Background

Risk factors previously identified for worse outcomes with SARS-CoV-2 infections include older age, male sex and specific comorbid conditions. An increased risk for poorer COVID-19 outcomes in people with multiple sclerosis (MS) are similar to the general population, but less is known about outcomes in minority groups with MS.

Objectives

To evaluate differences in outcomes of SARS-CoV-2 infection in non-Hispanic White and Black persons with multiple sclerosis.

Methods

COViMS is a North American registry for health care providers to report persons with MS who are infected with SARS-CoV-2, the virus that causes COVID-19 (cases). Cases are reported after 7 days and when the outcome of infection is reasonably certain. MS and clinically isolated syndrome cases were categorized using the Center for Disease Control and Prevention races (non-Hispanic Whites, and Black). Comorbidities related to COVID-19 outcomes were collected. Clinical outcomes examined were mortality alone, mortality and/or admissions to the intensive care unit (ICU) and mortality, ICU admissions and/or hospitalization. Age-adjusted mortality rates as of August 3, 2020 and 95% confidence intervals (CI) were calculated. Multivariable logistic regression was used to assess adjusted differences between races using odds ratios (OR) and 95% CIs. Covariates included sex, age, smoking (current, past, never), MS clinical course (relapsing, progressive), disease duration, ambulation (fully ambulatory, walks with assistance, non-ambulatory), individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease modifying therapy use (yes vs no).

Results

Of 734 patients reported, 421 (57.4%) Whites, and 194 (26.5%) Black patients were reported. Black cases were more likely to be younger (p=0.002), never smokers (p=0.002), have shorter MS duration (p<0.001), a relapsing MS course (p=0.03) and have comorbidities (p<0.001) compared to Whites. A higher proportion of Black patients had hypertension (40.2% vs 19.5%, p<0.001), and morbid obesity (17.0% vs 9.5%, p=0.007). Mortality rates increased with age and were not statistically different between Whites and Blacks (p=0.156). Black race was associated with increased odds of mortality and/or ICU admission (OR 3.8 [95%CI: 1.60, 8.96], p=0.002) and mortality, ICU admission and/or hospitalization (OR 2.0 [95%CI: 1.14, 3.54], p=0.016) after adjustment for covariates.

Conclusions

Within the COViMS registry, Black MS patients were younger and more likely to have comorbidities than White MS patients. Black MS patients had an increased risk for poorer outcomes compared to Whites even after adjusting for comorbidities at the time of COVID-19.

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

Emergence of SARS CoV-2 causing COVID-19 provoked the need to gather information on the overall outcomes and potential risks associated with morbidity and mortality in multiple sclerosis (MS) patients with COVID-19 infections. The COViMS registry was initiated as a rapid and efficient means to collect this data from North American health care providers.

Objectives

To describe the spectrum of outcomes in SARS CoV-2 infected North American MS patients and to ascertain characteristics associated with severe COVID-19 outcomes.

Methods

The COViMS registry requested that MS, neuromyelitis optica (NMO), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and radiographically isolated syndrome (RIS) patients with SARS-CoV-2 infection be reported after the outcome was reasonably certain. Data were de-identified and cross-sectional. Effort was made to harmonize with other international registries for COVID-19. Poor clinical outcomes assessed were: mortality, mortality and/or admission to the intensive care unit (ICU), and mortality, ICU admission and/or hospitalization. Associations between patient characteristics and these outcomes were evaluated using multivariable logistic regression. Covariates included sex, age, race, smoking, MS clinical course (relapsing, progressive), MS disease duration, ambulation (fully ambulatory, walks with assistance, non-ambulatory), individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease modifying therapy (DMT) use.

