Online ISSN : 1687-8329

    




Quick Search 
 
Author  
Year    
Title  
Vol:  

 
 
January2008 Vol.45 Issue:      1 Table of Contents
Full Text
PDF


The Impact of IFNβ-1a and IFNβ-1b on The Clinical and MRI Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Hassan Salama1, 2, Ahmed Azab2, M. Hazem2, Mabroka Ali1, Ali Sakal1, Fouad Hemada1
Departments of Neurology, Sebea Hospital, Tripoli, Libya1; Neurology, Mansoura University, Egypt2

ABSTRACT

Multiple Sclerosis (MS) is a common demyelinating and inflammatory disease of the CNS with a presumed autoimmune etiology. IFNβ-1a and IFNβ-1b have a proven treatment effect on RRMS presumably through its regulatory properties on T-cell activation and cytokines production. Here we studied the clinical and MRI effects of these drugs in four groups of clinically and laboratory (Cerebrospinal fluid evaluation revealed elevation of immunoglobulin (IgG) synthesis rate and oligoclonal bands) definite RRMS patients for 18 months. In IFNβ-1a group (n=25), the patients used IFNβ-1a 30µg (6MU) intramuscular once a week, the other three groups of IFNβ-1a (n=25) 22 µg (6MU), IFNβ-1a 44µg (n=25) and IFNβ-1b 8MU (0.25 mg) (n=25) were injected subcutaneously 3-time a week. In comparison with the pre-treatment values, reduction in the relapse rate was statistically significant in IFNβ-1a 44 µg, IFNβ-1a 30µg and IFNβ-1b 8MU groups more than IFNβ-1a 22 µg (P<0.001, 0.008, 0.001 and >0.5 respectively), and the mean EDSS significantly reduced in the IFNβ-1b (P<0.001), IFNβ-1a intramuscular (P<0.02) and 44ug IFNβ-1a (P<0.001), in contrast to 22ug IFNβ-1a treated patients (P>0.5). Moreover, IFNβ-1b (P<0.001) and 44ug IFNβ-1a (P<0.003) groups showed highly statistical significant reduction in MRI disease activity load (p<0.05) in comparison with 22ug IFNβ-1a (p<0.5) and IFNβ-1a intramuscular groups (p<0.07). The study confirmed also the effect of beta-IFNs on the short term physical disability scale (p<0.01) while they have no significant effect on long term disability scale (p>0.64). Additionally, beta-IFNs groups showed no statistically significant severe drugs adverse effects (p> 0.8) while revealed significant effects of recovered side effects (p<0.01). The common adverse effects of IFNβ that were significantly found (p<0.01), are flu-like symptoms, fatigue, chills and fever, injection site pain and local redness, headache, irregular menses and mild depression specially with IFNβ-1a intramuscular. No difference in the clinical suspicions of binding antibodies development to beta-IFNs was found. On the whole, all groups showed significant reduction of relapse frequency and MRI load with different values (p<0.01). In summary, this study does make available meaningful and helpful clinical and radiological data to the clinician regarding the relative efficacy of each therapy in RRMS. First, the results of our study suggest that IFNβ-1b 8MU and IFNβ-1a 44µg may be more optimal choices than IFNβ-1a 30µg intramuscular and IFNβ-1a 22µg at the currently available dose in treatment of RRMS patients. Secondly, the results do not differ from remarks made after 18 months of treatment in larger and more rigorously controlled studies. Thirdly, therapy does construct a difference and early treatment should be encouraged.

(Egypt J. Neurol. Psychiat. Neurosurg., 2008, 45(1): 57-63)

 




INTRODUCTION

 

Multiple sclerosis (MS) is a common demyelinating and inflammatory disease of the central nervous system (CNS) in young population with a presumed autoimmune etiology1. Despite the pathology of MS is located in CNS, the inflammatory/autoimmune processes are not entirely confined to the CNS but associated with T-cell activation and production of proinflammatory cytokines [e.g., tumor necrosis factor alpha (TNFa) and interleukin (IL)-12], adhesion molecules [e.g., intracellular adhesion molecule-1 (ICAM-1)], and soluble T-cell activation markers (e.g., IL-2 receptors), which reflect systemic immune abnormality2,3.

