The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing-remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis.

Immune response to SARS-CoV-2 vaccination in relation to peripheral immune cell profiles among patients with multiple sclerosis receiving ocrelizumab.

BACKGROUND: Vaccination has proven to be effective in preventing SARS-CoV-2 transmission and severe disease courses. However, immunocompromised patients have not been included in clinical trials and real-world clinical data point to an attenuated immune response to SARS-CoV-2 vaccines among patients with multiple sclerosis (MS) receiving immunomodulatory therapies. METHODS: We performed a retrospective study including 59 ocrelizumab (OCR)-treated patients with MS who received SARS-CoV-2 vaccination. Anti-SARS-CoV-2-antibody titres, routine blood parameters and peripheral immune cell profiles were measured prior to the first (baseline) and at a median of 4 weeks after the second vaccine dose (follow-up). Moreover, the SARS-CoV-2-specific T cell response and peripheral B cell subsets were analysed at follow-up. Finally, vaccination-related adverse events were assessed. RESULTS: After vaccination, we found anti-SARS-CoV-2(S) antibodies in 27.1% and a SARS-CoV-2-specific T cell response in 92.7% of MS cases. T cell-mediated interferon (IFN)-γ release was more pronounced in patients without anti-SARS-CoV-2(S) antibodies. Antibody titres positively correlated with peripheral B cell counts, time since last infusion and total IgM levels. They negatively correlated with the number of previous infusion cycles. Peripheral plasma cells were increased in antibody-positive patients. A positive correlation between T cell response and peripheral lymphocyte counts was observed. Moreover, IFN-γ release was negatively correlated with the time since the last infusion. CONCLUSION: In OCR-treated patients with MS, the humoral immune response to SARS-CoV-2 vaccination is attenuated while the T cell response is preserved. However, it is still unclear whether T or B cell-mediated immunity is required for effective clinical protection. Nonetheless, given the long-lasting clinical effects of OCR, monitoring of peripheral B cell counts could facilitate individualised treatment regimens and might be used to identify the optimal time to vaccinate.

Sirolimus leads to rapid and sustained clinical improvement of motor deficits in a patient with inclusion body myositis.

BACKGROUND AND PURPOSE: To provide further evidence for sirolimus, a mammalian target of rapamycin inhibitor, as a treatment strategy for patients with inclusion body myositis (IBM). METHODS: We acquired longitudinal clinical data and immunological assessments of CD8+ T-cell subsets in peripheral blood for evaluation of potential anti-inflammatory treatment effects of sirolimus. RESULTS: Therapy with sirolimus 2 mg/day by mouth led to rapid and sustained clinical improvement of motor symptoms for an observation period of more than 1 year. Treatment was well tolerated, with no occurrence of adverse effects. We did not observe a meaningful alteration of CD8+ T-cell subsets in our patient after 9 and 12 months compared to baseline. CONCLUSIONS: The significant and persistent clinical improvement highlights the use of sirolimus as a potential treatment option in patients with IBM. In light of the lack of immunological treatment effects observed for cytotoxic CD8+ T cells, further studies should investigate the potential myoprotective effects of sirolimus.

Pain, depression, and quality of life in adults with MOG-antibody-associated disease.

BACKGROUND AND PURPOSE: Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is an inflammatory autoimmune condition of the central nervous system. However, data on pain and depression have remained scarce. The aim of this study was to assess features of chronic pain and depression as well as their impact on health-related quality of life (hr-QoL) in MOGAD. METHODS: Patients with MOGAD were identified in the Neuromyelitis Optica Study Group registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory-Short Form, McGill Pain Questionnaire-Short Form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items. RESULTS: Twenty-two of 43 patients suffered from MOGAD-related pain (11 nociceptive, eight definite neuropathic, three possible neuropathic) and 18 from depression. Patients with neuropathic pain had the highest pain intensity and most profound activities of daily living (ADL) impairment. Fifteen patients reported spasticity-associated pain, including four with short-lasting painful tonic spasms. Later disease onset, profound physical impairment, and depression were associated with chronic pain. Physical QoL was more affected in pain sufferers (p < 0.001) than in pain-free patients, being most severely reduced by neuropathic pain (p = 0.016). Pain severity, visual impairment, and gait impairment independently predicted lower physical QoL. Depression was the only factor reducing mental QoL. Twelve patients still suffering from moderate pain (pain severity 4.6 ± 2.3) received pain medication. Only four out of 10 patients with moderate to severe depression took antidepressants. CONCLUSIONS: Being highly prevalent, pain and depression strongly affect QoL and ADL in MOGAD. Both conditions remain insufficiently controlled in real-life clinical practice.

