TITLE: Evaluating the Role of Corticosteroid Pulse Therapy in Patients With Secondary Progressive Multiple Sclerosis Receiving Mitoxantrone: A Double Blind Randomized Controlled Clinical Trial

  ABSTRACT.BACKGROUND:
Multiple sclerosis (MS) is a central nervous system disorder with periods of recurrence and recovery. Mitoxantrone has been approved for secondary progressive MS (SPMS) treatment but data lacks the role of corticosteroid pulse therapy in SPMS.

ABSTRACT.OBJECTIVES:
To evaluate the role of corticosteroid pulse therapy in patients with SPMS receiving mitoxantrone.

ABSTRACT.PATIENTS AND METHODS:
A double blind randomized controlled clinical trial was performed on 71 patients with SPMS referred to Shahid Sadoughi Hospital (Yazd, Iran) for receiving mitoxantrone in two groups. The first group (35 patients) received 20 mg mitoxantrone plus 500 mg methylprednisolone monthly for six months. The second group (36 patients) received the same dosage of mitoxantrone plus 100 CC of 5% dextrose water monthly for six months. Expanded disability status scale (EDSS), MRI plaques in both groups before and after the treatment completion and six months after the end of trial were compared together.

ABSTRACT.RESULTS:
28 men and 43 women enrolled in the study. MRI plaques number reduced in groups significantly (2.29 vs. 2.17) without significant difference between the groups (P = 0.782). Six months after trial completion, plaques number increased in groups without significantly difference (0.72 vs. 0.77, P = 0.611). The mean value of EDSS showed significant reduction at the end of treatment in groups (0.79 and 0.53) without significant difference between the groups (P = 0.953). Six months after trial completion, EDSS increased in groups without significant difference (0.35 vs. 0.43, P = 0.624).

ABSTRACT.CONCLUSIONS:
Corticosteroid pulse therapy in SPMS was effective in inflammatory process, but could not postpone or decline the neurodegenerative process and besides the imposing side effects could not result in significant improvement in EDSS and MRI plaques number in long term.

BODY.1. BACKGROUND:
Multiple sclerosis (MS) is a central nervous system disorder recognized by frequent attacks to optic nerve, spinal cord and brain with periods of recurrence and recovery which could result in disability mainly in youth (1). Clinical features are hemiparesis or paraparesis, paresthesia, blurred vision, diplopia, nistagmus, dysarthria, imbalance, deep sensation disturbance and bladder dysfunction (2). MS is divided into four types:  Relapse and remitting (RR): periods of relapse with complete recovery or some sequels.Primary progressive (PP): progression from the beginning with phases of Plato or mild improvement.Secondary progressive (SP): relapsing and remitting from the beginning and then progression.Progressive relapsing (PR): progression from the beginning with acute relapses without significant improvement (3).  Most patients with a relapsing-remitting course finally enter a chronic progressive condition (SPMS) with accumulating disability. Progression would continue with or without relapses with minor remissions between relapses (4). Sometimes it progresses constantly from the beginning (PPMS), usually occurs in cases with MS after the fourth decade. In progressive relapsing MS, the disease progresses from onset, with clear acute relapses and with or without full recovery (2). On the other hand, personal activities and social partnership of the individual are affected by disease (5). During the long period, inflammatory infiltrations decline (6), while neurodegenerative processes become a more prominent feature (7). Recent investigations revealed that inflammatory process in the brain occurs in RRMS and presents in the progressive course. Furthermore, in SPMS, inflammatory process in the meninges could be found. Interestingly, the extent of inflammatory process in the meninges correlates with the amount of neurodegeneration. Therefore, inflammatory process appears to drive tissue degeneration in some patients (8). In summary, the inflammatory process is less important during the course of SPMS, while neurodegeneration is the substrate that drives the accumulating neurological disability (9). Based on the role of inflammatory and neurodegenerative processes in pathophysiology of SPMS, many drugs have been tested to treat these processes. Box 1 shows approved, not approved but common use and under examination drugs for SPMS therapy (9).   Box 1.  Therapies for Secondary Progressive Multiple Sclerosis (SPMS) Approved Interferon Beta 1b Interferon Beta 1a Mitoxantrone 
 Not approved but common 
 Intravenous Immunoglobulin Corticosteroids Azathioprine Cyclophosphamide Mycophenolate 
 Under examination 
 Daclizumab Rituximab Hematopoietic stem cell transplantation Masitinib Fingolimod   Mitoxantrone (drug for breast cancer chemotherapy) has been approved for SPMS treatment since 2002 (10). Mild adverse effects are transient leukopenia, liver enzymes elevation, nausea, vomiting, transient alopecia, urine color change and urinary tract infection (11). Moreover, mitoxantrone has serious but uncommon adverse effects such as bone marrow suppression, acute leukemia, infertility (12) and cardio toxicity with cumulative dose of 140 mg/m2 (13). It could be prescribed 5 - 12 mg/m2 intravenously monthly or every three months (14). The probable effects of mitoxantrone are relapse reduction, expanded disability status scale (EDSS) improvement and slowing the disability progression (15). On the other hand, methylprednisolone has been used for progressive MS. Standard therapy for acute relapse of MS is pulse therapy with high dose of methylprednisolone 500 - 1000 mg/daily for 3 to 5 days (16). New evidences show that severity of clinical signs and symptoms reduce by this protocol (17). As treatment protocols in SPMS are still limited, corticosteroids are used in SPMS. Although its efficacy in SPMS is not proven, the role of corticosteroids in treatment of progressive MS is still obscured. Different studies showed that corticosteroids may improve inflammation, but at later stages degeneration can hardly be influenced (17-20). First dose of intravenous methylprednisolone is usually administered in hospital for safety reasons. Potentially severe adverse effects are epileptic seizures, psychotic reactions, cognitive decline, venous thrombosis, anaphylactic reactions and cardiac arrhythmias (21-25). Furthermore, one study suggested that co-administration of mitoxantrone and methylprednisolone may reduce the progression of disability in patients with PP-MS and SP-MS (26).

