Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study.

BACKGROUND: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis. OBJECTIVE: Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension. METHODS: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS < 6) at any time since LPSD). RESULTS: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3-14.9) years. Cladribine tablets-exposed population: 90.6% (N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%. CONCLUSION: With a median 10.9 years' follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets.

Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies.

BACKGROUND: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment. OBJECTIVE: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension. METHODS: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT (n = 433) and placebo (n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension (n = 98). RESULTS: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p < 0.0001), and qualifying or all severe relapses (all p < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment. CONCLUSION: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis.CLARITY: NCT00213135; CLARITY Extension: NCT00641537.

Increased multiple sclerosis disease activity in patients transitioned from fingolimod to dimethyl fumarate: a case series.

BACKGROUND: Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal. CASE PRESENTATION: We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490-1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses. CONCLUSION: The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.

BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).

Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study.

BACKGROUND: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis. OBJECTIVE: Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. METHODS: Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions). RESULTS: In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. CONCLUSION: Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population.

Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.

BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.

Impaired retinal microcirculation in multiple sclerosis.

BACKGROUND: The transparent ocular structure enables quantitative analysis of microvasculature of retina, a neuronal tissue affected by multiple sclerosis (MS). OBJECTIVE: The aim of this study was to determine whether the retinal blood flow velocity and flow volume at the macula are impaired in patients with relapsing remitting multiple sclerosis (RRMS). METHODS: A total of 17 RRMS patients and 17 age- and gender-matched healthy subjects were assessed. A retinal function imager was used to measure the blood flow velocity of retinal arterioles and venules and to calculate the total perifoveal blood flow volume. RESULTS: The blood flow velocities of the retinal arterioles (3.34 ± 0.89 mm/s) and venules (2.61 ± 0.6 mm/s) were significantly lower in MS patients than normal subjects (arteriole: 4.10 ± 0.87 mm/s; venule: 3.22 ± 0.65 mm/s, both p = 0.01). In addition, the total perifoveal blood flow volume in arterioles (3.74 ± 1.64 nL/s) and venules (3.81 ± 1.60 nL/s) were significantly lower in MS patients than in normal subjects (arteriole: 4.87 ± 1.41 nL/s, p = 0.02; venule: 4.71 ± 1.64 nL/s, p = 0.04). CONCLUSION: The impaired retinal microcirculation in RRMS patients indicates microvascular dysfunction in MS.

Clinical Expression of Multiple Sclerosis in Hispanic Whites of Primarily Caribbean Ancestry.

OBJECTIVE: The clinical characteristics of multiple sclerosis (MS) are not well defined in Hispanic populations. We hypothesized that disease presentation in Hispanic white (HW) patients will be different from non-Hispanic white (NHW) patients given their ancestral background and reported lower disease prevalence. This study was undertaken to compare HW of primarily Caribbean ancestry to NHW on clinical characteristics of MS. METHODS: We assessed 312 HW and 312 NHW patients with definite MS for clinical disease characteristics obtained through consented review of medical records. In order to assess the relationship between age-related phenotypes and ethnicity, linear regression was used. Logistic regression was used to assess the relationship between ethnicity and descriptors of disease presentation and severity as well as presence of neurological symptoms. RESULTS: We observed a significantly younger age at diagnosis (p = 1.38E-02) and age at exam (p = 2.36E-05) in HW. However, age at first symptom did not differ significantly between the two groups. Furthermore, within HW, the mean age at first symptom and age at diagnosis was significantly younger in those born in the United States (p < 1.00E-03 for both). Interestingly, we noted an increase in ambulatory disability in HW patients, primarily among those with relapsing disease (p = 4.18E-03). CONCLUSIONS: We found several differences in age-related phenotypes and disease severity between HW of primarily Caribbean origin and NHW patients. To our knowledge, this is the largest study to date that examined the clinical characteristics of MS in Hispanic patients of largely Caribbean origin.

CNS demyelinating disorder with mixed features of neuromyelitis optica and multiple sclerosis in HIV-1 infection. Case report and literature review.