Results

As of Aug 3, 2020, 764 patients from over 140 different practices were reported; 734 MS, 21 NMO, 4 MOGAD, and 5 RIS. MS patients were 73.4% female (73.4%), 65.2% Caucasian, with mean (SD) age of 48.2 (±13.5) years. Mean disease duration was 13.8 (±9.9) years. 70.9% were fully ambulatory. Ocrelizumab and dimethyl fumarate (DMF) were the top two DMTs used. Most (77.1%) were laboratory confirmed for SARS-CoV-2. Of MS cases, 6.1% died, 13.8% were admitted to the ICU and/or died, and 31.2% were either hospitalized, admitted to the ICU or died. Older age, non-ambulatory status and cardiovascular disease were associated with increased risk of poor outcomes. No specific DMT was associated with increased odds of mortality and mortality and/or ICU admission. Anti-CD20 DMT use showed an increased odds of mortality, ICU admission and/or hospitalization compared to DMF (OR: 2.53 95%CI [1.17, 5.50]).

Conclusions

The data provide reassurance that the MS registry population aligns with reported COVID-19 outcomes in the general North American population. While reported deaths are few, no clear association between a specific therapy and mortality has been seen after adjustment for age, sex, ambulatory status and comorbidities. Data collection continues.

Background

In CLARITY and CLARITY Extension (NCT00213135 and NCT00641537, respectively), treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates in patients with relapsing-remitting multiple sclerosis. Moreover, in the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by treatment with placebo for 2 years produced similar clinical benefits to 2 years of cladribine tablets treatment followed by an additional 2 years of treatment, but with a lower risk of higher grade lymphopenia.

Objectives

To assess, post hoc, the temporal occurrence of relapses up to 5 years after treatment initiation with cladribine tablets.

Methods

Patients enrolled into CLARITY treated with CT3.5, and those subsequently receiving CT3.5 (CC7) or placebo (CP3.5) in CLARITY Extension, were included for analysis. The main endpoint was all qualifying relapses reported in CLARITY or CLARITY Extension plus those that occurred during the variable bridging interval (range: 1 day to 118 weeks). A recurrent event analysis was performed to estimate mean cumulative number of relapses over time using a cumulative mean function estimate.

Results

A total of 433 patients from CLARITY treated with CT3.5 were included in this analysis; of these 284 patients entered CLARITY Extension (CP3.5, n=98; CC7, n=186). Recurrent event analysis for the CT3.5 population showed that annual increase in mean cumulative number of relapses was consistently low from Year 2 to Year 5 (range: 0.10–0.15) and was slightly higher in Year 1 (0.17); the 6-month increase in mean cumulative number of relapses was similar in the first 6 months and the second 6 months (0.08 and 0.09, respectively). There were no differences in mean cumulative number of relapses between the CP3.5 and CC7 groups from Year 2 to Year 5. In recurrent event analysis for the CT3.5 population, the yearly increments of mean cumulative function were constant and low from the second treatment to Year 5, supporting the durable efficacy of cladribine tablets (given no increase in relapses following completion of the two courses of cladribine tablets).

Conclusions

Annual increase in mean cumulative number of relapses occurred at a low annualized rate of 0.10 to 0.17 per year to 5 years, almost 4 years after the last dose of cladribine tablets and therefore consistent with durable efficacy. Results also support the early effect of cladribine tablets on relapses, which is apparent in the first year of treatment.

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.

Background

North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is a longitudinal registry studying the course of MS in the disease-modifying era.

Objectives

To examine motor performance metrics of upper and lower extremity function in NARCRMS participants at enrollment, using the Expanded Disability Status Scale (EDSS) and 25-foot walk times.

Methods

Recruitment began in 2016 and by June 24, 2020, 737 patients were enrolled at 25 MS sites across the US and Canada. People with any sub type of MS within 15 years of disease onset and an EDSS of up to 6.5 are eligible for enrollment. Various clinical metrics are collected including motor performance for upper and lower extremities. Our initial observations about EDSS, 25-foot timed walk and the 9-hole peg test are reported below