BODY.2. OBJECTIVES:
The purpose of the present study was to evaluate the role corticosteroid pulse therapy in patients with SPMS referred to Shahid Sadoughi Hospital (Yazd, Iran) for receiving mitoxantrone.

BODY.3. PATIENTS AND METHODS:
Our study was a double blind randomized clinical trial performed in Shahid Sadoughi Hospital (Referral, Specialized, Governmental, 576 beds and 22 sections) of Yazd, Iran on 82 patients (aged 20 to 50 years) with SPMS referred for receiving mitoxantrone [(trial code: IRCT201107145943N3), IRCT: Iran registry of clinical trials]. The sample size formula was:  (1).x =(z1
-α2+z1
- β)2×2S2d2  (S = 4 and d = 2.5).  The expected power was 80%. Normal assumption and repeated measurement assumption were checked precisely. Simple randomized sampling procedure was performed based on the study criteria using the "Random Allocation Software" program (Figure 1). Eleven patients withdrew the trial due to refractory vomiting (4 patients), urinary tract or gastrointestinal infection (3 patients) and unreliability to the treatment results (4 patients). Inclusion criteria were any patient with SPMS between 20 - 50 years old, progressive deterioration period of at least 6 months and less than 4 years, EDSS between 4.0 and 7. Exclusion criteria were immune deficiency, cancer, pregnancy, breast feeding, renal or heart failure, diabetes mellitus and tuberculosis. Patients with leukopenia during the injection (neutrophils less than 1500/mL) and those who had received corticosteroids within 6 months before the trial were excluded from the trial. Finally, 71 patients enrolled in the study and randomly assigned into two groups. The first group (35 patients) received 20 mg mitoxantrone plus 500 mg methylprednisolone intravenously and the other group (36 patients) received the same dose of mitoxantrone and 100 CC of 5% dextrose water monthly for consecutive six months. All patients were evaluated by neurological exam, especially expanded disability status scale (EDSS), MRI of the brain and spinal cord (1.5 Tesla, without contrast, T2 phase), cell blood count, hepatic tests and echocardiography before the treatment establishment. At the end of drug administration completion (sixth month), they were evaluated again by EDSS, MRI, blood cell count, hepatic tests and echocardiography. At the twelfth month they were evaluated repeatedly by EDSS and MRI plaque number. The patients, nurses administering the drugs and those registering the signs and symptoms of the patients were blinded to the study design. Neurologic examinations before and after the treatment were performed by one neurologist who was unaware of the treatment methods. Furthermore, by MRI study (1.5 Tesla, without contrast), the number of plaques in the brain and spinal cord were measured by a radiologist unaware of the type of treatments. At the sixth month, the above mentioned checkups were performed (by the same neurologist) and the number of plaques were measured (by the same radiologist) and compared to those before the trial establishment. Six months after the study completion, EDSS and MRI plaques were measured again. An informed consent was obtained from all patients. The ethics committee of Yazd University of Medical Sciences approved the study. Finally, gathered data was analyzed using statistical tests of t-test, chi-square, paired sample t-test and repeated measure ANOVA by SPSS version 11.5 software.  Figure 1.CONSORT Flow Diagram

