B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment
Øystein Fluge, Kristin Risa, Sigrid Lunde, Kine Alme, Ingrid Gurvin Rekeland, Dipak Sapkota, Einar Kleboe Kristoffersen, Kari Sørland, Ove Bruland, Olav Dahl, Olav Mella, Øystein Fluge, Kristin Risa, Sigrid Lunde, Kine Alme, Ingrid Gurvin Rekeland, Dipak Sapkota, Einar Kleboe Kristoffersen, Kari Sørland, Ove Bruland, Olav Dahl, Olav Mella
Abstract
Background: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.
Methods: In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.
Findings: Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.
Conclusion: In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.
Trial registration: ClinicalTrials.gov NCT01156909.
Conflict of interest statement
Competing Interests: Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS). Family members of WO2009083602 A1 are pending and some of them are granted, including US 7.914.785. The two authors ØF and OM are named as inventors in these applications and patents. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
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References
- Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, et al. (2003) Myalgic encephalomyelitis/ chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndr 11: 7–36.
- Nacul LC, Lacerda EM, Pheby D, Campion P, Molokhia M, Fayyaz S, et al. (2011) Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Med 9: 91 10.1186/1741-7015-9-91
- Albright F, Light K, Light A, Bateman L, Cannon-Albright LA (2011) Evidence for a heritable predisposition to Chronic Fatigue Syndrome. BMC Neurol 11: 62 10.1186/1471-2377-11-62
- Nacul LC, Lacerda EM, Campion P, Pheby D, Drachler Mde L, Leite JC, et al. (2011) The functional status and well being of people with myalgic encephalomyelitis/chronic fatigue syndrome and their carers. BMC Public Health 11: 402 10.1186/1471-2458-11-402
- Buchwald D, Pearlman T, Umali J, Schmaling K, Katon W (1996) Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. Am J Med 101: 364–370.
- Fluge O, Mella O (2009) Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol 9: 28 10.1186/1471-2377-9-28
- Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, et al. (2011) Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS One 6: e26358 10.1371/journal.pone.0026358
- Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 121: 953–959.
- Loge JH, Kaasa S, Hjermstad MJ, Kvien TK (1998) Translation and performance of the Norwegian SF-36 Health Survey in patients with rheumatoid arthritis. I. Data quality, scaling assumptions, reliability, and construct validity. J Clin Epidemiol 51: 1069–1076.
- Ware JE Jr., Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 30: 473–483.
- National Collaborating Centre for Primary Care (2007) National Institute for Health and Clinical Excellence: Guidance Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. London: Royal College of General Practitioners (UK)
- Jason LA, Brown A, Evans M, Sunnquist M, Newton JL (2013) Contrasting Chronic Fatigue Syndrome versus Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fatigue 1: 168–183.
- Ostergaard M, Baslund B, Rigby W, Rojkovich B, Jorgensen C, Dawes PT, et al. (2010) Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study. Arthritis Rheum 62: 2227–2238. 10.1002/art.27524
- Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E, et al. (2014) Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 82: 573–581. 10.1212/WNL.0000000000000125
- Schroder A, Oernboel E, Licht RW, Sharpe M, Fink P (2012) Outcome measurement in functional somatic syndromes: SF-36 summary scores and some scales were not valid. J Clin Epidemiol 65: 30–41. 10.1016/j.jclinepi.2011.03.012
- Cambridge G, Perry HC, Nogueira L, Serre G, Parsons HM, De La Torre I, et al. (2014) The effect of B-cell depletion therapy on serological evidence of B-cell and plasmablast activation in patients with rheumatoid arthritis over multiple cycles of rituximab treatment. J Autoimmun 50: 67–76. 10.1016/j.jaut.2013.12.002
- Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC (2006) Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 54: 613–620.
- Sellam J, Rouanet S, Hendel-Chavez H, Abbed K, Sibilia J, Tebib J, et al. (2011) Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis. Arthritis Rheum 63: 3692–3701. 10.1002/art.30599
- Huang H, Benoist C, Mathis D (2010) Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc Natl Acad Sci U S A 107: 4658–4663. 10.1073/pnas.1001074107
- Teng YK, Wheater G, Hogan VE, Stocks P, Levarht EW, Huizinga TW, et al. (2012) Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity. Arthritis Res Ther 14: R57 10.1186/ar3770
- Cambridge G, Leandro MJ, Teodorescu M, Manson J, Rahman A, Isenberg DA, et al. (2006) B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 54: 3612–3622.