Status of clinical research in neurology in Germany-A national survey.

BACKGROUND AND PURPOSE: To provide an overview on the status of clinical research in neurology in Germany. METHODS: German university hospitals, nonuniversity hospitals, and neurological medical practices were surveyed regarding their clinical research activities during the period 2013 to 2017. RESULTS: Fifty percent of university hospitals, 10.6% of nonuniversity hospitals, and 5.2% of medical practices in Germany responded to our questionnaire. More than 80% of the clinical studies conducted have been phase III/IV and noninterventional trials (NISs), whereas <1% have been phase I and 3.5% investigator-initiated trials (IITs). University hospitals have conducted most of the phase II-IV trials. NISs have been predominantly performed by medical practices. Fifty-six percent of the university hospitals and less of the nonuniversity institutions confirmed the implementation of standard operating procedures (SOPs). In university hospitals, on average, 11 physicians had acquired a good clinical practice certificate. Overall, 43% of all trials have been performed in neuroimmunology. CONCLUSIONS: The status of clinical research in neurology in Germany is predominated by NISs and late-phase trials, potentially due to a general lack of easily accessible funding, which leads to a highly competitive environment and fewer opportunities to perform early-phase clinical trials as well as IITs. Our results indicate that there is substantial need for structured support for creating and implementing SOPs to maintain quality standards and guarantee uniformity of performance. This survey assessed many aspects of clinical research and serves as guidance for providing ideas for structured improvement of clinical research in neurology in Germany.

The STING-IFN-ß-Dependent Axis Is Markedly Low in Patients with Relapsing-Remitting Multiple Sclerosis.

Cyclic GMP-AMP-synthase is a sensor of endogenous nucleic acids, which subsequently elicits a stimulator of interferon genes (STING)-dependent type I interferon (IFN) response defending us against viruses and other intracellular pathogens. This pathway can drive pathological inflammation, as documented for type I interferonopathies. In contrast, specific STING activation and subsequent IFN-ß release have shown beneficial effects on experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Although less severe cases of relapse-remitting MS (RRMS) are treated with IFN-ß, there is little information correlating aberrant type I IFN signaling and the pathologic conditions of MS. We hypothesized that there is a link between STING activation and the endogenous production of IFN-ß during neuroinflammation. Gene expression analysis in EAE mice showed that Sting level decreased in the peripheral lymphoid tissue, while its level increased within the central nervous system over the course of the disease. Similar patterns could be verified in peripheral immune cells during the acute phases of RRMS in comparison to remitting phases and appropriately matched healthy controls. Our study is the first to provide evidence that the STING/IFN-ß-axis is downregulated in RRMS patients, meriting further intensified research to understand its role in the pathophysiology of MS and potential translational applications.

Association of Clinical Relapses With Disease Outcomes in Multiple Sclerosis Patients Older Than 50 Years.

