Beta-interferons in multiple sclerosis: A single center experience in India

Background: Indian-Asian multiple sclerosis behaves somewhat differently from Western disease. It is not known if the response to β -interferon is also different. Aim: To demonstrate the decrease in relapses with β -interferon in Indian patients with multiple sclerosis. Patients and Methods: Patients with relapsing–remitting or secondary progressive multiple sclerosis with at least two relapses were started on β -interferon. Results: Sixteen patients were followed up for a period of 1–3 years. Fifteen had relapsing–remitting multiple sclerosis (MS). The mean number of relapses in these patients before interferons were started was 3.4. The mean yearly relapse rate was 1.3. The mean Kurtzke Expanded Disability Status Scale (EDSS) at the start of β -interferon therapy in relapsing–remitting MS was 1.7. Ten of these patients were on Avonex ® (interferon β 1a) and six (including the patient with secondary progressive MS) were on Betaferon ® (interferon β 1b). On follow-up, three patients (two on Avonex ® and one on Betaferon ® ) had relapses. The respective β -interferon being received by these patients was continued, with no further relapses. The remaining patients had no relapse or clinical or MRI progression after starting the drug. The side effect profile of the drug in these patients was favorable; although nearly all developed fever on the first day of the injection, only 50% of the patients continued to have fever after 3 months. Two patients developed psychiatric symptoms, requiring discontinuation of the drug. Conclusion: Our prospective follow-up study shows that β -interferons are safe and effective in Indian patients with relapsing–remitting or secondary progressive MS.


Introduction
After the landmark trial in 1993 [1] interferons assumed a central role in the management of multiple sclerosis (MS). Three diff erent β-interferon (IFN-β) products are approved for the management of relapsing-remitt ing multiple sclerosis (RRMS) and, to a certain extent, secondary progressive multiple sclerosis (SPMS). The benefi cial eff ects of β-interferon in MS are believed to be mainly related to its anti-infl ammatory eff ectswhich is based on reduced MHC class II expression and shift of cytokine production from Th1 to Th2 -as well as its direct eff ects in preserving the integrity of the blood-brain barrier. [2,3] Previous studies have suggested that Indian and Asian patients with MS behave somewhat diff erently from their Western counterparts. They have greater visual impairment initially and more optic nerve and spinal involvement, among other diff erences. [4][5][6][7][8][9][10][11][12] It is not known if these clinical diff erences in the behavior of the disease translate into variation in the response rate to β-interferons. A PubMed search using the words 'multiple sclerosis,' 'India,' and 'beta-interferon' failed to reveal any published series on the use of β-interferons in Indian patients with MS.
Against this background, we did a prospective follow-up study of Indian patients with MS in whom β-interferons were indicated. The aims of the study were as follows: • To demonstrate the decrease in relapses in these patients despite the previously documented variations in presentation when compared to Caucasian patients with MS • To determine the adverse event profi le of β-interferons

Patient population
This study was done at an armed forces tertiary care hospital located in south India and with a large dependent clientele. All patients were either serving or retired armed forces personnel or their dependents who were entitled to free treatment through the Armed Forces Medical Services.

Inclusion criteria
Only those patients were included who had been diagnosed to have MS according to McDonald's criteria. [13] The diagnosis was based on a detailed history, clinical examination, gadoliniumenhanced MRI of brain and spine, visual evoked potentials (VEP), and presence of oligoclonal IgG bands in cerebrospinal fl uid (CSF). The MRI criteria used were the same as those used in the diagnostic criteria, i.e., the criteria of Barkhof et al. as modifi ed by Tintore et al. [14,15] Brainstem auditory evoked Short Communication response (BAER) was also done in all patients who were included in the study.
Only patients who had at least two or more clinical att acks and were diagnosed to have RRMS or SPMS, as defi ned by an international survey, [16] were included in the study.

Exclusion criteria
Those patients with primary progressive multiple sclerosis (PPMS) or with progressive relapsing MS were excluded from the study.

Choice and dose of β-interferon
The choice of β-interferon was arbitrary. In this study either Avonex ® (interferon β1a) 30 µg intramuscularly once a week or Betaferon ® (interferon β1b) 250 µg subcutaneously every alternate day were used. We made no att empt to compare the relative effi cacies of the two β-interferons.

Baseline evaluation
Prior to starting β-interferon, each patient had their score on the Kurtzke Expanded Disability Status Scale (EDSS) recorded. [17] Follow-up evaluation Aft er starting interferon the patients were monitored monthly. During each visit a detailed history was taken and the fi ndings on clinical examination were recorded with respect to progression of symptoms or appearance of new signs. EDSS and blood counts were done every 3 months. Gadoliniumenhanced MRI of brain and spine was done yearly.

Clinical relapse
A clinical relapse was defined as the presence of a new symptom or sign lasting for at least 24 h and which was not associated with fever. If a patient had a relapse, the nature of the relapse was recorded, MRI was done, standard therapy for relapse was given, and the recovery was recorded.

Clinical progression
Clinical progression in the absence of relapse was defi ned as change in EDSS by one point.

Progression on MRI
Progression on MRI was defi ned as the appearance of a new gadolinium-enhancing lesion at a site different from that recorded earlier, appearance of a new T2-weighted lesion, or increase in the size of an old lesion.

