Background

The histaminergic tuberomammillary system through its varied connections control the circadian rhythm and regulate wakefulness and sleep, satiety and hunger, memory and learning, as well as energy and tiredness. Blocking brain histamine receptors lead to tiredness and sleep. In this study we examined if raising brain histamine levels can improve fatigue in severely fatigued patients with multiple sclerosis.

Objectives

To validate the concept that raising brain histamine will alleviate fatigue in severely fatigued patients with multiple sclerosis

Methods

A strategy was developed to raise brain histamine by loading patients with l-histidine, the precursor for histamine. Conversion systemically from l-histidine to histamine was blocked using histidine decarboxylase inhibitor, lodosyn, which has no access to the brain across the blood brain barrier.All subjects received a fixed dose lodosyn, 50 mg po bid. Three groups of l-histidine loading wereundertaken. Group-1 received 250 mg po bid, Group-2 500 mg po bid and group 3, 1 gm po bid. Pharmacokinetic (PK) and pharmacodynamic (PD) studies were conducted to measure blood and CSF l-histidine and histamine levels before and during treatment. Response to treatment was gauged using the visualanalogue fatigue scale (VAFS), Fatigue severity scale (FSS) and the modified fatigue impact scales (MFIS). To be considered a responder, patients had to improve in all three scales and show at least a 20% improvement from their mean screening/baseline MFIS scores.

Results

A dose-based response to improvement of fatigue was observed anywhere from 30% to 88% in MFIS scores with the least responders in Group 1 and most in Group 3. Improvement was noted in all three domains of the MFIS; the physical, cognitive and psychosocial. Improvement in the cognitive domain was associated with subjects reporting improved attention, concentration and improvement of the“brain fog”. Responders reported an overall sense of well being while others reported no change.

Conclusions

This proof -of-concept study has identified a population of MS patients with fatigue that respond to treatment using elevation of brain histamine. This novel approach opens up a new avenue to identify drugs that raise brain histamine as a mechanism of treatment of fatigue in MS and possibly other disorders with fatigue where histamine may play a pivotal role in the pathogenesis of this common and severely disabling symptom. Additionally this treatment could also provide an approach to help cognitive impairment in multiple sclerosis since raising brain histamine can facilitate also the enhanced release of a number of neurotransmitters including acetylcholine, implicated in the pathogenesis of cognitive impairment in various disorders including multiple sclerosis.

Background

The mechanism of action (MOA) of anti B-cell therapies in CNS demyelinating disorders associated with Aquaporin-4 antibody (AQP4-Ab) neuromyelitis optica spectrum disorders (NMOSD) is unknown. Restoration of immune tolerance by blocking self-antigen presentation by autoreactive B to T cells and return to immune homeostasis has been postulated as a MOA.

Presence of AQP4-Ab is a marker of breakdown of immune tolerance in NMOSD while their disappearance after initial positivity could signify restoration of immune homeostasis. The outcome of AQP4-Ab in NMOSD treated with rituximab has not previously been examined.

Objectives

To examine the evolution of AQP4-Ab status in a cohort of patients with CNS demyelinating disorders that were treated with rituximab.

Methods

Retrospective study of consecutive patients with recurrent optic neuritis or transverse myelitis treated with rituximab between 2006 and 2020. The data on AQP4-Ab status were obtained by chart review.

Results

A total of 51 patients who were on long-term monotherapy with rituximab 1 gm IV every 6 months were identified. All were clinically stable. All serology was obtained by commercial laboratories as reported in the respective clinical records. Twenty-nine patients were AQP4-Ab positive (57%) at some time using the ELISA or more recently, the cell-based assay. In 23 patients re-testing for serological status was undertaken at varied intervals. Serostatus changed in 10 patients with 4 patients previously seronegative now becoming seropositive, and 6 patients who were seropositive becoming seronegative. In some subjects where seroreversion occurred, when titers were reported, a decrease in titer over time occurred before becoming seronegative.

Conclusions

AQP4-Ab reactive status can revert to non-reactivity on rituximab therapy in some patients. The seroconversion, however, was not a marker for response to rituximab as a favorable clinical response was also observed in persistently seropositive patients as well. This previously unrecognized observation suggests that the change in AQP4-Ab status from positive to negative on rituximab therapy can be used as a potential marker to guide future randomized discontinuation trials of rituximab in a select group of clinically stable patients.