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