Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome

Russell, Ailsa; Hepgul, Nilay; Nikkheslat, Naghmeh; Borsini, Alessandra; Zajkowska, Zuzanna; Moll, Natalie; Forton, Daniel; Agarwal, Kosh; Chalder, Trudie; Mondelli, Valeria; Hotopf, Matthew; Cleare, Anthony J.; Murphy, Gabrielle; Foster, Graham R.; Wong, Terry; Schütze, Gregor; Schwarz, Markus J.; Harrison, Neil A.; Zunszain, Patricia A.; Pariante, Carmine M.

doi:10.1016/j.psyneuen.2018.11.032

Cited by 70 publications

(60 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…26 Similarly, in a model of IFN-α induced fatigue, Russell and colleagues showed that persist ent fatigue is not associated with peripheral immune activation. 27 Collectively, these data highlight our poor understanding of the mechanisms underpinning the symptomatology of primary Sjögren's syndrome and challenge the simple notion of peripheral immune activation being responsible for the symptoms. We found no significant differences between the PDF and HSB subgroups in objectively measured laboratory parameters.…”

Section: Discussionmentioning

confidence: 99%

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Howard-Tripp

Skelton

James

et al. 2019

The Lancet Rheumatology

102

View full text Add to dashboard Cite

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. MethodsWe did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. FindingsIn the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo.Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Howard-Tripp

Skelton

James

et al. 2019

The Lancet Rheumatology

102

View full text Add to dashboard Cite

show abstract

“…The origin of this neuroinflammatory dysregulation is unclear, with many competing hypotheses being proposed. EpsteineBarr and hepatitis viral infections have been implicated as potential causes, 14,65 with evidence that these viruses can persistently inhibit innate and adaptive immunity. Mitochondrial dysfunction has also been identified in patients with ME/CFS, 66 and the extracellular release of mitochondrial DNA in the hypothalamus has been proposed as an initiator of neuroinflammation via mast cell activation.…”

Section: Discussionmentioning

confidence: 99%

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Morris

Cooney

Sedghamiz

et al. 2019

Clinical Therapeutics

View full text Add to dashboard Cite

Purpose: The complex and varied presentation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has made it difficult to diagnose, study, and treat. Its symptoms and likely etiology involve multiple components of endocrine and immune regulation, including the hypothalamic-pituitaryadrenal axis, the hypothalamic-pituitary-gonadal axis, and their interactive oversight of immune function. We propose that the persistence of ME/CFS may involve changes in the regulatory interactions across these physiological axes. We also propose that the robustness of this new pathogenic equilibrium may at least in part explain the limited success of conventional single-target therapies. Methods: A comprehensive model was constructed of female endocrineeimmune signaling consisting of 28 markers linked by 214 documented regulatory interactions. This detailed model was then constrained to adhere to experimental measurements in a subset of 17 candidate immune markers measured in peripheral blood of patients with ME/ CFS and healthy control subjects before, during, and after a maximal exercise challenge. A set of 26 competing numerical models satisfied these data to within 5% error. Findings: Mechanistically informed predictions of endocrine and immune markers that were either unmeasured or exhibited high subject-to-subject variability pointed to possible context-specific overexpression in ME/CFS at rest of corticotropinreleasing hormone, chemokine (C-X-C motif) ligand 8, estrogen, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone 1, interleukin (IL)-23, and luteinizing hormone, and underexpression of adrenocorticotropic hormone, cortisol, interferon-g, IL-10, IL-17, and IL-1a. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrineeimmune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1a, IL-17, and cortisol; intermediate levels of progesterone and FSH; and high estrogen levels. Rituximab treatment was predicted to support partial remission in a smaller subset of patients with ME/ CFS, specifically those with low norepinephrine, IL-1a, chemokine (C-X-C motif) ligand 8, and cortisol

show abstract

“…While no single aetiological mechanism has been identified for FSDs, studies support the involvement of a variety of processes. Current hypotheses include processes involving both the body (e.g., immune system [22], autonomic nervous system [23], hypothalamo-pituitary axis [24], mitochondrial function [25]) and the brain and mind (processing and perception of bodily signals [6], central sensitisation [26], psychological adaptation [27]). This involvement of multiple processes is thought to be shared across individual syndromes [26,28], even though the specific processes involved may differ between individuals and syndromes.…”

Section: Developments In Understanding the Aetiological Mechanisms Unmentioning

confidence: 99%

Functional somatic disorders: discussion paper for a new common classification for research and clinical use

Burton

Fink

Henningsen

et al. 2020

BMC Med

187

133

View full text Add to dashboard Cite

Background: Functional somatic symptoms and disorders are common and complex phenomena involving both bodily and brain processes. They pose major challenges across medical specialties. These disorders are common and have significant impacts on patients' quality of life and healthcare costs. Main body: We outline five problems pointing to the need for a new classification: (1) developments in understanding aetiological mechanisms; (2) the current division of disorders according to the treating specialist; (3) failure of current classifications to cover the variety of disorders and their severity (for example, patients with symptoms from multiple organs systems); (4) the need to find acceptable categories and labels for patients that promote therapeutic partnership; and (5) the need to develop clinical services and research for people with severe disorders. We propose 'functional somatic disorders' (FSD) as an umbrella term for various conditions characterised by persistent and troublesome physical symptoms. FSDs are diagnosed clinically, on the basis of characteristic symptom patterns. As with all diagnoses, a diagnosis of FSD should be made after considering other possible somatic and mental differential diagnoses. We propose that FSD should occupy a neutral space within disease classifications, favouring neither somatic disease aetiology, nor mental disorder. FSD should be subclassified as (a) multisystem, (b) single system, or (c) single symptom. While additional specifiers may be added to take account of psychological features or co-occurring diseases, neither of these is sufficient or necessary to make the diagnosis. We recommend that FSD criteria are written so as to harmonise with existing syndrome diagnoses. Where currently defined syndromes fall within the FSD spectrumand also within organ system-specific chapters of a classificationthey should be afforded dual parentage (for example, irritable bowel syndrome can belong to both gastrointestinal disorders and FSD). Conclusion: We propose a new classification, 'functional somatic disorder', which is neither purely somatic nor purely mental, but occupies a neutral space between these two historical poles. This classification reflects both emerging aetiological evidence of the complex interactions between brain and body and the need to resolve the historical split between somatic and mental disorders.

show abstract

Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome

Cited by 70 publications

References 52 publications

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Functional somatic disorders: discussion paper for a new common classification for research and clinical use

Contact Info

Product

Resources

About