SARS-CoV-2 mRNA vaccines decouple anti-viral immunity from humoral autoimmunity.

mRNA-based vaccines dramatically reduce the occurrence and severity of COVID-19, but are associated with rare vaccine-related adverse effects. These toxicities, coupled with observations that SARS-CoV-2 infection is associated with autoantibody development, raise questions whether COVID-19 vaccines may also promote the development of autoantibodies, particularly in autoimmune patients. Here we used Rapid Extracellular Antigen Profiling to characterize self- and viral-directed humoral responses after SARS-CoV-2 mRNA vaccination in 145 healthy individuals, 38 patients with autoimmune diseases, and 8 patients with mRNA vaccine-associated myocarditis. We confirm that most individuals generated robust virus-specific antibody responses post vaccination, but that the quality of this response is impaired in autoimmune patients on certain modes of immunosuppression. Autoantibody dynamics are remarkably stable in all vaccinated patients compared to COVID-19 patients that exhibit an increased prevalence of new autoantibody reactivities. Patients with vaccine-associated myocarditis do not have increased autoantibody reactivities relative to controls. In summary, our findings indicate that mRNA vaccines decouple SARS-CoV-2 immunity from autoantibody responses observed during acute COVID-19.

Cutting Edge: Effect of Disease-Modifying Therapies on SARS-CoV-2 Vaccine-Induced Immune Responses in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS treated by diverse disease-modifying therapies that suppress the immune system. Severe acute respiratory syndrome coronavirus 2 mRNA vaccines have been very effective in immunocompetent individuals, but whether MS patients treated with modifying therapies are afforded the same protection is not known. This study determined that dimethyl fumarate caused a momentary reduction in anti-Spike (S)-specific Abs and CD8 T cell response. MS patients treated with B cell-depleting (anti-CD20) or sphingosine 1-phosphate receptor agonist (fingolimod) therapies lack significant S-specific Ab response. Whereas S-specific CD4 and CD8 T cell responses were largely compromised by fingolimod treatment, T cell responses were robustly generated in anti-CD20-treated MS patients, but with a reduced proportion of CD4+CXCR5+ circulating follicular Th cells. These data provide novel information regarding vaccine immune response in patients with autoimmunity useful to help improve vaccine effectiveness in these populations.

Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis.

BACKGROUND: In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia. OBJECTIVE: We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate in routine practice. METHODS: Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6-month intervals following dimethyl fumarate initiation. RESULTS: Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 109/l) decreased by ∼39% (95% confidence interval: -41.1 to -37.2) by month 6 and 44% (95% confidence interval: -46.6 to -42.1) by month 12. CD4+ and CD8+ T-cell subsets strongly correlated with absolute lymphocyte count, with greater decreases from baseline to 6 months vs 6-12 months, and in CD8+ vs CD4+ T cells. Prior natalizumab was not a risk factor for lymphopenia. CONCLUSION: Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia.

Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype.

Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.

S1P1 deletion differentially affects TH17 and Regulatory T cells.

Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL-17A Cre and Foxp3 Cre mice, respectively. Deletion of S1P1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P1 in Treg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P1 not only regulated the egress of Treg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the Treg cells found in S1P1-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector Treg. Our results provide novel insight into the functions of S1P1 and potential impact of long term fingolimod use on Th17 and Treg cell biology and general health in MS patients.

Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis.

BACKGROUND: Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis. OBJECTIVE: To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials. METHODS: Patients who were treatment naive (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36). RESULTS: Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS. CONCLUSION: Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.

Distinct T cell signatures define subsets of patients with multiple sclerosis.

OBJECTIVE: We investigated T cell responses to myelin proteins in the blood of healthy controls and 2 groups of patients with relapsing-remitting multiple sclerosis (RRMS) who exhibited lesions either predominantly in the brain or predominantly in the spinal cord in order to assess whether distinct neuroinflammatory patterns were associated with different myelin protein-specific T cell effector function profiles and whether these profiles differed from healthy controls. METHODS: Peripheral blood mononuclear cells were obtained from patients with brain-predominant RRMS, patients with spinal cord-predominant RRMS, and age-matched healthy controls and analyzed by enzyme-linked immunosorbent spot assays to quantify interferon gamma-secreting (Th1) and interleukin 17-secreting (Th17) cells responding directly ex vivo to myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). RESULTS: Although MBP and MOG elicited different responses, patients with multiple sclerosis (MS) who had spinal cord-predominant lesions exhibited significantly higher Th17:Th1 ratios in response to both MBP and MOG compared to patients with brain-predominant MS. Incorporating the cytokine responses to both antigens into logistic regression models showed that these cytokine responses were able to provide good discrimination between patients with distinct neuroinflammatory patterns. CONCLUSIONS: Our findings suggest that the localization of lesions within the brain vs the spinal cord in patients with MS is associated with different effector T cell responses to myelin proteins. Further investigation of the relationship between T cell effector function, antigen specificities, and lesion sites may reveal features of pathogenic pathways that are distinct to patients with different neuroinflammatory patterns.