Comparison of follow-up MRI
The MRI done on follow-up was visually compared to the baseline MRI. The comparison was not blinded.

Adverse event monitoring
With respect to the adverse events aft er β-interferon injection, the following data was recorded: appearance of fever, duration of fever, persistence of fever aft er 3 months, myalgia, headache, injection site pain, skin reactions, or psychiatric manifestation.

Data recording and statistical analysis
All analysis was done aft er recording the data on a Microsoft Excel sheet. No statistical comparison was done among any groups.

Results
Sixteen patients were diagnosed as MS and satisfi ed the inclusion criteria of the study. There were nine males. The mean age at onset of symptoms was 33.5 years (range 20-52 years). The fi rst clinical feature at onset of disease and the clinical features encountered during the course of illness are shown in Table 1. Fift een patients had RRMS and one had SPMS when β-interferon was initiated. VEP showed prolonged P100 latencies in 14 (87.5%) patients, while BAER was abnormal in 6 (37.5%). Oligoclonal band was detected in the cerebrospinal fl uid (CSF) of 12/14 (85.7%) patients; two patients did not undergo CSF examination.

SPMS
The patient with SPMS had seven relapses initially. The last relapse was 2 years before starting β-interferon. Aft er the last relapse he had shown progression of motor symptoms. At the time of initiating β-interferon the EDSS score was 6.

Interferon distribution
Ten patients were initiated on Avonex ® and six on Betaferon ® in the doses mentioned earlier. The patient with SPMS received Betaferon ® . The mean follow-up period was 2.25 years (range: 1-3.25 years).

Relapses
Two patients on Avonex ® and one on Betaferon ® had relapses. All three relapses occurred in the first year after starting β-interferon and were documented with new MRI lesions. The recovery was complete aft er giving steroids. β-Interferon was continued in all three patients with no further relapses during a mean follow-up period of 1.5 years. Adverse events β-Interferon had to be discontinued in two of our patients, both of whom were on Avonex ® . The fi rst patient was a known case clinical profi le of MS in India. One of the diff erences revealed in previous studies include older age at presentation, [8] though some Indian studies have also reported onset at slightly earlier age. [4,7,9,10] Male predominance has been documented in some Indian studies, [4,7] however there are other Indian studies that have documented female predominance. [8,9,11] Indian and Asian studies have documented visual impairment as a common initial symptom. [4,6,7,11,12] A few series have shown relatively litt le clinical involvement of the cerebellum [6,7,10,11] ; however, this has been disputed since the advent of MRI, which has provided evidence of greater cerebellum involvement. The opticospinal variety of MS too has been reported more commonly in Indian patients. [7,11] Most experts agree that the Indian-Asian patient with MS behaves a litt le diff erently from the Caucasian patient. Do these diff erences aff ect the response to β-interferon? This small case series att empted to answer this question. There are no documented case series of the use of β-interferons in MS in Indian patients.

Follow-up MRI
This study has shown that aft er starting β-interferon all patients who could tolerate the drug had a signifi cant reduction in the relapse rate. Most patients had no relapse at all during followup for a mean period of 2.25 years. There was no progression of clinical fi ndings, as documented by a stable EDSS score, and no fresh lesions on MRI. The patient with SPMS too showed no clinical or radiological progression.
Overall, the drug was well tolerated. Most patients had minor Gupta, et al.: Interferons in Indian patients with multiple sclerosis of schizophrenia in remission and off all drugs. Seven years aft er discontinuing all drugs for schizophrenia, she had developed RRMS, with some residual defi cit aft er each relapse. She was started on IFN β1a (Avonex ® ). Two months aft er starting the drug she had a relapse of the schizophrenic symptoms, with suicidal tendencies, and the drug had to be stopped. She was then started on glatiramer acetate; she has been taking this drug for the last 2 years and is relapse free. The second patient developed features of depression and suicidal ideas within 2 weeks of starting the β-interferon, and the drug had to be discontinued.
The other adverse events that occurred after initiating interferons are shown in Table 2. All patients developed fever aft er the fi rst dose but, 3 months aft er the start of the injections, only 50% continued to have fever aft er each dose. The fever responded to a single dose of paracetamol in all cases. No patient had fever lasting for more than 24 h, the mean duration of the fever being 9 h. Myalgia and body aches occurred in nearly three-fourth of our patients aft er each injection.
Headache was the other symptom reported. None of our patients reported injection site pain, skin changes, or necrosis.

Discussion
Previous studies have brought out certain diff erences in the  side eff ects, as mentioned earlier. [17,18] β-Interferons should be avoided in patients with a history of major psychiatric symptoms.
Nearly 85% of our patients also had oligoclonal bands in the CSF. This fi gure is similar to those reported from the West in large series [19] as well as in some Indian series. [20] However, other series from India have reported lower fi gures, [9] implying a genetic basis. The high fi gure in our study could be due to the fact that all our patients had clinically active disease with a high relapse rate and a high lesion load on MRI.
Our study has shown that Indian patients with MS respond well to β-interferons. This is despite the view that Indian-Asian patients with MS have a slightly diff erent clinical profi le. Indian patients also tolerate the drug well. This study has implications for the management of Indian patients with MS and is the only study to date that has demonstrated the benefi ts of β-interferons in this population.