Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease that leads to irreversible damage to the brain and spinal cord. The goal of so-called "immune reconstitution therapies" (IRTs) is to achieve long-term disease remission by eliminating a pathogenic immune repertoire through intense short-term immune cell depletion. B cells are major targets for effective immunotherapy in MS. OBJECTIVES: The aim of this study was to analyze the gene expression pattern of B cells before and during IRT (i.e., before B-cell depletion and after B-cell repopulation) to better understand the therapeutic effects and to identify biomarker candidates of the clinical response to therapy. METHODS: B cells were obtained from blood samples of patients with relapsing-remitting MS (n = 50), patients with primary progressive MS (n = 13) as well as healthy controls (n = 28). The patients with relapsing MS received either monthly infusions of natalizumab (n = 29) or a pulsed IRT with alemtuzumab (n = 15) or cladribine (n = 6). B-cell subpopulation frequencies were determined by flow cytometry, and transcriptome profiling was performed using Clariom D arrays. Differentially expressed genes (DEGs) between the patient groups and controls were examined with regard to their functions and interactions. We also tested for differences in gene expression between patients with and without relapse following alemtuzumab administration. RESULTS: Patients treated with alemtuzumab or cladribine showed on average a > 20% lower proportion of memory B cells as compared to before IRT. This was paralleled by profound transcriptome shifts, with > 6000 significant DEGs after adjustment for multiple comparisons. The top DEGs were found to regulate apoptosis, cell adhesion and RNA processing, and the most highly connected nodes in the network of encoded proteins were ESR2, PHB and RC3H1. Higher mRNA levels of BCL2, IL13RA1 and SLC38A11 were seen in patients with relapse despite IRT, though these differences did not pass the false discovery rate correction. CONCLUSIONS: We show that B cells circulating in the blood of patients with MS undergoing IRT present a distinct gene expression signature, and we delineated the associated biological processes and gene interactions. Moreover, we identified genes whose expression may be an indicator of relapse risk, but further studies are needed to verify their potential value as biomarkers.

Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity.

Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.

Graves' disease with spontaneous resolution following ocrelizumab in primary progressive multiple sclerosis.

Objectives. Immune reconstitution therapies (IRT), which include antibody-based cell-depleting therapies targeting CD52+ (alemtuzumab) or CD20+ (rituximab, ocrelizumab) leukocytes, are approved for the treatment of multiple sclerosis. Thyroid autoimmunity is a common adverse effect of alemtuzumab treatment, Graves' disease (GD) being the most prevalent manifestation. To date, thyroid autoimmunity events have not been reported with CD20-targeting monoclonal antibodies. Case Report. A 59-year-old woman with primary progressive multiple sclerosis with no prior personal history of thyroid disease or autoimmunity, was diagnosed with GD 6 months following the first ocrelizumab infusion. She was asymptomatic and had no signs of ophthalmopathy. Due to the temporal association of GD diagnosis with ocrelizumab infusion, absence of symptoms and our experience with alemtuzumab-induced GD, we decided for an active surveillance strategy and antithyroid drugs were not started. She underwent spontaneous resolution of hyperthyroidism with thyroid-stimulating hormone (TSH) receptor antibodies (TRAb) negativity and a mild and transitory period of subclinical hypothyroidism, while she continued the biannually ocrelizumab administration schedule. To present date, she has maintained close clinical and biochemical surveillance with normal TSH, free thyroxine (fT4) and free triiodothyronine (fT3) levels and undetectable TRAb. Conclusions. This is the first case of GD reported after ocrelizumab administration. The timing, onset and course of this case is similar to alemtuzumab-induced GD, usually interpreted as an "immune reconstitution syndrome"; however, ocrelizumab cell count depletion is inferior in severity, cell population affected and duration of depletion. This case highlights the importance of pre-screening and follow-up with thyroid function tests in patients treated with ocrelizumab. As a novel therapeutic antibody, further investigation is required to unravel the causes of thyroid autoimmunity.