Relapses Requiring Intravenous Steroid Use and Multiple-Sclerosis-related Hospitalizations: Integrated Analysis of the Delayed-release Dimethyl Fumarate Phase III Studies.

PURPOSE: The purpose was to report the effects of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on the number of relapses requiring intravenous (IV) steroids and multiple sclerosis (MS)-related hospitalizations using integrated data from the Phase III DEFINE and CONFIRM studies. METHODS: DEFINE and CONFIRM were randomized, double-blind, placebo-controlled, multicenter studies that evaluated the efficacy and safety of DMF over a 2-year period in patients with relapsing-remitting MS (RRMS). Patients were randomized (1:1:1) to receive oral DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only). Eligible subjects (aged 18-55 years) had an EDSS score of 0-5.0 and experienced either ≥1 relapse in the 12 months or had ≥1 gadolinium-enhanced lesion on brain MRI in the 6 weeks, before randomization. Data DEFINE and CONFIRM were pooled and analyzed using a negative binomial regression model (adjusted for study and region). Data obtained after subjects switched to an alternative MS therapy were not included in the analysis. Only relapses confirmed by the Independent Neurology Evaluation Committee were included in the analysis of relapses requiring IV steroids. FINDINGS: The study population (intention-to-treat) comprised 2301 patients who received either placebo (n = 771), DMF BID (n = 769), or DMF TID (n = 761). Baseline demographic and disease characteristics were generally well balanced among treatment groups. Throughout the 2-year studies, the total number of relapses treated with methylprednisolone was 402, 221, and 209 in the placebo, DMF BID, and DMF TID groups, respectively. A smaller proportion of patients in the DMF BID (168 of 769 [21.8%]) and DMF TID (151 of 761 [19.8%]) groups experienced ≥1 relapse requiring IV steroids compared with the placebo group (284 of 771 [36.8%]). The total number of MS-related hospitalizations over 2 years was 136, 94, and 74 in the placebo, DMF BID, and DMF TID groups. A smaller proportion of patients in the DMF BID (73 of 769 [9.5%]) and DMF TID (57 of 761 [7.5%]) groups had ≥1 MS-related hospitalization compared with the placebo group (104 of 771 [13.5%]). IMPLICATIONS: DMF is an effective and well tolerated therapy for RRMS. In addition to clinical benefits, the use of DMF may be associated with reduced patient burden and health economic savings, resulting from a decrease in resource utilization associated with relapses. ClinicalTrials.gov identifiers: NCT00420212 and NCT00451451.

Efficacy of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis: integrated analysis of the phase 3 trials.

OBJECTIVE: Obtain a more precise estimate of the efficacy of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) in relapsing multiple sclerosis (MS) and examine the consistency of DMF's effects across patient subgroups stratified by baseline demographic and disease characteristics. METHODS: A prespecified integrated analysis of the randomized, double-blind, placebo-controlled, Phase 3 DEFINE and CONFIRM trials was conducted. RESULTS: The intent-to-treat population comprised 2301 patients randomized to receive placebo (n = 771) or DMF 240 mg twice daily (BID; n = 769) or three times daily (TID; n = 761). At 2 years, DMF BID and TID reduced the annualized relapse rate by 49% and 49% (both P < 0.0001), risk of relapse by 43% and 47% (both P < 0.0001), risk of 12-week confirmed disability progression by 32% (P = 0.0034) and 30% (P = 0.0059), and risk of 24-week confirmed disability progression by 29% (P = 0.0278) and 32% (P = 0.0177), respectively, compared with placebo. In a subset of patients (MRI cohort), DMF BID and TID reduced the mean number of new/enlarging T2-hyperintense lesions by 78% and 73%, gadolinium-enhancing lesion activity by 83% and 70%, and mean number of new nonenhancing T1-hypointense lesions by 65% and 64% (all P < 0.0001 vs. placebo). Effects were generally consistent across patient subgroups. INTERPRETATION: The integrated analysis provides a more precise estimate of DMF's efficacy. DMF demonstrated a robust reduction in disease activity and a consistent therapeutic effect across patient subgroups.

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study.

OBJECTIVE: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. METHODS: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). RESULTS: DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. CONCLUSIONS: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.

Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies.

