Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption

Markus Tölle, Helma Freitag, Michaela Antelmann, Jelka Hartwig, Mirjam Schuchardt, Markus van der Giet, Kai-Uwe Eckardt, Patricia Grabowski, Carmen Scheibenbogen, Markus Tölle, Helma Freitag, Michaela Antelmann, Jelka Hartwig, Mirjam Schuchardt, Markus van der Giet, Kai-Uwe Eckardt, Patricia Grabowski, Carmen Scheibenbogen

Abstract

(1) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmunological disease. There is evidence for an autoimmune mechanism for ME/CFS with an infection-triggered onset and dysfunction of ß2-adrenoreceptor antibodies (ß2AR-AB). In a first proof-of-concept study, we could show that IA was effective to reduce ß2AR-AB and led to improvement of various symptoms. (2) Five of the ME/CFS patients who had clinical improvement following treatment with a five-day IA were retreated in the current study about two years later with a modified IA protocol. The severity of symptoms was assessed by disease specific scores during a follow-up period of 12 months. The antibodies were determined by ELISA. (3) The modified IA treatment protocol resulted in a remarkable similar clinical response. The treatment was well tolerated and 80-90% decline of total IgG and ß2AR-AB was achieved. Four patients showed a rapid improvement in several clinical symptoms during IA therapy, lasting for six to 12 months. One patient had no improvement. (4) We could provide further evidence that IA has clinical efficacy in patients with ME/CFS. Data from our pilot trial warrant further controlled studies in ME/CFS.

Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; immunoadsorption; ß2 adrenoreceptor autoantibody.

Conflict of interest statement

M.T. received research grants from Fresenius Medical Care, speaker’s honoraria from Baxter International, and Diamed Medizintechnik. C.S. received research grants and speakers’ honoraria from Fresenius Medical Care. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Treatment protocols of both studies. X indicates the point of time when immunoadsorption (IA) was conducted, black arrows when blood samples were collected, and blue arrow for immunoglobulin G (IgG) supplementation.
Figure 2
Figure 2
Absolute IgG and autoantibody levels during treatment. Total and ß1, ß2, M3, and M4 IgG in the serum before and during IA. X indicates the point of time when IA was conducted. Gray area indicates reference range of serum levels.
Figure 3
Figure 3
Relative IgG and autoantibody levels during treatment. Relative changes of total IgG and ß1, ß2, M3, and M4 autoantibody concentration in the serum before and during first IA 2016 (left) and second IA (right). The daily levels are depicted as x-fold change to day 1 level for each single patient. X indicates the single IA, arrow when patients received 10 g IgG i.v.
Figure 4
Figure 4
Patients condition before first and second treatment. Symptom scores before first IA (triangle) and second IA (circle). Symptoms are indicated as 0 (absent) to 10 (most severe). Sum of each patient is displayed in the upper right corner (left: IA1, right: IA2).
Figure 5
Figure 5
Development of symptoms during IA. Symptom scores for fatigue, cognitive score, muscle pain and immune score during IA1 (left) and IA2 (right) are shown for each patient (3 unchanged, 4 slight, 5 marked improvement, 6 complete disappearance, 2 slight increase, 1 marked increase). The line indicates level 3 for unchanged symptoms.
Figure 6
Figure 6
Development of symptoms during 12 months follow-up. Symptom scores for fatigue, cognitive score, muscle pain and immune score during first IA (left) and second IA (right) are shown for each patient (3 unchanged, 4 slight, 5 marked improvement, 6 complete disappearance, 2 slight increase, 1 marked increase). The line indicates level 3 for unchanged symptoms.
Figure 7
Figure 7
FACT-F score follow-up. Score of FACT-F questionnaire assessing severity of fatigue before and up to 12 months after first IA (left) in comparison to second IA (right) for each patient. Scoring of FACT-F fatigue questionnaire ranges from 0 (strongly fatigued) to a maximum of 52 (without fatigue). Dotted line indicates the individual pretreatment score before IA.

