Is Chronic Fatigue Syndrome an Autoimmune Disease?

For decades, a heated debate has raged over the nature of the illness known variously as chronic fatigue syndrome (CFS) and/or myalgic encephalomyelitis (ME). Historically, the two warring camps have been divided between “it’s all in their heads” and “we’re still looking.” But while both sides have consistently referred to CFS/ME as an “enigma,” it turns out the source of the illness may very well have been under everyone’s nose the whole time.

In the May 2013 issue of Discover Magazine, an article by Jill Neimark bearing the intriguing title, “Are B-Cells to Blame for Chronic Fatigue Syndrome?,” chronicled a remarkable discovery: wiping out the B-cells of patients with CFS/ME can actually cure the illness.

In 2007 Øystein Fluge and Olav Mella, two Norwegian oncologists at Haukeland University Hospital in Bergen, Norway, accidentally discovered that rituximab, a drug employed to treat Hodgkin’s lymphoma (as well as autoimmune disorders such as rheumatoid arthritis and Wegener's granulomatosis) cured several of their patients with CFS/ME. The news made instant headlines.

Inspired by their success, Fluge and Mella conducted a pilot study of rituximab on three patients with CFS/ME. The patients were given rituximab in an open-label trial (that is, the patients knew they were receiving the drug). All three patients experienced significant improvement; two of them responded within six weeks and the third had a delayed response, occurring six months after treatment. The positive effects lasted for between 16 and 44 weeks. After relapse, the patients were administered another dose of rituximab, with the same positive results. The investigators hypothesized that B-cells of the immune system might play a significant role in CFS, at least for a subset of patients, and that “CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function.”

The positive results of this, as well as a second open-label trial, led Drs. Fluge and Mella to conduct a larger study with a more rigorous design to test the effects of the drug. In 2009 they initiated a double-blind, placebo-controlled phase trial with 30 CFS/ME patients. As in the earlier open-label studies, the responses to rituximab were significant. Sustained overall improvements were noted in 67% of the patients (as opposed to 13% of the control group). Four of the rituximab patients showed improvement past the study period. The authors concluded that the delayed responses starting from 2–7 months after rituximab treatment, in spite of rapid B-cell depletion, “suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses.”

The unprecedented success of these small trials has led to a $2.1 million privately funded initiative spearheaded by the Norwegian nonprofit group, ME and You.

This is all very topical, but is it news? Dr. Paul Cheney, an immunologist, and one of the physicians who treated CFS/ME patients during the Incline Village outbreak, stated nearly thirty years ago that CFS/ME was the result of immune system upregulation. In fact, the prevailing theory during the 1980s and 1990s was that the immune systems of people with CFS simply did not shut off after the initial infection, but remained on “high.” This was considered the driving force behind CFS/ME, and, not coincidentally, is the basis for autoimmune disease.

Nonetheless, the idea that CFS/ME was an autoimmune disease languished for decades, even though the on-the-ground evidence has been apparent all along. The waxing and waning symptoms that are typical of CFS/ME are also typical of autoimmune diseases. Frequent comorbidities of CFS/ME with autoimmune diseases - e.g. Sjögren’s Syndrome and Hashimoto’s disease - were tip-offs that an autoimmune process was involved. And even if researchers didn’t care to take symptoms and comorbidity into account, there were dozens of studies documenting immune system abnormalities, particularly increased inflammatory cytokines, as well as a high incidence of markers such as antinuclear antibodies (ANA), and anti-cardiolipin antibodies (ACA), both of which are associated with autoimmunity.

The sad fact is that although the evidence was there, it was ignored. In a recent review of the accumulated evidence for autoimmunity in CFS/ME (in a chapter titled “Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Parallels with Autoimmune Disorders”) Ekua Brenu and associates site over 180 related articles. Their conclusion? "CFS/ME may have a potential to be described as autoimmune, as this is the only consistent immunological abnormality associated with CFS/ME.”

Given the thorough nature of the review, Brenu's conclusion, however cautious, is warranted. And, bearing out Brenu's review, as well as the rituximab studies, in March 2013 a UK study by Bradley et al found an increased number of naïve B-cells in patients with CFS/ME. An increase in naïve B-cells is a hallmark of autoimmune disease.  In short, if it walks like a duck, and it quacks like a duck, it’s a duck.

Apropos of the rituximab studies, and as an excuse for not noticing the duck-like nature of CFS/ME, Neimark quotes rheumatologist Jonathan Edwards as saying, “T-cells were in fashion for a long time. B-cells were just considered boring.” It is hard to imagine that the absence of research on fully half of the immune system could be due to the whims of fashion, but whimsy is only part of the explanation for this exercise in mass denial. The other component is that the major players in our health care system - government agencies, researchers, physicians, insurance companies – have had a vested interest in perpetuating the myth that CFS/ME is an unknown and unknowable entity.

Norwegians, apparently, have less invested in the myth. When the results of Fluge and Mella’s rituximab study were made public, the Norwegian Directorate of Health Deputy Director Bjørn Guldvog was prompted to issue a televised apology. "I think that we have not cared for people with ME to a great enough extent,” he said. “I think it is correct to say that we have not established proper health care services for these people, and I regret that."

We look forward to hearing something similar from the CDC.

References:

1. Neimark, Jill. “Are B-Cells to Blame for Chronic Fatigue Syndrome?” Discover Magazine. May, 2013.

2. Fluge, Øystein, Olav Mella. “Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series.” BMC Neurol. 2009 Jul 1;9:28

3. Fluge, Øystein, Ove Brulan, Kristin Risa, Anette Storstein, Einar K. Kristoffersen, Dipak Sapkota, Halvor Næss, Olav Dahl, Harald Nyland, Olav Mella. “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(10): e26358. doi:10.1371/journal.pone.0026358

4. “Will MEandYou be the first to crowdfund a clinical trial?” ME and You.

5. Hokama, Yoshitsugi, Cara Empey Campora, Cynthia Hara, Tina Kuribayashi, Diana Le Huynh, and Kenichi Yabusaki. “Anticardiolipin Antibodies in the Sera of Patients with Diagnosed Chronic Fatigue Syndrome.” Journal of Clinical Laboratory Analysis. 23 : 210–212 (2009).

6. Brenu, Ekua W., Lotti Tajouri, Kevin J. Ashton, Donald R. Staines and Sonya M. Marshall-Gradisnik. “Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Parallels with Autoimmune Disorders” in Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution. Spaska Angelova Stanilova, ed. InTech. March 2013.

7. Bradley, A. S.,  B. Ford, A. S. Bansal. "Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls". Clinical & Experimental Immunology. Volume 172, Issue 1, pages 73–80, April 2013.

A shorter version of this article was originally published on Blogcritics on April 7, 2013 as "Is Chronic Fatigue Syndrome an Autoimmune Disease?"

Who Took the “ID” Out of CFIDS?

Et tu, Brute?

First published on Blogcritics as "Chronic Fatigue and Immune Dysfunction: Who Took the “ID” Out of CFIDS?"

Does anyone remember CFIDS, aka Chronic Fatigue and Immune Dysfunction Syndrome? Back in the 1990s this was the accepted term for what is now called CFS, or, if you are so inclined, CFS/ME. The ID was quietly dropped by researchers and doctors about 10 years ago in favor of Steven Straus’s infamous legacy: chronic fatigue syndrome. Everyone agrees that CFS is a confusing, misleading and utterly dismissive name for the illness. Not only does it harm people who have CFS, it harms people who don’t.

In a recent study of patients newly diagnosed with MS, nearly one-third had been diagnosed with CFS (or with the even more vague, “fatigue”) for one to two years prior to being diagnosed with MS. Imagine how many other patients with incipient cancer, heart disease, liver disease, diabetes (to name a few “fatiguing” illnesses) have had the catch-all diagnosis of CFS slapped on them simply because they were tired. The term CFS has been just as much a curse to those patients, whose correct diagnoses and treatments have been delayed by years, as it has been to patients with CFIDS.

Who did this? Who managed to drop the all-important feature of immune dysfunction from the name? After all, it is obvious that people with CFIDS have an immune dysfunction. Chronicity is, in fact, the product of an altered immune system. With a fully functioning immune system, the host recovers. Immune dysfunction is not just a feature of chronic disease, it is its definition.

What’s more, the furor over what to call the “Disease of a Thousand Names” has only intensified since the ID dropped about. Prior to the deletion of the ID, people who had been diagnosed with ME (on one side of the Atlantic) and CFIDS (on the other) maintained a cordial relationship. Since the change, they are at each other’s throats. People with ME do not want to be diagnosed with an illness that not only reduces all their symptoms to the “f” word, but is doggedly lumped into some ill-defined category of mental illness.

Who did this? Who managed to divide what was once a unified community into squabbling sororities? The CFIDS community could, and did, accomplish so much when it spoke with one voice: national organizations, political lobbies, well-subscribed magazines. Now, it is factionalized, torn apart by the desire to achieve maximum distance from the stigma of "fatigue."

An even more disturbing consequence of dropping the ID is that supposed friends, clinicians who once championed the cause, have not only slipped into using the term CFS, but are adding insult to injury by dropping the S part and referring to this illness, which not only destroys lives, but can eradicate them, simply as “chronic fatigue.” It’s bad enough that the patients call their illness “chronic fatigue,” but Nancy Klimas, head of the Neuro Immune Institute and world-renowned CFIDS specialist, should know better.