PURPOSE: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years. METHODS: Patients with RRMS were randomly assigned to receive delayed-release DMF 240 mg PO BID or TID or matching placebo for up to 2 years (96 weeks). As a tertiary end point in both studies, patient-reported HRQoL was assessed using the Physical and Mental Component Summaries (PCS and MCS, respectively) of the 36-item Short Form Health Survey (SF-36); global assessment of well-being, as measured on a visual analog scale (VAS); and the EuroQoL-5D (EQ-5D) VAS, administered at baseline and at weeks 24, 48, and 96. Higher scores suggested better HRQoL. FINDINGS: The integrated analysis included 2301 patients treated with delayed-release DMF BID (n = 769) or TID (n = 761) or placebo (n = 771). The mean PCS and MCS scores at baseline were lower overall compared with those reported in the general US population and were ≥5 points lower (a clinically meaningful difference) in patients with a baseline Expanded Disability Status Scale (EDSS) score of ≥2.5 compared with those in patients with a baseline EDSS score of 0. At 2 years, mean PCS and MCS scores were increased from baseline in the patients treated with delayed-release DMF, whereas the mean PCS and MCS scores were decreased from baseline in the placebo group; the difference in PCS and MCS scores was significant for the delayed-release DMF BID and TID groups compared with placebo. SF-36 subscale scores generally remained stable or were improved relative to baseline in patients treated with delayed-release DMF and decreased in patients receiving placebo; improvements were significant for delayed-release DMF BID and TID versus placebo on most subscales. Compared with that in the placebo group, the proportions of patients in the delayed-release DMF groups exhibiting a ≥5-point improvement in SF-36 score were significantly higher. The following factors were found to be predictive of improved PCS and MCS scores at 2 years: delayed-release DMF treatment, lower baseline EDSS score, age ≤40 years (PCS only), and corresponding lower baseline PCS or MCS score. Changes from baseline in VAS and EuroQoL-5D scores were generally consistent with changes in SF-36 scores. IMPLICATIONS: These HRQoL benefits parallel the improvements in clinical and magnetic resonance imaging end points with delayed-release DMF, suggesting that delayed-release DMF treatment improves patient-perceived health status as well as neurologic and physical functioning. ClinicalTrials.gov identifiers: NCT0042012; NCT00451451.

Effects of BG-12 (dimethyl fumarate) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: findings from the CONFIRM study.

Multiple sclerosis (MS) has a significant impact on health-related quality of life (HRQoL) with symptoms adversely affecting many aspects of everyday living. BG-12 (dimethyl fumarate) demonstrated significant efficacy in the phase III studies DEFINE and CONFIRM in patients with relapsing-remitting MS. In CONFIRM, HRQoL was worse in patients with greater disability at baseline, and who relapsed during the study, and improved with BG-12 treatment. Mean Short Form-36 Physical Component Summary scores for BG-12 increased over 2 years and scores for placebo decreased. Coupled with clinical and neuroradiological benefits, these HRQoL results further support BG-12 as an effective oral treatment for relapsing MS.

BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease, affecting more than 2.5 million people worldwide with more 400,000 cases in the United States alone. There has been considerable improvement in the treatment of MS, with the introduction of disease-modifying drugs; however, new oral therapies may provide additional benefit by providing an alternative treatment modality and the potential for improved adherence by avoiding the injection-associated side effects and anxiety encountered with some first-line agents. BG-12 (dimethyl fumarate) is an oral agent approved in the United States for the treatment of relapsing forms of MS. SCOPE: We review published literature about what is known about the mechanism of action of BG-12, and key efficacy and safety findings from three clinical studies in patients with relapsing-remitting MS (RRMS). FINDINGS: Data from preclinical studies have demonstrated that BG-12 may promote anti-inflammatory and cytoprotective activities that are mediated, at least in part, by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway. Studies in animals have shown a protective effect of BG-12 on neuronal, axonal and myelin integrity. Results from a phase 2 study and two randomized double-blind placebo-controlled phase 3 studies, CONFIRM and DEFINE, have shown that BG-12 provides clinical and radiologic efficacy in patients with RRMS. At 2 years, BG-12 240 mg twice and three times daily reduced annualized relapse rate (CONFIRM primary endpoint) by 44% and 51% and the risk of relapse (DEFINE primary endpoint) by 49% and 50%, respectively, compared with placebo (all p < 0.001). BG-12 was generally well tolerated and had an acceptable safety profile, with a similar incidence of adverse events across treatment groups. CONCLUSIONS: BG-12 may have cytoprotective and anti-inflammatory properties that contribute to its efficacy among patients with RRMS. Findings from phase 2 and 3 studies further support BG-12 as an effective initial therapy. ClinicalTrials.gov ID: NCT00168701; NCT00420212: NCT00451451.

Multiple autoimmune-associated variants confer decreased IL-2R signaling in CD4+ CD25(hi) T cells of type 1 diabetic and multiple sclerosis patients.