An African-American male presented with bilateral visual impairment, gait difficulties, and bladder and bowel incontinence raising concerns for multiple sclerosis (MS) or neuromyelitis optica (NMO). He was identified to be HIV-1 infected with high viral load and low CD4+ counts. Magnetic resonance imaging (MRI) of the brain was abnormal, but atypical for MS. MRI of the cervical and thoracic spinal cord showed multiple areas of myelitis with a longitudinally extensive thoracic transverse myelitis that showed enhancement with gadolinium suggestive of NMO. Cerebrospinal fluid showed oligoclonal IgG bands but did not show reactivity to aquaporin 4. Patient underwent treatment for the acute exacerbation with intravenous corticosteroids and treatment of the HIV infection with highly active antiretroviral therapy (HAART). A year later, his viral load was <20 copies/ml and CD4+ counts were normal. Vision did not significantly improve, but his ambulation improved from a near total non-ambulatory state to ambulating without aids and resolution of the bladder and bowel incontinence. A demyelinating disorder of the central nervous system (CNS) like MS or NMO has been previously reported in the context of HIV infection. The remarkable improvement of symptoms has also been previously reported with HAART, and these observations have led to clinical trials of MS with HAART therapy in the absence of HIV infection. We reviewed the few cases of CNS demyelinating disorders with HIV infection reported in the literature and speculate on the mechanisms of pathogenesis.

Identification and management of subclinical disease activity in early multiple sclerosis: a review.

IMPORTANCE: Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of disease activity relies on relapse rates and magnetic resonance imaging (MRI) lesion activity, but inclusion of other early, often "hidden," indicators of disease activity may describe a more comprehensive picture of MS. OBSERVATIONS: Early indicators of MS disease activity other than relapses and MRI activity, such as cognitive impairment, brain atrophy, and fatigue, are not typically captured by routine disease monitoring. Furthermore, silent progression (neurological decline not clearly captured by standard methods) may occur undetected by relapse and MRI lesion activity monitoring. Consequently, patients considered to have no disease activity actually may have worsening disease, suggesting a need to revise MS management strategies with respect to timely initiation and escalation of disease-modifying therapy (DMT). Traditionally, first-line MS treatment starts with low- or moderate-efficacy therapies, before escalating to high-efficacy therapies (HETs) after evidence of breakthrough disease activity. However, multiple observational studies have shown that early initiation of HETs can prevent or reduce disability progression. Ongoing randomized clinical trials are comparing escalation and early HET approaches. CONCLUSIONS AND RELEVANCE: There is an urgent need to reassess how MS disease activity and worsening are measured. A greater awareness of "hidden" indicators, potentially combined with biomarkers to reveal silent disease activity and neurodegeneration underlying MS, would provide a more complete picture of MS and allow for timely therapeutic intervention with HET or switching DMTs to address suboptimal treatment responses.

Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment.

The recent success of anti-CD20 monoclonal antibody therapies in the treatment of multiple sclerosis (MS) has highlighted the role of B cells in the pathogenesis of MS. In people with MS, the inflammatory characteristics of B-cell activity are elevated, leading to increased pro-inflammatory cytokine release, diminished anti-inflammatory cytokine production and an accumulation of pathogenic B cells in the cerebrospinal fluid. Rituximab, ocrelizumab, ofatumumab, ublituximab and BCD-132 are anti-CD20 therapies that are either undergoing clinical development, or have been approved, for the treatment of MS. Despite CD20 being a common target for these therapies, differences have been reported in their mechanistic, pharmacological and clinical characteristics, which may have substantial clinical implications. This narrative review explores key characteristics of these therapies. By using clinical trial data and real-world evidence, we discuss their mechanisms of action, routes of administration, efficacy (in relation to B-cell kinetics), safety, tolerability and convenience of use. Clinicians, alongside patients and their families, should consider the aspects discussed in this review as part of shared decision-making discussions to improve outcomes and health-related quality of life for people living with MS.

A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.

BACKGROUND: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis. METHODS: We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. RESULTS: Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients). CONCLUSIONS: Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135.)

Secondary hypogammaglobulinemia in patients with multiple sclerosis on anti-CD20 therapy: Pathogenesis, risk of infection, and disease management.

Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.

A plain language summary on assessing the long-term effectiveness of cladribine tablets in people living with relapsing multiple sclerosis: The CLASSIC-MS study.

WHAT IS THIS SUMMARY ABOUT?: Previous studies have shown that people living with multiple sclerosis (MS) treated with cladribine tablets have fewer relapses (where new symptoms occur or existing symptoms get worse for 24 hours or more) and delayed disability progression (slowing down of the disease getting worse). The CLASSIC-MS study looked at the long-term effectiveness of treatment with cladribine tablets in people living with MS who had taken part in the original CLARITY and CLARITY Extension clinical studies. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets maintained their mobility (the ability to move freely) for longer and experienced other positive effects long after their treatment ended, including being less likely to need further treatment for their MS. WHAT DO THE RESULTS MEAN?: The results obtained from CLASSIC-MS show that the benefits of taking cladribine tablets carry on even when patients stop taking the treatment.