Practical Recommendations from the Gulf Region on the Therapeutic Use of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis: Impact of the Latest Real-World Evidence on Clinical Practice.

Cladribine tablets (CladT), like alemtuzumab, acts as an immune reconstitution therapy. However, CladT is administered orally (alemtuzumab is given by infusion) and without the potential for serious side effects that limit the therapeutic use of alemtuzumab in multiple sclerosis (MS). Treatment with CladT, given initially as short courses of treatment 1 year apart, provides years of freedom from MS disease activity in responders to treatment. The appearance of mild or moderate MS disease activity after the initial 2 years of treatment may prompt careful follow-up or a further course of CladT, depending on the nature of the activity and individual circumstances. The appearance of severe MS disease activity requires a switch to an alternative high-efficacy disease-modifying treatment (DMT). The accumulating data from CladT-treated people with MS in real-world studies, including those with follow-up durations extending for years beyond the initial treatment, have demonstrated long-term freedom from MS disease activity in a good proportion of patients. This clinical experience has also confirmed that treatment with CladT is generally safe and well tolerated. The best time to prescribe a high-efficacy DMT is the subject of debate, with evidence that earlier versus later use of such agents may provide more effective long-term protection from disability progression. High-efficacy DMTs have traditionally been reserved for use in people with MS and high disease activity on presentation or breakthrough disease on one or more DMTs, as per the current product labels. The latest evidence from real-world studies suggests that CladT is effective and safe in DMT-naïve patients, including those with shorter disease duration.

[Experience in the use of cladribine for the treatment of patients with highly active forms of multiple sclerosis in the Moscow region]. / Opyt ispol'zovaniya kladribina dlya lecheniya patsientov s vysokoaktivnym techeniem rasseyannogo skleroza v Moskovskoi oblasti.

OBJECTIVE: To assess the efficacy and safety of cladribine in patients with highly active multiple sclerosis (MS) in the Moscow region. MATERIAL AND METHODS: The analysis was based on data from 62 patients treated with cladribine between March 2021 and January 2024. The diagnosis of VAMS was confirmed in 51 patients, PPMS in 4 patients, and SPMS with exacerbations was diagnosed in 7 cases. Of these, 3 patients completely completed therapy more than a year ago, 20 people received 2 courses of the drug less than a year ago, 39 patients underwent 1 course of therapy. The effect of cladribine on reducing disease activity and progression, as well as the safety of therapy, was evaluated. RESULTS: After 1 course, the number of patients with activity decreased by 66.4%, after 2 years of therapy - by 72.7%. The mean annual frequency of exacerbations decreased from 1.32 to 0.2 after 12 months, and to 0.086 exacerbations per year after 24 months. The level of disability assessed by the EDSS scale remained virtually unchanged throughout the follow-up. The most common adverse events were haematological abnormalities in the form of lymphopenia and leukopenia. Most patients had mild grade 1-2 lymphopenia on the toxicity scale and recovered to the recommended values (>0.8·109/l) by the beginning of the second course of therapy. No cases of serious adverse events were reported. CONCLUSIONS: The results obtained indicate the high efficacy and favorable safety profile of cladribine and are consistent with the data of clinical trials of the drug.

Alemtuzumab-induced thyroid eye disease successfully treated with a single low dose of rituximab.

Introduction: Secondary thyroid autoimmunity, especially Graves' disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment. Case presentation: A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy. Conclusion: RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.

Evaluation of therapy satisfaction with cladribine tablets in patients with RMS: Final results of the non-interventional study CLEVER.

