Comparison of two individualized administration schemes of rituximab based on memory B cells monitoring in AQP4 positive disorder

International audienceBackground: Individualized dosing schedule of rituximab based of memory B-cells count has been demonstrated to be safe and effective for the treatment of patients with AQP4-antibody disorder.Objective: To compare the efficacy of two different individualized administration schemes of rituximab for the treatment of patients with AQP4-antibody disorder. Design/Methods: Adult patients with AQP4-antibody disorder treated with rituximabat the Multiple Sclerosis Center of Marseillewere included in a prospective observational study. Patients were treated using an individualized dosing schedule adapted to the biological effect of rituximab monitored by monthly memory B-cells counts. Between January 2012 and August 2016, rituximab re-infusion was performed only when memory B-cells reached 0.05% of the peripheral blood mononuclear cells ('original scheme'). Becauserelapses occurred after 6 months in several patients, we decided in August 2016 to optimize the protocol. Before 6 months, patients were re-treated if memory B-cells reached the threshold of 0.05%. At 6 months, patients were re-treated regardless of the level of memory B-cells if memory B-cells had not reemerged before ('optimized scheme'). Annual relapse rates were compared between the two administration schemes. Only data of patients treated during at least one year using one of the two schemes were included in the analysis.Results: Fifteen patients were treated using the 'original scheme' during at least one year (mean duration: 28 months (13 - 55)). In these patients mean annual relapse rate was 0.35 (0-1.6). Twenty-nine patients were treated using the 'optimized scheme' during at least one year (mean duration 22 months (13 - 25)). In these patients mean annual relapse rate was 0.04 (0-0.7). In patients first treated with the 'original scheme' and secondly with the 'optimized scheme' (n=15) relapse rate decreased from 0.35 (0-1.6) to 0 (p< 0.001).Conclusions: Compared to the non-individualized classical 6 months rituximab administration scheme, the present individualized 'optimized scheme' enables to detect rapid reemergence of memory B-cells before 6 months without the risk of relapse after 6 months inherent to the individualized 'original scheme'

Modulation of tPA, PAI-1 and PAI-2 antigen and mRNA levels by EGF in the A431 cell line.

International audienceIt has been reported that EGF treatment enhances uPA but not tPA in the A431 epidermoid carcinoma cell line. To determine whether the absence of tPA modulation by EGF could be due to the action of inhibitors, we assayed tPA, PAI-1, PAI-2 and tPA/PAI-1 complexes by immunological assays and zymography in A431 serum-free medium. We found that, under conditions in which EGF had no effect on tPA activity, tPA antigen increased with a concomitant rise of tPA/PAI-1 complexes, indicating the action of an inhibitor. Both tPA antigen and tPA/PAI-1 complexes were modulated by EGF in a time and concentration dependent manner. tPA/PAI-1 complex levels were lower than tPA levels, suggesting the presence of other inhibitors. Immunological assays detected PAI-2 in addition to PAI-1 and showed a time and dose response to EGF. Modulation of tPA and the anti-activators by the growth factor was confirmed by identification of the corresponding transcripts with cDNA probes. We conclude that the net plasminogen activator activity in A431 cells is the result of a balance between activators and inhibitors

Modulation of tPA, PAI-1 and PAI-2 antigen and mRNA levels by EGF in the A431 cell line.

International audienceIt has been reported that EGF treatment enhances uPA but not tPA in the A431 epidermoid carcinoma cell line. To determine whether the absence of tPA modulation by EGF could be due to the action of inhibitors, we assayed tPA, PAI-1, PAI-2 and tPA/PAI-1 complexes by immunological assays and zymography in A431 serum-free medium. We found that, under conditions in which EGF had no effect on tPA activity, tPA antigen increased with a concomitant rise of tPA/PAI-1 complexes, indicating the action of an inhibitor. Both tPA antigen and tPA/PAI-1 complexes were modulated by EGF in a time and concentration dependent manner. tPA/PAI-1 complex levels were lower than tPA levels, suggesting the presence of other inhibitors. Immunological assays detected PAI-2 in addition to PAI-1 and showed a time and dose response to EGF. Modulation of tPA and the anti-activators by the growth factor was confirmed by identification of the corresponding transcripts with cDNA probes. We conclude that the net plasminogen activator activity in A431 cells is the result of a balance between activators and inhibitors

Urinary tract infections and multiple sclerosis: Recommendations from the French Multiple Sclerosis Society

International audienceObjectives: Establish recommendations for the management of UTIs in MS patients.Background: Urinary tract infections (UTIs) are common during multiple sclerosis (MS) and are one of the most common comorbidities potentially responsible for deaths from urinary sepsis.Methods: The recommendations attempt to answer three main questions about UTIs and MS. The French Group for Recommendations in MS (France4MS) did a systematic review of articles from PubMed and universities databases (01/1980-12/2019). The RAND/UCLA appropriateness method, which has been developed to synthesize the scientific literature and expert opinions on health care topics, was used for reaching a formal agreement. 26 MS experts worked on the full-text review and a group of 70 multidisciplinary health care specialists validated the final evaluation of summarized evidences.Results: UTIs are not associated with an increased risk of relapse and permanent worsening of disability. Only febrile UTIs worsen transient disability through the Uhthoff phenomenon. Some immunosuppressive treatments increase the risk of UTIs in MS patients and require special attention especially in case of hypogammaglobulinemia. Experts recommend to treat UTIs in patients with MS, according to recommendations of the general population. Prevention of recurrent UTIs requires stabilization of the neurogenic bladder. In some cases, weekly oral cycling antibiotics can be proposed after specialist advice. Asymptomatic bacteriuria should not be screened for or treated systematically except in special cases (pregnancy and invasive urological procedures).Conclusion: Physicians and patients should be aware of the updated recommendations for UTis and MS

Immunization and multiple sclerosis: Recommendations from the French Multiple Sclerosis Society

International audienceObjectives: To establish recommendations on immunization for patients with multiple sclerosis (MS).Background: Vaccines have been suspected in the past to trigger MS and relapses. With the extension of the immunoactive treatment arsenal, other concerns have been raised more recently about an increased risk of infection or a decreased effectiveness of immunization in immunosuppressed patients.Methods: The French Group for Recommendations into Multiple Sclerosis (France4MS) performed a systematic search of papers in Medline and other university databases (January 1975-June 2018). The RAND/UCLA appropriateness method was chosen to review the scientific literature and to formalize the degree of agreement among experts on 5 clinical questions related to immunization and MS. Readers from the steering committee conducted a systematic analysis, wrote a critical synthesis and prepared a list of proposals that were evaluated by a rating group of 28 MS experts. The final version of the recommendations was finally reviewed by a reading group of 110 health care professionals and classified as appropriate, inappropriate or uncertain.Results: Neurologists should verify the vaccination status as soon as MS is diagnosed and before disease-modifying treatments (DMTs) are introduced. The French vaccination schedule applies to MS patients and seasonal influenza vaccination is recommended. In the case of treatment-induced immunosuppression, MS patients should be informed about the risk of infection and the vaccination standards of the French High Council of Health should be applied. Live attenuated vaccines are contra-indicated in patients recently treated with immunosuppressive drugs, including corticosteroids; other vaccines can be proposed whatever the treatment, but their effectiveness may be partly reduced with some drugs.Conclusion: Physicians and patients should be aware of the updated recommendations for immunizations of patients with MS