Role of IL-16 in CD4(+) T cell-mediated regulation of relapsing multiple sclerosis

In an important article published in Nature Medicine, Liu and colleagues described a novel CD4+ FoxA1+ regulatory T (Treg) cell population as distinct regulators of relapsing-remitting multiple sclerosis (RRMS) and experimental autoimmune encephalomyelitis (EAE). CD4+ FoxA1+ Treg cells appear as key regulators of responsiveness to therapy with interferon beta (IFN-β) in RRMS patients. Data indicate that CD4+ FoxA1+ FOXP3− Treg cells develop within the central nervous system (CNS), and a potential of cerebellar granule neurons (CGN) in generation of CD4+ FoxA1+ PD-L1hiFOXP3− Treg cells from encephalitogenic CD4+ T cells. A CD4 co-receptor specific ligand, IL-16, governs trafficking and biological properties of CD4+ T cells irrespective of their activation state. Functions of IL-16, relevant to Treg cells, include expansion of CD4+CD25+ T cells in long-term cultures with IL-2, de novo induction of FOXP-3 and migration of FOXP-3+ T cells. IL-16 is highly conserved across species including human and mouse. CGN and neurons in hippocampus contain neuronal-IL-16 (NIL-16), splice variant of immune IL-16, and express CD4 molecule. In a CD4-dependent manner, IL-16 supports cultured CGN survival. Concomitant studies of RRMS lesions and corresponding MOG35–55-induced relapsing EAE in (B6 × SJL)F1 (H-2b/s) mice discovered similar roles of IL-16 in regulation of relapsing disease. In RRMS and EAE relapse, peak levels of IL-16 and active caspase-3 correlated with CD4+ T cell infiltration and levels of T-bet, Stat-1(Tyr701), and phosphorylated neurofilaments of axonal cytoskeleton [NF (M + H) P], suggesting a role of locally produced IL-16 in regulation of CD4+ Th1 inflammation and axonal damage, respectively. IL-16 was abundantly present in CD4+ T cells, followed by CD20+ B, CD8+ T, CD83+ dendritic cells, and Mac-1+ microglia. Apart from lesions, bioactive IL-16 was located in normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) in RRMS brain and spinal cord. A cytokine IL-16 emerges as an important regulator of relapsing MS and EAE. Better understanding of immune cell-neuron interactions mediated by IL-16 will foster development of more specific CD4+ T cell subset-targeted therapies to prevent or ameliorate progression of neuroinflammation and axonal and neuronal damage. Translational studies necessitate corresponding EAE models

Treatment with Cladribine Tablets Beyond Year 4: A Position Statement by Southeast European Multiple Sclerosis Centers

Based on the results of the pivotal CLARITY study, cladribine tablets were approved for use in the European Union in 2017 as a high-efficacy therapy for highly active relapsing-remitting multiple sclerosis (MS). Cladribine tablets are used as an induction therapy: half of the total dose is given in year 1 and the other half in year 2. In the CLARITY Extension trials, repeating the dose routinely in years 3 and 4, was not associated with significantly improved disease control. However, there is very limited evidence on how to manage people with MS (pwMS) beyond year 4, which is increasingly important because more and more patients are now ≥ 4 years after cladribine treatment. Overall, postapproval data show that treatment with two cladribine cycles effectively controls disease activity in the long term. However, there is general agreement that some pwMS with suboptimal response could benefit from retreatment. This study reviews the practical aspects of using cladribine tablets, summarizes the evidence from clinical trials and real-world studies on the safety and efficacy of cladribine, and proposes a treatment algorithm developed by expert consensus for pwMS previously treated with cladribine. In brief, we propose that additional courses of cladribine tablets should be considered in patients with minimal (no relapses, 1-2 new lesions) or moderate (1 relapse, 3-4 new lesions) disease activity, while significant disease activity (> 1 relapse, > 3 new lesions) or progression should warrant a switch to another high-efficacy treatment (HET). More evidence is needed to improve the treatment guidelines for pwMS who previously received cladribine

Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study

Objectives: To evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability. Methods: In this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle. Results: In healthy controls, T1w/T2w ratio increased until 50-60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (β from -1.168 to 0.286, p≤0.040). Conclusions: T1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases

Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

<p>Abstract</p> <p>Background</p> <p>Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved.</p> <p>Results</p> <p>We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels.</p> <p>Conclusions</p> <p>We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.</p

Role preferences of people with Multiple Sclerosis: image-revised, computerized self-administered version of the control preference scale