BACKGROUND: Cladribine tablets for the treatment of relapsing multiple sclerosis (RMS) are administered in two pulsed treatment courses in two consecutive years, totalling a maximum of 20 treatment days. Here we present data collected shortly after the launch of cladribine tablets, focusing on the patient's perspective. The objective was to investigate patients' perceived effectiveness, tolerability, and convenience, as well as global satisfaction of and with cladribine tablets. METHODS: CLEVER was a non-interventional multicentre study conducted in Germany from 12/2017 to 7/2020. Adult patients with RMS initiating therapy with cladribine tablets were included. Observation time per patient was 24 weeks, comprising 3 visits (baseline, week 4 and 24). The primary endpoint was overall treatment satisfaction at week 24, assessed by the Treatment Satisfaction Questionnaire for Medication 14 items (TSQM 1.4). Subgroup analyses included stratification by prior treatment. RESULTS: In total, 491 patients (69.2 % female; mean (±SD) age 40.3 (±11.5) years, 85.1 % pre-treated, median EDSS 2.5) initiated therapy with cladribine tablets and were included in the analysis. At week 24, the mean (±SD) global TSQM satisfaction score was 75.6 (±19.0). For patients switching from either injectables or oral medication, the change in therapy satisfaction from baseline to week 24 was positive in all TSQM domains with clinically meaningful effect sizes in the global satisfaction and side effects domains. Most patients (85.5 %) remained relapse-free over 24 weeks. Out of 491 patients, 187 (38.1 %) experienced at least one adverse event and 8 patients (1.6 %) one serious adverse event. CONCLUSION: Treatment satisfaction with cladribine tablets was high. The switch from prior injectables or oral medication translated into increased treatment satisfaction at week 24 with clinically meaningful effects in the global satisfaction and side effects domains. Effectiveness and safety were consistent with results from clinical studies.

Plasma Cytokine Expression and Immune Reconstitution in Early and Delayed Anti-HIV 96-Weeks Treatment: A Retrospective Study.

HIV is an immunodeficiency disease with emergence of inadequate corresponding reconstruction therapies. Pyroptosis of CD4+T cell is mainly caused by immune activation and inflammation that cannot be reduced by successful antiretroviral therapy (ART) alone. Coinfections because of CD4+T cell reconstitution failure can occur. Anti-inflammatory treatment determines the success of immune reconstitution. In our experiment, only a few cytokines could recover to normal level following a 2-year antiretroviral treatment in early ART initiation, which is consistent with current findings about adjuvant HIV anti-inflammatory therapy. Early infection is often accompanied by a more severe inflammatory response. Innate immunity cytokines like granulocyte macrophage-colony stimulating factor, IFN-γ induced protein 10 kDa, and tumor necrosis factor-α exhibited the most elevated levels among all kinds of inflammatory cytokines. The correlation analysis showed at least eight cytokines contributing to the changes of CD4/CD8 ratio.

The preclinical data and immunologic rationale for hematopoietic stem cell transplantation in autoimmunity.

The development of autoimmune diseases (ADs) is thought to be caused by a dysfunction of the intrinsic ability of our immune system for "self-nonself" discrimination. Following the breakdown of "self-tolerance," an orchestrated immune cascade develops, involving B- and T-lymphocytes and autoantibodies that target self-antigens. An imbalance of the regulatory immune network and a suitable genetic background, along with external (infectious and environmental) triggers, are all important contributors to the outbreak of clinical autoimmunity. Immunotherapies for ADs can be classified into treatments that are given continuously (chronic treatments) and therapies that are applied only once or intermittently, aiming to induce partial or complete reconstitution of the immune system [immune reconstitution therapies (IRTs)]. The principle underlying IRTs is based on the depletion of mature immune cells and the rebuilding of the immune system. During this process of immune reconstitution, a substantial change in the lymphocyte repertoire occurs, which may explain the impressive and long-term beneficial effects of IRTs, including the possibility of induction of tolerance to self-antigens. Hematopoietic (or bone marrow) stem cell transplantation (HSCT or BMT) represents the prototype-and the most radical type-of IRT therapy. The rationale for HSCT or BMT for the treatment of severe ADs is based on convincing proof in preclinical studies, utilizing various animal models of autoimmunity. More than 30 years' worth of pioneering experiments in various models of ADs have shown that HSCT can lead to substantial improvement or even cure of the autoimmune syndromes and induction of long-term tolerance to autoantigens. The success of treatment depends on how completely the autoantigen-reactive lymphocytes and memory cells are eradicated by the conditioning chemotherapy, which is administered in a single dose before the transplantation. The most successful conditioning methods in animal models of ADs are total body irradiation (TBI) and high-dose cyclophosphamide (CY). These preclinical studies, summarized in this review, have provided important data about the therapeutic potential of HSCT in human ADs and the associated mechanisms of action and have contributed to the formulation of guidelines for clinical applications of autologous or allogeneic HSCT/BMT in refractory autoimmunity.

