B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment
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{"title"=>"B-lymphocyte depletion in myalgic encephalopathy/chronic fatigue syndrome. An open-label phase II study with rituximab maintenance treatment", "type"=>"journal", "authors"=>[{"first_name"=>"Øystein", "last_name"=>"Fluge", "scopus_author_id"=>"6602991079"}, {"first_name"=>"Kristin", "last_name"=>"Risa", "scopus_author_id"=>"54391752900"}, {"first_name"=>"Sigrid", "last_name"=>"Lunde", "scopus_author_id"=>"56769582000"}, {"first_name"=>"Kine", "last_name"=>"Alme", "scopus_author_id"=>"53663166600"}, {"first_name"=>"Ingrid Gurvin", "last_name"=>"Rekeland", "scopus_author_id"=>"56770061600"}, {"first_name"=>"Dipak", "last_name"=>"Sapkota", "scopus_author_id"=>"25225935800"}, {"first_name"=>"Einar Kleboe", "last_name"=>"Kristoffersen", "scopus_author_id"=>"7003970751"}, {"first_name"=>"Kari", "last_name"=>"Sørland", "scopus_author_id"=>"56769944700"}, {"first_name"=>"Ove", "last_name"=>"Bruland", "scopus_author_id"=>"7005318708"}, {"first_name"=>"Olav", "last_name"=>"Dahl", "scopus_author_id"=>"7101971144"}, {"first_name"=>"Olav", "last_name"=>"Mella", "scopus_author_id"=>"7004099256"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"605565670", "sgr"=>"84938831118", "issn"=>"19326203", "pmid"=>"26132314", "scopus"=>"2-s2.0-84938831118", "doi"=>"10.1371/journal.pone.0129898", "isbn"=>"1932-6203"}, "id"=>"f9a0dff3-d62a-3bf9-9994-f132ed90dbfc", "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.", "link"=>"http://www.mendeley.com/research/blymphocyte-depletion-myalgic-encephalopathychronic-fatigue-syndrome-openlabel-phase-ii-study-rituxi", "reader_count"=>11, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Other"=>1, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Other"=>1, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Nursing and Health Professions"=>1, "Medicine and Dentistry"=>3, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Psychology"=>1, "Immunology and Microbiology"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Neuroscience"=>{"Neuroscience"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>1}

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  • {"files"=>["https://ndownloader.figshare.com/files/2158385"], "description"=>"<p><sup>a</sup>: Clinically significant responders, including 14 major and four moderate responders.</p><p><sup>b</sup>: Patients with no clinically significant response, including one patient with a marginal response and nine non-responders.</p><p><sup>c</sup>: Baseline self-reported symptom scores assessed for the preceding 3-months period before start of intervention (scale 1–10; 1: no symptom, 5: moderate symptom, 10: very severe symptom, see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s003\" target=\"_blank\">S1 Fig</a>).</p><p><sup>d</sup>: Fatigue score was the mean score for the four symptoms: Fatigue, Malaise after exertion, Need for rest, Daily functioning.</p><p><sup>e</sup>: Cognitive score was the mean score for the three symptoms: Concentration ability, Memory disturbance, Mental tiredness.</p><p><sup>f</sup>: Pain score was the mean score for the two dominating pain symptoms, from Muscle pain, Headache, Joint pain, Cutaneous pain (if pretreatment score at least 4).</p><p><sup>g</sup>: ME/CFS overall score was the patient’s interpretation of overall symptom burden at baseline.</p><p><sup>h</sup>: Baseline self-reported Function level (scale 0–100%, in which 100% denotes a completely healthy state), according to a form with examples (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s005\" target=\"_blank\">S3 Fig</a>).</p><p><sup>i</sup>: SF-36 norm-based scores at baseline (population mean approximately 50).</p><p>Baseline self-reported symptom scores, baseline Function level, and baseline norm-based SF-36 scores, for 28 patients receiving rituximab induction and maintenance treatment.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470592, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.t002", "stats"=>{"downloads"=>4, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Baseline_self_reported_symptom_scores_baseline_Function_level_and_baseline_norm_based_SF_36_scores_for_28_patients_receiving_rituximab_induction_and_maintenance_treatment_/1470592", "title"=>"Baseline self-reported symptom scores, baseline Function level, and baseline norm-based SF-36 scores, for 28 patients receiving rituximab induction and maintenance treatment.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158383"], "description"=>"<p><sup>1</sup>: The numbers refer to corresponding plots in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s006\" target=\"_blank\">S4</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s007\" target=\"_blank\">S5</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s008\" target=\"_blank\">S6</a> Figs (i.e. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s006\" target=\"_blank\">S4A</a> means <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s006\" target=\"_blank\">S4 Fig</a> panel A) for each of 28 individual patients receiving rituximab maintenance treatment. Among 18 patients fulfilling the predefined response criterion, clinical significance (CS) was determined post-hoc as Major (MajR, n = 14) or Moderate (ModR, n = 4). One patient had a marginal response (MargR) and nine patients were non-responders (NonR).</p><p>*: one patient (last row in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.t001\" target=\"_blank\">Table 1</a>) had an allergic reaction to the first rituximab infusion and did not receive induction treatment or complete follow-up.</p><p><sup>2</sup>: F: female, M: male. Age in years.</p><p><sup>3</sup>: Indicating infection preceding ME/CFS onset. Mono: mononucleosis; Viral: viral infection not otherwise specified; GI: gastrointestinal infection; Airway: upper airways infection; Borrelia: Borrelia infection; Pneum.: pneumonia.</p><p><sup>4</sup>: ME/CFS disease duration given in years (y). ME/CFS severity categorized as mild: mild grade; mild/mod: mild to moderate grade; mod: moderate grade, mod/sev: moderate to severe grade; sev: severe grade (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#sec007\" target=\"_blank\">Materials and Methods</a>).</p><p><sup>5</sup>: Previous participation in clinical studies on ME/CFS. Pilot: pilot patient. KTS-1: participated in the KTS-1-2008 study; Pl,NoR: previously given placebo in KTS-1-2008 with no clinical response; Rx,R-Re: previously given rituximab in KTS-1-2008 (or as pilot) with clinical response and later relapse; Rx,NoR: previously given rituximab in KTS-1-2008 with no clinical response; No: the patient had not participated in previous studies. *: this patient (corresponding to <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s006\" target=\"_blank\">S4 Fig</a> panel L) was a participant in KTS-1-2008 and also a pilot patient for this study.</p><p><sup>6</sup>: Autoimmune diseases (AD) among first-degree relatives were present for 12 out of 29 included patients (41%). These AD included rheumatoid arthritis (in relatives of seven patients), Sjøgren’s syndrome (in relatives of two patients), ulcerative colitis (in relatives of three patients), thyroiditis (in relatives of two patients). Also, glomerulonephritis, lupus, juvenile arthritis, psoriasis, multiple sclerosis (all present in relatives of single patients).</p><p><sup>7</sup>: Rx infus: number of rituximab (Rx) infusions given to each patient (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#sec007\" target=\"_blank\">Materials and Methods</a>, and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#sec016\" target=\"_blank\">Results</a>).</p><p><sup>8</sup>: Clinical response periods according to predefined criteria, i.e. periods of <i>Fatigue score</i> ≥ 4.5 for at least six consecutive weeks which must include at least one recording of <i>Fatigue score</i> >5.0 during the response period. The numbers show the intervals with clinical response given in weeks during follow-up.</p><p><sup>9</sup>: Response durations defined as the sum of individual clinical response periods during follow-up, and given in weeks. *: This patient had a moderate improvement from 58–112 weeks, and with a mean <i>Fatigue score</i> exactly 5.0 in the interval 80–112 weeks. He did not fulfill strict response criteria, but was post-hoc judged as a moderate responder.</p><p>**: This patient fulfilled predefined response criteria, but had a short lasting and late response period, interpreted post-hoc as probably not related to intervention and not clinically significant.</p><p><sup>10</sup>: Clinical response status at end of study. Also shown the time of last recording for each patient. Yes: still in clinical response at end of follow-up; No: not in clinical response at end of follow-up; OoSt: out of study, also indicating time point during follow-up; SR: slight symptom increase but still in response;</p><p>*: allergic reaction to first rituximab infusion, did not complete induction therapy or follow-up.</p><p><sup>11</sup>: LON: late onset neutropenia; Airw.inf.: several airways infections; Rx-Wor: indicating number of transient worsening of ME/CFS-symptoms after rituximab infusions; Allergy: allergic reaction to rituximab; BC: breast cancer; ITP: idiopathic thrombocytopenic purpura (also indicated in the corresponding panels in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s006\" target=\"_blank\">S4</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s007\" target=\"_blank\">S5</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s008\" target=\"_blank\">S6</a> Figs);</p><p>*See comment: this patient had improvement during follow-up assessed by SF-36 scores and selfreported Function level, but did not fulfill criteria for clinical response; MargR KTS-1: this patient had a marginal response duration in the previous KTS-1-2008 study; No sign. response: not interpreted as a clinically significant response.