The use of alemtuzumab in patients with relapsing-remitting multiple sclerosis: the Gulf perspective.

Over the past decade, the development of high-efficacy disease-modifying therapies (DMTs) has been responsible for more effective management of relapsing-remitting multiple sclerosis (RRMS). However, the gaps in optimal care for this complex disease remain. Alemtuzumab (Lemtrada®) is a highly efficacious DMT that shows better patient outcomes and therapeutic benefits, but its use is under-recognized in the Gulf region. Experts in the care of multiple sclerosis shared their opinions based on study data and daily clinical experience in identifying the appropriate patient profile suitable for alemtuzumab's therapeutic benefits. Age, disease activity and severity, disability status, physician experience, and economic condition are some of the key indicators for alemtuzumab use.

Immune Reconstitution Therapy or Continuous Immunosuppression for the Management of Active Relapsing-Remitting Multiple Sclerosis Patients? A Narrative Review.

The majority of disease-modifying drugs (DMDs) available for the management of active relapsing-remitting multiple sclerosis (RMS) depend on continuous drug intake for maintained efficacy, with escalation to a more active drug when an unacceptable level of disease activity returns. Among continuously applied regimens, interferons and glatiramer acetate act as immunomodulators, while dimethyl fumarate, fingolimod, ocrelizumab, natalizumab and teriflunomide are associated with continuous immunosuppression. By contrast, immune reconstitution therapy (IRT) provides efficacy that outlasts a short course of treatment. Autologous hemopoietic stem cell transplantation is perhaps the classic example of IRT, but this invasive and intensive therapy has challenging side-effects. A short treatment course of a pharmacologic agent hypothesized to act as an IRT, such as Cladribine Tablets 3.5 mg/kg or alemtuzumab, can provide long-term suppression of MS disease activity, without need for continuous treatment (the anti-CD20 mechanism of ocrelizumab has the potential to act as an IRT, but is administered continuously, at 6-monthly intervals). Cladribine Tablets 3.5 mg/kg shows some selectivity in targeting adaptive immunity with a lesser effect on innate immunity. The introduction of IRT-like disease-modifying drugs (DMDs) challenges the traditional maintenance/escalation mode of treatment and raises new questions about how disease activity is measured. In this review, we consider a modern classification of DMDs for MS and its implications for the care of patients in the IRT era.

Distinct HLA class I and II genotypes and haplotypes are associated with multiple sclerosis in Bahrain.

Multiple sclerosis (MS) has become prevalent in the Arabian Gulf area with high incidence in Bahrain due to environmental influences and genetic susceptibilities, but there is a lack of study into human leukocyte antigen (HLA) types in patients with MS in Bahrain. The present study aimed to study the HLA types expressed in MS patients compared with in control subjects. Blood samples from 50 Bahraini patients with MS and 50 Bahraini control subjects' were subjected to HLA tissue typing by polymerase chain reaction using sequence-specific primers. In comparison with those in control subjects, the allele frequencies of HLA class-I antigens A2, A9, A19, B5, B35 and B40 were higher in MS patients. For class II antigens, the allele frequencies of DR3, DR4 and DR16 were higher in MS patients. The allele frequency of DR15 was lower in MS patients than in control subjects but the difference was not statistically significant (P=0.138). The higher prevalence of the HLA-ABDR allele was common among the female patients with MS, in relapse remission stage, in cases with higher expanded disability status scale scores and with disease duration between 4 and 9 years. Haplotype HLA-A2-B40-DR2 exhibited significantly higher frequency in MS patients compared with in control subjects (P=0.03). In conclusion, the results indicated different alleles associated with MS compared with previous reviews. The present study supports the importance of identifying genetic susceptibilities and targets for therapies in specific populations and individuals, to personalize disease management in terms of prediction, protective measures and treatment.

Interleukin 1 receptor antagonist and 2'-5'-oligoadenylate synthetase-like molecules as novel biomarkers for multiple sclerosis patients in Bahrain.

BACKGROUND: Multiple sclerosis (MS) is a multi-factorial disease of the Central Nervous System (CNS) affecting young adults leading to significant disabilities over time. MS is now believed to be prevalent in Arabian Gulf area with high incidence due to environmental factors and unknown genetic variations. The objectives of this study was to detect up-regulated potential genes that might be involved in neuroinflammatory process in MS patients in Bahrain and to measure the protein levels of the expressed genes. METHODS: A microarray was used to investigate mRNA expression from 12 MS patients and 12 control subjects in Bahrain where the mRNA came from peripheral blood leukocytes. Also, 80 MS patients and 80 control subjects were analyzed to measure serum protein levels of the expressed genes by ELISA. RESULTS: The data showed 15,480 genes expressed from over 47,000 transcripts and variants. Only 5 genes were significantly up-regulated in MS patients vs control subjects; namely TNF-AIP6, IL-1RA, OASL, CLC and DOCK4 (p < 0.05). Conversely, KIAA0125 gene was significantly down-regulated (p < 0.0003). Analysis of the effector molecules of the up-regulated genes revealed that 83 MS patients had positive serum level of OASL, 87 MS patients had positive serum levels of IL-1RA, and none of the 88 MS patients showed detectable serum levels of TNF-AIP6, CLC or DOCK4. CONCLUSIONS: OASL and IL-1RA genes were strongly expressed in MS patients and that their effector molecules may be considered as biomarkers associated with the inflammatory process of the disease and possibly treatment response.

