Treatment with TNF-alpha inhibitor Etanercept (Enbrel®) with moderate and severe CFS/ME - an open prestudy
Purpose:
Cause of chronic fatigue syndrome (CFS / ME) is unknown. Our studies show that a subgroup of CFS / ME patients have response for B-lymphocyte depletion using anti-CD20 antibody Rituximab. The hypothesis is that CFS / ME may be an autoimmune disease.
1/3 of CFS / ME patients had no response after B-cell depletion. An alternative could be the use of TNF inhibitors such as etanercept (Enbrel). Enbrel is administered by subcutaneous injection weekly and binds to the cytokine TNF-alpha. There are no scientific studies that have evaluated Enbrel in CFS / ME. An report from a meeting shows a significant effect in six patients. Other unpublished stories do also exist.
Enbrel may cause risk of infections and paradoxical disturbances in the immune system.
The drug is still widely used as therapy for rheumatoid arthritis, with acceptable side effect profile.
We want to give Enbrel for up to one year, with up to 15 patients with moderate and severe CFS / ME, including patients with no response after Rituximab therapy.
Project Framework:
Project start 2012.02.01
Project end: 2014.12.31
Treatment with etanercept (Enbrel®), as weekly subcutaneous injections of Enbrel 50 mg, given up to one year (52 weeks).
Justification for the choice of data and method
The Cancer Department, with collaboration of the Department of Neurology (Haukeland University Hospital) conducted clinical studies to evaluate the B-lymphocyte depletion using the monoclonal anti-CD20 antibody rituximab against the symptoms of chronic fatigue syndrome (CFS / ME). We performed first a pilot study with three patients (Fluge and Mella, BMC Neurology, 2009), and then a double-blind, placebo-controlled, randomized study of 30 patients (Fluge et al., Plos One, 2011). These are described in the attached proposal.
Our hypothesis is that CFS / ME, which is often preceded by infection, can be a form of autoimmune disease. The assumption is based on the gradient of response and relapse after B-cell depletion. While the B-cells are reduced to very low levels in peripheral blood within a few weeks, the "delay" from 2 to 7 months before the start of the clinical response, which may be consistent with the gradual elimination of autoantibodies. Response rate and the timing of response and relapse is consistent with what can be seen after Rituximab treatment in rheumatoid arthritis for example. Overweight women, a proven genetic predisposition and the presence of other autoimmune diseases in the family are other factors that suggest a possible autoimmune pathogenesis.
However, we have not yet discovered this ourselves, and ongoing laboratory work is needed to show disease etiology and pathogenesis. B-cell depletion is a fundamental intervention in the immune system and multiple interpretations for our results could be due to something else than fall in autoantibodies levels, as stated in the project description.
In the randomized study where the patients received rituximab, 1/3 had no evidence of clinical response. Given that our assumption that CFS / ME can be a form of autoimmune disease are correct, there are several possibilities for mechanisms for non-response. For some patients it may be very high level of presumptive autoantibodies initially, so that the patient does not "reach" to eliminate these (half-life 3-5 weeks) after prolonged (12 months) B-cell depletion.
For other patients, it may be that the presumptive autoantibodies produced by fully mature plasma cells in a very small extent affected by anti-CD20 antibody, while such treatment is more effective where autoantibody are produced by more "early" plasma blasters(?). Other mechanisms for non-response may be that for some patients other variables than B-cells are of more importance for symptom maintenance.
Such processes could include T-cell activation and the effect of aberrant cytokines such as Tumor Necrosis Factor alpha (TNF), which is an important pro-inflammatory mediator. It has regulatory properties of the immune system to other cells such as regulatory T cells.
Finally, many patients with CFS / ME diagnosis could have other conditions that are not immune-mediated, such as primary psychiatric disorders associated with fatigue.
An alternative for patients with typical CFS / ME illness defined by strict diagnostic criteria which didn’t experience an effect with Rituximab, is the TNF-α inhibitor Enbrel.
In autoimmune diseases such as arthritis, the effects by Rituximab is often seen after a few weeks, when mediated via elimination of cytokines directly.
Enbrel will therefore not be able to cure an autoimmune condition, but is often effective as a reliever. Enbrel is administered by subcutaneous injection once week (see project description). Etanercept acts by binding to TNF, and thus inhibits binding of TNF to receptors on the cell surface, with consequent inhibition TNF-mediated cellular response.
Also affected a number of biological responses associated with such cytokines and adhesion molecules that are induced or regulated by TNF. Injection of proinflammatory cytokines, such as IL-1, IL-6 and TNF, directly into the brains of experimental animals, can cause a clinical picture resembling CFS / ME, with decreased motor activity, sleep problems, altered fluid and food intake and signs of cognitive problems. Systemically administered IL-6 and TNF in humans can cause inflammatory symptoms, including fatigue.
There are no published scientific studies that evaluated the use of Enbrel in CFS / ME. However, there is a report available where six CFS / ME patients received treatment with etanercept with good clinical effect, but these results have not been published later (Lamprecht K. American Association of Chronic Fatigue Syndrome, Seattle, 2001). In addition, single unpublished case histories are available.
The Cancer Department at Haukeland University Hospital has had contact with a 35 year old woman who had severe CFS / ME with a typical clinical picture from 16 years of age. For many years she was significantly isolated and disabled by the condition.
She had a moderate rheumatoid arthritis when she was 27 years old and started as 31-year-old with Enbrel subcutaneously every week. She have now used the drug for the last 5 years. She tells how much Enbrel after 2-3 weeks did for her condition, with significant clinical effect on all symptoms related to her CFS / ME. She describes clearly how the ME disease is still present, and that she must be aware of how much energy she uses. She has experienced a major change in quality of life. Such description is consistent with our idea that CFS / ME can be a form of autoimmune disease.
Enbrel may have more side effects than rituximab, and is somewhat more associated with risk for infections and paradoxical disorders of the immune system. Drugs are still widely used as therapy for rheumatoid arthritis with good results and acceptable side effect profile. Toxicity profile by use of Enbrel in CFS / ME is unknown.
We want to try treatment with Enbrel on up to 15 patients with moderate and severe CFS / ME, including patients who have had no response after Rituximab therapy with maintenance (5 infusions and 12-month follow-up), with weekly subcutaneous injections for up to one year.