BODY.4. RESULTS:
Of 71 patients who completed the study, 28 patients were males (39.4%) and 43 females (60.6%). Age, sex and disease duration were not different significantly between the groups (P > 0.05). Demographic features are shown in Table 1. The main index evaluated in this study was the number of plaques in MRI of patients in the both groups before and after the treatment (sixth month and twelfth month). The mean number of MRI plaques showed significant reduction in the both groups after the treatment (P value < 0.05), but difference between the groups was not significant (P value = 0.782). Although the number of plaques increased in the both groups during 6 months after trial completion, the difference was not significant between the groups (P value = 0.611) (Table 2). EDSS reduced significantly in the both groups at the end of treatment completion (P value < 0.05), but the difference between the groups was not significant (P value = 0.953). During six months after treatment completion, EDSS increased in the both groups, but the difference was not significant (P value = 0.624) (Table 3).   Table 1.  Demographic Features of the Groups Variations Groups P Value Mitoxantrone + MP Mitoxantrone 
 Age  
 a 
 36.5 ± 9.2 35.7 ± 10.6 0.735 
 Male/Female 
 3/4 4/5 1 
 Disease duration, mo  
 a 
 69.1 ± 45.6 74.8 ± 42.2 0.587 a Values are presented as mean± SD.   Table 2.  Comparing MRI Plaques Between the Groups a , b Groups MRI Plaques Number  c Before the Treatment End of the Treatment 6 Months After Treatment Completion 
 Mitoxantrone + MP 
 10.6 ± 4.37 8.31 ± 4.06 9.03 ± 3.56 
 Mitoxantrone 
 10.8 ± 4.56 8.63 ± 3.95 9.4 ± 4.33 a P value between before and the end of treatment was 0.782. b P value between before the treatment and six months after the treatment completion was 0.611. c values are presented as mean ± SD.   Table 3.  EDSS of Groups During the Study a , b Groups EDSS  c Before the Treatment End of the Treatment 6 Months After the Treatment Completion 
 Mitoxantrone + MP 
 5.40 ± 1.46 4.61 ± 1.87 4.96 ± 1.63 
 Mitoxantrone 
 5.17 ± 2.10 4.64 ± 2.16 5.07 ± 1.92 a P value comparing EDSS changes before the treatment and end of the treatment between the groups was 0.953. b P value comparing EDSS changes before the treatment and end of the treatment between the groups was 0.624. c values are presented as mean ± SD. 

