Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

BACKGROUND Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015. OBJECTIVES To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS. SEARCH METHODS CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022. SELECTION CRITERIA Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS. DATA COLLECTION AND ANALYSIS Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach. MAIN RESULTS We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence). AUTHORS' CONCLUSIONS We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects

Generation and Cyclization of Unsaturated Carbamoyl Radicals Derived from S-4-Pentynyl Carbamothioates under Tin-Free Conditions.

The radical reaction of benzenethiol with S-4-pentynyl carbamothioates provides a valuable protocol for the tin-free generation of carbamoyl radicals, which arise from intramolecular substitution reaction at sulfur by the initial sulfanylvinyl radicals. The procedure can be usefully employed to achieve N-benzylcarbamoyl radical 5-exo and 4-exo cyclizations leading, respectively, to pyrrolidinones and azetidinones

EBM, guidelines, protocols: Knowledge, attitudes and utilization in the era of law on professional responsibility and safety of health care

Introduction. Introduction. The knowledge of principles and methods of Evidence Based Medicine (EBM) and the use of Clinical Practice Guidelines to inform clinical decisions are recognised as key instruments to improve the quality of care. In Italy the Parliament has revised the legal system that rules the responsibilities of health professionals and health care safety, prescribing health professionals to adhere to guidelines and good practice recommendations. The objective of the study was to evaluate guidelines and clinical pathways developed at local level and to assess knowledge and attitudes of healthcare workers toward EBM and guidelines. Methods. At the l'ASL 5 Liguria La Spezia we performed a census of all the documents registered as "guidelines" or "clinical pathways" at the Direzione Generale by the end of May 2016. We assessed their methodological quality by the "Recognition Card for Clinical Pathways Production and Revision Activity" prepared by the Ligurian Region. We conducted semi-structured interviews to assess attitudes and knowledge of healthcare workers. Results. We found 17 clinical pathways, 41% contained organizational/management recommendations, and 59% contained mainly clinical recommendations. 41% was produced by assimilating already existing guidelines. 29% did not describe the method of production. Only one document linked directly each recommendation with scientific evidence. 10 healthcare workers out of 32 invited actually accepted to conduct the interview. Respondents showed a positive attitude toward the EBM and guidelines but a poor knowledge of the methodology of production and the instruments and principles for critical appraising of scientific literature. Nobody knew the GRADE approach. The most relevant barriers identified were: lack of time, poor knowledge of English and statistical methods, poor applicability of the international guidelines to local setting and real patients encountered in clinical practice. Discussion. Despite the initiatives of the legislator toward civil responsibility and safety of care that should increase the use of guidelines, we found an overall poor knowledge of the concepts of EBM and method of guidelines production. Though the attitudes of responders to the interview were positive, barriers to use seemed to be predominant and considered more as obstacles than as a stimulus. In peripheral settings or in hospitals of medium/small size, clinical guidelines could remain confined to a merely juridical role, with weak impact on professional practice

Immunomodulators and immunosuppressants for progressive multiple sclerosis: a network meta-analysis (Protocol)