Differential upregulation of the hypothetical transmembrane protein 66 (TMEM66) in multiple sclerosis patients with potential inflammatory response.

The prevalence of multiple sclerosis (MS) in the Gulf region has markedly increased during the last decade, but the mechanisms of the disease have not been investigated. The present study aimed to understand the molecular processes involved in the disease development of the recently emerged MS in this population using microarray technology to investigate differentially-expressed novel genes in MS patients compared to healthy-matched subjects. The expression of the upregulated genes was confirmed by quantitative polymerase chain reaction (qPCR). Furthermore, gene cloning, protein expression and purification were performed followed by testing of the obtained recombinant protein on biological assays, including cell proliferation and cytokine mRNA detection by reverse transcriptase-qPCR. The results showed that out of ~50,000 genes, the hypothetical transmembrane protein-66 gene (TMEM66) exhibited a 3 times higher expression in MS patients compared to healthy subjects. The TMEM66 gene was cloned and its protein showed marked immunological activity relevant to MS since significant proliferation (P<0.05) and augmented induction of the proinflammatory cytokines, interleukin (IL)-6, interferon-γ, tumor necrosis factor-α, and the chemokines, chemokine ligand 5/chemokine receptor 5, macrophage inflammatory protein 1α (MIP-1α) and MIP-1ß were recorded, but not the anti-inflammatory cytokines, IL-4 or IL-2. In conclusion, TMEM66 may be associated with the molecular events of MS and may be considered as an MS biomarker for future personalized medicine management approaches.

Natalizumab treatment for multiple sclerosis: Middle East and North Africa regional recommendations for patient selection and monitoring.

BACKGROUND: Natalizumab, a highly specific α4-integrin antagonist, , has recently been registered across the Middle East and North Africa region. It improves clinical and magnetic resonance imaging (MRI) outcomes and reduces the rate of relapse and disability progression in relapsing-remitting multiple sclerosis (MS). Natalizumab is recommended for patients who fail first-line disease-modifying therapy or who have very active disease. Progressive multifocal leukoencephalopathy is a rare, serious adverse event associated with natalizumab. We aim to develop regional recommendations for the selection and monitoring of MS patients to be treated with natalizumab in order to guide local neurological societies. METHODS: After a review of available literature, a group of neurologists with expertise in the management of MS met to discuss the evidence and develop regional recommendations to guide appropriate use of natalizumab in the region. RESULTS: Disease breakthrough is defined as either clinical (relapse or disability progression) or radiological activity (new T2 lesion or gadolinium-enhancing lesions on MRI), or a combination of both. Natalizumab is recommended as an escalation therapy in patients with breakthrough disease based on its established efficacy in Phase III studies. Several factors including prior immunosuppressant therapy, anti-John Cunningham virus (JCV) antibody status and patient choice will affect the selection of natalizumab. In highly active MS, natalizumab is considered as a first-line therapy for naive patients with disabling relapses in association with MRI activity. The anti-JCV antibody test is used to assess anti-JCV antibody status and identify the risk of PML. While seronegative patients should continue treatment with natalizumab, anti-JCV antibody testing every 6 months and annual MRI scans are recommended as part of patient monitoring. In seropositive patients, the expected benefits of natalizumab treatment have to be weighed against the risks of PML. Clinical vigilance and follow-up MRI scans remain the cornerstone of monitoring. After 2 years of natalizumab therapy, monitoring should include more frequent MRI scans (every 3-4 months) for seropositive patients, and the risk-benefit ratio should be reassessed and discussed with patients. CONCLUSIONS: Recommendations have been developed to guide neurologists in the Middle East and North Africa on patient selection for natalizumab treatment and monitoring.

Characteristics of multiple sclerosis in the Middle East with special reference to the applicability of international guidelines to the region.

We have reviewed the clinical literature with reference to the local applicability of guidelines for the diagnosis and management of multiple sclerosis (MS) in the Middle East. There is a substantial burden of MS in the region: the prevalence of the disease appears to have increased markedly in recent decades, with a faster rate of increase in female vs. male patients. The aetiology and presentation of MS appears to be broadly similar in the Middle East to that in other regions. Interferon-ß is the most commonly used treatment for MS in the Middle East, as elsewhere, although it is unclear to what extent economic constraints act as a barrier to accessing this treatment. Similarly, limited available data suggest that the availability of MRI scanners appears to be lower in the Middle East than in more developed nations. Little is known concerning other potential barriers to treatment. There is a need for further research on aspects of management of MS beyond the pharmacological aspects of treatment to assess fully the potential barriers to the adoption of international guidelines for the diagnosis and management of the disease in the Middle East.