</p><p><sup>12</sup>: SF-36mean5 is the mean of raw scores for the five SF-36 subdimentions Physical function, Bodily pain, Vitality, General health, and Social function (scales 0–100), shown at 0, 15, 20 or 24, and 36 months follow-up (in three patients last recording at 31, 33 and 35 months, respectively); nd: not done.</p><p><sup>13</sup>: Self-reported Function level, given as per cent (0–100%) in which 100% denotes completely healthy, according to a form with examples (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s005\" target=\"_blank\">S3 Fig</a>), recorded at 0, 15, 24 and 36 months follow-up (in three patients last recording at 31, 33 and 35 months, respectively); nd: not done.</p><p>ME/CFS disease characteristics and selected response data, for 29 patients included in the study.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470590, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.t001", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ME_CFS_disease_characteristics_and_selected_response_data_for_29_patients_included_in_the_study_/1470590", "title"=>"ME/CFS disease characteristics and selected response data, for 29 patients included in the study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158379"], "description"=>"<p>SF-36 (Norwegian ver. 1.2) forms were recorded at baseline and at 3, 6, 10, 15, 20, 24, 30 and 36 months. SF-36 raw scores (mean, SEM) are shown for 27 patients, for the subdimensions Physical function (panel A), Bodily pain (panel C), Vitality (panel E), Social function (panel G) and Mental health (panel I). In panels B, D, F, H and J are shown the corresponding SF-36 raw scores separately for 13 major responders, four moderate responders, and 10 patients with no clinical significant response (one marginal responder and nine non-responders). One pilot patient (major responder, withdrew from study after 32 months) did not fill in SF-36 forms. One included patient did not receive induction rituximab infusions due to an allergic reaction to the first infusion, and did not fill in SF-36 forms. One major responder was withdrawn from study after 24 months due to being diagnosed with a T2N0 breast cancer. Out of four moderate responders, one withdrew from the study after 25 months, and one after 32 months. Out of 10 patients with no clinically significant response one withdrew from study after 12 months, and four patients after approximately 24 months follow-up.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470586, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.g005", "stats"=>{"downloads"=>6, "page_views"=>35, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SF_36_questionnaire_raw_scores_/1470586", "title"=>"SF-36 questionnaire, raw scores.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158374"], "description"=>"<p>Consort Flow Diagram for the KTS-2-2010 study, with enrollment, allocation to induction and maintenance rituximab treatment, and follow-up showing number of patients who withdrew from study before 36 months.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470581, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.g001", "stats"=>{"downloads"=>2, "page_views"=>41, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Consort_2010_Flow_Diagram_for_the_KTS_2_2010_study_/1470581", "title"=>"Consort 2010 Flow Diagram for the KTS-2-2010 study.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158388"], "description"=>"<p><sup>a</sup>:SF-36 (Norwegian ver. 1.2) for the subdimensions Physical function, Bodily pain, General health, Vitality, Social function, Mental health, and mean of five subdimentions (“SF-36mean5”), with raw scores (scale 0–100), from 27 patients receiving rituximab induction and maintenance treatment, including 17 patients with clinically significant responses (major and moderate) and 10 patients with no significant response (marginal or no response) during follow-up. One pilot patient did not fill in SF-36 forms. Including follow-up from baseline until 24 months, 15 out of 189 forms were missing (7.9%). Out of 17 patients with clinically significant responses, one patient withdrew due to diagnosis of a T2N0 breast cancer at 24 months follow-up, and two moderate responders withdrew from follow-up after 25 and 32 months, respectively. Out of 10 patients with no clinically significant response, one patient withdrew from study after 12 months, and four patients after 24–26 months follow-up.