Category: Treatment

Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Objectives: In this six-year follow-up study, we used patient-reported outcome measures (PROMs) to compare values at baseline, at 18 months, and at six-year follow up from the CycloME and the RituxME trials.

Methods: Based on the hypothesis that ME/CFS in a subgroup of patients is a variant of an autoimmune disease, we performed two clinical trials between 2014 and 2017. The RituxME trial was a randomized, double-blind and placebo-controlled phase III trial of 151 patients, assessing the B-cell depleting antibody rituximab. The CycloME trial was an open-label phase II trial of 40 patients using intravenous cyclophosphamide. Here we report six-year follow-up from both trials, using the Short Form 36 Physical Function (SF-36 PF) and DePaul short form (DSQ-SF) questionnaires.

Result: Of the patients available after six years, 75.7% of RituxME and 94.4% of CycloME patients participated. In the RituxME rituximab group, the mean SF-36 PF scores were 32.9 at baseline, 42.4 at 18 months and 45.5 at six years. In the placebo group, the mean SF-36 PF scores were 32.3 at baseline, 45.5 at 18 months and 43.1 at six years. In the CycloME trial, mean SF-36 PF increased from 35.4 at baseline to 54.4 at 18 months, and 56.7 at six years. At six-year follow-up, 44.1% of cyclophosphamide-, 27.6% of rituximab- and 20.4% of placebo-treated patients had an SF-36 PF ≥ 70, and further, 17.6%, 8.6% and 7.4% of the corresponding patient groups had an SF-36 PF ≥ 90, which is within normal range. In terms of worsening at six years, 5.9% of cyclophosphamide-treated, 10.3% of rituximab-, and 14.8% of placebo-treated patients had a drop in SF-36 PF of 20 points or more from baseline. There were no serious unexpected adverse reactions.

Conclusions: After six years, 44.1% of the cyclophosphamide group scored an SF-36 PF of at least 70, and 17.6% of at least 90, suggesting that cyclophosphamide in a subgroup may modulate the disease course in a beneficial way. However, cyclophosphamide carries toxicity concerns and should not be used for ME/CFS patients outside clinical trials. Rather, these data should encourage efforts to better understand the disease mechanisms and to search for targeted and less toxic immune modulatory treatment for this patient group.

Source: Rekeland IG, Sørland K, Neteland LL, Fosså A, Alme K, Risa K, Dahl O, Tronstad KJ, Mella O, Fluge Ø. Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLoS One. 2024 Jul 23;19(7):e0307484. doi: 10.1371/journal.pone.0307484. PMID: 39042627; PMCID: PMC11265720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265720/ (Full text)

Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified.

The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development.

TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3’s expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.

Source: Löhn M, Wirth KJ. Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone. J Transl Med. 2024 Jul 5;22(1):630. doi: 10.1186/s12967-024-05412-3. PMID: 38970055; PMCID: PMC11227206. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227206/ (Full Text)

Successful Subcutaneous Immunoglobulin Therapy in a Case Series of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigma with no curable treatment options at hand. Although patients with ME/CFS are a heterogeneous group, a large proportion of patients present with an infection-driven symptomatology, making them potential responders to immunologic treatments, such as immunoglobulin (IG). Previous studies on IG treatment in patients with ME/CFS have not been consistent but have described beneficial effects in subgroups of patients.

Methods: Here we present data on a series of cases (n = 17) with infection-related ME/CFS (as defined by disease history and ongoing recurrent infections) treated with subcutaneous low-dose IG (0.06 g/kg/mo) over 5 weeks with continuous monitoring of symptoms.

Findings: Patients were predominantly female (65%) with mild-to-moderate disease severity (82%) and with poor self-reported quality of life (median, 25 on a 0-100 scale) and working ability (median, 5 on a 0-100 scale) before treatment. After 5 weeks of treatment with low-dose IG, significant improvements in symptoms, quality of life, and working ability were noted (all P < 0.05). Among the 7 patients who reported the highest benefit of the treatment, quality of life increased by 35 units (on a 0-100 scale), with 1 patient reporting complete elimination of ME/CFS symptoms. No serious side effects were detected with the treatment.

Implications: In this limited-sized case series, we found pronounced beneficial effects of low-dose IG in a large proportion of patients with infection-related ME/CFS. Further well-controlled studies are needed to verify the potential benefits of IG treatment in patients with ME/CFS with infection-driven symptomatology.

Source: Sjogren P, Bragée B, Britton S. Successful Subcutaneous Immunoglobulin Therapy in a Case Series of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clin Ther. 2024 Jun 22:S0149-2918(24)00131-0. doi: 10.1016/j.clinthera.2024.05.010. Epub ahead of print. PMID: 38910072.