BODY.5. DISCUSSION:
In our trial, age, sex and duration of disease were not different statistically between the groups (P > 0.05). Today, the use of MRI makes it easier to evaluate patients with MS, in a way that it is possible to assess the activity of disease without clinical symptoms; furthermore, it can be used as a measurement criterion (27, 28). However due to limited facilities of our trial, the use of gadolinium contrast and obtaining MRI serially were not possible. Previous studies showed that mitoxantrone decreased the number of plaques in secondary progressive MS from 52% to 89% compared to placebo or methylprednisolone (15, 29-31). Our study showed that MS plaques decreased in both groups significantly (P < 0.05), but there was no difference between the groups (P > 0.05), so adding methylprednisolone to mitoxantrone had no significant influence on the number of plaques reduction. The number of plaques increased in both groups during six months after trial completion, but the difference between groups was not significant. It means that adding methylprednisolone to mitoxantrone had no influence on MRI plaques significantly. Numerous studies implicated the efficacy of mitoxantrone on declining EDSS or slowing disability progression (15, 30, 32). Also studies comparing the efficacy of mitoxantrone plus methylprednisolone to methylprednisolone alone (29) or mitoxantrone compared to methylprednisolone (33) show advantage of mitoxantrone use in reducing disability of secondary progressive MS.  Our study showed that the mean EDSS in the group treated with mitoxantrone decreased from 5.17 to 4.64 after the treatment and in the group treated with mitoxantrone and methylprednisolone, this decrement was from 5.4 to 4.6. Both these decrements were significant (P < 0.05), but the difference between the groups was not significant (P > 0.05). EDSS increased in both groups during six months after drug administration completion, but the difference was not significant. Although its efficacy in SPMS is not proven, the importance of glucocorticosteroids in treatment of progressive MS is still undisputed. The results of different trials suggest that glucocorticosteroids may improve inflammation, but at later stages degeneration can hardly be influenced (9). Table 4 shows paradoxes in efficacy of glucocorticosteroids therapy in MS. The strong points of our study were highly cooperative patients, study design and low missing values. The weak points were lack of MRI with contrast (due to high cost) and follow-up duration.   Table 4.  Studies Regarding Corticosteroids Therapy in Multiple Sclerosis Study Type of MS Root of Treatment Result 
 Bergamaschi et al. (1993) ( 18 )  
 PMS 1000 mg IVMP daily for 6 days 1- Delay in progression in progressive MS in 18 patients, whereas a worsening was present in 13 patients. 2- Disability was not affected by repeated IVMP 
 Frequin et al. (1994) ( 19 ) 
 RRMS and RPMS 1000 mg IVMP for 10 days, the application was repeated depending on sustaining deterioration on repeated clinical examinations Reduction in the relapse rate 
 Goodkin et al. (1998) ( 20 ) 
 SPMS 500 mg IVMP bimonthly over 2 years Delay of onset on ongoing disease progression 
 Zivadinov et al. (2001) ( 34 ) 
 RRMS 1000 mg IVMP was given every 4 months for 3 years and then every 6 months for the subsequent 2 years. Slows development of T1 black holes, prevents or delays whole-brain atrophy and disability progression. 
 Pirko et al. (2004) ( 35 ) 
 PPMS or SPMS Pulses of IVMP every month 1- Improvement in fatigue, spasticity and motor strength. 2- Acute exacerbations were occurred in 9 of 10 patients. 
 Zingler et al. (2005) ( 26 ) 
 PPMS and SPMS 10 cycles of combined mitox and MP. The intervals between the individual cycles were systematically prolonged from 3 months initially to 12 months Mitox. combined with MP beneficially reduces the progression of disability in patients with PP-MS and SP-MS. 
 Araujo et al. (2008) ( 36 ) 
 PPMS Periodic use of IVMP (30 mg/kg) Decreased EDSS and postponed clinical worsening 
 Cohen et al. (2009) ( 11 ) 
 RRMS Adding low-dose oral methotrexate(20 mg weekly) or every other month IVMP (1000 mg/day for 3 days) to interferon beta-1a No benefit ( The primary endpoint was new or enlarged T2 lesion number at month 12 vs. baseline) 
 Sorensen et al. (2009) ( 37 ) 
 RRMS Oral MP given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a Reduction in relapse rate 
 Ravnborg et al. (2010) ( 38 ) 
 RRMS Monthly pulses of IVMP in combination with interferon beta-1a No effect on disability progression   This study concluded that there were no significant differences in the clinical and radiologic results and long-term prognosis of patients with SPMS treated with mitoxantrone plus methylprednisolone versus mitoxantrone alone. Corticosteroid pulse therapy in SPMS was effective in inflammatory process, but could not postpone or decline the neurodegenerative process and besides the imposing adverse effects could not result in significant improvement in EDSS and MRI plaques number in long term. More studies should be performed for drawing certain conclusions.

Question: Compared to Mitoxantrone only what was the result of Mitoxantrone + methylprednisolone on Expanded disability status scale?
Evidence: MRI plaques number reduced in groups significantly (2.29 vs. 2.17) without significant difference between the groups (P = 0.782). Six months after trial completion, plaques number increased in groups without significantly difference (0.72 vs. 0.77, P = 0.611)
Answer: no significant difference