The Place of Immune Reconstitution Therapy in the Management of Relapsing Multiple Sclerosis in France: An Expert Consensus.

The treatment strategy in relapsing multiple sclerosis (RMS) is a complex decision requiring individualization of treatment sequences to maximize clinical outcomes. Current local and international guidelines do not provide specific recommendation on the use of immune reconstitution therapy (IRT) as alternative to continuous immunosuppression in the management of RMS. The objective of the program was to provide consensus-based expert opinion on the optimal use of IRT in the management of RMS. A Delphi method was performed from May 2022 to July 2022. Nineteen clinical assertions were developed by a scientific committee and sent to 14 French clinical experts in MS alongside published literature. Two consecutive reproducible anonymous votes were conducted. Consensus on recommendations was achieved when more than 75% of the respondents agreed or disagreed with the clinical assertions. After the second round, consensus was achieved amongst 16 out of 19 propositions: 13 clinical assertions had a 100% consensus, 3 clinical assertions a consensus above 75% and 3 without consensus. Expert-agreed consensus is provided on topics related to the benefit of the early use of IRT from immunological and clinical perspectives, profiles of patients who may benefit most from the IRT strategy (e.g. patients with family planning, patient preference and lifestyle requirements). These French expert consensuses provide up-to-date relevant guidance on the use of IRT in clinical practice. The current program reflects status of knowledge in 2022 and should be updated in timely manner when further clinical data in IRT become available.

Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis.

Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3-4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS.

Multiple sclerosis patients treated with cladribine tablets: expert opinion on practical management after year 4.

Multiple sclerosis (MS) is a chronic, progressive neurological disease involving neuroinflammation, neurodegeneration, and demyelination. Cladribine tablets are approved for immune reconstitution therapy in patients with highly active relapsing-remitting MS based on favorable efficacy and tolerability results from the CLARITY study that have been confirmed in long-term extension studies. The approved 4-year dosing regimen foresees a cumulative dose of 3.5 mg/kg administered in two cycles administered 1 year apart, followed by 2 years of observation. Evidence on managing patients beyond year 4 is scarce; therefore, a group of 10 neurologists has assessed the available evidence and formulated an expert opinion on management of the growing population of patients now completing the approved 4-year regimen. We propose five patient categories based on response to treatment during the first 4-year regimen, and corresponding management pathways that envision close monitoring with clinical visits, magnetic resonance imaging (MRI) and/or biomarkers. At the first sign of clinical or radiological disease activity, patients should receive a highly effective disease-modifying therapy, comprising either a full cladribine regimen as described in regulatory documents (cumulative dose 7.0 mg/kg) or a comparably effective treatment. Re-treatment decisions should be based on the intensity and timing of onset of disease activity, clinical and radiological assessments, as well as patient eligibility for treatment and treatment preference.