References

    1. Carruthers B.M., van de Sande M.I., De Meirleir K.L., Klimas N.G., Broderick G., Mitchell T., Staines D., Powles A.C., Speight N., Vallings R., et al. Myalgic Encephalomyelitis: International Consensus Criteria. J. Intern. Med. 2011;270:327–338. doi: 10.1111/j.1365-2796.2011.02428.x.
    1. Chu L., Valencia I.J., Garvert D.W., Montoya J.G. Onset Patterns and Course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Pediatr. 2019;7:12. doi: 10.3389/fped.2019.00012.
    1. Clayton E.W., Biaggionni I., Cockshell S., Vermeculen R., Snell C., Rove K. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. The National Academies Press; Washington, DC, USA: 2015.
    1. Rowe P.C., Underhill R., Friedman K.J., Gurwitt A., Medow M.S., Schwartz M.S., Speight N., Stewart J.M., Vallings R., Rowe K.S. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Front. Pediatr. 2017;5 doi: 10.3389/fped.2017.00121.
    1. Valdez A.R., Hancock E.E., Adebayo S., Kiernicki D.J., Proskauer D., Attewell J.R., Bateman L., DeMaria A.J., Lapp C.W., Rowe P.C., et al. Estimating Prevalence, Demographics, and Costs of ME/CFS Using Large Scale Medical Claims Data and Machine Learning. Front. Pediatr. 2019;6:412. doi: 10.3389/fped.2018.00412.
    1. Sotzny F., Blanco J., Capelli E., Castro-Marrero J., Steiner S., Murovska M., Scheibenbogen C. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Evidence for an autoimmune disease. Autoimmun. Rev. 2018;17:601–609. doi: 10.1016/j.autrev.2018.01.009.
    1. Steiner S., Becker S.C., Hartwig J., Sotzny F., Lorenz S., Bauer S., Löbel M., Stittrich A.B., Grabowski P., Scheibenbogen C. Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset. Front. Immunol. 2020;11 doi: 10.3389/fimmu.2020.00578.
    1. Klein R., A Berg P. High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: Evidence for a clinical entity of both disorders. Eur. J. Med. Res. 1995;1:21–26.
    1. Maes M., Mihaylova I., Kubera M., Leunis J.C., Twisk F.N., Geffard M. Igm-Mediated Autoimmune Responses Directed against Anchorage Epitopes Are Greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Me/Cfs) Than in Major Depression. Metab. Brain Dis. 2012;27:415–423. doi: 10.1007/s11011-012-9316-8.
    1. Ortega-Hernandez O.-D., Cuccia M., Bozzini S., Bassi N., Moscavitch S., Diaz-Gallo L.M., Blank M., Agmon-Levin N., Shoenfeld Y. Autoantibodies, Polymorphisms in the Serotonin Pathway, and Human Leukocyte Antigen Class II Alleles in Chronic Fatigue Syndrome. Ann. N. Y. Acad. Sci. 2009;1173:589–599. doi: 10.1111/j.1749-6632.2009.04802.x.
    1. Löbel M., Grabowski P., Heidecke H., Bauer S., Hanitsch L., Wittke K., Meisel C., Reinke P., Volk H.-D., Fluge Ø., et al. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav. Immun. 2016;52:32–39. doi: 10.1016/j.bbi.2015.09.013.
    1. Tanaka S., Kuratsune H., Hidaka Y., Hakariya Y., Tatsumi K.-I., Takano T., Kanakura Y., Amino N. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int. J. Mol. Med. 2003;12:225–230. doi: 10.3892/ijmm.12.2.225.
    1. Yamamoto S., Ouchi Y., Nakatsuka D., Tahara T., Mizuno K., Tajima S., Onoe H., Yoshikawa E., Tsukada H., Iwase M., et al. Reduction of [11C](+)3-MPB Binding in Brain of Chronic Fatigue Syndrome with Serum Autoantibody against Muscarinic Cholinergic Receptor. PLoS ONE. 2012;7:e51515. doi: 10.1371/journal.pone.0051515.
    1. Hartwig J., Sotzny F., Bauer S., Heidecke H., Riemekasten G., Dragun D., Meisel C., Dames C., Grabowski P., Scheibenbogen C. IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS. Brain Behav. Immun. Health. 2020;3 doi: 10.1016/j.bbih.2020.100047.
    1. Wirth K., Scheibenbogen C. A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors. Autoimmun. Rev. 2020;19:102527. doi: 10.1016/j.autrev.2020.102527.