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: We will perform network meta-analysis to assess the relative effectiveness and safety of immunomodulatory and immunosuppressive treatments for people with multiple sclerosis in progressive forms of the condition. Background Description of the condition Multiple sclerosis (MS) is the most common immune-mediated, chronic inflammatory demyelinating disease of the central nervous system (CNS). In 85% of affected people the disease is characterised at onset by relapses followed by complete or partial recovery (relapsing–remitting phase). Relapses correspond to the clinical expression of focal inflammation and subsequent loss of the myelin sheath surrounding axons in the CNS. In a proportion of patients, increasing with time, the course turns into a secondary progressive phase (SPMS), typically 15 to 20 years from onset. In about 10-15% of people affected by MS the progressive course is not preceded by relapses (primary progressive multiple sclerosis (PPMS)). About 40% of people with PPMS or SPMS show relapses during the course of the disease. However, new activity becomes less frequent over time, while microglial activation and neurodegeneration become more relevant (Calabrese 2012). A recent classification of MS clinical course (or “phenotype”) introduced the concepts of “disease activity” and “disease progression” (Lublin 2014). The former is based on the presence of clinical relapse or new or gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Active forms of MS occur when the inflammatory process is ongoing, sometimes without corresponding clinical manifestations if the inflamed region of the CNS is clinically silent. Disease progression occurs when there is clinical evidence of disability worsening, independent of relapses, over a given period of time, in patients who are in a progressive phase of the disease (Lublin 2014). The current classification includes: (i) active or inactive relapsing MS (RMS), with or without worsening; (ii) active or inactive primary MS (PMS) or secondary progressive MS (SPMS), with or without progression; (iii) clinically isolated syndrome (CIS); (iv) radiologically isolated syndrome (RIS). The definition of “progressive-relapsing” MS was abandoned (Lublin 2014). Furthermore, the concept of MS as a two-stage disease has been recently questioned by increasing evidence, both from MRI and pathological studies, of a complex interplay between inflammatory and subtle neurodegenerative processes (Progression Independent from Relapse Activity, PIRA) even in the early stages of the disease (Giovannoni 2022). The identification of "smouldering" progression in a consistent proportion of people with either active or inactive MS demands for a more thorough assessment to define progressive MS, with relevant implications for future trials (e.g. appropriate selection of patients in trials on anti-inflammatory drugs, evaluation of neuroprotective/neurorestorative agents,). Multiple sclerosis represents a substantial health burden at a global level, since it affect young people during their productive life, the mean age of diagnosis being 32 years (Walton 2020). The global incidence and prevalence of MS are increasing. From 1990 to 2016 the age-standardised prevalence of MS increased by 10.4% (9.1 to 11.8). About 2.8 million people worldwide are affected by MS (35.9 per 100,000 population), a figure which has increased by about half-million since 2013. The global pooled incidence rate is 2.1 per 100,000 persons/year (Walton 2020, GBD 2019). No current treatment is effective at stopping the natural course of MS towards progressive disability. Current MS treatments include disease-modifying treatments (DMTs) based on immune-modulating or immune-suppressing drugs, which are distinguished from symptomatic drugs for the treatment of specific symptoms of MS (eg. urinary incontinence or retention, muscular spasms, painful sensitive symptoms). Providing effective and safe treatments for progressive MS (PMS) is particularly challenging due to incomplete understanding of the pathogenesis of progression. Moreover, while inflammation seem to provide a pivotal contribution to progression, other pathological changes - including cortical demyelination, axonal loss and mitochondrial dysfunction - also seem to be important (Dutta 2014; Lassmann 2012) and may represent different therapeutic targets in PMS. Despite several new DMTs becoming available for the treatment of RMS and PMS in recent years, uncertainty remains regarding whether some of them may represent a preferable choice when starting pharmacological treatment and which ones should be subsequently considered for the management of more advanced stages of the disease course (Reich 2018). Relatively few studies directly compare different DMTs or assess the sequential use of specific DMT combinations, therefore clinical practice guidelines on MS treatment usually do not recommend one DMT over the other. The variability of recommendations concerning specific drugs among different guidelines in part reflects differences in the decisions by regulatory drug agencies and local health policies (Ghezzi 2018). A previous Cochrane systematic review and network meta-analysis of randomized controlled studies (RCT) (Filippini 2013) appraised the available evidence for the efficacy and safety of available DMTs compared to placebo and any other active drug in RMS and PMS. The authors concluded that, for the nine disease modifying agents used in 18 trials including people with progressive MS, and the 3 trials including both relapsing and progressive forms, few studies were of high certainty and no drug was shown to be effective in preventing disability progression in people with MS by pairwise or network meta-analysis (Filippini 2013). The time elapsed since the search date of Filippini 2013 (February 2012) supports the need for an updated analysis, especially given the availability of more DMTs for progressive forms of MS

Otogenic lateral sinus thrombosis in children: proposal of an experience-based treatment flowchart

Purpose: To describe the prevalent clinical, laboratory, and radiological features of otogenic lateral sinus thrombosis (OLST) in children; to identify clinical predictors of outcome; to propose a management algorithm derived from experience. Methods: A retrospective review was conducted of the clinical records of patients with OLST, treated in a single tertiary care referral center for pediatric disease from 2006 to 2017. The inclusion criteria were pediatric age (0–16 years) and OLST diagnosis confirmed by a pre- and post-contrast CT or venography–MRI scan. Primary outcome measures were early (1–2 months) and late (6 months) sinus recanalization assessed by means of neuroimaging. Results: Twenty-five patients (8 females and 17 males; mean age = 6 ± 3 years) were included. A genetic abnormality associated with thrombophilia was found in 24 (96%) patients. At diagnosis, anticoagulant treatment with low-molecular-weight heparin (LMWH) was started in all subjects, while surgical treatment (mastoidectomy and tympanostomy tube insertion) was performed in 16/25 (64%) patients. Follow-up neuroimaging showed lateral sinus recanalization in 12/25 (48%) patients after 1–2 months and in 17/25 (68%) after 6 months. At multivariate logistic regression analysis, no significant predictors of the early and late neuroradiological outcome were found. Conclusions: All children with OLST should be screened for thrombophilia to decide on treatment duration and to assess the need for future antithrombotic prophylaxis. Immediately after diagnosis, anticoagulant treatment with LMWH should be started according to the international guidelines. Instead, our experience suggests that surgical treatment should not be indicated in all patients, but decided on a case-to-case basis