Rituximab targets short-lived autoreactive plasma cells more consistently than the more long-lived protective plasma cells [19,20]. infusion until start of clinical response was 23 weeks (range 866). 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 exhibited increase in B-cell lymphoma risk for elderly ME/CFS BCX 1470 methanesulfonate patients, suggest that ME/CFS may be a variant of an autoimmune disease. == Trial registration == ClinicalTrials.govNCT01156909 == Introduction == Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology characterized by severe fatigue and post-exertional malaise, cognitive disturbances, pain, sleep problems, sensory hypersensitivity and several symptoms related to immune and autonomic function. ME/CFS according to Canadian diagnostic criteria [1] comprises approximately 0.10.2% of the population [2], and must be distinguished from BCX 1470 methanesulfonate general fatigue probably affecting ten times as many. A genetic predisposition for ME/CFS has been exhibited [3]. ME/CFS has profound impact SLC2A2 on quality of life for patients and caretakers [4]. The symptom burden is heavy [5], and the disease carries high socioeconomic costs. Patients with severe ME/CFS suffer major functional impairments and often a range of debilitating symptoms. No standard drug treatment has been established, mostly due to lack of knowledge of the underlying disease mechanisms. We have performed a pilot case series of three patients suggesting clinical activity for B-cell depletion using the monoclonal anti-CD20 antibody rituximab [6]. The case series was followed by a small, randomized, double-blind and placebo-controlled phase II study of 30 patients given either rituximab (two infusions two weeks apart), or placebo, with follow-up for 12 months [7]. The primary endpoint was unfavorable, i.e. there was no difference between the rituximab and placebo groups at 3 BCX 1470 methanesulfonate months follow-up. There was, however, a significant difference in favor of the rituximab group in the course ofFatigue scoreduring follow-up, most evident between 610 months follow-up, and with clinical responses in 2/3 of BCX 1470 methanesulfonate the patients receiving rituximab. The symptom improvements were delayed, starting 28 months after initial and rapid B-cell depletion [7], suggesting that ME/CFS in a subgroup of patients could be a variant of an autoimmune disease involving B-lymphocytes and elimination of long-lived antibodies. According to protocol for the previous randomized KTS-1-2008 study, patients assigned to the placebo group should be given the opportunity to participate in a new open-label study with rituximab. The protocol for the present study was designed to learn about the therapeutic efficacy of rituximab maintenance treatment, for response rates and response durations. Also, the experiences could form the basis for design of a future randomized, double-blind and placebo-controlled trial. Therefore, we have now performed this open-label phase II study (KTS-2-2010) using rituximab induction (two infusions two weeks apart) followed BCX 1470 methanesulfonate by rituximab maintenance infusions after 3, 6, 10 and 15 months, and with follow-up for three years. == Materials and Methods == == Ethics == The study, including one amendment, was approved by the Regional Ethical Committee in Norway, no 2010/1318-4, and by the.