BACKGROUND AND OBJECTIVES: Relapse and MRI activity usually decline with aging but are replaced by progression independent of relapse activity (PIRA) in patients with multiple sclerosis (PwMS). However, several older PwMS continue to experience clinical relapses, and the impact on their disease remains undetermined. We aimed to determine the impact of an index relapse on disease outcomes in patients older than 50 years and to identify risk factors of disadvantageous outcomes. METHODS: We performed a secondary analysis from 3 prospective cohorts in Germany. We evaluated all PwMS 50 years and older with a relapse ≤60 days before a baseline visit and at least 18 months of follow-up compared with a control cohort of PwMS without a relapse. Patients were stratified according to age ("50-54" vs "55-59" vs "60+") or disease outcomes ("stable" vs "active" vs "progressive," according to the Lublin criteria). We analyzed relapses, MRI activity, relapse-associated worsening, and PIRA. Regression analysis was performed to evaluate the association of specific baseline risk factors and treatment regimen changes with disease outcomes at month 18. RESULTS: A total of 681 patients were included in the "relapse cohort" (50+: 361; 55+: 220; 60+: 100). The "control cohort" comprised 232 patients (50+: 117; 55+: 71; 60+: 44). Baseline epidemiologic parameters were balanced among cohorts and subgroups. We observed increased abundance of inflammatory activity and relapse-independent disability progression in the "relapse" vs "control" cohort. In the "relapse" cohort, we identified 273 patients as "stable" (59.7%), 114 patients as "active" (24.9%), and 70 patients as "progressive" (15.3%) during follow-up. Cardiovascular risk factors (CVRFs) and older age at baseline were identified as risk factors of progressive, whereas disease-modifying treatment (DMT) administration at baseline favored stable disease. DMT during follow-up was associated with stable over active, but not over progressive disease. DISCUSSION: A relapse-suggesting underlying active disease-in PwMS older than 50 years was associated with continued disease activity and increased risk of PIRA. Presence of CVRF and absence of DMT at baseline appeared as risk factors of disadvantageous disease courses. An escalation of DMT switch was associated with stable over active but not progressive disease.

Immune Response to Seasonal Influenza Vaccination in Multiple Sclerosis Patients Receiving Cladribine.

Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration.

Effect of Previous Disease-Modifying Therapy on Treatment Effectiveness for Patients Treated With Ocrelizumab.

BACKGROUND AND OBJECTIVES: B cell-depleting antibodies were proven as effective strategy for the treatment of relapsing multiple sclerosis (RMS). The monoclonal antibody ocrelizumab was approved in 2017 in the United States and in 2018 in the European Union, but despite proven efficacy in randomized, controlled clinical trials, its effectiveness in the real-world setting remains to be fully elucidated. In particular, most study patients were treatment naive or switched from injectable therapies, whereas oral substances or monoclonal antibodies made up >1% of previous treatments. METHODS: We evaluated ocrelizumab-treated patients with RMS enrolled in the prospective cohorts at the University Hospitals Duesseldorf and Essen, Germany. Epidemiologic data at baseline were compared, and Cox proportional hazard models were applied to evaluate outcomes. RESULTS: Two hundred eighty patients were included (median age: 37 years, 35% male patients). Compared with using ocrelizumab as a first-line treatment, its use as a third-line therapy increased hazard ratios (HRs) for relapse and disability progression, whereas differences between first- vs second-line and second- vs third-line remained smaller. We stratified patients according to their last previous disease-modifying treatment and here identified fingolimod (FTY) (45 patients, median age 40 years, 33% male patients) as a relevant risk factor for ongoing relapse activity despite 2nd-line (HR: 3.417 [1.007-11.600]) or 3rd-line (HR: 5.903 [2.489-13.999]) ocrelizumab treatment, disability worsening (2nd line: HR: 3.571 [1.013-12.589]; 3rd line: HR: 4.502 [1.728-11.729]), and occurrence of new/enlarging MRI lesions (2nd line: HR: 1.939 [0.604-6.228]; 3rd line: HR: 4.627 [1.982-10.802]). Effects were persistent throughout the whole follow-up. Neither peripheral B-cell repopulation nor immunoglobulin G levels were associated with rekindling disease activity. DISCUSSION: Our prospectively collected observational data suggest suboptimal effectiveness of ocrelizumab in patients switching from FTY compared with those switching from other substances or having been treatment naive. These findings support previous studies indicating abated effectiveness of immune cell-depleting therapies following FTY treatment in patients with RMS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RMS, previous treatment with FTY compared with previous treatment with other immunomodulating therapies decreases the effectiveness of ocrelizumab.

Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod-potentials and risks of subsequent highly active agents.

A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.

Comparative effectiveness of natalizumab versus ocrelizumab in multiple sclerosis: a real-world propensity score-matched study.

Background: For treatment of relapsing-remitting multiple sclerosis (RRMS), a broad range of disease-modifying therapies (DMT) is available. However, few comparative effectiveness studies between different drugs have been performed. Objectives: This study aimed to compare the efficacy and treatment continuation of natalizumab and ocrelizumab in a real-world cohort of patients with relapsing-remitting multiple sclerosis (RRMS) from two German university hospitals. Methods: We performed a retrospective analysis of RRMS patients who initiated treatment with natalizumab or ocrelizumab between January 2016 and April 2019 at the German university hospitals of Mainz and Düsseldorf. Bayesian propensity score matching was conducted to correct for differences in baseline characteristics. Our primary outcome was no evidence of disease activity [NEDA-3: no relapses, no confirmed disability progression, and no magnetic resonance imaging (MRI) activity] and its subcomponents. Secondary outcomes included measurement of neurofilament light chain (NfL) in serum, analysis of premature discontinuation, and evidence of rebound activity in patients switching from natalizumab to ocrelizumab. Results: We identified 63 patients starting treatment with natalizumab and 76 patients starting with ocrelizumab. Binary logistic regression showed that treatment with natalizumab or a higher number of relapses in the previous year were independently associated with a higher risk for relapses. Patients receiving natalizumab had a higher probability of premature discontinuation of therapy (p = 0.002). After propensity score matching of the two treatment arms, 55 patients remained per group. NEDA-3 after 30 months of follow-up was reached by 53.1% in the ocrelizumab group and 36.1% in the natalizumab group (p = 0.177). Ocrelizumab was superior to natalizumab concerning the occurrence of relapses in log-rank test (p = 0.019). NfL levels in serum were low under both treatments. Patients who switched from natalizumab to ocrelizumab showed no increased rebound activity. Discussion: This study provides class IV evidence that treatment of RRMS patients with ocrelizumab and natalizumab show comparable effectiveness in combined endpoints, while ocrelizumab might be more effective in preventing the occurrence of relapses.

A national, multi-center study in Germany to assess implementation of infusion management, treatment satisfaction and quality of life in MS patients receiving alemtuzumab.

BACKGROUND: Alemtuzumab is an anti-CD52 antibody approved for the treatment of relapsing remitting multiple sclerosis (RRMS). The summary of product characteristics (SmPC) provides recommendations on the administration of alemtuzumab to prevent or reduce the risk of serious side effects associated with alemtuzumab infusion, including myocardial ischemia, hemorrhagic stroke, arterial dissection, and pulmonary alveolar hemorrhage. However, real-world implementation of alemtuzumab infusion management recommendations has not been previously assessed. METHODS: Here we provide a large-scale multi-center (in- and outpatient) observational study on alemtuzumab infusion management in daily clinical care in Germany (ALEMLL08025; INFUSE-MS; NIS-no. 364). Parameters of infusion management - including infusion administration, clinical and laboratory monitoring - were assessed, compared between study centers and the occurrence of infusion-associated reactions (IARs) was documented. Moreover, the TSQM and MSIS-29 questionnaires were used to quantify patient satisfaction and health-related quality of life. RESULTS: 140 RRMS patients were enrolled in this study. Alemtuzumab infusion regimes (treatment course 1 and 2) were comparable between infusion sites and in accordance with recommendations by the SmPC. Standardization of infusion management was associated with a satisfactory safety profile. IARs were usually mild, headache (13.6%), rash (10.7%), and pyrexia (6.4%) being the most common ones. TSQM and MSIS-29 scores denoted high patient satisfaction and health-related quality of life among RRMS patients treated with alemtuzumab. CONCLUSION: In conclusion, our results indicate that infusion management of alemtuzumab is highly standardized and in line with the SmPC. Alemtuzumab treatment and implementation of infusion management recommendations are associated with a satisfactory safety profile regarding the occurrence of IARs, a high patient satisfaction and health-related quality of life as important indicators for the quality of MS care.

Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis.

BACKGROUND: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing-remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. METHODS: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. RESULTS: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. CONCLUSION: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE.

Vaccine-based clinical protection against SARS-CoV-2 infection and the humoral immune response: A 1-year follow-up study of patients with multiple sclerosis receiving ocrelizumab.

Introduction: Given the varying severity of coronavirus disease 2019 (COVID-19) and the rapid spread of Severe-Acute-Respiratory-Syndrome-Corona-Virus-2 (SARS-CoV-2), vaccine-mediated protection of particularly vulnerable individuals has gained increasing attention during the course of the pandemic. Methods: We performed a 1-year follow-up study of 51 ocrelizumab-treated patients with multiple sclerosis (OCR-pwMS) who received COVID-19 vaccination in 2021. We retrospectively identified 37 additional OCR-pwMS, 42 pwMS receiving natalizumab, 27 pwMS receiving sphingosine 1-phosphate receptor modulators, 59 pwMS without a disease-modifying therapy, and 61 controls without MS (HC). In OCR-pwMS, anti-SARS-CoV-2(S)-antibody titers were measured prior to the first and after the second, third, and fourth vaccine doses (pv2/3/4). The SARS-CoV-2-specific T cell response was analyzed pv2. SARS-CoV-2 infection status, COVID-19 disease severity, and vaccination-related adverse events were assessed in all pwMS and HC. Results: We found a pronounced and increasing anti-SARS-CoV-2(S)-antibody response after COVID-19 booster vaccinations in OCR-pwMS (pv2: 30.4%, pv3: 56.5%, and pv4 90.0% were antibody positive). More than one third of OCR-pwMS without detectable antibodies pv2 developed positive antibodies pv3. 23.5% of OCR-pwMS had a confirmed SARS-CoV-2 infection, of which 84.2% were symptomatic. Infection rates were comparable between OCR-pwMS and control groups. None of the pwMS had severe COVID-19. An attenuated humoral immune response was not associated with a higher risk of SARS-CoV-2 infection. Discussion: Additional COVID-19 vaccinations can boost the humoral immune response in OCR-pwMS and improve clinical protection against COVID-19. Vaccines effectively protect even OCR-pwMS without a detectable COVID-19 specific humoral immune response, indicating compensatory, e.g., T cell-mediated immunological mechanisms.

Skin Reactions in Patients With Multiple Sclerosis Receiving Cladribine Treatment.

OBJECTIVE: To report 77 patients with multiple sclerosis (MS) who developed skin-related adverse events (AEs) following treatment with cladribine. METHODS: We evaluated our prospective bicentric cladribine cohort. Cladribine-treated patients with a skin AE were identified. RESULTS: Two hundred thirty-nine cladribine-treated patients with MS were evaluated. Seventy-seven patients (32%) showed at least 1 skin AE at median 1 month after cladribine initiation (range: 1-12). Within first 3 months following last cladribine exposition, hair thinning (n = 28, 12%), skin rash (n = 20; 8%), mucositis (n = 13, 5%), and pruritus (n = 6, 3%) were observed. Furthermore, 35 patients (15%) developed herpes virus infections (time since last cladribine exposition: median 83 [range: 10-305]). In 15 patients, herpes zoster infection was severe (CTCAE grade ≥ 3) and required hospitalization. Delayed skin AEs (≥3 months after a cladribine treatment cycle) involved 1 case of leukocytoclastic vasculitis and 2 cases of alopecia areata. Finally, 2 patients presented with in total 3 isolated precancerous lesions (1 leukoplakia simplex and 2 actinic keratosis) and 1 patient developed a squamous cell carcinoma. CONCLUSION: Skin AEs are common in patients with MS treated with cladribine. Until risk management plans have been adjusted to include these phenomena, clinicians should perform a thorough clinical follow-up and in suspicious cases seek early interdisciplinary support. In light of the observed delayed skin reactions, we further emphasize the necessity of careful clinical surveillance of cladribine-treated patients for yet undescribed secondary autoimmune events. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that skin-related AEs are frequent in patients with MS following cladribine in a real-world setting.

