Figure - available from: Therapeutic Advances in Neurological Disorders
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Pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP) and potential targets of disease-modifying treatments (DMTs). Antigen presentation leads to activation of macrophages, T cells and B cells [inhibited by dimethyl fumarate (DMF)]. Migration of T cells over the blood–nerve barrier (BNB) and further production of chemokines prompt macrophages to the myelin sheath. Demyelination is triggered by T-cell and macrophage-mediated cytotoxicity. Antibodies produced by B cell–derived plasma cells [impaired by anti-CD20 agents, inebilizumab, cladribine and Bruton’s tyrosine kinase (BTK) inhibitors] recognize myelin antigens and lead to complement (inhibited by eculizumab) and macrophage activation. Created with BioRender.com.
Source publication
Despite advances in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other common autoimmune neuropathies (AN), still-many patients with these diseases do not respond satisfactorily to the available treatments. Repurposing of disease-modifying therapies (DMTs) from other autoimmune conditions, particularly multi...
Citations
... Several new treatment options with improved side effect profiles compared to conventional chemotherapeutics for neurological autoimmune disorders, such as multiple sclerosis, but also for rare neuromuscular disorders, such as myasthenia gravis, were approved in recent years, leading to a shift of the therapeutic landscape. However, for immune-mediated neuropathies, these progresses are still lacking [1]. There are several reasons for this, e.g., the heterogeneity and the rarity of the diseases. ...
... Treatment alternatives in rare autoimmune neuropathies such as NSVN are urgently needed to either halt disease progression or minimize long-term and short-term side effects of other immunosuppressants. Drug repurposing might be a valuable tool as studies for these rare diseases due to their heterogeneity are hard to conduct [1]. ...
Objectives
This case series reports clinical features and outcome of four patients with non-systemic vasculitic neuropathy (NSVN) treated with the anti-CD20 agent rituximab.
Methods
Clinical, electrophysiological and biopsy data were retrospectively obtained and evaluated. Only patients with pathological definite or probable NSVN were included. Extensive clinical and laboratory work-up excluded systemic vasculitis. Follow-up data for at least 12 months and up to five years is provided. Outcome of the patients was assessed using the MRC-Sum Score, Prineas Score and Neurological Symptom Score.
Results
Two of four patients treated with rituximab achieved disease remission and one patient remained stable under anti-CD20 therapy after a required treatment switch due to toxic side effects of cyclophosphamide. One patient deteriorated under rituximab induction. Rituximab was well tolerated in all patients.
Discussion
Anti-CD20 therapy might be an alternative in NSVN patients requiring further treatment escalation or treatment switch due to side effects of corticosteroids or cyclophosphamide.
... 90 There are no current trials in CIDP, although this is a potentially important drug class for future consideration and availability of long-term data on haematological disorders may facilitate their application in the field of inflammatory neuropathy. 91,92 Conclusions CIDP is a disabling but treatable disorder, with a high response rate to available first-line treatments. The therapeutic management of CIDP is in practice highly dependent on accurately measuring outcome, timing and amplitude of improvement, all in relation to baseline function and gains that may be expected by each individual patient. ...
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable autoimmune disorder, for which different treatment options are available. Current first-line evidence-based therapies for CIDP include intravenous and subcutaneous immunoglobulins, corticosteroids and plasma exchanges. Despite lack of evidence, cyclophosphamide, rituximab and mycophenolate mofetil are commonly used in circumstances of refractoriness and, more debatably, of perceived overdependence on first-line therapies. Rituximab is currently the object of a randomized controlled trial for CIDP. Based on case series, and although rarely considered, haematopoietic autologous stem cell transplants may be effective in refractory disease, with low mortality and high remission rates. A new therapeutic option has appeared with efgartigimod, a neonatal Fc receptor blocker, recently shown to significantly lower relapse rate versus placebo, after withdrawal from previous immunotherapy. Other neonatal Fc receptor blockers, nipocalimab and batoclimab, are under study. The C1 complement-inhibitor SAR445088, acting in the proximal portion of the classical complement system, is currently the subject of a new study in treatment-responsive, refractory and treatment-naïve subjects. Finally, Bruton Tyrosine Kinase inhibitors, which exert anti-B cell effects, may represent another future research avenue. The widening of the therapeutic armamentarium enhances the need for improved evaluation of treatment effects and reliable biomarkers in CIDP.