Cladribine Tablets for Relapsing-Remitting Multiple Sclerosis: A Clinician's Review.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by inflammation and demyelination for which there is currently no cure; therefore, the aim of therapy is to reduce the risk of relapse and disability progression. The treatment options for MS have increased greatly in recent years with the development of several disease-modifying therapies (DMTs) and the advent of immune reconstitution therapy (IRT). IRTs are administered in short-dosing periods to produce long-term effects on the immune system. Treatment with an IRT is based on the 3Rs: reduction, repopulation, and reconstitution of lymphocytes, which leads to restoration of immune effector functions. Cladribine tablets represent a selective, high-efficacy, oral form of IRT for patients with MS that targets lymphocytes and spares innate immune cells. Patients require only two weekly treatment courses, with each course comprising two treatment weeks, in Years 1 and 2; therefore, cladribine tablets are associated with a lower monitoring burden than many other DMTs, while short dosing periods can help to improve adherence. This review provides an overview of IRT and offers the clinician's perspective on the current MS treatment landscape, with a focus on practical advice for the management of patients undergoing treatment with cladribine tablets based on the most recent evidence available, including risks associated with COVID-19 and recommendations for vaccination in patients with MS.

Thyroid Storm in a Patient With Alemtuzumab-Induced Graves' Disease: A Case Report.

Thyroid storm (TS) is a rare and life-threatening medical emergency, most commonly caused by Graves' disease (GD). GD can be induced by immune reconstitution therapy (IRT) such as alemtuzumab (ALZ), a humanized monoclonal antibody against CD52, which is shown to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Here, we present a rare case of TS developing in a 39-year-old female with ALZ-induced GD, managed with antithyroid medication followed by thyroidectomy. There is some evidence that ALZ-induced GD may behave less aggressively than conventional GD. However, physicians should be aware that severe thyrotoxicosis and thyroid storm can happen, which requires prompt recognition and aggressive therapy.

Long-term management of multiple sclerosis patients treated with cladribine tablets beyond year 4.

INTRODUCTION: Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis (RMS) since 2017. A full treatment course comprises two treatment cycles given 1 year apart, followed by two treatment-free years. The management of cladribine-treated patients beyond year 4 needs to be addressed as patients have now passed the initial 4 years since European Medical Agency approval. AREAS COVERED: A panel of neurologists and a neuroradiologist experienced in MS treatment/monitoring evaluated clinical trial data and real-world evidence and proposed recommendations for the management of cladribine-treated patients beyond year 4. EXPERT OPINION: Continuous monitoring of disease activity during the treatment-free period is important. Subsequent management depends on the presence or absence of inflammatory disease activity, determined in the absence of consistent guidelines via practice-driven neurological decision criteria. Persisting or newly occurring inflammatory disease activity is an indication for further treatment, i.e. either re-initiation of cladribine or switching to another highly effective disease-modifying therapy. The decision to retreat or switch should be based on clinical and radiological evaluation considering disease course, treatment history, and safety aspects. In the absence of disease activity, either retreatment can be offered, or the treatment-free period can be extended under structured monitoring.