</p><p><sup>b</sup>: in two patients the last SF-36 forms were completed at 33 and 35 months, respectively.</p><p><sup>c</sup>: “SF-36mean5” denotes mean value of raw scores for the five SF-36 subdimensions Physical function, Bodily pain, Vitality, General health, and Social function.</p><p>SF-36 raw scores (scale 0–100) in 17 patients with clinically significant responses, and in 10 patients with no significant response, at baseline and during follow-up<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#t004fn001\" target=\"_blank\"><sup>a</sup></a>.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470595, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.t004", "stats"=>{"downloads"=>4, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SF_36_raw_scores_scale_0_100_in_17_patients_with_clinically_significant_responses_and_in_10_patients_with_no_significant_response_at_baseline_and_during_follow_up_a_/1470595", "title"=>"SF-36 raw scores (scale 0–100) in 17 patients with clinically significant responses, and in 10 patients with no significant response, at baseline and during follow-up<sup>a</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158404", "https://ndownloader.figshare.com/files/2158405", "https://ndownloader.figshare.com/files/2158406", "https://ndownloader.figshare.com/files/2158407", "https://ndownloader.figshare.com/files/2158408", "https://ndownloader.figshare.com/files/2158409", "https://ndownloader.figshare.com/files/2158410", "https://ndownloader.figshare.com/files/2158411", "https://ndownloader.figshare.com/files/2158412"], "description"=>"<div><p>Background</p><p>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.</p><p>Methods</p><p>In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m<sup>2</sup>) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.</p><p>Findings</p><p>Major or moderate responses, predefined as lasting improvements in self-reported <i>Fatigue score</i>, 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.</p><p>Conclusion</p><p>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.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href=\"http://www.clinicaltrials.gov/ct2/show/NCT01156909\" target=\"_blank\">NCT01156909</a></p></div>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470607, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0129898.s001", "https://dx.doi.org/10.1371/journal.pone.0129898.s002", "https://dx.doi.org/10.1371/journal.pone.0129898.s003", "https://dx.doi.org/10.1371/journal.pone.0129898.s004", "https://dx.doi.org/10.1371/journal.pone.0129898.s005", "https://dx.doi.org/10.1371/journal.pone.0129898.s006", "https://dx.doi.org/10.1371/journal.pone.0129898.s007", "https://dx.doi.org/10.1371/journal.pone.0129898.s008", "https://dx.doi.org/10.1371/journal.pone.0129898.s009"], "stats"=>{"downloads"=>16, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_B_Lymphocyte_Depletion_in_Myalgic_Encephalopathy_Chronic_Fatigue_Syndrome_An_Open_Label_Phase_II_Study_with_Rituximab_Maintenance_Treatment_/1470607", "title"=>"B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158382"], "description"=>"<p>B-lymphocyte numbers from immunophenotyping of peripheral blood during follow-up are shown, at baseline and 3, 6, 12, 15, 20, 24, 30 and 36 months follow-up. The red dots represent mean value at each time point, for patients with either major or moderate clinical response (n = 16). The blue squares denote the mean values for patients with no significant response (n = 10). The value zero for B-lymphocytes in peripheral blood was substituted by 0.1 (to enable plotting on the log scale). B-lymphocyte counts x 10<sup>6</sup>/L (normal range 110–449). The error bars denote mean ± 95% CI. B-cell data during follow-up were not available for the two pilot patients (both major responders). According to an amendment, seven patients received further rituximab infusions in addition to the six infusions stated in the initial protocol. Two major responders received five and four rituximab additional rituximab infusions, respectively. Four moderate responders received five, four, three and three additional rituximab infusions. One non-responder received two additional rituximab infusions.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470589, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.g007", "stats"=>{"downloads"=>3, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD19_B_lymphocytes_in_peripheral_blood_during_follow_up_/1470589", "title"=>"CD19+ B-lymphocytes in peripheral blood during follow-up.