... Even though the PNS, compared to the CNS, offers a significant neuro-regenerative potential and constitutes, from a pharmacological pointof-view, an easier target than the CNS with its blood-brain barrier, this is most often neglected in pre-clinical and clinical studies of immunemediated neuropathies. They concentrate on the acute effector phases of the diseases to find new immunomodulatory pathways, treatments, or biomarkers for disease activity or treatment response (Kohle et al., 2023a). Further, most studies regarding neuro-regeneration in the PNS are conducted in models like sciatic nerve transection, which show substantial differences in the pathophysiology of immune-mediated neuropathies and display great limitations regarding their direct translation (Griffin et al., 2010). ...
... Further, most studies regarding neuro-regeneration in the PNS are conducted in models like sciatic nerve transection, which show substantial differences in the pathophysiology of immune-mediated neuropathies and display great limitations regarding their direct translation (Griffin et al., 2010). E.g., Guillain-Barré syndrome and chronic inflammatory demyelinating neuropathy exhibit pathological hallmarks of heterogeneous demyelination and axonal damage due to infiltration of inflammatory cells, which are also seen in experimental autoimmune neuritis (EAN) (Kohle et al., 2023a). In difference to nerve transection, completely interrupted nerve fibers are rarely observed, as well as secondary denervation of the muscles due to Wallerian degeneration, resulting in a higher probability for regenerating nerve fibers to follow the original paths along an intact basal lamina for correct innervations of muscle agonists and antagonists (Griffin et al., 2010). ...
... Repurposing of known drugs like monastrol could be a valuable tool to address this void, especially as immune-mediated neuropathies constitute rare and heterogeneous diseases with debilitating consequences. Further, large and well-characterized cohorts and biomarkers or image-based established disease activity markers are missing (Kohle et al., 2023a). ...
... Between 1993 and 2023, we have autografted a group of 1570 persons with immune-related neurological diseases: 1549 with MS and 21 CIDP [18]. In 2018, the first aHSCT in a patient with CIDP was performed in our center and 21 autologous transplant cases were completed in 2018-2023. ...
... The role of lymphocytes T, although it's described as a complicated and multifaceted process, on this point they suggest that activated T lymphocytes invade peripheral nerve where produce and secrete cytokines, they can also break down endoneurial proteins by the secretion of matrix metalloproteinases. The altered expression of rise in number of natural killer T cells that might influence in the regulatory cytokines can determinate the clinical features of the patients with CIDP [18][19][20]. Even though T cell subsets have the ability to terminate the acute inflammatory process by secreting inhibitory cytokines, the failure of this function can result in CIDP refractory [21]. ...
... In contrast, neuroregenerative approaches are lacking. Notably, missing interest in developing new drugs due to the rarity and heterogeneity of autoimmune neuropathies is a well-recognized problem [4]. Consequently, repurposing of known drugs may be valuable for establishing novel treatment choices [5]. ...
... Intact mitochondria and increased mitochondrial metabolism on the other hand, are the driving motor of neuronal regeneration [10]. 2,4-Dinitrophenol (DNP) showed promising in vitro and in vivo results in neurodegenerative diseases like Parkinson's Disease [11,12], but also in the animal model of Multiple Sclerosis, experimental autoimmune encephalomyelitis [13], the central "counterpart" of autoimmune neuritis [4]. DNP can alter cells' energy levels by uncoupling the mitochondrial energy production, leading to decreased reactive oxygen species. ...
Objective:
We evaluated the potential neuro-regenerative effects of the mitochondrial uncoupler 2,4-Dinitrophenol in experimental autoimmune neuritis, an animal model for an acute autoimmune neuropathy.
Methods:
Experimental autoimmune neuritis was induced in Lewis rats. Different concentrations of 2,4-Dinitrophenol (1 mg/kg, 0.1 mg/kg and 0.01 mg/kg) were applied during the recovery phase of the neuritis (at days 18, 22 and 26) and compared to the vehicle. Any effects were assessed through functional, electrophysiological, and morphological analysis via electron microscopy of all groups at day 30. Additional immune-histochemical analysis of inflammation markers and remyelination of the sciatic nerves were performed for the dosage of 1 mg/kg and control.
Results:
No enhancement of functional or electrophysiological recovery was observed in all 2,4-Dinitrophenol-treated groups. Cellular inflammation markers of T cells (CD3 + ) were comparable to control, and an increase of macrophages (IbA1 + ) invasion in the sciatic nerves was observed. Treatment with 2,4-Dinitrophenol reduced axonal swelling in myelinated and unmyelinated fibers with an increased production of brain-derived neurotrophic factor.
