treatment with a-ifn appears to be safe even after 4 years at the dosage used.

The supposed beneficial effect observed during the first two years is lost when the treatment is stopped.

The continuation of the treatment probably mantains a positive biological activity on the course of MS.

MRI evaluation agrees well with the patients’ clinical pattern. The lymphocyte subset follow-up does not seem to correlate with the clinical evolution of the disease.

Our positive results in patients older than 40 are not consistent with those of Kastrukoff & coll.⁶, who used lymphoblastoid a-ifn (5 MIU daily by subcutaneous injection for 6 months) in 100 MS patients mainly over the age of 40, but with a chronic progressive course.

The study of Durelli & coll.⁷ agrees in part with our results, even if from a different point of view. In fact, their positive results were obtained on 20 patients with a mean age of 35, but with a dosage of a-ifn of 9 MIU intramuscularly every other day, which was significantiy higher than ours. In conclusion, we can say that dosage and age are the crucial points in programming trials on interferons. It is very likely that an intermediate dosage of 6 MIU every three days may conciliate the problem of side effects and that of efficacy in young patients. In this way the additional important cost problem may in part be solved, provided that, according to the researchers’ current opinion, this treatment should be continued for many years.

Acknowledgments: This study was supported by a grant from the Italian Ministry of Scicntific Research and Technology (40%), and from AISM (Italian Multiple Sclerosis Society).

1. Massaro A.R., Cioffi R.P., Laudisio A., Tonali P.: Human recombinant alpha-2A-interferon in multiple sclerosis: results of a two-year pilot study. Schweizer Arch. Neurol. Psych., 142: 512-513, 1991.
2. Massaro A.R. Scivoletto G., Laudisio A., Tonali P.: Two year pilot study on human recombinant alpha-2A-interferon in multiple sclerosis. J. Neuroimmunol., S1: 86, 1991.
3. Kurtzke J.F.: Clinical manifestations of multiple sclerosis. Handbook of Clinical Neurology, vol. 9, Vinken P.J. & Bruyn G.W. Eds., Amsterdam 1970, pp. 161-216.
4. Massaro A.R.: Notes on the therapy of multiple sclerosis. Ital. J. Neurol. Sci., 13 (s14): 137-143, 1992.
5. Andersson M. & coll.: Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report.
6. Kastrukoff L.F. & coll.: Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. I. Clinical and MRI evaluation. Neurology, 40: 477-486, 1990.
7. Durelli L. & coll.: Chronic systemic high-dose recombinant interferon alpha-2A reduces exacerbation rate, MRI signs of disease activity, and lymphocyte interferon-gamma production in relapsing-remitting multiple sclerosis. Neurology, 44: 406-413, 1994.

This paper appeared in the volume "Proceedings of the 10th Congress ECTRIMS" , I. Milonas ed., University Studio Press, Thessaloniki 1995, pp. 54-58.

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