Systems Modeling Reveals Shared Metabolic Dysregulation and Novel Therapeutic Treatments in ME/CFS and Long COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex, multisystemic conditions that pose ongoing challenges to healthcare professionals. Emerging research suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating possible shared metabolic dysfunctions. This study aims to systematically explore these shared metabolic disturbances and their potential treatments.

Utilizing our novel metabolic modeling method, GPMM, we identified the key metabolic irregularities in patients with ME/CFS and Long COVID, notably the downregulation of the alanine and aspartate metabolism pathway, and the arginine and proline metabolism pathway.

Genome-wide knockout analyses indicated that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. Further metabolic assessments in Long COVID patients highlighted the significant downregulation of ASP in both blood and muscle, supporting our predictions.

Consequently, we propose that the combination of l-ornithine and l-aspartate (LOLA) offers a promising approach to alleviate metabolic symptoms in both ME/CFS and Long COVID patients. This study not only elucidates the shared metabolic pathways in ME/CFS and Long COVID but also positions LOLA as a viable candidate for future clinical trials.

Source: Gong-Hua Li, Feifei Han, Qing-Peng Kong, Wenzhong Xiao. Systems Modeling Reveals Shared Metabolic Dysregulation and Novel Therapeutic Treatments in ME/CFS and Long COVID. bioRxiv 2024.06.17.599450; doi: https://doi.org/10.1101/2024.06.17.599450 https://www.biorxiv.org/content/10.1101/2024.06.17.599450v1.full (Full text)

Multimodal treatment strategies for homebound people with severe ME/CFS: a scoping review

Abstract:

Purpose: This scoping review aims to provide an overview of previously published treatment strategies that are multimodal, rather than purely drug-based and may be considered for home- or bedbound ME/CFS patients. Thus, the focus lies upon the analyses of telemedicine as well as home treatment elements. In addition, the evaluation and assessment methods used in these studies will be further discussed.

Methods: Using the scoping review method, a literature analysis was conducted resulting in a total of 14 publications which met the predefined criteria. Inclusion was based on models applicable to housebound individuals with ME/CFS, focusing on social medicine and psychological support services rather than individual drug strategies.

Results: The analysis demonstrated that the appropriate treatment methods were predominantly home visits (n=5) or a telemedicine format (n=7). Studies which used alternative settings were included if conversion to a telemedicine format was viable. The important factors highlighted in several studies (n=8), when considering this patient group, were individualisation and flexibility of the treatment methods – and thus the ability to address the day-to-day levels of impairment. The explicit involvement of families in the treatment plan were described in a total of six studies. In ten articles, the treatment concept was additionally evaluated, predominantly using questionnaires (n=7), whilst the questionnaires used were not consistent. Qualitative evaluations were invariably conducted using Brown and Clarke‘s thematic analysis (n=3).

Conclusion: Publications on multimodal treatment strategies for homebound ME/CFS patients are rare. However approaches using home visits or telemedicine are described. The majority of identified publications addressed the need for individualised as well as flexible patient care, whilst some were dedicated to the added value of involving the patients’ family. The data outline the specific challenges associated with the care of severely affected ME/CFS patients that should also be considered in the context of research.

Source: Mayer-Huber S, Kircher A, Eberhartinger M, Stojanov S, Behrends U. Multimodale Behandlungsstrategien für hausgebundene Menschen mit schwerem ME/CFS: ein Scoping Review. Gesundheitswesen. 2024 May 10. German. doi: 10.1055/a-2323-4108. Epub ahead of print. PMID: 38729210. https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2323-4108

A Narrative Review on Gut Microbiome Disturbances and Microbial Preparations in ME/CFS: Implications for Long COVID

Abstract:

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS) and Long COVID are characterized by debilitating post-exertional malaise and other core symptoms related to immune dysregulation resultant from post-viral infection, including mitochondrial dysfunction, chronic neuroinflammation and gut dysbiosis. The reported associations between altered microbiota composition and cardinal symptoms of ME/CFS and Long COVID, suggesting that use of microbial preparations, such as probiotics, by restoring the homeostasis of the brain-immune-gut axis may help in the management of symptoms in both conditions.

Therefore, this review aims to investigate the implications of alerted gut microbiome and assess the evidence supporting use of microbial-based preparations, including probiotics, synbiotics, postbiotics alone and/or in combination with other nutraceuticals in the management of fatigue, inflammation, as well as neuropsychiatric and gastrointestinal symptoms among patients with ME/CFS and Long COVID.