Who did this? Who trivialized this illness among formerly committed researchers and clinicians? Who robbed CFIDS patients of their defenders?

Benjamin Natelson.

In 2002, Benjamin Natelson, noted CFIDS researcher, was given a grant by the NIH to do a meta-analysis of immune studies in CFIDS patients. Meta-analyses are not research studies, they are simply analyses of studies that have been performed in the past. Because meta-analyses basically serve as Cliffs Notes for researchers who are too pressed for time to read the original work, their ultimate value to the research community has been questioned. Natelson’s meta-analysis, entitled “Evidence for the Presence of Immune Dysfunction in Chronic Fatigue Syndrome,” examined 79 studies of immune function in CFIDS patients. Natelson found that that there was no consistent immune dysfunction. Some studies indicated that there were increased pro-inflammatory cytokines, others found increased anti-inflammatory cytokines.

Given the fact that one of the hallmarks of CFIDS is waxing and waning symptoms, this "inconsistency" should not have come as a surprise. The immune dysfunction that characterizes CFIDS is that it both under- and over-responds. Immune, as well as neuro-endocrine, swings are the inevitable outcome of the loss of homeostasis that lies at the heart of the illness.

Natelson ignored this aspect of immune dysfunction, just as he ignored the one consistent piece of data he found across these studies – low natural killer (NK) cell function. He concluded that, “the available evidence does not support chronic fatigue syndrome as being due to any consistent immunological dysfunction … we believe that the term “chronic fatigue syndrome” is preferable to the older “chronic fatigue and immune dysfunction syndrome.”

Aside from the damaging consequences of this conclusion, it turns out that Natelson was wrong.

In 2012, a group of Australian researchers headed by Ekua Brenu completed the first longitudinal study of immune function in patients with CFS/ME (CFIDS). This was the first time researchers had examined immune function over a long period of time, in this case, 12 months. The value of longitudinal studies to measure immune function is that the immune system is a moving target. It responds instantly to environmental input. Even the best short-term study of the immune system can’t give researchers more than a snapshot.

The Brenu study found that patients with CFIDS do indeed have an immune system dysfunction. It is the same immune dysfunction that most other studies have found over the past two decades: low NK function. The natural killer cells of CFIDS patients ignore invaders, tumor cells among them (which is perhaps why so many people diagnosed with CFIDS in the 1980s went on to develop lymphomas). The authors concluded that because cytotoxic activity was consistently decreased during the course of the 12-month study it “may be a suitable biomarker for diagnosing CFS/ME.”

Notwithstanding the tantalizing possibility that a biomarker may have finally been found, the real clincher came at the end of the discussion section, where the authors explained why previous short-term studies had been equivocal:

“Cytokine release in CFS/ME patients undergoes shifts during the course of the disease where patients may present with either an amplified or depressed anti-inflammatory or pro-inflammatory cytokine profile. These alterations in cytokine secretion may occur during the course of the disease and at different times causing either a shift towards a predominant Th1 or Th2 immune response in CFS/ME This makes it difficult to establish a unique CFS/ME-like inflammatory cytokine profile. The observed pattern of cytokine distribution among our CFS/ME patients is consistent with equivocal findings in the literature. In adolescents with CFS/ME, cytokine secretions have been observed to be correlated with seasonal variations. Therefore, CFS/ME may be associated with oscillations in pro and anti-inflammatory cytokines, supporting the heterogeneity and multifactorial nature of the disease and the diversity in symptom presentations.”

That paragraph alone should have heralded a new age in CFIDS research. It should have stimulated a lively discussion. It should have prompted a retraction of Natelson’s damning conclusion. It should have reinserted the ID.

But instead of doing any of those things, it was ignored, not just by the broader scientific community, but by CFIDS researchers, clinicians and, saddest of all, by those who would have benefitted the most - the patients. We are now lying in the bed that has been made for us.

And it is a hard one.

References:

Berger JR, Pocoski J, Preblick R, Boklage S. “Fatigue Heralding Multiple Sclerosis,” Mult Scler. 2013 Feb 25. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/23439577

Natelson, Benjamin H., Mohammad H. Haghighi, and Nicholas M. Ponzio. "Evidence for the Presence of Immune Dysfunction in Chronic Fatigue Syndrome." Clin Diagn Lab Immunol. 2002 July; 9(4): 747–752. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC120010/

Ekua W Brenu, Mieke L van Driel, Donald R Staines, Kevin J Ashton, Sharni L Hardcastle, James Keane, Lotti Tajouri, Daniel Peterson, Sandra B Ramos, and Sonya M Marshall-Gradisnik. “Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis.” J Transl Med 2012; 10: 88 doi: 10.1186/1479-5876-10-88.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464733/