- Calich AL, Puechal X, Pugnet G, London J, Terrier B, Charles P, et al. (2014) Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener's). Results of a single-center cohort study on 66 patients. J Autoimmun 50: 135–141. 10.1016/j.jaut.2014.03.002
- Chang CM, Warren JL, Engels EA (2012) Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. Cancer 118: 5929–5936. 10.1002/cncr.27612
- Thieblemont C, Bertoni F, Copie-Bergman C, Ferreri AJ, Ponzoni M (2014) Chronic inflammation and extra-nodal marginal-zone lymphomas of MALT-type. Semin Cancer Biol 24: 33–42. 10.1016/j.semcancer.2013.11.005
- Jacobson DL, Gange SJ, Rose NR, Graham NM (1997) Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84: 223–243.
- Eaton WW, Rose NR, Kalaydjian A, Pedersen MG, Mortensen PB (2007) Epidemiology of autoimmune diseases in Denmark. J Autoimmun 29: 1–9.
- Li H, Yu X, Liles C, Khan M, Vanderlinde-Wood M, Galloway A, et al. (2014) Autoimmune basis for postural tachycardia syndrome. J Am Heart Assoc 3: e000755 10.1161/JAHA.113.000755
- Kohr D, Singh P, Tschernatsch M, Kaps M, Pouokam E, Diener M, et al. (2011) Autoimmunity against the beta2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain 152: 2690–2700. 10.1016/j.pain.2011.06.012
- Goebel A, Blaes F (2013) Complex regional pain syndrome, prototype of a novel kind of autoimmune disease. Autoimmun Rev 12: 682–686. 10.1016/j.autrev.2012.10.015
- Lewis I, Pairman J, Spickett G, Newton JL (2012) Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome. J Intern Med.
- Bradley AS, Ford B, Bansal AS (2013) Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls. Clin Exp Immunol 172: 73–80. 10.1111/cei.12043
- Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, Johnston S, et al. (2013) The Role of Adaptive and Innate Immune Cells in Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis. Int Immunol.
- Elfaitouri A, Herrmann B, Bolin-Wiener A, Wang Y, Gottfries CG, Zachrisson O, et al. (2013) Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis. PLoS One 8: e81155 10.1371/journal.pone.0081155
- Maes M, Leunis JC (2014) Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett 35: 577–585.
- Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, et al. (2015) Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv 1: e1400121.
- Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, et al. (2015) Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry.
- Avivi I, Stroopinsky D, Katz T (2013) Anti-CD20 monoclonal antibodies: beyond B-cells. Blood Rev 27: 217–223. 10.1016/j.blre.2013.07.002
- Bouaziz JD, Yanaba K, Venturi GM, Wang Y, Tisch RM, Poe JC, et al. (2007) Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice. Proc Natl Acad Sci U S A 104: 20878–20883.
- Wolach O, Shpilberg O, Lahav M (2012) Neutropenia after rituximab treatment: new insights on a late complication. Curr Opin Hematol 19: 32–38. 10.1097/MOH.0b013e32834da987
- Arai Y, Yamashita K, Mizugishi K, Nishikori M, Hishizawa M, Kondo T, et al. (2014) Risk factors for late-onset neutropenia after rituximab treatment of B-cell lymphoma. Hematology.
- Rowe KS (1997) Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents. J Psychiatr Res 31: 133–147.
- Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P (2009) The late adverse events of rituximab therapy-rare but there! Leuk Lymphoma 50: 1083–1095. 10.1080/10428190902934944
- Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, et al. (2010) Effectiveness of rituximab treatment in primary Sjogren's syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 62: 960–968. 10.1002/art.27314
- Mok CC (2013) Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther 8: 87–100. 10.2147/DDDT.S41645
- Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E (2013) Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One 8: e66308 10.1371/journal.pone.0066308
- Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Parks D, et al. (2011) Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol 68: 1156–1164. 10.1001/archneurol.2011.103
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