Source: Jurek, J.M.; Castro-Marrero, J. A Narrative Review on Gut Microbiome Disturbances and Microbial Preparations in ME/CFS: Implications for Long COVID. Preprints 2024, 2024042021. https://doi.org/10.20944/preprints202404.2021.v1  https://www.preprints.org/manuscript/202404.2021/v1 (Full text available as PDF file)

Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neuro-cognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between Arterial Pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age=24.1 years) and 15 ME/CFS patients (mean age=21.8 years). All ME/CFS patients had postural tachycardia syndrome (POTS).

A 10-minute 60⁰ head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P <0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS vs. control. In ME/CFS, HUT significantly decreased CBV compared to control (-22.5% vs -8.7%, p<0.005).

To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n=4 N-back during HUT in ME/CFS similar to control (ME/CFS=38.5±5.5 vs. ME/CFS+PE= 65.6±5.7 vs. Control 56.9±7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. While CO2 and Acetazolamide had no effect on PhSI in ME/CFS, PE caused a significant reduction in PhSI (ME/CFS=0.80±0.03 vs ME/CFS+PE= 0.69±0.04, p< 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in ME/CFS patients, perhaps related to improved neurovascular coupling, cerebral autoregulation and maintenance of CBV.

Source: Medow MS, Stewart JM. Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance. Am J Physiol Regul Integr Comp Physiol. 2024 Apr 29. doi: 10.1152/ajpregu.00071.2024. Epub ahead of print. PMID: 38682242. https://journals.physiology.org/doi/abs/10.1152/ajpregu.00071.2024 (Full text available as PDF file)

Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis

Abstract:

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Source: Yi-Dan Zhang, Li-Na Wang. Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis. Front. Endocrinol., 09 April 2024, Sec. Neuroendocrine Science, Volume 15 – 2024 | https://doi.org/10.3389/fendo.2024.1373748 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1373748/full

The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives

Abstract:

Like other infections, a SARS-CoV-2 infection can also trigger Post-Acute Infection Syndromes (PAIS), which often progress into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS, characterized by post-exercise malaise (PEM), is a severe multisystemic disease for which specific diagnostic markers or therapeutic concepts have not been established.

Despite numerous indications of post-infectious neurological, immunological, endocrinal, and metabolic deviations, the exact causes and pathophysiology remain unclear. To date, there is a paucity of data, that changes in the composition and function of the gastrointestinal microbiota have emerged as a potential influencing variable associated with immunological and inflammatory pathways, shifts in ME/CFS. It is postulated that this dysbiosis may lead to intestinal barrier dysfunction, translocation of microbial components with increased oxidative stress, and the development or progression of ME/CFS.

In this review, we detailed discuss the findings regarding alterations in the gastrointestinal microbiota and its microbial mediators in ME/CFS. When viewed critically, there is currently no evidence indicating causality between changes in the microbiota and the development of ME/CFS. Most studies describe associations within poorly defined patient populations, often combining various clinical presentations, such as irritable bowel syndrome and fatigue associated with ME/CFS.

Nevertheless, drawing on analogies with other gastrointestinal diseases, there is potential to develop strategies aimed at modulating the gut microbiota and/or its metabolites as potential treatments for ME/CFS and other PAIS. These strategies should be further investigated in clinical trials.

Source: Andreas Stallmach, Stefanie Quickert, Christian Puta, Philipp A. Reuken. The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives. Front. Immunol., 27 March 2024, Sec. Microbial Immunology, Volume 15 – 2024. https://doi.org/10.3389/fimmu.2024.1352744 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1352744/full (Full text)

A Case Report of Chronic Epipharyngitis With Chronic Fatigue Treated With Epipharyngeal Abrasive Therapy (EAT)

Abstract:

A case of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with chronic epipharyngitis was treated with epipharyngeal abrasive therapy (EAT). The symptoms of ME/CFS improved along with the improvement of chronic epipharyngitis. The patient was followed up with endocrine and autonomic function tests.

Endocrine function tests included salivary cortisol and salivary α-amylase activity. Salivary α-amylase activity was stimulated by EAT. EAT improved the diurnal variability of salivary cortisol secretion. Autonomic function tests included heart rate variability analysis by orthostatic stress test. EAT normalized parasympathetic and sympathetic reflexes over time and regulated autonomic balance.

Based on the improvement of symptoms and test results, EAT was considered effective for ME/CFS. A literature review was conducted on the mechanism of the therapeutic effect of EAT on ME/CFS.

Source: Hirobumi I. A Case Report of Chronic Epipharyngitis With Chronic Fatigue Treated With Epipharyngeal Abrasive Therapy (EAT). Cureus. 2024 Feb 23;16(2):e54742. doi: 10.7759/cureus.54742. PMID: 38405656; PMCID: PMC10884883. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10884883/ (Full text)