IFN-β drugs are found to correlate with clinical improvement in MS patients and may be of value in our attempt to control or adapting the disease processes and MS disability. This study was undertaken to evaluate whether different types of IFN-β drugs, IFNβ-1a and IFNβ-1b, may involve modulation of the autoimmune pathogenic processes of MS, immunomodulatory effects and clinical outcomes in MS patients4,5.

 

PATIENTS AND METHODS

 

This collaborative study between Sebea Hospital and neurology department in Mansoura University was done and integrated hundred clinically definite MS patients with a relapsing/remitting disease pattern. All patients were submitted to CSF examination for OCB, IgG index and evoked potentials including visual and auditory evaluations. The clinical characteristics of the patients are shown in Table (1). These patients were not treated with any immunomodulatory or immunosuppressive drugs at least three months prior to the study.

The first group, 25 patients (18F/7M) were assigned to receive beta-IFN-1a (AVONEX) at 30mcg (6 million units) i.m. a week, their ages were between 24 and 59 years old (39.5±7), their mean and SD of pretreatment ambulatory Kurtzke Expanded Disability Status Scale (EDSS) scores were 3.5±1.2 and MS duration was 7.9±5.4 years.

The second group, 25 patients started beta-IFN-1a (REBIF) at 22 mcg s.c. every other day, their ages were  between  20 and 54  years old (33.5±8), 19F/6M, their ambulatory with Kurtzke Expanded Disability Status Scale (EDSS) scores were 4.3±1.1 and MS duration was 9.1±4.4.

The third group had been on beta-IFN-1a (REBIF), 44 mcg s.c. every other day. Their ages were between 18 and 61 years (37.4±6), 19F/6M, mean EDSS and SD was 3.4±1.5 and MS duration was 8.1±6.4.

The fourth group, 25 patients (20F/5M) were assigned to receive beta-IFN-1b (BETAFERON) at 250mcg s.c. (8 million International unit) every other day, their ages were between 18 and 58 years (38.6±7), their pretreatment ambulatory with Kurtzke Expanded Disability Status Scale (EDSS) scores were 3.8±1.6 and MS duration was 8.5±5.4.

All patients were submitted to complete clinical evaluation every three months and documented EDSS for each patient at each visit.

All patients had an initial MRI of the brain consistent with MS, while the second and third MRI was done for all after a year and at 18 months of the therapies. Patients with significant medical or psychiatric illness; patients who had pacemakers, aneurysm clips, other metal implants, or shrapnel fragments present and patients with claustrophobia were excluded.

In this study, the drugs drawbacks were recorded and documented for each patient. EDSS and relapse or exacerbations symptoms were meticulously brought together in a six points follow up plan, before the initiation of the treatments (first point) and three, six, nine, 12 and 18 months after the treatments. Patients in relapse were not excluded from the assays throughout the study. The study was approved by the Institutional Human Subjects Study.

Measurements of MRI-assessed disease activity, pretreatment and at 12 and 18 months posttreatment, were done with Images obtained by applying a T1-weighted sequence after administration of an intravenous bolus of 10 mL of 0.5-mol/L gadolinium–diethyl-triaminepentaacetic acid (Gd-DTPA) (Magnevist, Berlex Laboratories, Wayne, NJ).

A Student’s t-test for normally distributed variables and the Mann-Whitney rank-sum test for non-normally distributed variables were used for data analysis. A p value of < 0.05 was considered statistically significant.

 

RESULTS AND DISCUSSION

 

Demographic distribution of all groups is cross- matched as much as possible about to insignificant differences for evaluation of IFN-β efficacy among patients. Even though, there were irrelevant discrepancies in sex, pretreatment EDSS and MS duration among all patients’ groups (Table 1)6. The common signs & symptoms and evoked potentials results of all patients are comparable with the frequent manifestations of RRMS (Tables 2 and 3)7,8,9.

The study revealed that treatment with beta-IFN significantly reduced the total EDSS over 18 months of 6 points follow up scales. they did not make any significant differences in early 3 points follow up, nevertheless in last 3 points IFNβ-1b 44µg, Beta-IFN-1a 30µg and Beta-IFN-1b 0.25mg showed significant reduction of EDSS as well as increased the time to first relapse, hospitalizations, severity of relapses and disease activity assessed by magnetic resonance imaging (MRI) in respect of Beta-IFN-1a 22µg (Figs. 1 & 2 and Table 4)10,11.

The observed difference in EDSS and relapse rate could be explained by the frequency and dose-related approach of beta-IFNs12.

In all MS groups, they showed statistical difference in reduction of disability in relation to baseline. Interferon-beta is generally well tolerated and the common side effects are Flu-like syndrome, fever, injection site reactions, headache, Myalgia, Fatigue symptoms complex that were clinically controllable. On-alternate-day interferon beta-1b 250 µg is more effective than interferon beta-1a given once a week13,14.

Generally speaking, statistically analysis showed that the reduction in relapse rate was statistically significant in IFNβ-1a 44 µg, IFNβ-1a 30µg and IFNβ-1b 8MU groups more than IFNβ-1a 22 µg (P<0.04, 0.05, 0.01 and >0.61 respectively). The mean EDSS was significantly reduced in the IFNβ-1b (P<0.01), IFNβ-1a IM (P<0.05) and 44ug IFNβ-1a (P<0.03) groups, in contrast to 22ug IFNβ-1a treated patients (P>0.5)10,12.

The study confirmed also the effect of beta-IFNs on the short term physical disability scale (p<0.01) while they have no significant effect on long term scale (p>0.64)10.

Moreover, IFNβ-1b (P<0.01) and 44ug IFNβ-1a (P<0.05) groups showed highly statistical significant reduction in MRI disease activity load (p<0.01) in comparison with IFNβ-1a 22ug (p<0.05) and IFNβ-1a intramuscular groups (p<0.01)15,16.

Additionally, beta-IFN groups showed no significant statistically difference in severe adverse effects (p> 0.5) while transitory side effects revealed significant data (p<0.01). The common adverse effects of IFNβ that had been significantly found (p<0.01), were flu-like symptoms such as fatigue, chills and fever, injection site pain and local redness, headache, irregular menses and mild depression specially with IFNβ-1a intramuscular17,18.

The clinical suspicions of binding antibodies development to beta-IFNs were not found over the whole study period. On the whole, all groups showed significant reduction of relapse frequency and disease activity assessed by magnetic resonance imaging (MRI) (p<0.01). This could be due to the relative effects of the treatment on the serum levels of certain cytokines and immune regulatory effects on MS inflammatory processes. Further experiments revealed the same occurrence to beta-IFN in all treatment groups15,17,19.

It has been proposed that the regulatory effects of beta-IFN may be attributable to inhibition of inflammatory responses of predominantly T-cell populations. More importantly, the beta-IFN appears to produce multiple effects on the immune system. No significant long term drugs side effects were associated with beta-IFN therapy20.


 

Table 1. Demographic data and clinical characteristics of MS patients.