Implication of genetic variants in primary microRNA processing sites in the risk of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a well-established genetic contribution to susceptibility. Over 200 genetic regions have been linked to the inherited risk of developing MS, but the disease-causing variants and their functional effects at the molecular level are still largely unresolved. We hypothesised that MS-associated single-nucleotide polymorphisms (SNPs) affect the recognition and enzymatic cleavage of primary microRNAs (pri-miRNAs). METHODS: Our study focused on 11 pri-miRNAs (9 primate-specific) that are encoded in genetic risk loci for MS. The levels of mature miRNAs and potential isoforms (isomiRs) produced from those pri-miRNAs were measured in B cells obtained from the peripheral blood of 63 MS patients and 28 healthy controls. We tested for associations between SNP genotypes and miRNA expression in cis using quantitative trait locus (cis-miR-eQTL) analyses. Genetic effects on miRNA stem-loop processing efficiency were verified using luciferase reporter assays. Potential direct miRNA target genes were identified by transcriptome profiling and computational binding site assessment. FINDINGS: Mature miRNAs and isomiRs from hsa-mir-26a-2, hsa-mir-199a-1, hsa-mir-4304, hsa-mir-4423, hsa-mir-4464 and hsa-mir-4492 could be detected in all B-cell samples. When MS patient subgroups were compared with healthy controls, a significant differential expression was observed for miRNAs from the 5' and 3' strands of hsa-mir-26a-2 and hsa-mir-199a-1. The cis-miR-eQTL analyses and reporter assays pointed to a slightly more efficient Drosha-mediated processing of hsa-mir-199a-1 when the MS risk allele T of SNP rs1005039 is present. On the other hand, the MS risk allele A of SNP rs817478, which substitutes the first C in a CNNC sequence motif, was found to cause a markedly lower efficiency in the processing of hsa-mir-4423. Overexpression of hsa-mir-199a-1 inhibited the expression of 60 protein-coding genes, including IRAK2, MIF, TNFRSF12A and TRAF1. The only target gene identified for hsa-mir-4423 was TMEM47. INTERPRETATION: We found that MS-associated SNPs in sequence determinants of pri-miRNA processing can affect the expression of mature miRNAs. Our findings complement the existing literature on the dysregulation of miRNAs in MS. Further studies on the maturation and function of miRNAs in different cell types and tissues may help to gain a more detailed functional understanding of the genetic basis of MS. FUNDING: This study was funded by the Rostock University Medical Center (FORUN program, grant: 889002), Sanofi Genzyme (grant: GZ-2016-11560) and Merck Serono GmbH (Darmstadt, Germany, an affiliate of Merck KGaA, CrossRef Funder ID: 10.13039/100009945, grant: 4501860307). NB was supported by the Stiftung der Deutschen Wirtschaft (sdw) and the FAZIT foundation. EP was supported by the Landesgraduiertenförderung Mecklenburg-Vorpommern.

Opportunities and Obstacles Associated With Sequential Immune Reconstitution Therapy for Multiple Sclerosis: A Case Report.

Cladribine is an effective disease-modifying treatment for relapsing-remitting multiple sclerosis that acts as an immune reconstitution therapy and is administered in a pulsed manner. Despite its efficacy, severe disease reactivation early after treatment represents a serious clinical problem, and clear evidence to guide the management of such a situation is lacking. Here, we describe the case of a patient experiencing considerable disease activity during the 1st year after the initiation of cladribine treatment. The patient was switched to alemtuzumab and, therefore, received double immune reconstitution therapy. Data regarding this approach are lacking, and real-world observations may be of interest. Despite achieving good control of disease activity, we observed several serious infectious complications. Our results suggest that sequential immune reconstitution therapies may be effective; however, at the price of higher susceptibility to infections.

Management of relapsing-remitting multiple sclerosis in Qatar: an expert consensus.

Healthcare systems vary greatly between countries. International, evidence-based guidelines for the management of multiple sclerosis (MS) may need to be adapted for use in particular countries. Two years ago, the authors published a comprehensive consensus guideline for the management of MS in Qatar. Since that time, the availability of disease-modifying treatments for relapsing-remitting MS (RRMS), and our understanding of how to apply those treatments, has increased. The authors present an update to our guidance, focussing on the management of relapsing-remitting RRMS. In particular, the authors consider the optimal use of different DMTs in patients presenting with mild, medium or high disease activity.

Long-term management of multiple sclerosis patients treated with cladribine tablets: an expert opinion.

INTRODUCTION: Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis. A full treatment course comprises two treatment cycles given with 1 year of intermission. Further dosing is not routinely recommended in years 3 and 4. AREAS COVERED: The long-term management of patients treated with oral cladribine has not been fully defined on the basis of clinical studies as of yet. The authors provide their expert opinion on this. EXPERT OPINION: Based on available evidence and experience from routine clinical use, the authors suggest a structured approach to the long-term management of patients treated with cladribine tablets according to their responder type, i. e. the degree and timing of disease activity, if any, after treatment initiation. Informed treatment decisions require structured patient monitoring by established clinical and imaging parameters. In patients with relevant disease activity in year 3 or 4 and beyond, the use of additional cycle(s) of oral cladribine might become an option. For patients requiring a treatment switch, the choice of therapies primarily includes moderately to highly effective MS drugs.

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.