Intrathecal Immunoglobulin Synthesis in MS—A Complete Reappraisal

Multiple sclerosis (MS) is characterized by the intrathecal synthesis (ITS) of immunoglobulins (Igs), which, although nonspecific, is the strongest biological marker. Since no specific target has been elucidated, this synthesis is considered to be disease‐irrelevant. We demonstrate that this synthesis provides pertinent information about the pathophysiological processes involved. Quantification of ITS is based on an approximation intrinsically underestimating its level and it remains constant in MS, albeit sometimes at a low level. B‐cell maturation seems to be initiated within the cervical lymph nodes and B‐cells traffic on both sides of the blood‐brain barrier by rounds of bidirectional traffic. During this process, they undergo somatic hypermutation, which is the hallmark of antigen‐driven antibody maturation, suggesting that most of the ITS is probably directed against as yet unknown targets. Alternatively, examining”non‐disease‐relevant” ITS in the light of meningeal tertiary lymphoid organs provides new insights into the pathophysiology of MS. Although no specific target has yet been identified in MS, recent developments in the search for targeted antigens point to non‐conventional antigens (posttranslationally modified proteins or oxidized products) of which a few are promising for future research

Plasma Exchange in Severe Attacks of Neuromyelitis Optica

Background. Neuromyelitis optica (NMO) attacks are poorly controlled by steroids and evolve in stepwise neurological impairments. Assuming the strong humoral response underlying NMO attacks, plasma exchange (PLEX) is an appropriate technique in severe NMO attacks. Objective. Presenting an up-to-date review of the literature of PLEX in NMO. Methods. We summarize the rationale of PLEX in relation with the physiology of NMO, the main technical aspects, and the available studies. Results. PLEX in severe attacks from myelitis or optic neuritis are associated with a better outcome, depending on PLEX delay (“time is cord and eyes”). NMO-IgG status has no influence. Finally, we build up an original concept linking the inner dynamic of the lesion, the timing of PLEX onset and the expected clinical results. Conclusion. PLEX is a safe and efficient add-on therapy in NMO, in synergy with steroids. Large therapeutic trials are required to definitely assess the procedure and define the time opportunity window

Intrathecal IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments

Intrathecal IgG synthesis is a key biological feature of multiple sclerosis (MS). When acquired early, it persists over time. A growing body of evidence suggests that intrathecal Ig-secreting cells may be pathogenic either by a direct action of toxic IgG or by locally secreting bystander toxic products. Intrathecal IgG synthesis depends on the presence of CNS lymphoid organs, which are strongly linked at anatomical level to cortical subpial lesions and at clinical level to the impairment slope in progressive MS. As a consequence, targeting CNS lymphoid lesions could be a valuable new target in MS, especially during the progressive phase. As intrathecal IgGs are end-products of these lymphoid lesions, intrathecal IgG synthesis may be considered as a specific marker of the persistence of these inflammatory lesions. Here we review the effect upon intrathecal IgG synthesis of all drugs ever used in MS. Except for steroids, all these therapeutic strategies, including rituximab, failed to decrease intrathecal IgG synthesis, with the exception of a questionable incomplete action of natalizumab. Thus, IgG synthesis is a robust marker of persistent intrathecal inflammation and its complete normalization should be one of the goals in future therapeutic strategies

Does Disease-Irrelevant Intrathecal Synthesis in Multiple Sclerosis Make Sense in the Light of Tertiary Lymphoid Organs?

Although partly disease-irrelevant, intrathecal Ig synthesis is a typical feature of multiple sclerosis (MS) and is driven by the tertiary lymphoid organs (TLO). A long-known hallmark of this non-specific intrathecal synthesis is the MRZ pattern, an intrathecal synthesis of Ig against measles, rubella and zoster viruses, which could also be involved in a wide range of pathogens. However, this non-specific synthesis is highly problematic since brain TLO should not be able to drive the clonal expansion of lymphocytes against alien antigens that are thought to be absent in MS brain.We propose to explain the paradox of non-specific intrathecal synthesis by discussing the natural properties of TLO. In fact, besides local antigen-driven clonal expansion, circulating plasmablasts and plasma cells (PC) are non-specifically recruited from blood and gain access to survival niches in the inflammatory CNS. This mechanism, which has been described in other inflammatory disorders, takes place in the TLO. As a consequence, PCs recruited in brain mirror the individual’s history of immunization and intrathecal synthesis of IgG in MS may target a broad range of common infectious agents, a hypothesis in line with epidemiological data. Moreover, the immunization schedule and its timing may interfere with PC recruitment. If this hypothesis is correct, the reaction against EBV appears paradoxical: although early infection of MS patients is systematic, intrathecal synthesis is far lower than expected, suggesting a crucial interaction between MS onset and timing of EBV infection. A growing body of evidence suggests that the non-specific intrathecal synthesis observed in MS is also common in many chronic CNS inflammatory disorders. Assuming that cortical TLO in MS are associated with typical sub-pial lesions, we have coined the concept of ‘TLO-pathy’ to describe these lesions and take examples of them from non-MS disorders

Plasma exchange in severe attacks of neuromyelitis optica,”Multiple

Background. Neuromyelitis optica (NMO) attacks are poorly controlled by steroids and evolve in stepwise neurological impairments. Assuming the strong humoral response underlying NMO attacks, plasma exchange (PLEX) is an appropriate technique in severe NMO attacks. Objective. Presenting an up-to-date review of the literature of PLEX in NMO. Methods. We summarize the rationale of PLEX in relation with the physiology of NMO, the main technical aspects, and the available studies. Results. PLEX in severe attacks from myelitis or optic neuritis are associated with a better outcome, depending on PLEX delay ("time is cord and eyes"). NMO-IgG status has no influence. Finally, we build up an original concept linking the inner dynamic of the lesion, the timing of PLEX onset and the expected clinical results. Conclusion. PLEX is a safe and efficient add-on therapy in NMO, in synergy with steroids. Large therapeutic trials are required to definitely assess the procedure and define the time opportunity window

No Early Effect of Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE Clinical Trial)

Background. The progressive phase of multiple sclerosis (MS) is characterized by an intrathecal (IT) compartmentalization of inflammation, involving B-cells within meningeal follicles, and resisting all the available immunosuppressive treatments. A new therapeutic paradigm may be to target this inflammation by injecting immunosuppressive drugs inside the central nervous system compartment. Methods. We designed a single-center, open-label, randomized, controlled, phase II study designed to evaluate the safety and efficacy of IT rituximab in progressive MS (EFFRITE trial; ClinicalTrial Registration NCT02545959). Patients were randomized into three arms (1 : 1 : 1): control group, IT rituximab (20 mg, IT) group, and intravenous+IT (IV+IT) group. The main outcome was a change in levels of CSF biomarkers of inflammation (osteopontin). Secondary outcomes were changes in levels of CSF biomarkers of axonal loss (neurofilament light chain) and clinical and MRI changes. Results. Ten patients were included (2 : 4 : 4). No adverse event occurred. OPN level remained stable in CSF at each time point, whereas NFL had slightly decreased (-8.7%) at day 21 (p=0.02). Clinical parameters remained stable and leptomeningeal enhancements remained unchanged. Conclusion. Clinical outcome and biomarkers of inflammation were not dramatically modified after IT injection of rituximab, probably due to its limited efficiency in CSF. Drug issues for future studies are discussed