 

 

Group

n

Treatment

Age

Sex

MS duration (year)

Pre-EDSS

Post-EDSS

p value

1

25

Beta-IFN-1a 30µg IM

39.5±7

18F/7M

7.9±5.4

2.92±0.25

2.13±0.33

0.02

2

25

Beta-IFN-1a 22µg SC

33.5±8

19F/6M

9.1±4.4

3.21±0.13

2.51±0.27

0.12

3

25

Beta-IFN-1a 44µg SC

37.4±6

19F/6M

8.1±6.4

3. 24±0.54

2.17±/0.4

0.002

4

25

Beta-IFN-1b 0.25mg SC

38.6±7

20F/5M

8.5±5.4

3. 36±0.83

2.31±/0.37

0.001

RR, relapsing-remitting MS; EDSS, Expanded Disability Scale Score; Pre-EDSS, baseline EDSS; Post-EDSS, EDSS at 18 months after treatment

Table 2. Common Signs and Symptoms among MS patients’ groups.

 


 

IFNβ-1a 30mcg group (n=25)

IFNβ-1a 22mcg group (n=25)

IFNβ-1a 44mcg group (n=25)

IFNβ-1b 250mcg group (n=25)

Main

S & S %

Associated S & S %

Main

S & S %

Associated S & S %

Main

S & S %

Associated S & S %

Main

S & S %

Associated S & S %

Motor

24

20

36

24

32

28

20

32

Sensory

56

28

60

16

44

36

48

44

Optic

48

16

52

24

48

20

60

20

Cerebellar

24

16

8

36

20

32

16

36

Brainstem

20

40

12

8

8

24

8

28

Fatigue

44

32

20

40

12

28

20

32

Autonomic

8

24

8

20

4

28

8

20

Cognative & Nonspecific

16

28

8

16

4

24

8

16

S & S = presenting signs and symptoms,  p value = 0.18

 

 

Table 3. Positive Evoked potentials among MS patients.

 

 

VEPs

n (%) of positive cases

BAEPs

n (%) of positive cases

IFNβ-1a 30mcg group (n=25)

21 (84)

18 (72)

IFNβ-1a 22mcg group (n=25)

20(80)

17 (68)

IFNβ-1a 44mcg group (n=25)

22 (88)

15 (60)

IFNβ-1b 250mcg group (n=25)

19 (76)

14 (56)

 

 

Table 4. Pre- and 18-month post-treatment MRI disease activity among MS patients.

 

 

Nonenhanced lesions (mean±SD)

Enhanced lesions (mean±SD)

Total lesion load (mean±SD)

p value (f value) intragroup

Pre-treatment

Post-treatment

Pre-treatment

Post-treatment

Pre-treatment

Post-treatment

Non-enhanced

Enhanced

Total

IFNβ-1a 30mcg group (n=25)

Lesion Load

8.4±4.2

7.1±3.2

1.1±1.2

0.6±0.5

9.4±5.5

7.7±4.6

0.26 (1.26)

0.02 (15.3)

<0.05

(3.95)

IFNβ-1a 22mcg group (n=25)

Lesion Load

11.2±4.8

9.7±4.1

1.7±1.1

0.8±1.3

12.9±5.6

10.5±4.9

0.1(2.66)

0.04 (8.65)

<0.05

(5.95)

IFNβ-1a 44mcg (n=25)

Lesion Load

12.9± 5.3

10.9±5.8

2.3±1.8

1.1±0.56

15.02±5.4

12.02±5.8

0.31(1.01)

0.01

(55.69)

<0.05

(8.91)

IFNβ-1b 250mcg (n=25)

Lesion Load

11.9± 4.2

10.1±4.8

2.5±1.6

1.0±0.75

14.4±5.4

11.12±4.8

0.32(1.01)

0.001

(55.69)

<0.05 (8.91)

Lesion Load

p valu

<0.05

<0.05

<0.05

<0.05

<0.05

<0.007

 

f value

6.11

4.48

2.6

2.96

6.77

4.94

 

 

 

Fig. (1): The efficacy of beta-IFN on EDSS

 

Fig. (2): The positive effects of immunomodulator drugs over 18 months on relapsing rate (p value=0.001).

Table 5. Short-term adverse effects of immuno-modulator drugs.

