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ObjectiveTo determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS.MethodsTo be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required.ResultsTwo hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1–9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening–free survival (95% confidence interval [CI]) was 85.5% (76.9%–94.1%) at 5 years and 71.3% (57.8%–84.8%) at 10 years. In patients with progressive MS, disability worsening–free survival was 71.0% (59.4%–82.6%) and 57.2% (41.8%–72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT (p = 0.001; mean EDSS change per year −0.09 [95% CI −0.15% to −0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14–0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.ConclusionsaHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.Classification of EvidenceThis study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

Background: Autologous haematopoietic stem cell transplantation (aHSCT) is a valuable option in aggressive relapsing–remitting multiple sclerosis (MS), but its efficacy in secondary progressive (SP)-MS is still controversial. Objective: Assessing efficacy of aHSCT in SP-MS by clinical-radiological outcomes. Methods: Open-label monocentric retrospective study enrolling consecutive SP-MS patients treated with BEAM-aHSCT in the period 1999–2016. Results: In total, 26 SP-MS patients with moderate–severe disability were included. Progression-free survival (PFS) at years 5 and 10 after aHSCT were, respectively, 42% and 30%. Out of 16 patients who worsened, only 6 patients (23% overall) maintained continuous disability accrual (CDA), whereas 10 patients stabilized following one single-step Expanded Disability Status Scale (EDSS) worsening. CDA-free survival was 74% at 5–10 years. No relapses or magnetic resonance imaging (MRI) activity were reported, thus no evidence of disease activity (NEDA)-3 corresponded to PFS. Annualized rate of brain atrophy (AR-BVL) normalized after 1 year in 55% of the cases analysed (12/22). Conclusion: BEAM-aHSCT halted CDA and normalized AR-BVL in most of the treated patients, inducing long-term remission of inflammatory activity at a median follow-up of 99 months (range 27–222). These data suggest that CDA might still be mainly driven by inflammation in a subgroup of SP-MS and could therefore be reversed by treatments. CDA should be analysed independently from any isolated disability worsening.

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) are known to affect immune response to antigens and possibly to SARS-CoV2 vaccine. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech, Inc or mRNA-1273, Moderna Tx, Inc). A blood collection for the measure of SARS-CoV-2 antibody before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche Diagnostics). Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariate analysis, the antibody levels of patients on ocrelizumab (178-fold decrease, p

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18–4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (

Over the last months, due to coronavirus disease (COVID-19) pandemic, containment measures have led to important social restriction. Healthcare systems have faced a complete rearrangement of resources and spaces, with the creation of wards devoted to COVID-19 patients. In this context, patients affected by chronic neurological diseases, such as amyotrophic lateral sclerosis (ALS), are at risk to be lost at follow-up, leading to a higher risk of morbidity and mortality. Telemedicine may allow meet the needs of these patients. In this commentary, we briefly discuss the digital tools to remotely monitor and manage ALS patients. Focusing on detecting disease progression and preventing life-threatening conditions, we propose a toolset able to improve ALS management during this unprecedented situation.

Background The natural history of multiple sclerosis (MS) following discontinuation of a first-line disease-modifying treatment (DMT) in relapsing-remitting (RR-) MS patients is controversial, as few data are available on the risk of disease reactivation. This study aims to investigate the disease course after DMT discontinuation in selected RR-MS patients, exploring potential predictive factors of disease reactivation. Methods RR-MS patients, aged 18-65, who had discontinued a first-line DMT were selected from 1107 clinical records. Relapses, disability worsening and new brain lesions, before and after DMT interruption, were retrospectively evaluated. Potentially predictive baseline characteristics of disease reactivation were also analysed. Results N= 60 patients were included, median age and treatment duration were 47.8 (22.1-64.3) and 7.2 (0.5-17.8) years respectively. Median clinical follow-up after discontinuation was 4.6 (0.5-16.6) years. No disease rebound occurred. Mean annualized disease activity and relapse rate after discontinuation were both lower than during treatment(0.10±0.05 vs 0.15 ±0.05; p=0.017). A NEDA-3 period on treatment ≥5.5 years was associated with a low rate (7.7%) and a low risk of new disease activity (aHR 0.16, CI 0.03-0.78, p=0.024; Cox regression model multivariate analysis). The patients with NEDA-3 period threshold above 5.5 years showed a higher probability of surviving to disease reactivation than others (p=0.014). Conclusion In most of the MS patients who showed a long NEDA-3 period while on treatment remission of disease activity persists following first-line DMT discontinuation, suggesting that prolonged suppression of disease activity on treatment can determine long term sustained remission of the disease also in absence of treatment.