Background: The Control Preference Scale (CPS) is the most frequently used measure of patients’ preferred roles in treatment decisions. We revised the original CPS and developed a new computerized patient self-administered version (eCPS). We used the eCPS to assess role preferences, and their determinants, in Italian and German people with multiple sclerosis (MS). Methods: New cartoons were produced, based on MS health professional and patient input/feedback and previous findings, and pilot tested on 26 Italian and German MS patients. eCPS acceptability and reliability (weighted kappa statistic, wK) in comparison to the original tool, was determined in 92 MS patients who received both CPS versions in random order. Results: The new cartoons were well accepted and easily interpreted by patients, who reported they based their choices mainly on the text and considered the images of secondary importance. eCPS reliability was moderate (wK 0.53, 95% confidence interval [CI] 0.40–0.65) and similar to the test-retest reliability of face-to-face administration assessed in a previous publication (wK 0.65, 95% CI 0.45–0.81). Higher education (odds ratio [OR] 3.74, 95% CI 1.00–14.05) and German nationality (OR 10.30, 95% CI 3.10–34.15) were associated with preference for an active role in the logistic model. Conclusions: The newly devised eCPS was well received and considered easy to use by MS patients. Reliability was in line with that of the original version. Role preference appears affected by cultural characteristics and (borderline statistical significance) education.</br

EAN Guideline on Palliative Care of People with Severe, Progressive Multiple Sclerosis

Background and Purpose: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. Methods: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients–Intervention– Comparator–Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20m without resting (Expanded Disability Status Scale score >6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. Results: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient’s wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. Conclusions: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs

Risk knowledge of people with relapsing-remitting multiple sclerosis:Results of an international survey

Background Adequate disease and treatment-related risk knowledge of people with Multiple Sclerosis (pwMS) is a prerequisite for informed choices in medical encounters. Previous work showed that MS risk knowledge is low among pwMS and role preferences are different in Italy and Germany. Objective We investigated the level of risk knowledge and role preferences in 8 countries and assessed putative variables associated with risk knowledge. Methods An online-survey was performed based on the Risk knowledge questionnaire for people with relapsing-remitting MS (RIKNO 2.0), the electronic Control Preference Scale (eCPS), and other patient questionnaires. Inclusion criteria of participants were: (1) age 18 years, (2) a diagnosis of relapsing-remitting MS (RRMS), (3) being in a decision making process for a disease modifying drug. Results Of 1939 participants from Germany, Italy, the Netherlands, Serbia, Spain and Turkey, 986 (51%) (mean age 38.6 years [range 18–67], 77% women, 7.8 years of disease duration) completed the RIKNO 2.0, with a mean of 41% correct answers. There were less than 50 participants in the UK and Estonia and data were not analysed. Risk knowledge differed across countries (p &lt; 0.001). Variables significantly associated with higher risk knowledge were higher education (p &lt; 0.001), previous experience with disease modifying drugs (p = 0.001), correct answer to a medical data interpretation question (p &lt; 0.001), while higher fear for wheelchair dependency was negatively associated to risk knowledge (p = 0.001). Conclusion MS risk knowledge was overall low and differed across participating countries. These data indicate that information is an unmet need of most pwMS.</p

Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis

Background and purpose: Patient and public involvement in clinical practice guideline development is recommended to increase guideline trustworthiness and relevance. The aim was to engage multiple sclerosis (MS) patients and caregivers in the definition of the key questions to be answered in the European Academy of Neurology guideline on palliative care of people with severe MS. Methods: A mixed methods approach was used: an international online survey launched by the national MS societies of eight countries, after pilot testing/debriefing on 20 MS patients and 18 caregivers, focus group meetings of Italian and German MS patients and caregivers. Results: Of 1199 participants, 951 (79%) completed the whole online survey and 934 from seven countries were analysed: 751 (80%) were MS patients (74% women, mean age 46.1) and 183 (20%) were caregivers (36% spouses/partners, 72% women, mean age 47.4). Participants agreed/strongly agreed on inclusion of the nine pre-specified topics (from 89% for ‘advance care planning’ to 98% for ‘multidisciplinary rehabilitation’), and <5% replied ‘I prefer not to answer’ to any topic. There were 569 free comments: 182 (32%) on the pre-specified topics, 227 (40%) on additional topics (16 guideline-pertinent) and 160 (28%) on outcomes. Five focus group meetings (three of MS patients, two of caregivers, and overall 35 participants) corroborated the survey findings. In addition, they allowed an explanation of the guideline production process and the exploration of patient-important outcomes and of taxing issues. Conclusions: Multiple sclerosis patient and caregiver involvement was resource and time intensive, but rewarding. It was the key for the formulation of the 10 guideline questions and for the identification of patient-important outcomes

Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.Published versio