 

 

IFNβ-1a 30mcg  (n=25)

IFNβ-1a 22mcg (n=25)

IFNβ-1a 44mcg (n=25)

IFNβ-1b 250mcg (n=25)

Flu-like syndrome

16 (64%)

15 (60%)

17 (68%)

15 (60%)

Fever

13 (52%)

9 (36%)

10 (40%)

8 (32%)

Headache

10 (40%)

7 (28%)

8 (32%)

9 (32%)

Injection site reaction

8 (32%)

10 (40%)

11 (44%)

10 (40%)

Myalgia

6 (24%)

6 (24%)

5 (20%)

6 (24%)

Fatigue

13 (52%)

12 (48%)

13 (52%)

10 (40%)

Spasticity

2 (8%)

3 (12%)

3 (12%)

2 (8%)

Depression

2 (8%)

1 (4%)

0

0

Altered Thyroid function

0

0

0

0

Leucopenia

1 (4%)

1 (4%)

2 (8%)

1 (4%)

Increased Liver enzymes

2 (8%)

1 (4%)

1 (4%)

1 (4%)

X2

151.7

86.6

96.6

92.9

p value

<0.008

<0.005

<0.024

< 0.01

 

 


REEFRENCES

 

1.      PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998; 352: 1498-504.

2.      Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383:787-793.

3.      Allegretta M, Nicklas JA, Sriram S, Albertini RJ, Abramsky O. T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 1990; 247:718.

4.      Arnason BG, Dayal A, Qu ZX, Jensen MA, Genc K, Reder AT. Mechanisms of action of interferon-beta in multiple sclerosis. Springer Semin Immunopathol 1996; 18(1):125-48.

5.      Yong VW, Chabot S, Stuve O, Williams G. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology 1998;51:682–9.

6.      Compston DAS. Risk factors for multiple sclerosis: Race or place [editorial]. J Neurol Neurosurg Psychiatry 1991; 54:821-823 (b).

7.      Beer S, Rösler KM, Hess CW. Diagnostic value of paraclinical tests in multiple sclerosis: relative sensitivities and specificities for reclassification according to the Poser committee criteria. J Neurol Neurosurg Psychiatry 1995; 59:152-159.

8.      Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review). Report of the Quality Standards Sub-committee of the American Academy of Neurology. Neurology 2000; 54:1720–5.

9.      Comi G, Leocani L, Medaglini S, et al. Measuring evoked responses in multiple sclerosis. Multiple Sclerosis 1999; 5:263-267.

10.    PRISMS Study Group. Long-term efficacy of interferon beta-1a in relapsing MS. Neurology 2001; 56:1628–36.

11.    Clanet M, et al, for the European IFNbeta-1a Dose Comparison Study Investigators. Interferon β-1a in relapsing multiple sclerosis: four-year extension of the European IFNβ-1a Dose-Comparison Study. Mult Scler 2004; 10:139–44.

12.    Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl JMed 2000; 343:1430–8.

13.    Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, Montanari E, Zaffaroni M. Independent Comparison of Interferon (INCOMIN) Trial Study Group.Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicenter study (INCOMIN). Lancet 2002; 359(9316):1453-60.

14.    Berlex Laboratories. Summary basis for approval. FDA official document for license of interferon beta-1b (Betaseron). Richmond, CA:Berlex Laboratories 1993.

15.    Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AI, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002; 346: 158-64.

16.    Filippi M. Enhanced magnetic resonance imaging in multiple sclerosis. Mult Scler 2000; 6(5):320-6.

17.    Durelli L, et al, for the Independent Comparison of Interferon (INCOMIN) Trial Study Group. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicentre study (INCOMIN). Lancet 2002; 359:1453–60.

18.    Haas J, Firzlaff M. Twenty-four-month comparison of immunomodulatory treatments-a retrospective open label study in 308 RRMS patients treated with beta interferons or glatiramer acetate (Copaxone). Eur J Neurol 2006; 12: 425-31.