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158381"], "description"=>"<p>Mean values of SF-36 raw scores for the five subdimensions Physical function (PF), Bodily pain (BP), Vitality (V), Social function (SF) and General health (GH) are shown (denoted “SF-36mean5”, scale 0–100), at baseline and at 3, 6, 10, 15, 20, 24, 30 and 36 months follow-up. SF-36mean5 scores for each time point during follow-up were compared to baseline scores. P-values were calculated using Repeated Measures One-way ANOVA, with Dunnett’s multiple comparison adjustments, and are indicated at the top of each panel. ns: not significant; **: p<0.01; ***: p<0.001; ****: p<0.0001. To be able to analyze for differences at each time point relative to baseline, a missing value at a time point for a patient was replaced with value interpolated between the previous and next values during follow-up for that patient (but not replaced in the plot). Panel A shows “SF-36mean5” (raw) scores for 27 patients in this study. One pilot patient did not fill in SF-36 forms. In addition 22/243 (9.1%) data were missing, including for patients out of study before end of follow-up, as explained in M&M. Panel C shows “SF-36mean5” scores for 17 patients with clinically significant response (data from pilot 2, and in addition 10/153 (6.5%) data were missing). Panel E shows “SF-36mean5” scores for 10 patients with no clinically significant response during follow-up (12/90 (13.3%) data were missing). Panels B, D and F show self-reported Function levels (according to a form with examples, see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#pone.0129898.s005\" target=\"_blank\">S3 Fig</a>), at baseline and at 15, 24 and 36 months. In panel B for 28 patients included in the KTS-2-2010 study, in panel D for 18 patients with clinically significant responses, and in panel F for 10 patients without clinically significant responses. In panels B and D, two moderate responders registered their Function level at 32 and 33 months (instead of 36 months), respectively. Panel G shows a correlation plot between “SF-36mean5” raw scores and self-reported Function levels (both with scale 0–100), with pooled data from baseline and at 15, 24 and 36 months follow-up. Panel H shows a Bland-Altman plot for difference (“SF-36mean5”—Function level) versus average.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470588, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.g006", "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Function_level_and_8220_SF_36mean5_8221_/1470588", "title"=>"Function level and “SF-36mean5”.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158378"], "description"=>"<p>Nine patients from the placebo group in the previous randomized KTS-1-2008 study were included in the present KTS-2-2010 study with rituximab induction and maintenance treatment. The mean <i>Fatigue scores</i> for consecutive 3-months intervals, until 12 months follow-up, were compared using General Linear Model (GLM) for repeated measures. Four time intervals with mean <i>Fatigue scores</i> in each were included in the comparison. Main effect for the interaction between time and intervention group (rituximab maintenance versus the patient’s own “historic” placebo) was assessed.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470585, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.g004", "stats"=>{"downloads"=>6, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Historic_comparison_of_Fatigue_scores_for_nine_patients_given_placebo_in_KTS_1_2008_and_rituximab_maintenance_in_KTS_2_2010_/1470585", "title"=>"Historic comparison of Fatigue scores for nine patients given placebo in KTS-1-2008, and rituximab maintenance in KTS-2-2010.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158377"], "description"=>"<p>In panel A, response durations within the three years (156 weeks) follow-up are shown, for 14 major responders and four moderate responders. In panel B, time points for <i>start</i> of clinical responses are shown, for major and moderate responders. In both panels A and B, the 11 red dots denote patients with still ongoing clinical response at 156 weeks (end of study), while the 7 black squares denote patients experiencing partial or full relapse during the 36 months follow-up period. The overall response criterion was a <i>Fatigue score</i> ≥ 4.5 for a minimum of six consecutive weeks, which must include at least one recording of <i>Fatigue score</i> > 5.0 during the response period. Single response periods and the sum of response periods during follow-up were recorded as response duration.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470584, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.g003", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_response_durations_after_rituximab_maintenance_therapy_within_36_months_follow_up_/1470584", "title"=>"Clinical response durations after rituximab maintenance therapy, within 36 months follow-up.