    1. Fujii H., Sato W., Kimura Y., Matsuda H., Ota M., Maikusa N., Suzuki F., Amano K., Shin I., Yamamura T., et al. Altered Structural Brain Networks Related to Adrenergic/Muscarinic Receptor Autoantibodies in Chronic Fatigue Syndrome. J. Neuroimaging. 2020 doi: 10.1111/jon.12751.
    1. Fluge Ø., Bruland O., Risa K., Storstein A., Kristoffersen E.K., Sapkota D., Næss H., Dahl O., Nyland H., Mella O. Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS ONE. 2011;6:e26358. doi: 10.1371/journal.pone.0026358.
    1. Fluge Ø., Risa K., Lunde S., Alme K., Rekeland I.G., Sapkota D., Kristoffersen E.K., Sørland K., Bruland O., Dahl O., et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS ONE. 2015;10:e0129898. doi: 10.1371/journal.pone.0129898.
    1. Padmanabhan A., Connelly-Smith L., Aqui N., Balogun R.A., Klingel R., Meyer E., Pham H.P., Schneiderman J., Witt V., Wu Y., et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J. Clin. Apher. 2019;34:171–354. doi: 10.1002/jca.21705.
    1. Stummvoll G., Schmaldienst S., Smolen J.S., Derfler K., Biesenbach P. Lupus nephritis: Prolonged immunoadsorption (IAS) reduces proteinuria and stabilizes global disease activity. Nephrol. Dial. Transplant. 2011;27:618–626. doi: 10.1093/ndt/gfr239.
    1. Dandel M., Wallukat G., Englert A., Hetzer R. Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. Atheroscler. Suppl. 2013;14:203–211. doi: 10.1016/j.atherosclerosissup.2012.10.029.
    1. Wallukat G., Müller J., Hetzer R. Specific Removal of β1-Adrenergic Autoantibodies from Patients with Idiopathic Dilated Cardiomyopathy. N. Engl. J. Med. 2002;347:1806. doi: 10.1056/NEJM200211283472220.
    1. Scheibenbogen C., Loebel M., Freitag H., Krueger A., Bauer S., Antelmann M., Doehner W., Scherbakov N., Heidecke H., Reinke P., et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS ONE. 2018;13:e0193672. doi: 10.1371/journal.pone.0193672.
    1. Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: A new tool for the assessment of outcomes in cancer anemia and fatigue. Semin. Hematol. 1997;34:13–19.
    1. Bell D.S. The Doctor’s Guide to Chronic Fatigue Syndrome: Understanding, Treating, and Living with Cfids. Da Capo Press; Boston, MA, USA: 1995. Reprint, Reprint edition (18 January 1995)
    1. Scherbakov N., Szklarski M., Hartwig J., Sotzny F., Lorenz S., Meyer A., Grabowski P., Doehner W., Scheibenbogen C. Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. ESC Heart Fail. 2020;7:1064–1071. doi: 10.1002/ehf2.12633.
    1. Heine J., Ly L.-T., Lieker I., Slowinski T., Finke C., Prüss H., Harms L. Immunoadsorption or plasma exchange in the treatment of autoimmune encephalitis: A pilot study. J. Neurol. 2016;263:2395–2402. doi: 10.1007/s00415-016-8277-y.
    1. Dandel M., Wallukat G., Englert A., Lehmkuhl H., Knosalla C., Hetzer R. Long-Term Benefits of Immunoadsorption in Β1-Adrenoceptor Autoantibody-Positive Transplant Candidates with Dilated Cardiomyopathy. Eur. J. Heart. Fail. 2012;14:1374–1388. doi: 10.1093/eurjhf/hfs123.
    1. Cabral-Marques O., Marques A., Giil L.M., De Vito R., Rademacher J., Günther J., Lange T., Humrich J.Y., Klapa S., Schinke S., et al. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat. Commun. 2018;9:5224. doi: 10.1038/s41467-018-07598-9.
    1. Perez E.E., Orange J.S., Bonilla F., Chinen J., Chinn I.K., Dorsey M., El-Gamal Y., Harville T.O., Hossny E., Mazer B., et al. Update on the use of immunoglobulin in human disease: A review of evidence. J. Allergy Clin. Immunol. 2017;139:S1–S46. doi: 10.1016/j.jaci.2016.09.023.
    1. Whiting P.F., Bagnall A.-M., Sowden A.J., Cornell J.E., Mulrow C.D., Ramirez G. Interventions for the Treatment and Management of Chronic Fatigue Syndrome. JAMA. 2001;286:1360–1368. doi: 10.1001/jama.286.11.1360.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe