Gottfries – American ME and CFS Society

Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies

Abstract:

Metabolic profiling studies have recently indicated dysfunctional mitochondria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This includes an impaired function of pyruvate dehydrogenase complex (PDC), possibly driven by serum factor(s), which leads to inadequate adenosine triphosphate generation and excessive lactate accumulation. A reminiscent energy blockade is likely to occur in primary biliary cholangitis (PBC), caused by anti-PDC autoantibodies, as recently proposed. PBC is associated with fatigue and post-exertional malaise, also signifying ME/CFS. We herein have investigated whether ME/CFS patients have autoreactive antibodies that could interfere with mitochondrial function.

We found that only 1 of 161 examined ME/CFS patients was positive for anti-PDC, while all PBC patients (15/15) presented significant IgM, IgG, and IgA anti-PDC reactivity, as previously shown. None of fibromyalgia patients (0/14), multiple sclerosis patients (0/29), and healthy blood donors (0/44) controls showed reactivities. Anti-mitochondrial autoantibodies (inner and outer membrane) were negative in ME/CFS cohort. Anti-cardiolipin antibody levels in patients did not differ significantly from healthy blood donors.

In conclusion, the impaired mitochondrial/metabolic dysfunction, observed in ME/CFS, cannot be explained by presence of circulating autoantibodies against the tested mitochondrial epitopes.

Source: Nilsson I, Palmer J, Apostolou E, Gottfries CG, Rizwan M, Dahle C, Rosén A. Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies. Front Med (Lausanne). 2020 Mar 31;7:108. doi: 10.3389/fmed.2020.00108. eCollection 2020. https://www.frontiersin.org/articles/10.3389/fmed.2020.00108/full (Full text)

Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed.

Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria).

Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens.

We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.

Source: Blomberg J, Rizwan M, Böhlin-Wiener A, Elfaitouri A, Julin P, Zachrisson O, Rosén A, Gottfries CG. Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front Immunol. 2019 Aug 14;10:1946. doi: 10.3389/fimmu.2019.01946. eCollection 2019 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702656/ (Full article)

Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Abstract:

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease.

A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension.

A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Source: Jonas Blomberg, Gerhard Gottfries, Amal Elfaitouri, Muhammad Rizwan and Anders Rosén. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Hypothesis and Theory Article, Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229 (Full article)

Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia

Abstract:

BACKGROUND: Patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B12 injections, in vital combination with oral folic acid. However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders.

OBJECTIVE: To evaluate clinical data from patients with ME, with or without fibromyalgia, who had been on B12 injections at least once a week for six months and up to several years.

METHODS: 38 patients were included in a cross-sectional survey. Based on a validated observer’s rating scale, they were divided into Good (n = 15) and Mild (n = 23) responders, and the two groups were compared from various clinical aspects.

RESULTS: Good responders had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, while 70% of Mild responders (p<0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis. In addition to ME, the higher number of patients with fibromyalgia among Mild responders was bordering on significance (p<0.09). Good responders rated themselves as “very much” or “much” improved, while Mild responders rated “much” or “minimally” improved.

CONCLUSIONS: Dose-response relationship and long-lasting effects of B12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia. It’s important to be alert on co-existing thyroid dysfunction, and we suspect a risk of counteracting interference between B12/folic acid and certain opioid analgesics and other drugs that have to be demethylated as part of their metabolism. These issues should be considered when controlled trials for ME and fibromyalgia are to be designed.

Source: Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, Gottfries CG. Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PLoS One. 2015 Apr 22;10(4):e0124648. doi: 10.1371/journal.pone.0124648. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406448/ (Full article)

Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis

Abstract:

Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen.

The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected.

When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

Source: Elfaitouri A, Herrmann B, Bölin-Wiener A, Wang Y, Gottfries CG, Zachrisson O, Pipkorn R, Rönnblom L, Blomberg J. Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis. PLoS One. 2013 Nov 28;8(11):e81155. doi: 10.1371/journal.pone.0081155. ECollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842916/ (Full article)

Immune modulation with a staphylococcal preparation in fibromyalgia/chronic fatigue syndrome: relation between antibody levels and clinical improvement

Abstract:

The aims of this study were to evaluate the serological response to treatment with staphylococcal vaccine in fibromyalgia/chronic fatigue syndrome patients and to explore the relationship between serological response and clinical effect.

Twenty-eight patients, half of whom served as controls, were recruited from a 6-month randomised trial in which repeated administration of the staphylococcal toxoid vaccine Staphypan Berna (Berna Biotech, Switzerland) was tested against placebo. Antibody status against extracellular toxins/enzymes, cell-wall components, and enterotoxins was evaluated at baseline and at endpoint. The clinical response to treatment was recorded in rating scales.

In the group receiving active treatment, significant serological changes were recorded, whereas no significant changes were found in controls. Treatment led to a significantly increased capacity of serum to neutralise alpha-toxin and a significant increase in serum IgG to alpha-toxin and lipase. Furthermore, the increase in these parameters combined paralleled the improvement in clinical outcome. Thus, the greater the serological response, the greater was the clinical effect.

In conclusion, this explorative study has shown that repeated administration of the Staphypan Berna vaccine in patients with fibromyalgia/chronic fatigue syndrome causes a serological response to several staphylococcal antigens, particularly to certain extracellular toxins and enzymes. The results further show that this response is related to the clinical outcome of treatment.

Source: Zachrisson O, Colque-Navarro P, Gottfries CG, Regland B, Möllby R. Immune modulation with a staphylococcal preparation in fibromyalgia/chronic fatigue syndrome: relation between antibody levels and clinical improvement. Eur J Clin Microbiol Infect Dis. 2004 Feb;23(2):98-105. Epub 2004 Jan 20. http://www.ncbi.nlm.nih.gov/pubmed/14735403

Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome–a randomised controlled trial

Abstract:

We have previously conducted a small treatment study on staphylococcus toxoid in fibromyalgia (FM) and chronic fatigue syndrome (CFS). The aim of the present study was to further assess the efficacy of the staphylococcus toxoid preparation Staphypan Berna (SB) during 6 months in FM/CFS patients.

One hundred consecutively referred patients fulfilling the ACR criteria for FM and the 1994 CDC criteria for CFS were randomised to receive active drug or placebo. Treatment included weekly injections containing 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.6 ml, 0.8 ml, 0.9 ml, and 1.0 ml SB or coloured sterile water, followed by booster doses given 4-weekly until endpoint.

Main outcome measures were the proportion of responders according to global ratings and the proportion of patients with a symptom reduction of > or =50% on a 15-item subscale derived from the comprehensive psychopathological rating scale (CPRS). The treatment was well tolerated. Intention-to-treat analysis showed 32/49 (65%) responders in the SB group compared to 9/49 (18%) in the placebo group (P<0.001). Sixteen patients (33%) in the SB group reduced their CPRS scores by at least 50% compared to five patients (10%) in the placebo group (P< 0.01). Mean change score on the CPRS (95% confidence interval) was 10.0 (6.7-13.3) in the SB group and 3.9 (1.1-6.6) in the placebo group (P<0.01). An increase in CPRS symptoms at withdrawal was noted in the SB group.

In conclusion, treatment with staphylococcus toxoid injections over 6 months led to significant improvement in patients with FM and CFS. Maintenance treatment is required to prevent relapse.

Source: Zachrisson O, Regland B, Jahreskog M, Jonsson M, Kron M, Gottfries CG. Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome–a randomised controlled trial. Eur J Pain. 2002;6(6):455-66. http://www.ncbi.nlm.nih.gov/pubmed/12413434

A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale)

Abstract:

OBJECTIVE: To construct an observer’s rating scale sensitive to change for measuring severity and treatment outcome in fibromyalgia (FM) and chronic fatigue syndrome (CFS) patients.

METHODS: A selection of items from the Comprehensive Psychopathological Rating Scale (CPRS) were repeatedly rated and used as outcome measure of a 24-week treatment study. In the study 100 women, fulfilling the criteria for both FM and CFS, received intermittent injections of a staphylococcus toxoid or placebo. Nine CPRS-items with high baseline incidence (cutoff 70%) were extracted and validated against global ratings and the Fibromyalgia Impact Questionnaire (FIQ). The fibromyalgia and chronic fatigue syndrome rating scale (the FibroFatigue scale) was thereafter formed based upon the extracted items and three supplemented ones. The interrater reliability was tested in 27 consecutive patients of both sexes.

RESULTS: The FibroFatigue scale is an observer’s rating scale with 12 items measuring pain, muscular tension, fatigue, concentration difficulties, failing memory, irritability, sadness, sleep disturbances, and autonomic disturbances (items derived from the CPRS) and irritable bowel, headache, and subjective experience of infection (new items). There was a statistically significant correlation between the CPRS-extracted items and global ratings as well as with the FIQ. The interrater reliability of the new scale was excellent (correlation coefficient.98), irrespective of the patients’ gender.

CONCLUSION: The FibroFatigue scale seems to be a reliable and valid measuring instrument with capacity to monitor symptom severity and change during treatment of FM/CFS patients.

Source: Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG. A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res. 2002 Jun;52(6):501-9. http://www.ncbi.nlm.nih.gov/pubmed/12069875

Effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome

Abstract:

Positive results of pilot studies of the effect of staphylococcus toxoid vaccine in patients with fibromyalgia and chronic fatigue syndrome were the incitement to the present, placebo-controlled study. It included 28 patients who fulfilled the criteria for both fibromyalgia and chronic fatigue syndrome.

The effect of vaccination with a staphylococcus toxoid was compared with the effect of injections of sterile water. Psychometric assessment was made using 15 items from the comprehensive psychopathological rating scale (CPRS), Zung’s self-rating depression scale and clinical global impressions (CGI). The visual analogue scale (VAS) was used to measure pain levels, and a hand-held electronic pressure algometer was used to measure pressure pain thresholds.

Significant improvement was seen in seven of the 15 CPRS items in the vaccine group when pretreatment values were compared to post-treatment values. In CPRS <<fatiguability>>, there were significant intergroup differences, and in CPRS <<pain>> intergroup differences bordered on significance. There was no significant improvement in CPRS items in the placebo group.

Clinical global impressions showed significant improvement in the vaccine-treated group, and VAS did so in both groups. In a follow-up study of 23 patients, the vaccine treatment was continued for 2-6 years. Fifty percent were rehabilitated successfully and resumed half-time or full-time work. The results of this study support the authors>> hypothesis that treatment with staphylococcus toxoid may be a fruitful strategy in patients with fibromyalgia and chronic fatigue syndrome.

Source: Andersson M, Bagby JR, Dyrehag L, Gottfries C. Effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome. Eur J Pain. 1998;2(2):133-142. http://www.ncbi.nlm.nih.gov/pubmed/10700309