Dalfampridine effects on cognition, fatigue, and dexterity.

OBJECTIVES: Dalfampridine exerts beneficial effects on walking ability in a subgroup of patients with multiple sclerosis (MS). These patients are termed "responders". Here, we investigated whether the responder status with respect to mobility measures would determine whether dalfampridine treatment exerts a beneficial effect on other MS symptoms. We therefore assessed walking ability, upper limb function, cognition, fatigue, visual evoked potentials (VEPs), depression, and quality of life in patients before and after dalfampridine treatment. METHODS: Patients with MS and impaired mobility were recruited. Maximal walking distance, timed 25 Foot Walk, nine hole peg test, paced auditory serial addition test (PASAT), fatigue severity scale (FSS), VEPs, Beck Depression Inventory (BDI), EuroQol five dimensional questionnaire, and quality of life visual analogue scale were determined before and after 12-14 days of dalfampridine treatment. Repeated measures analysis of variance was applied to determine the effect of dalfampridine treatment. RESULTS: Of the 34 patients who completed the study, 22 patients were responders and 12 patients nonresponders, according to their performance in mobility measures. Treatment effects for the entire patient cohort were observed for PASAT (p = .029) and BDI (p = .032). Belonging to the responder cohort did not predict the response to treatment in these tests. For the FSS, response to dalfampridine treatment was dependent on the responder status (p = .001) while no effects in the total patient cohort were observed (p = .680). Other neurological functions remained unaltered. For VEP latencies, no significant improvements were detected. CONCLUSION: In this study, we observed beneficial effects of dalfampridine on cognition, depression, and fatigue. These effects were not limited to patients who responded to dalfampridine with improved mobility measures. These findings underscore the need to assess the beneficial effects of dalfampridine on neurological deficits in MS patients in additional randomized clinical trials.

Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells.

BACKGROUND AND OBJECTIVES: Cladribine is a cytotoxic drug which ameliorates the clinical course of relapsing-remitting multiple sclerosis. In addition to cytotoxicity, the mode of action may include immunomodulatory mechanisms. This in vitro study was designed to investigate cladribine's effects on cell function after the removal of cladribine to distinguish cytotoxic versus immunomodulatory effects. METHODS: Cells were incubated in the absence or presence of cladribine (1 × 10(-8) M to 1 × 10(-5) M) for 72 h. Cladribine was removed from the cell culture and surviving peripheral blood mononuclear cells were cultured up to 58 days to determine the immunomodulatory effects of cladribine on cell function (e.g., proliferation and cytokine release). RESULTS: In the long-term, brief cladribine exposure did not impair the proliferation of surviving peripheral blood mononuclear cells. However, it induced an anti-inflammatory shift in the cytokine milieu with significantly enhanced release of IL-4 (Days 9 and 44, p<0.01; Day 58, p<0.05) and IL-5 (Day 9, p<0.01), resulting in an increased IL-4/INF-gamma ratio (Days 9 and 44, p<0.01; Day 58, p<0.05). Additionally, a trend towards an increased IL-10 production was observed. No changes were found in the production of IFN-gamma, TNF-alpha, IL-6, IL-8, IL-17A, IL-23 or NGF-beta. CONCLUSIONS: In vitro cladribine exposure induces a sustained anti-inflammatory shift in the cytokine profile of surviving peripheral blood mononuclear cells. This immunomodulatory action might contribute to cladribine's beneficial effects in the treatment of multiple sclerosis.