Results

EDSS and 25-foot walk times were available in 632 patients and upper extremity function in 609 patients. A mean walking speed of 4.96 seconds was recorded in patients with an EDSS of 0 (n=105). 5.11 was the mean speed until an EDSS of 3.0 (n=39) where a mean speed of 5.41 seconds was recorded. Walking truly became affected at an EDSS of 3.5 (n=27) where a mean speed of 6.48 seconds was recorded. Thereafter mean speed progressively declined at every EDSS increase. For an EDSS of 4.0 (n=28), mean speed was 7.78 seconds; for an EDSS of 4.5 (n=6), mean speed was 9.16 seconds and continued to increase until an EDSS of 6.5 (n=11) where mean speed was 19.1 seconds. For the 9-hole peg test, patients with an EDSS of 0 (n=101) had a mean speed of 20.3 seconds in the dominant and 21 seconds in the non-dominant hand. Hand function remained unimpaired until an EDSS of 2.0 and significant slowing occurred in patients with EDSS ranging from 2.5 to 6.5. For an EDSS of 2.5 (n=44), mean speed was 25.3 seconds in the dominant and 24.4 seconds in the non-dominant hand. For an EDSS of 4.0 (n=26), mean speed was 26.3 seconds in the dominant and 26.0 seconds in the non-dominant hand. For an EDSS of 6.5 (n=11), hand function had declined to a mean speed of 40.1 seconds for the dominant and 56.4 seconds for the non-dominant hand.

Conclusions

A linear correlation of the 25-foot walk speed to EDSS increases was remarkable, reiterating the commonly held belief that the EDSS is a “walking scale”. Decline in hand function at an EDSS of 2.5 was unexpected since hands are often perceived to be unaffected early in MS and seldom observed as impaired by patients. Progressive decline of hand function at every EDSS increase would suggest that the 9-HP test is a good marker of declining hand function and should be included in clinical monitoring of patients.

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.

Background

North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is a longitudinal registry studying the course of MS in the disease-modifying era.

Objectives

To examine motor performance metrics of upper and lower extremity function in NARCRMS participants at enrollment, using the Expanded Disability Status Scale (EDSS) and 25-foot walk times.

Methods

Recruitment began in 2016 and by June 24, 2020, 737 patients were enrolled at 25 MS sites across the US and Canada. People with any sub type of MS within 15 years of disease onset and an EDSS of up to 6.5 are eligible for enrollment. Various clinical metrics are collected including motor performance for upper and lower extremities. Our initial observations about EDSS, 25-foot timed walk and the 9-hole peg test are reported below

Results

EDSS and 25-foot walk times were available in 632 patients and upper extremity function in 609 patients. A mean walking speed of 4.96 seconds was recorded in patients with an EDSS of 0 (n=105). 5.11 was the mean speed until an EDSS of 3.0 (n=39) where a mean speed of 5.41 seconds was recorded. Walking truly became affected at an EDSS of 3.5 (n=27) where a mean speed of 6.48 seconds was recorded. Thereafter mean speed progressively declined at every EDSS increase. For an EDSS of 4.0 (n=28), mean speed was 7.78 seconds; for an EDSS of 4.5 (n=6), mean speed was 9.16 seconds and continued to increase until an EDSS of 6.5 (n=11) where mean speed was 19.1 seconds. For the 9-hole peg test, patients with an EDSS of 0 (n=101) had a mean speed of 20.3 seconds in the dominant and 21 seconds in the non-dominant hand. Hand function remained unimpaired until an EDSS of 2.0 and significant slowing occurred in patients with EDSS ranging from 2.5 to 6.5. For an EDSS of 2.5 (n=44), mean speed was 25.3 seconds in the dominant and 24.4 seconds in the non-dominant hand. For an EDSS of 4.0 (n=26), mean speed was 26.3 seconds in the dominant and 26.0 seconds in the non-dominant hand. For an EDSS of 6.5 (n=11), hand function had declined to a mean speed of 40.1 seconds for the dominant and 56.4 seconds for the non-dominant hand.

Conclusions

A linear correlation of the 25-foot walk speed to EDSS increases was remarkable, reiterating the commonly held belief that the EDSS is a “walking scale”. Decline in hand function at an EDSS of 2.5 was unexpected since hands are often perceived to be unaffected early in MS and seldom observed as impaired by patients. Progressive decline of hand function at every EDSS increase would suggest that the 9-HP test is a good marker of declining hand function and should be included in clinical monitoring of patients.