This case series of B-cell depletion was initiated after an original clinical observation of unexpected and markedly improved CFS symptoms in a patient treated for Hodgkin's disease with the MIME chemotherapy regimen. We speculated that the initial observed effect was related to Mtx, which is given in moderate doses in the MIME regimen (30 mg/m2
/3 weeks, comparable to weekly doses used in the treatment of connective tissue diseases (5–15 mg/m2
/week). We postulated that a main mechanism inducing the symptoms in CFS is a deregulation of the immune system involving B-lymphocytes directly or indirectly. B-cell depletion was induced with an anti-CD20 monoclonal antibody, as is standard practice with few side effects in patients with B-cell lymphomas, rheumatoid arthritis and related connective tissue diseases [15
There were no clinical indications that the development of Hodgkin's lymphoma in patient 1 (after six years of stable CFS), or of testicular seminoma in patient 2 (after five years of stable CFS), caused their fatigue symptoms. As premedication before rituximab treatment, the patients were given a single dose of dexamethasone 8 mg orally. It is highly unlikely that this medication should influence the symptom courses reported, as no significant improvements were seen before at least six weeks follow-up.
All three patients, with 7–10 years of CFS disease duration, had substantial relief of all symptoms related to CFS after rituximab intervention. Patients 1 and 2 had a marked symptom improvement from approximately 6 to 12–16 weeks, thereafter slowly increasing symptoms (yet still a benefit 6 months after treatment). Patient 3 had slight symptom improvement from 6 to 26 weeks after treatment, thereafter a major recovery of all symptoms lasting until 40 weeks after treatment, followed by a gradual worsening the following month. The clinical effect achieved was significant with a major impact on quality of life in all the three patients, assessed by the patients and their families. However, the clinical improvements were transient. Following retreatment with rituximab a similar pattern of responses occurred in all three patients, however, of longer duration than at the first treatment (patients 1 and 2). Patient 3 had again the impressive response on all CFS symptoms approximately 5 months after the second rituximab treatment, in line with the course after her first intervention. Also, patient 1 had a new substantial CFS symptom improvement starting from 10 weeks after start of weekly oral low-dose Mtx. In addition, patients 1 and 2 had a third course of rituximab treatment, again with very similar initial major responses as experienced in their previous interventions (however with limited follow-up so far).
The mechanism behind the apparent effects of B-cell depletion seen in this case series is not obvious. As in rheumatoid arthritis [12
], the improvement was delayed in time compared to the rapid fall in blood B-cell counts. Considering the time course of symptom relief with gradual improvement starting six weeks after rituximab infusion, and with also a late and major response in patient 3, a plausible mechanistic explanation is reduced antibody or autoantibody production by B-cell clones. It is worth noting that patients 1 and 2 had other autoimmune diseases (autoimmune thyroiditis and diabetes mellitus type I, respectively) and may thus represent a particular subset of CFS patients. Patient 3 had no history of autoimmune disease. The kinetics of CFS symptom relapse could also be compatible with an autoimmune mechanism. However, the relatively early symptom relapse starting 12–16 weeks after rituximab treatment in patient 1 and 2, at a time point when CD19+ B-cells could not yet be detected in peripheral blood, indicates that the target of a putative autoimmune process is carefully regulated and present in small amounts. In a study of rituximab treatment in patients with rheumatoid arthritis, the B-cell levels did not correlate with clinical response [17
]. The kinetics of B-cell return after rituximab treatment vary [18
]. The presence of serum autoantibodies in CFS has been investigated, with varying results [19
]. In some studies, an increase in proportion of CD20+ CD5+ B-cells has been observed, an immunophenotype associated with autoantibody-production [9
]. Also, increased Th2-type immune response seen in CFS might be associated with an autoimmune mechanism [8
]. The different roles of B-cells in autoimmune diseases have recently been reviewed [24
]. An autoimmune hypothesis could be supported by experimental use of plasma exchange to eliminate putative autoantibodies. To our knowledge, such data have not been reported in the literature.
In a study, a subset of CFS patients harboured IgM antibodies to either Epstein-Barr virus [14
], or cytomegalovirus [25
], and were thought to have an ongoing viral infection. This subset of CFS patients improved following valacyclovir treatment [26
]. In the present case series, the three patients did not show evidence of ongoing infection using standard serologic tests or PCR analyses during follow-up. However, they all had mononucleosis prior to CFS development and may thus represent a special subset of CFS patients. As an alternative hypothesis, patients with ongoing infection with a B-lymphotropic virus could perhaps profit from B-cell lysis and depletion.
Among the most consistent immunological abnormalities detected in CFS patients are T- and NK-cell dysfunctions [10
], and decreased intracellular perforin [28
]. The B- and T-cell functions are mutually related. B-cells produce proinflammatory cytokines, they are regulators of other effector cells in the immune system, and are efficient antigen-presenting cells. Rituximab can therefore also exhibit effects on T-cell mediated immunity, and also on NK-cell and dendritic cell functions, see review [29
]. Some placebo effect could be present in our study, although the time course of symptom relief and worsening in all three patients, suggests an objective effect on the underlying mechanism of the disease. However, the need for a placebo control group when evaluating intervention in CFS has been demonstrated [30
]. Apart from one event of localized and uncomplicated herpes zoster, no unexpected toxicity has occurred with 17–19 months follow-up. Due to the still unknown aetiology of CFS, the toxicity of B-cell depletion therapy is unknown. Toxicity data from treatment of B-cell malignancies are extensive, while the safety considerations in rheumatic diseases are being evaluated in long-term follow-up of patients enrolled in clinical trials [31
A remarkable feature of this case series is that all three patients had improvement of all CFS related symptoms following the B-cell depletion. One patient with sufficient follow-up had response also to weekly, oral Mtx. This indicates that a main mechanism of symptom development is touched by the drug manipulation. We anticipate that a subset of patients with CFS will benefit from anti-CD20 B-cell depletion therapy. The tolerance to B-cell depletion was good in our patients, based on 17 – 19 months follow-up.
In conclusion, this first report in the literature of B-cell depleting therapy in CFS patients strongly suggests a clinical benefit, and that B-cell depletion may be an effective drug intervention for this common, disabling disease. B-cell depletion therapy in CFS should thus be further explored.