In neuro Behçet disease with multiple sclerosis‐like features, diagnosis could be challenging. Here, we studied the cerebrospinal fluid and serum inflammatory profile of 11 neuro Behçet and 21 relapsing‐remitting multiple sclerosis patients. Between the soluble factors analyzed (MMP9, TNF α, IL6, CXCL13, CXCL10, CXCL8, IFN γ, IL10, IL17, IL23, and others) we found MMP9 increased in neuro Behçet serum compared to multiple sclerosis and decreased in cerebrospinal fluid. Furthermore, neuro Behçet analysis of circulating natural killer CD56DIM subset suggests their potential involvement in increased MMP9 production. We believe that these findings may have a translational utility in clinical practice.

Objectives In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the "central vein sign") improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). Methods In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3-dimensional T2*-weighted and T2-fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. Results MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behcet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjogren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. Interpretation The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283-294.

ObjectiveCladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data.MethodsData from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity.ResultsAll weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis.ConclusionIn patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity.Classification of evidenceThis study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). Objective: To investigate the effectiveness and safety of rituximab in relapsing–remitting (RR) and progressive MS. Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

We reported the case of a John Cunningham virus (JCV) and human herpesvirus 6 (HHV-6) mediated progressive multifocal leukoencephalopathy (PML) after human stem cell transplant, reactivated 6 months later in absence of immunosuppressive therapy, successfully treated with anti-5HT2A receptors agents and antiviral therapy. Few cases of JCV and HHV-6 coinfection associated PML are described in literature and the role of HHV-6 in the pathogenesis and prognosis of PML is not completely clear. Our case suggests that, in a possible PML, the research of HHV-6 and JCV should be always performed on cerebrospinal fluid (CSF) and on blood samples and in case of detection of HHV-6 DNA a chromosomally integrated human herpesvirus 6(ciHHV-6) should be excluded. Furthermore we recommend to start an appropriate therapy with antiviral and anti-5HT2A receptors agents in case of possible PML due to JCV and HHV-6 coinfection.

Background Severe multiple sclerosis reactivation following second line treatment withdrawal, defined “rebound syndrome”, is becoming a prominent issue to consider when deciding to discontinue a treatment. In particular disease recurrence after cessation of fingolimod is actually poorly characterized as to date, only case reports and small case series have been described. Case presentation We herewith describe 2 cases of severe disease reactivation associated to a high number of brain gadolinium enhancing lesions at magnetic resonance imaging (MRI) despite high dose steroid treatment, observed a few weeks after cessation of fingolimod administration, causing a substantial and persistent worsening of patient disability that required long term hospitalization. The severity of the neurological symptom worsening and of the brain lesion largely exceeded the disease activity observed during treatment. Conclusions Our patients developed a rebound syndrome after ceasing fingolimod treatment, defined as the development of severe neurological symptoms and multiple new or enhancing lesions exceeding previous activity. Further analysis are needed to identify patients at greatest risk of a rebound syndrome.

Objective To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients. Methods This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring). Results 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1–11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis. Interpretation We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.

