Monday, March 25, 2013

Oncologist Professor Mella: Rituximab treatment suggests that ME/CFS is an autoimmune disease


Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

  • Øystein Fluge mail,
  • Ove Bruland,
  • Kristin Risa,
  • Anette Storstein,
  • Einar K. Kristoffersen,
  • Dipak Sapkota,
  • Halvor Næss,
  • Olav Dahl,
  • Harald Nyland,
  • Olav Mella



Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

Methods and Findings

In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients.
The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.


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 present findings will impact future research efforts in CFS.

Trial registration NCT00848692
See also: Study demonstrates that 95% of ME/CFS Patients have Anticardiolipin Antibodies, suggesting that ME/CFS may be an autoimmune condition

Saturday, March 23, 2013

MEandYou: 90 Days to Raise $1.2 Million for Rituximab Trial!

Dr. Maria Gjerpe, an ME patient for 30 years, explains how and why MEandYou are going to crowdfund a Rituximab study:
Within 90 days we are going to raise 7 million Norwegian krone ($1.2 million) to fund a study on 140 ME/CFS patients at Haukeland Hospital in Bergen, Norway.
Will we – the patients, relatives, friends – be the first in the world to crowdfund a clinical trial? And can we engage both sides of the Atlantic to make it happen? Yes!
In 2011, a study at Haukeland Hospital on the use of the immunosuppressive medication Rituximab against ME attracted international attention. Two-thirds of the patients in the study experienced significant improvement after being treated with the drug. Read more>>

Friday, March 22, 2013

Alterations in T-cells along with the specific signature of NK cell phenotype in ME/CFS

Journal of Translational Medicine 2013, 11:68 doi:10.1186/1479-5876-11-68 Published: 20 March 2013:

Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome

Marta Curriu, Jorge Carrillo, Marta Massanella, Josepa Rigau, José Alegre, Jordi Puig, Ana M Garcia-Quintana,Jesus Castro-Marrero, Eugènia Negredo, Bonaventura Clotet, Cecilia Cabrera and Julià Blanco

For all author emails, please log on.
Journal of Translational Medicine 2013, 11:68 doi:10.1186/1479-5876-11-68
Published: 20 March 2013

Abstract (provisional)


Chronic Fatigue Syndrome (CFS) is a debilitating neuro-immune disorder of unknown etiology diagnosed by an array of clinical manifestations. Although several immunological abnormalities have been described in CFS, their heterogeneity has limited diagnostic applicability.


Immunological features of CFS were screened in 22 CFS diagnosed individuals fulfilling Fukuda criteria and 30 control healthy individuals. Peripheral blood T, B and NK cell function and phenotype were analyzed by flow cytometry in both groups.


CFS diagnosed individuals showed similar absolute numbers of T, B and NK cells, with minor differences in the percentage of CD4+ and CD8+ T cells. B cells showed similar subset frequencies and proliferative responses between groups. Conversely, significant differences were observed in T cell subsets. CFS individuals showed increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells, and lower proliferative responses in vitro and in vivo. Moreover, CD8 T cells from the CFS group showed significantly lower activation and frequency of effector memory cells. No clear signs of T-cell immunosenescence were observed. NK cells from CFS individuals displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined. Overall, T cell and NK cell features clearly clustered CFS individuals.


Our findings suggest that alterations in T-cell phenotype and proliferative response along with the specific signature of NK cell phenotype may be useful to identify CFS individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Thursday, March 21, 2013

Georgetown University Researchers find physical proof that Gulf War illness is caused by damage to the brain


Kelly Kennedy, USA TODAY March 21, 2013:

WASHINGTON — Researchers say they have found physical proof that Gulf War illness is caused by damage to the brain — and that proof may ultimately help civilians who suffer from chronic fatigue syndrome and fibromyalgia.

Using fMRI machines, the Georgetown University researchers were able to see anomalies in the bundle of nerve fibers that interpret pain signals in the brain in 31 Gulf War veterans. The research will be published Wednesday in PLOS ONE journal.
The findings are "huge," because an fMRI allows doctors to diagnose a person with Gulf War illness quickly, said James Baraniuk, senior author and professor of medicine at Georgetown University Medical Center. The research, he said, also shows that Gulf War illness is not psychological.
An fMRI, or "functional" MRI, is a scan that measures activity by detecting how blood flows through the brain.
Many veterans have had difficulties getting benefits and treatment for a service-connected condition because doctors assumed they were either faking it or suffering from post-traumatic stress. "That's a problem with all physicians — VA, military or civilian," Baraniuk said. "If it doesn't fall within their small world of known diseases, then the patient is nuts."
Gulf War illness is a series of symptoms that has affected more than 250,000 veterans of the 1991 war against Iraq in response to Iraq's invasion of Kuwait.
Baraniuk said the correlation of anomalies in the brain's white matter with Gulf War illness has not been studied before. Researchers, he said, also found that fatigue and pain worsen congruently in the veterans.
Read more>>

Wednesday, March 20, 2013

Ban the use of the new somatic symptom disorder in the DSM-5 before it devastates Millions of people

The new somatic symptom disorder in DSM-5 risks mislabeling many people as mentally ill