Conclusion:
Our findings do not support the hypothesis that repurposing of the mitochondrial uncoupler 2,4-Dinitrophenol exerts functionally relevant neuro-regenerative effects in autoimmune neuritis.
... Experimental set-ups often concentrate on diminishing the inflammatory reaction or promoting neuro-protection. In EAN, the time-point of disease induction is known and neuro-protective or antiinflammatory treatments start during the disease induction phase or with the beginning of the first symptoms [43]. In GBS, an induction phase also occurs, as several GBS patients report an infectious event weeks before symptom onset. ...
Background
Autoimmune neuropathies can result in long-term disability and incomplete recovery, despite adequate first-line therapy. Kinesin-5 inhibition was shown to accelerate neurite outgrowth in different preclinical studies. Here, we evaluated the potential neuro-regenerative effects of the small molecule kinesin-5 inhibitor monastrol in a rodent model of acute autoimmune neuropathies, experimental autoimmune neuritis.
Methods
Experimental autoimmune neuritis was induced in Lewis rats with the neurogenic P2-peptide. At the beginning of the recovery phase at day 18, the animals were treated with 1 mg/kg monastrol or sham and observed until day 30 post-immunisation. Electrophysiological and histological analysis for markers of inflammation and remyelination of the sciatic nerve were performed. Neuromuscular junctions of the tibialis anterior muscles were analysed for reinnervation. We further treated human induced pluripotent stem cells-derived secondary motor neurons with monastrol in different concentrations and performed a neurite outgrowth assay.
Results
Treatment with monastrol enhanced functional and histological recovery in experimental autoimmune neuritis. Motor nerve conduction velocity at day 30 in the treated animals was comparable to pre-neuritis values. Monastrol-treated animals showed partially reinnervated or intact neuromuscular junctions. A significant and dose-dependent accelerated neurite outgrowth was observed after kinesin-5 inhibition as a possible mode of action.
Conclusion
Pharmacological kinesin-5 inhibition improves the functional outcome in experimental autoimmune neuritis through accelerated motor neurite outgrowth and histological recovery. This approach could be of interest to improve the outcome of autoimmune neuropathy patients.
Purpose:
To report a case of uveitis associated with multiple sclerosis (MS) that was refractory to multiple lines of therapy but achieved remission with tocilizumab.
Methods:
We conducted a retrospective analysis of the patient's medical record including clinical, biological and imaging data.
Results:
A 33-year-old female patient with a history of MS inactive for 5 years on teriflunomide, and no significant medical or ophthalmological history, presented with bilateral granulomatous panuveitis. Initial examination revealed a visual acuity of 0.4 logMAR and 1.3 logMAR in the right eye and the left eye, respectively, along with a significant anterior chamber flare in both eyes, posterior synechiae, large granulomatous keratic precipitates, bilateral vitritis, bilateral macular edema with foveolar pigment epithelial detachment, and significant bilateral venous and arterial vasculitis. The patient underwent several lines of treatment, all of which proved unsuccessful, including corticosteroids alone or in combination with azathioprine, methotrexate, and mycophenolate mofetil. As a final therapeutic option, tocilizumab was initiated, leading to the remission of uveitis. One year later, the uveitis remained inactive under a 5 mg/day prednisone regimen.
Conclusions:
Tocilizumab appears to be an efficient option for managing uveitis associated with MS and may be a valuable choice for clinicians dealing with such cases.
Introduction/Aims
Objective outcome measures in children undergoing treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are lacking. The aim of the study was to record serial grip strength and motor nerve conduction studies to assess interval change.
Methods
This was a retrospective review of 16 children (8 females and 8 males; median age, 9.7 years; interquartile range, 6–13 years) with CIDP followed at a tertiary children's hospital from 2013 to 2021. Subjects were treated with intravenous immunoglobulin (IVIG). Right and left grip strength measurements were obtained at each clinic visit using a handheld dynamometer. Annual right median motor nerve conduction study data were recorded during the study period.
Results
Mean duration of follow‐up was 2.9 years. Grip strength (right: 0.19 kg/month, p < 0.001; left 0.23 kg/month, p < 0.001) and median F‐wave latencies (−0.23/month, p = 0.015) showed significant improvement over time. Akaike information criterion showed time + IVIG frequency <21 days as best fit for grip strength and distal compound muscle action potential amplitude.
Discussion
Our study results indicate serial grip strength measurements are a feasible and objective way to assess motor strength improvement in children with CIDP receiving immunotherapy.