19.    Giovannoni G, Goodman A. Neutralizing anti-IFN-beta antibodies: how much more evidence do we need to use them in practice? Neurology 2005; 65:6–8.

20.    Dhib-Jalbut S. Mechanisms of interferon beta action in multiple sclerosis. Mult Scler 1997; 3: 397-401.

الملخــص العربـــى

 

التأثير الإكلينيكي والاستجابة بالرنين المغناطيس لعقار البيتافيرون (أ) و(ب)

في مرض  التصلبات المتناثرة بالجهاز العصبي المركزي

 

يعتبر مرض التصلبات المتناثرة أكثر الأمراض المناعية شيوعا بالجهاز العصبي المركزي ويؤدي إلى العجز في سن مبكرة. إن السبب الحقيقي وراء هذا المرض غير معروف يقينا ولكن يعزي  إلي الأمراض المناعية ولذلك تم تجربة أدوية المناعية ومنها دواء البيتافيرون-1 (أ) و 1 (ب) و كلها تعمل من خلال التأثير على الخلايا المناعية (T-cell) و السيتوكين (Cytokines).

إن البيتافيرون بجميع أشكاله التجارية قد أدي إلي نتائج إكلينيكية جيدة ذات قيمة إحصائية وكانت هناك علاقة مهمة بين النتائج والجرعة وعدد مرات الحقن لهذه الأدوية. كما أن البيتافيرون اظهر نتائج ذات قيمة إحصائية من حيث التأثير على شكل الرنين المغناطيسي ونشاط التصلبات المتناثرة بالجهاز العصبي المركزي.

وقد قمنا بدراسة هذه العقاقير على أربع مجموعات من المرضي كل مجموعة بها خمسة و عشرون مريضا وقد راعينا أن تكون المتغيرات بين هذه المجموعات متقاربة من حيث السن – النوع – تاريخ المرض – المقياس الإكلينيكي لنسبة العجز الحركي (EDSS) بحيث تقل تأثير هذه العوامل إحصائيا على النتائج الفعلية لعقار البيتافيرون.

وقد لوحظ تراجع نسبة النكسات للمرض خلال فترة البحث التي امتدت إلى ثماني عشر شهرا و تم متابعة المرضي كل ثلاثة شهور علي مقياس EDSS وقد وجد أن اقل العقاقير تأثيرا على هذا المقياس عقار البيتافيرون-1 (أ) وبجرعة 22 ميكروجرام مقارنة بباقي الجرعات. وأيضا وجد أن المرضي أظهروا تحسنا بالنسبة إلي مقياس EDSS على مدي ثماني عشر شهرا ذات قيمة إحصائية عالية وخصوصا مع عقار بيتا فيرون بجرعة 44 ميكروجرام و250 ميكروجرام. ولم يكن الدواء ذات تأثير ملحوظ  علي درجة العجز علي المدى الطويل.

رجوعا للآثار الجانبية للدواء وجد أن له  مضاعفات عابرة ذات قيمة إحصائية عالية مثل الصداع - أعراض شبيهه بالأنفلونزا – ارتفاع درجة حرارة الجسم- الإرهاق – الألم واحمرار مكان الحقن – الاكتئاب – وعدم انتظام الدورة الشهرية عند النساء. ويبدو أن هذه الأعراض كانت عابرة وتمت معالجاتها ولم يصب مريض واحد بأعراض شديدة تم علي أثرها إيقاف الدواء.

من كل هذا يجب أن يوجه النظر إلي أن هذا البحث يعول علية بالاختيار المبكر لعقار البيتافيرون في علاج مرض التصلبات المتناثرة ويجب مراعاة زيادة الجرعة وعدد مرات الحقن التي تعطي نتائج أكثر إرضاء للمريض كما أظهرت النتائج التي تتفق في كثير منها مع الأبحاث المنشورة بهذا المجال.

 



2008 � Copyright The Egyptian Journal of Neurology,
Psychiatry and Neurosurgery. All rights reserved.

Powered By DOT IT