Polyomavirus JC (JCPyV) reactivation and development of progressive multifocal leukoencephalopathy is a health concern in multiple sclerosis patients under natalizumab therapy. Here, the JCPyV microRNA-J1-3p and microRNA-J1-5p expressions and genomic variability were investigated in blood and urine samples of multiple sclerosis patients before and under natalizumab therapy and in healthy controls. The two JCPyV microRNAs were detected in the JCPyV-DNA-positive peripheral blood mononuclear cell samples and in the exosomes derived from plasma and urine obtained from JCPyV-DNA-positive and JCPyV-DNA-negative patients. In particular, the increased JCPyV microRNA expression in samples of multiple sclerosis patients under natalizumab therapy was consistent with the high JCPyV-DNA positivity observed in these samples. Moreover, JCPyV microRNA genomic region showed few nucleotide differences in samples obtained from blood and urine of multiple sclerosis patients and healthy controls. Overall, these data suggest a potential role of the JCPyV microRNA expression in counteracting the viral reactivation to maintain JCPyV asymptomatic persistence in the host.

Objective To confirm CXCL10 over production in bone marrow mesenchymal stem cells (MSCs) and circulating monocytes isolated from multiple sclerosis patients (MS) and identify predate cell molecular signature; to extend this analysis after autologous hematopoietic stem cell transplantation (AHSCT) to test if therapy has modifying effects on MSCs and circulating monocytes. Methods MSCs and monocytes were isolated from 19 MS patients who undergone AHSCT before and seven of them at least 3 years after transplant. CXCL10 production was detected after LPS/IFN-γ stimulation. TLR4 signaling pathways were investigated by means of transcription factors phosphorylation/activation level. RT-PCR of activated transcription factors was performed to quantify their expression. All experiments were conducted in parallel with 24 matched healthy donors (HD). Results CXCL10 expression was significantly increased in both peripheral circulating monocytes and BM MSCs compared to HD. We showed that CXCL10 production is determined by an altered signaling pathway downstream TLR4, with the involvement of STAT-1, NF-κB, p38, JNK, and CREB. All upregulated transcription factors are more phosphorylated in MS patient sample. These features are not modified after AHSCT. Interpretation We demonstrated that in MS two different cell lineages are characterized by significantly increased production of CXCL10, due to altered signaling pathways of innate immune reaction mediated by TLR4, probably associated with disease phenotype. This characteristic is not modified by AHSCT, suggesting that when T and B lymphocytes are reset, other possible components of MS pathology, such as CXCL10 over production, do not determine therapy outcome.

Objective Recently autologous haematopoietic stem cell transplantation (AHSCT) has been introduced for the treatment of severe forms of multiple sclerosis (MS). As little data are available on bone marrow (BM) of MS patients undergoing AHSCT, we investigated the morphological and phenotypic characteristics of MS BM. Methods BM biopsies of 14 MS patients screened for AHSCT and 10 control patients were evaluated to assess cellularity, morphology, immunological profile and bone marrow microenvironment. Immunohistochemistry analysis was performed to evaluate the expression of CD3, CD4, CD8, CD20, CD68, CD45, MMP-9. Results 8 out of 14 MS (57%) patients showed a reduction of age-related bone marrow cellularity, possibly due to previous immunosuppressive therapies. There were no differences in the T CD3+ lymphocyte expression rate amongst MS and the control patients, the CD4/CD8 ratio (2:1) was maintained as was the rate of B lymphocytes. We found an increased, although not significant, MMP-9 expression (9.2%) in the bone marrow of MS patients, when compared to the control patients (6.3%). Conclusion The BM of MS patients showed a reduced cellularity and CD45+ cells content in comparison to the controls. A slightly increased expression of MMP-9 was also shown, possibly confirming an involvement of this compartment in the pathogenesis of the disease.

Therapeutic decisions largely depend on our knowledge of the natural history of a disease. Most of the available data derive from clinical series of cases [1–7]. Only in one study [8] were 123 subjects identified as having gallstones by cholecystographic screening of a healthy population and followed prospectively for up to 20 years. These, however, were mainly white American faculty members of the University of Michigan and extrapolation of the results to the general population would be difficult.

