Mark Dolev

Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis

Abstract.Acute exacerbations may complicate the course of pregnancy and the postpartum period in patients with relapsing-remitting multiple sclerosis (RRMS). To evaluate relapse rate and the effect of immunomodulatory treatment with intravenous immunoglobulin (IVIg) during pregnancy and the postpartum period we retrospectively analysed the data of 108 pregnant RRMS patients. Group I patients were not treated, Group II patients were treated with IVIg 0.4 g/kg body weight/day for 5 consecutive days within the first week after delivery with additional booster doses of 0.4 g/kg body weight/day at 6 and 12 weeks postpartum (defined as 12 weeks after labor), and Group III patients were treated continuously with IVIg during gestation and the postpartum period (0.4 g/kg body weight/day for 5 consecutive days within the 6–8 weeks of gestation with additional booster doses of 0.4 g/kg body weight/day once every 6 weeks until 12 weeks postpartum). All patients underwent antenatal care and fetal ultrasonographic surveillance examinations. Relapse rate per woman per year during the pregnancy and the postpartum period as well as neonatal outcome data and IVIg related adverse events were analysed.Relapse rate per woman per year for patients treated with IVIg for the whole pregnancy and postpartum period (Group III, N = 28) compared with the untreated Group I patients (N = 39) were as follows: first trimester 0.43 vs. 0.72, second trimester 0.15 vs. 0.61, third trimester 0.0 vs. 0.41, and postpartum period 0.28 vs.1.33 (p < 0.05). Patients treated with IVIg only during the postpartum period (Group II, N = 41) also showed a decrease in relapse rate compared with untreated Group I patients, 0.58 vs. 1.33 (p = 0.012). The mean maternal age, disease duration, gestational age at delivery and fetal delivery weight did not significantly differ between the three groups. Mode of delivery, obstetrical complications, the use of epidural analgesia and breast-feeding, did not affect postpartum relapse rate. No severe adverse events were associated with IVIg treatment either during the pregnancy or postpartum period for the patients and newborns.We conclude that in RRMS patients IVIg treatment could be considered as an optional treatment to reduce the incidence of pregnancy and postpartum-related relapses. Further randomized double-blind studies are needed to confirm our findings.

Modeling of cognitive impairment by disease duration in multiple sclerosis: a cross-sectional study.

Background/Aims Large-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross-sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years. Methods 1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms. Results Cognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p = 0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p = 0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p = 0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years. Conclusions The rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health.

Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study

Context: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. Objective: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. Design, settings, participants: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. Intervention: Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months. Main outcome measure: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. Results: Alfacalcidol decreased the mean relative FIS score as compared with placebo (–41.6% vs. –27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. Conclusion: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.

The Month of Birth and the Incidence of Multiple Sclerosis in the Israeli Population

Background: Recent studies on date of birth of multiple sclerosis (MS) patients showed a spring peak and an autumn nadir. We examined the effect of date of birth in a large group of MS patients and non-MS patients, compared to the general population in Israel. Methods: A retrospective analysis was performed in a large cohort of MS patients and patients with other neurological disorders. The date of birth, gender, and country of birth were identified for each patient. The results were compared to a national database. Results: There were 2,264 MS patients and 1,758 patients with other diagnoses. No significant peak or nadir in the date of birth was identified in either group, both in patients born in Israel or in immigrants. No difference was found compared to the national birth rate. When we controlled for the country of birth, there was no difference. Conclusion: An increased frequency of MS patients born in the months of April and May was considered as a proof of maternal influence. The results of our study show that this finding is not consistent worldwide. The month of birth was not found to be a significant factor in Israeli MS patients.

Methylprednisolone‐induced liver injury: Case report and literature review

Drug-induced liver injury (DILI) is one of the common causes of liver diseases, and is accompanied by high morbidity and mortality. An important but challenging issue in managing this disease is an accurate and early diagnosis. Currently, there have been no specific markers or diagnostic tests for DILI and the diagnosis is performed after excluding other causes for liver diseases. With regard to the treatment, steroids are usually safe as far as hepatotoxicity is concerned; moreover, they are also the treatment of choice for autoimmune hepatitis (AIH). While reported methylprednisolone (MT)induced hepatotoxicity is rare, it may cause severe liver injury that recurs with repeated administrations, leading to a poor outcome. A timely recognition of this complication and early withdrawal of the drug may prevent the progression of hepatic injury. In this we reported a case of high-dose MT-induced acute hepatitis confirmed by liver histology in a patient with multiple sclerosis (MS) together with the relevant literature review.