BMJ 2013; 346 doi: (Published 19 March 2013)
Cite this as: BMJ 2013;346:f1580

  1. Allen Frances, chair of the DSM-IV task force
Author Affiliations
This new condition suggested in the bible of mental health diagnoses lacks specificity, says Allen Frances
The fuzzy boundary between psychiatry and general medicine is about to experience a seismic shift. The next edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) is scheduled for release this May amid controversy about many of its new disorders. Among these, DSM-5 introduces a poorly tested diagnosis—somatic symptom disorder—which risks mislabeling a sizeable proportion of the population as mentally ill.
The relation between psychiatry and the rest of medicine has been difficult to manage both for mental health practitioners and for primary care doctors, and this is even more problematic for patients caught in-between. The boundary has never been clear cut or static but has shifted back and forth depending on new findings and fashions. The realm of psychiatry would shrink, and that of medicine would expand, whenever advancing science discovered a cause for a previously poorly understood presentation. The classic example of this is “general paresis of the insane,” which went from psychiatry to neurology as soon as the spirochete was identified as the causal agent.
In DSM-5, “somatic symptom disorder” appears in a new section, “Somatic symptoms and related disorders,” which replaces the “Somatoform disorders” section found in DSM-IV. This new category will extend the scope of mental disorder classification by eliminating the requirement that somatic symptoms must be “medically unexplained.” In DSM-5, the focus shifts to “excessive” responses to distressing, chronic, somatic symptoms with associated “dysfunctional thoughts, feelings, or behaviors.”
The overinclusiveness of this diagnosis is suggested by the results of the DSM-5 field trial study reported by the somatic symptom disorder work group at the 2012 annual meeting of the American Psychiatric Association. Somatic symptom disorder captured 15% of patients with cancer or heart disease and 26% with irritable bowel syndrome or fibromyalgia, and it had a high false positive rate of 7% among healthy people in the general population.1 The rate of psychiatric disorder among medically ill patients is unknown, but these rates seem high, and the burden of proof before introducing any new diagnosis is that it has a favourable risk to benefit ratio. Yet the proposed diagnosis is unsupported by any substantial evidence on its likely validity and safety and was strongly opposed by patients, families, caregivers, and advocacy organizations.2
The DSM-5 definition of somatic symptom disorder is loose. It requires only one bodily symptom that is distressing or disruptive to daily life, which lasts at least six months. It also requires one of the following psychological or behavioral responses: disproportionate thoughts about the seriousness of symptom(s); persistently high level of anxiety about symptom(s); or excessive time and energy spent on health concerns.3 This is far looser than the (rarely used) definition of somatization disorder in DSM-IV. This required a history of many medically unexplained symptoms before the age of 30 years that occurred over several years and which resulted in treatment being sought or psychosocial impairment. A total of eight or more medically unexplained symptoms were needed from four specified symptom groups, with at least four pain and two gastrointestinal symptoms.4
Previous DSM criteria have always included reminders to clinicians to rule out other explanations before concluding that any mental disorder is present. I suggested to the working group that similar reminders should be included this time and that before somatic symptom disorder is diagnosed clinicians should consider whether the health concerns are completely unrealistic or whether an underlying medical disorder might account for them. I also suggested that clinicians should consider whether symptoms might be caused by one of several mental disorders that often present with physical problems (such as depression, generalized anxiety, or panic disorder). 

The DSM-5 working group reviewed these suggestions and rejected them.
Misapplication of these catch-all criteria, especially in harried primary care practice, may result in inappropriate diagnoses of mental disorder and inappropriate medical decision making.5 Millions of people could be mislabeled, with the burden falling disproportionately on women, because they are more likely to be casually dismissed as “catastrophizers” when presenting with physical symptoms.
A false positive diagnosis of somatic symptom disorder harms patients because it may result in any underlying medical causes being missed. It also subjects patients to stigma, inappropriate drugs, psychotherapy, and iatrogenic disease; disadvantages them in decisions relating to employment, education, and healthcare entitlements; skews their self perceptions and those of family and friends; and places parents of children with chronic illness at risk of accusation of “overinvolvement” or of maintaining “sick role behavior.”
Every diagnostic decision is a delicate balancing act between definitions that will result in too much versus too little diagnosis—the DSM-5 work group chose a remarkably sensitive definition that is also remarkably non-specific. This reflected a consistent bias throughout DSM-5 to expand the boundaries of psychiatric diagnosis with what I believe was insufficient attention to the risks of the ensuing false positive mislabeling.
The DSM-5 diagnosis of somatic symptom disorder is based on subjective and difficult to measure cognitions that will enable a “bolt-on” diagnosis of mental disorder to be applied to all medical conditions, irrespective of cause. ICD-11 (International Classification of Diseases, 11th revision) is now being prepared by some of the same people who worked on DSM-5.6 7 Unless ICD-11 applies a higher standard of evidence and risk benefit analysis, it may repeat the mistake of casually mislabeling the physically ill as also mentally disordered.8
The late Thomas Szasz once said: “In the days of the Malleus, if the physician could find no evidence of natural illness, he was expected to find evidence of witchcraft: today, if he cannot diagnose organic illness, he is expected to diagnose mental illness.”9 Szasz’s general critique of psychiatry was too broad, but he was correct when it comes to the loosely defined somatic symptom disorder in DSM-5. Clinicians are best advised to ignore this new category. When a psychiatric diagnosis is needed for someone who is overly worried about medical problems the more benign and accurate diagnosis is adjustment disorder.


Cite this as: BMJ 2013;346:f1580


  • I thank Suzy Chapman, patient advocate, Poole, UK, of Dx Revision Watch, for valuable comments and suggestions.
  • Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: I will publish two books that include references to DSM-5 (Saving Normal and Essentials of Psychiatric Diagnosis) and I chaired the DSM-IV task force.
  • Provenance and peer review: Not commissioned; externally peer reviewed.




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