IL-2 receptor (IL-2R) signaling is essential for optimal stability and function of CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Treg); a cell type that plays an integral role in maintaining tolerance. Thus, we hypothesized that decreased response to IL-2 may be a common phenotype of subjects who have autoimmune diseases associated with variants in the IL2RA locus, including T1D and MS, particularly in cells expressing the high affinity IL-2R alpha chain (IL-2RA or CD25). To examine this question we used phosphorylation of STAT5 (pSTAT5) as a downstream measure of IL-2R signaling, and found a decreased response to IL-2 in CD4(+)CD25(hi) T cells of T1D and MS, but not SLE patients. Since the IL2RArs2104286 haplotype is associated with T1D and MS, we measured pSTAT5 in controls carrying the rs2104286 risk haplotype to test whether this variant contributed to reduced IL-2 responsiveness. Consistent with this, we found decreased pSTAT5 in subjects carrying the rs2104286 risk haplotype. Reduced IL-2R signaling did not result from lower CD25 expression on CD25(hi) cells; instead we detected increased CD25 expression on naive Treg from controls carrying the rs2104286 risk haplotype, and subjects with T1D and MS. However the rs2104286 risk haplotype correlated with increased soluble IL-2RA levels, suggesting that shedding of the IL-2R may account in part for the reduced IL-2R signaling associated with the rs2104286 risk haplotype. In addition to risk variants in IL2RA, we found that the T1D-associated risk variant of PTPN2rs1893217 independently contributed to diminished IL-2R signaling. However, even when holding genotype constant at IL2RA and PTPN2, we still observed a significant signaling defect in T1D and MS patients. Together, these data suggest that multiple mechanisms converge in disease leading to decreased response to IL-2, a phenotype that may eventually lead to loss of tolerance and autoimmunity.

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study.

In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics.

In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling.

Patients with multiple sclerosis (MS) manifest demyelination and neurodegeneration mediated in part by CD4(+) T cells that have escaped regulation. Resistance of pathogenic effector T cells (T(effs)) to suppression by regulatory T cells (T(regs)) has been demonstrated in several autoimmune diseases. Although impairment in T(reg) number and function has been observed in relapsing-remitting MS (RRMS), T(eff) resistance has not been well studied in this disease. To determine whether T(eff) resistance contributes to failed tolerance in RRMS, we performed T(reg) suppression assays with T(effs) from either RRMS patients not on immunomodulatory therapy or healthy individuals. T(eff) resistance was present in the T(effs) of RRMS patients with active disease but not from patients with inactive disease. Interleukin-6 (IL-6) and phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) promote T(eff) resistance to T(regs), and we found an increase in IL-6 receptor α (IL-6Rα) expression and elevated IL-6 signaling as measured by pSTAT3 in our RRMS subjects. Further, the impaired suppression in RRMS subjects correlated with an increase in IL-6Rα surface expression on CD4(+) T cells and an increase in pSTAT3 in response to IL-6. To address whether the enhanced pSTAT3 contributed to T(eff) resistance in active RRMS patients, we blocked STAT3 phosphorylation and found that impaired suppression was reversed. Therefore, enhanced IL-6R signaling through pSTAT3, in some cases through increased IL-6Rα expression, contributed to T(eff) resistance in active RRMS. These markers may aid in determining disease activity and responsiveness to immunomodulatory therapies in RRMS.

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

BACKGROUND: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).

FDA-approved preventative therapies for MS: first-line agents.

Relapsing-remitting multiple sclerosis is highly variable in its presentation and disease course. The approach to initiating first-line preventative therapies must focus on individualizing treatment strategies. Careful discussion of available treatment options and appropriate expectations regarding outcomes is important to ensure a successful start. Early treatment is recommended, as is on-going monitoring of patients who may choose to forego therapy.

Prenatal findings in a fetus with contiguous gene syndrome caused by deletion of Xp22.3 that includes locus for X-linked recessive type of chondrodysplasia punctata (CDPX1).

The X-linked recessive type of chondrodysplasia punctata (CDPX1) is a skeletal disorder that is characterized by stippled calcification at an epiphyseal nucleus and the surrounding soft tissue, short stature and an unusual face because of nasal hypoplasia. In most of the patients, this condition is noted after birth because of a characteristic face or respiratory problems. Here, we report a fetus with CDPX1. Two-dimensional ultrasound examination revealed unexplained polyhydramnios and a male fetus. Fetal biometry showed shortened long bones. Three-dimensional ultrasonography clearly demonstrated a hypoplastic nose with a depressed nasal bridge and contracture of wrists and fingers. Chromosome analysis of the amniotic fluid cells revealed the 46,Y,del(X)(p22.3) karyotype. Fluorescence in situ hybridization revealed a deletion of subtelomeric sequences at the Xpter and STS gene, but not a deletion of the KAL gene. The genomic copy number analysis demonstrated terminal deletion of 8.33 Mb that included SHOX, CSF2RA, XG, ARSE, NLGN4 and STS genes. We think that our case presents typical features of a fetus with this disorder and will be of great help in prenatal ultrasound diagnosis.