Neuromyelitis optica spectrum disorder (NMOsd) is a group of demyelinating disorders recently redefined and associated with NMO-IgG/anti-aquaporin 4 antibodies. Because NMOsd is of unknown prevalence worldwide, we conducted a retrospective, cross-sectional study of 850 patients with demyelinating disorders hospitalized in North East Tuscany from 1998 to 2006 to examine the prevalence of NMO and related disorders among unselected consecutive neurological patients with inflammatory CNS diseases and to evaluate the clinical phenotype spectrum of identified cases. Clinical data were updated after at least 2 years of follow-up. An immunofluorescence technique was used to detect NMO-IgG on rat brain tissue. Sera from other 828 neurological patients, 65 non-neurological patients and 50 healthy donors served as controls. The prevalence of NMOsd was 1.5%, with a MS:NMOsd ratio of 42.7. Among 13 NMOsd patients, 77% had long spinal cord lesions, 38% had severe optic neuritis and 23% had brain or brainstem lesions. Only 56% had clinically definite NMO at follow-up. The final EDSS score ranged from 1 to 10, mainly depending on brainstem involvement occurrence. Our findings confirm a low prevalence of NMO and related disorders among demyelinating inflammatory diseases in a Caucasian population. Moreover, this study demonstrates an unexpectedly high prevalence of limited and atypical variants of this disease, not previously documented.

Objective: To evaluate the frequency of JC polyomavirus (JCPyV) infection and anti-JCPyV antibodies in patients with multiple sclerosis under natalizumab therapy. Methods: Presence of anti-JCPyV antibodies and JCPyV DNA was analyzed in 39 patients with relapsing-remitting multiple sclerosis undergoing natalizumab therapy. Anti-JCPyV antibodies were evaluated in serum by a 2-step virus-like particle-based ELISA assay (Stratify), and JCPyV DNA was evaluated in peripheral blood mononuclear cells, plasma, and urine by quantitative PCR. The anti-JCPyV antibodies were evaluated in serum samples collected at the same time or later than those collected for DNA analysis. Results: JCPyV DNA was detected in 59% of patients, and anti-JCPyV antibodies were present in 67%. JCPyV DNA occurred more often in blood than in urine. Anti-JCPyV antibodies were observed in 70% of the JCPyV-infected patients, and JCPyV DNA was detected in 50% of the patients without anti-JCPyV antibodies. When JCPyV DNA was investigated in blood and urine the frequency of infection was higher than previously described. Conclusion: Under these experimental conditions, with respect to the observed frequency of JCPyV infection, the sensitivity of the anti-JCPyV antibody assay was lower than expected.

Azathioprine is an immunosuppressive agent that reduces relapse rates in patients with multiple sclerosis (MS), but its efficacy in suppressing new brain lesions has never been evaluated.To evaluate the efficacy of azathioprine therapy on new brain lesion suppression in MS.Open-label treatment vs baseline study.Outpatient MS clinical center at a university hospital.Fourteen patients with relapsing-remitting MS of short duration and at least 3 gadolinium-enhancing (Gd+) brain lesions observed within 6 months before treatment.Azathioprine, up to 3 mg/kg daily, individually adjusted according to blood lymphocyte number and the occurrence of adverse events.Brain Gd+ lesions evaluated by monthly magnetic resonance imaging for 6 months before and 6 months during treatment and new T2 lesions evaluated during the same periods and after an additional 6 months.The treatment reduced to 0 the median Gd+ lesion number and volume per magnetic resonance image (P.001 for both), resulting in a Gd+ lesion number reduction of 50% or more in 12 of 14 patients (P.01). An equivalent reduction in the new T2 lesion number was observed (P.02); this activity also persisted during the additional treatment period evaluated using this outcome measure (P.01). The median azathioprine dose administered (2.6-2.8 mg/kg daily) reduced the mean blood lymphocyte count to 57% of the baseline value. Adverse events were transient or reversible with dose adjustment.This study indicates for the first time that azathioprine, administered at lymphocyte-suppressing doses, is effective in reducing MS new brain inflammatory lesions and is well tolerated.