Suppressed RNA-polymerase 1 pathway is associated with benign multiple sclerosis.

Benign multiple sclerosis (BMS) occurs in about 15% of patients with relapsing-remitting multiple sclerosis (RRMS) that over time do not develop significant neurological disability. The molecular events associated with BMS are not clearly understood. This study sought to underlie the biological mechanisms associated with BMS. Blood samples obtained from a cohort of 31 patients with BMS and 36 patients with RRMS were applied for gene expression microarray analysis using HG-U133A-2 array (Affymetrix). Data were analyzed by Partek and pathway reconstruction was performed by Ingenuity for the most informative genes (MIGs). We identified a differing gene expression signature of 406 MIGs between BMS patients, mean±SE age 44.5±1.5 years, 24 females, 7 males, EDSS 1.9±0.2, disease duration 17.0±1.3 years, and RRMS patients, age 40.3±1.8 years, 24 females, 12 males, EDSS 3.5±0.2, disease duration 10.9±1.4 years. The signature was enriched by genes related RNA polymerase I (POL-1) transcription, general inflammatory response and activation of cell death. The most significant under-expressed pathway operating in BMS was the POL-1 pathway (p = 4.0*10−5) known while suppressed to activate P53 dependent apoptosis and to suppress NFκB induced inflammation. In accordance, of the 30 P53 target genes presented within the BMS signature, 19 had expression direction consistent with P53 activation. The transcripts within the pathway include POL-1 transcription factor 3 (RRN3, p = 4.8*10−5), POL-1 polypeptide D (POLR1D, p = 2.2*10−4), leucine-rich PPR-motif containing protein (LRPPRC p = 2.3*10−5), followed by suppression of the downstream family of ribosomal genes like RPL3, 6,13,22 and RPS6. In accordance POL-1 transcript and release factor PTRF that terminates POL-1 transcription, was over-expressed (p = 4.4*10−3). Verification of POL-1 pathway key genes was confirmed by qRT-PCR, and RRN3 silencing resulted in significant increase in the apoptosis level of PBMC sub-populations in RRMS patients. Our findings demonstrate that suppression of POL-1 pathway induce the low disease activity of BMS.

Polymerase-1 pathway activation in acute multiple sclerosis relapse

BACKGROUND Increased expression of RNA polymerase 1 (POL1) molecular pathway was reported to be associated with increased disease activity in patients with multiple sclerosis (MS). However, the operating molecular mechanisms that characterize the pattern of acute MS relapse activity has not been thoroughly studied. OBJECTIVE To assess POL1 pathway expression during acute MS relapse. METHODS We studied POL1 pathway associated biomarkers during the first acute optic neuritis attack of MS, and in relapsing-remitting MS patients treated with disease-modifying drugs (DMDs) experiencing an acute MS relapse or a radiological relapse using gene expression microarrays and quantitative RT-PCR. RESULTS In MS patients (N = 6) during the first acute optic neuritis attack POL1 pathway activation was evident by over-expression of POL1 related network including transcription factor UBTF and downstream components of Assembly of RNA POL1 complex (p=1.92E-03). POL1 related biomarkers RRN3, POLR1D and LRPPRC were over-expressed x1.6 (p = .002), ×1.7 (p = .01) and x2.0 (p = .001) times higher respectively, in MS patients (N = 30) during acute clinical relapse as compared with remission. Similarly, in MS patients (N = 21) that presented with a radiological relapse, we observed significant activation of POL1 related biomarkers including RRN3 (p = .01), POLR1D (p = .002), POLR1E (p = .0001) and LRPPRC (p = .006), as compared with remission, as well as overexpression of a large group of genes encoding ribosomal proteins like RPS6KA3 (p = 7.2E-6), RRP8 (p = .0002) and RPCS9 (p = .0008). CONCLUSIONS Our findings demonstrated increased POL1 pathway activity in acute MS relapse and suggest that targeted inactivation of POL1 pathway represent a novel strategy for a better treatment of acute MS relapse.