Bruton's Tyrosine Kinase Inhibitors: The Next Frontier of B-Cell-Targeted Therapies for Cancer, Autoimmune Disorders, and Multiple Sclerosis.

Bruton's tyrosine kinase (BTK) is an important protein belonging to the tyrosine kinase family that plays a key role in the intracellular signaling and proliferation, migration, and survival of normal and malignant B-lymphocytes and myeloid cells. Understanding the role of BTK in the B-cell signaling pathway has led to the development of BTK inhibitors (BTKi) as effective therapies for malignancies of myeloid origin and exploration as a promising therapeutic option for other cancers. Given its central function in B-cell receptor signaling, inhibition of BTK is an attractive approach for the treatment of a wide variety of autoimmune diseases that involve aberrant B-cell function including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Here, we review the role of BTK in different cell signaling pathways, the development of BTKi in B-cell malignancies, and their emerging role in the treatment of MS and other autoimmune disorders.

Disease stability over five years in people with multiple sclerosis treated with cladribine tablets: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article originally published in the journal Advances in Therapy. Cladribine tablets are approved for treating people with relapsing multiple sclerosis (shortened to MS). People with MS take cladribine tablets for 2 periods of 4 to 5 days per year. This analysis looks at the results from 2 studies called the CLARITY and CLARITY Extension studies. These studies looked at what effect a 2-year course of treatment with cladribine tablets had on disability over 5 years in people with MS. HOW WAS THE ANALYSIS CARRIED OUT?: In this analysis, researchers measured disability worsening at regular intervals during the 2-year treatment period in the CLARITY study and thereafter in the 2-year CLARITY Extension study. As many patients had a bridging interval between CLARITY and CLARITY extension, the researchers were able to assess disability over a 5-year timeframe. WHAT WERE THE RESULTS?: When measurements were taken at Year 5 of the study, disability remained stable in more than half of participants. Over the 5-year period, 70% of participants did not experience persistent disease worsening that lasted more than 6 months. WHAT DO THE RESULTS MEAN?: Researchers concluded that a 2-year course of cladribine tablets may provide long-term benefits on disability for up to 5 years. Clinical Trial Registration: NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration: NCT00641537 (ClinicalTrials.gov).

Relapses in people with multiple sclerosis treated with cladribine tablets followed for up to 5 years: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article originally published in the Multiple Sclerosis Journal. The article presents the results from the CLARITY and CLARITY Extension studies, which looked at how well cladribine tablets work in treating people with multiple sclerosis (shortened to MS). Cladribine tablets are a medication approved for treating relapsing forms of MS. This study looked at how treatment with cladribine tablets affects the frequency and severity of relapses in people with MS. A relapse is when new symptoms develop or old symptoms return or get worse after a period of stability or improvement. WHAT HAPPENED IN THE STUDIES?: In the CLARITY study, 870 people received either cladribine tablets (3.5 mg/kg, the approved dose) or placebo (a dummy pill). After the CLARITY study ended, some participants who received cladribine tablets chose to take part in a second study called the CLARITY Extension study. Of these participants, 98 were given placebo for 2 more years following an interval period of up to 10 months between participating in each study. WHAT WERE THE RESULTS?: People with MS who were treated with cladribine tablets for 2 years in the CLARITY study had lower risks of any relapse compared with those given placebo. Participants taking placebo (after cladribine tablets) in the CLARITY Extension study experienced these same benefits, which continued for up to 3 more years after having received cladribine tablets in the CLARITY study. WHAT DO THE RESULTS MEAN?: Researchers concluded the recommended 2-year dosing of cladribine tablets may reduce the number and severity of relapses in people with MS for up to 5 years. Clinical Trial Registration: NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration: NCT00641537 (ClinicalTrials.gov).

COVID-19 in the pregnant or postpartum MS patient: Symptoms and outcomes.

Women with multiple sclerosis (MS) are often of childbearing age. Thirty-six women with MS who were pregnant (n = 27) or within 6 weeks postpartum (n = 9) were reported in the North American COViMS registry and their COVID-19 outcomes were described. One pregnant and one postpartum woman were hospitalized. No deaths occurred. To compare COVID-19 clinical outcomes in pregnant and postpartum females with females who were not pregnant or postpartum, a 1:2 propensity score match was performed. While not powered to detect small differences, it was reassuring that no increased risks for those with MS who were pregnant/postpartum were revealed.