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158375"], "description"=>"<p><i>Fatigue score</i> was recorded every second week, always compared to baseline, as the mean of four fatigue-related symptoms (scale 0–6; 3: no change from baseline; 4, 5, 6: slight, moderate, major improvement, respectively; 2, 1, 0: slight, moderate, major worsening, respectively). Panel A shows <i>Fatigue scores</i> for the time intervals 0–6, 6–12, 12–18, 18–24, 24–30 and 30–36 months, with means and 95% CI for each time interval. In panel B the corresponding <i>Fatigue scores</i> are shown for each time interval during follow-up, divided between 18 patients with clinically significant responses, and 10 patients with either marginal response (n = 1) or no response (n = 9). Out of 10 patients with no clinically significant response, one patient withdrew from study after 12 months, and four patients after 24–26 months follow-up. Out of 18 patients with clinically significant responses, one withdrew from study after 24 months due to a diagnosis of T2N0 breast cancer, two moderate responders withdrew after 25 and 32 months, respectively, and one major responder withdrew after 32 months.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470582, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.g002", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Self_reported_Fatigue_scores_for_28_patients_receiving_rituximab_induction_and_maintenance_treatment_/1470582", "title"=>"Self-reported Fatigue scores for 28 patients receiving rituximab induction and maintenance treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-01 03:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/2158387"], "description"=>"<p><sup>a</sup>:SF-36 (Norwegian ver. 1.2) data during follow-up, for 27 patients receiving rituximab induction and maintenance treatment, including 17 patients with, and 10 without, clinically significant response. SF-36 scores (mean, SD) for Physical health summary score, Mental health summary score, and both norm-based scores (with population mean 50, according to US 1998) and raw scores (scale 0–100) for the subdimensions Physical function, Role physical, Bodily pain, General health, Vitality, Social function, Role emotional, and Mental health, are shown. One pilot patient did not fill in SF-36 forms. Including baseline until 24 months follow-up, 15 out of 189 forms were missing (7.9%). Out of 17 patients with clinically significant responses, one withdrew from study after 24 months due to a diagnosis of T2N0 breast cancer, and two patients withdrew from follow-up after 25 and 32 months, respectively. Out of 10 patients with no clinically significant response, one patient withdrew from study after 12 months, and four patients after 24–26 months follow-up. Thus, the mean SF-36 scores at 30 and 36 months will be influenced by fewer non-responders included in the analyses.</p><p><sup>b</sup>: in two patients, the last SF-36 forms were completed at 33 and 35 months, respectively.</p><p>SF-36 scores for 27 patients receiving rituximab induction and maintenance treatment, norm-based and raw scores, at baseline and during follow-up<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129898#t003fn001\" target=\"_blank\"><sup>a</sup></a>.</p>", "links"=>[], "tags"=>["105 weeks", "symptom flares", "disease prevalence", "29 patients", "maintenance rituximab infusions", "36 months.FindingsMajor", "response durations", "12 months", "69 weeks", "18 patients", "rituximab infusions", "15 months", "23 weeks", "placebo group", "pilot case series", "rituximab infusion", "156 weeks study period", "rituximab maintenance infusions", "ii", "Randomized Study", "rituximab maintenance treatment", "saline infusions", "nct"], "article_id"=>1470593, "categories"=>["Uncategorised"], "users"=>["Øystein Fluge", "Kristin Risa", "Sigrid Lunde", "Kine Alme", "Ingrid Gurvin Rekeland", "Dipak Sapkota", "Einar Kleboe Kristoffersen", "Kari Sørland", "Ove Bruland", "Olav Dahl", "Olav Mella"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0129898.t003", "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SF_36_scores_for_27_patients_receiving_rituximab_induction_and_maintenance_treatment_norm_based_and_raw_scores_at_baseline_and_during_follow_up_a_/1470593", "title"=>"SF-36 scores for 27 patients receiving rituximab induction and maintenance treatment, norm-based and raw scores, at baseline and during follow-up<sup>a</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-07-01 03:37:57"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"16", "full-text"=>"18", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"14", "full-text"=>"18", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
  • {"unique-ip"=>"22", "full-text"=>"23", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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