Wednesday, July 29, 2015

Researchers’ discovery may explain difficulty in treating Lyme disease

June 1, 2015 by Greg St. Martin @

North­eastern Uni­ver­sity researchers have found that the bac­terium that causes Lyme dis­ease forms dor­mant per­sister cells, which are known to evade antibi­otics. This sig­nif­i­cant finding, they said, could help explain why it’s so dif­fi­cult to treat the infec­tion in some patients.
It hasn’t been entirely clear why it’s dif­fi­cult to treat the pathogen with antibi­otics since there has been no resis­tance reported for the causative agent of the dis­ease,” explained Uni­ver­sity Dis­tin­guished Pro­fessor Kim Lewis, who led the North­eastern research team.
In other chronic infec­tions, Lewis’ lab has tracked the resis­tance to antibi­otic therapy to the pres­ence of per­sister cells—which are drug-​​tolerant, dor­mant vari­ants of reg­ular cells. These per­sister cells are exactly what they’ve iden­ti­fied here in Bor­relia burgdor­feri, the bac­terium that causes Lyme disease.
The researchers have also reported two approaches—one of them quite promising—to erad­i­cate Lyme dis­ease, as well as poten­tially other nasty infections.
Lewis and his col­leagues pre­sented their find­ings in a paper pub­lished online last week in the journal Antimi­cro­bial Agents and Chemotherapy. He co-​​authored the paper with North­eastern doc­toral stu­dents Bijaya Sharma and Autumn Brown, both PhD’16; recent grad­uate Nicole Matluck, S’15, who received her Bach­elor of Sci­ence in Behav­ioral Neu­ro­science; and Linden T. Hu, a pro­fessor of mol­e­c­ular biology and micro­bi­ology at Tufts University.
The research was sup­ported by grants from the Lyme Research Alliance and the National Insti­tutes of Health.
Lyme dis­ease affects 300,000 people annu­ally in the U.S., according to the Cen­ters for Dis­ease Con­trol and Pre­ven­tion, and is trans­mitted to people via bites from infected black­legged ticks. If caught early, patients treated with antibi­otics usu­ally recover quickly. How­ever, about 10 to 20 per­cent of patients, par­tic­u­larly those diag­nosed later, who have received antibi­otic treat­ment may have per­sis­tent and recur­ring symp­toms including arthritis, muscle pain, fatigue, and neu­ro­log­ical prob­lems. These patients are diag­nosed with Post-​​treatment Lyme Dis­ease Syndrome.
In addi­tion to iden­ti­fying the pres­ence of these per­sister cells, Lewis’ team also pre­sented two methods for wiping out the infection—both of which were suc­cessful in lab tests. One involved an anti-​​cancer agent called Mit­o­mycin C, which com­pletely erad­i­cated all cul­tures of the bac­terium in one fell swoop. How­ever, Lewis stressed that, given Mit­o­mycin C’s tox­i­city, it isn’t a rec­om­mended option for treating Lyme dis­ease, though his team’s find­ings are useful to helping to better under­stand the disease.
The second approach, which Lewis noted is much more prac­tical, involved pulse-​​dosing an antibi­otic to elim­i­nate per­sis­ters. The researchers intro­duced the antibi­otic a first time, which killed the growing cells but not the dor­mant per­sis­ters. But once the antibi­otic washed away, the per­sis­ters woke up, and before they had time to restore their pop­u­la­tion the researchers hit them with the antibi­otic again. Four rounds of antibi­otic treat­ments com­pletely erad­i­cated the per­sis­ters in a test tube.
This is the first time, we think, that pulse-​​dosing has been pub­lished as a method for erad­i­cating the pop­u­la­tion of a pathogen with antibi­otics that don’t kill dor­mant cells,” Lewis said. “The trick to doing this is to allow the dor­mant cells to wake up.”
He added: “This gives you an idea that you could, in prin­ciple, estab­lish a sim­ilar reg­i­ment for treating patients for this and other chronic diseases.”
Lewis is a fac­ulty member in the biology depart­ment and directs Northeastern’s Antimi­cro­bial Dis­covery Center. Over the past decade he has led pio­neering work on this spe­cial­ized class of cells pro­duced by all pathogens known as per­sis­ters. Ear­lier this year, Lewis, biology pro­fessor Slava Epstein, and other col­leagues pub­lished ground­breaking researchin Nature pre­senting a new antibi­otic that kills pathogens without encoun­tering any detectable resistance.
In pre­vious work, Lewis’ lab iden­ti­fied a com­pound called ADEP that causes dor­mant per­sister cells in MRSA to self-​​destruct. This com­pound was among the first options the researchers tried out to combat Lyme dis­ease. But it didn’t work, and nei­ther did com­bi­na­tions of stan­dard antibi­otics used to treat the dis­ease. The team thought it had hit a dead end yet remained vig­i­lant in its quest to iden­tify promising alter­na­tive options.
What we came up with was the pulse-​​dosing reg­imen, which worked beau­ti­fully,” Lewis explained. “I think this could be very useful, espe­cially for antibi­otics for which resis­tance doesn’t rapidly develop.”
Though the researchers iden­ti­fied the pres­ence of these per­sister cells, they also note in their paper that the mech­a­nisms by which the per­sis­ters are able to sur­vive remain unknown. More work in this area will be required, they wrote.

Saturday, July 25, 2015

Gene expression factors differentiate fibromyalgia, ME/CFS, depression and healthy controls from each other

@ PubMed:

  Arthritis Care Res (Hoboken).  2015 Jun 19. doi: 10.1002/acr.22639. [Epub ahead of print]

  Gene expression factor analysis to differentiate pathways linked to fibromyalgia, chronic fatigue syndrome, and depression in a diverse patient sample.

  Iacob E, Light AR, Donaldson GW, Okifuji A, Hughen RW, White AT, Light KC.


  To determine if independent candidate genes can be grouped into meaningful biological factors and if these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia (FMS) while controlling for co-morbid depression, sex, and age.

  We included leukocyte mRNA gene expression from a total of 261 individuals including healthy controls (n=61), patients with FMS only (n=15), CFS only (n=33), co-morbid CFS and FMS (n=79), and medication-resistant (n=42) or medication-responsive (n=31) depression. We used Exploratory Factor Analysis (EFA) on 34 candidate genes to determine factor scores and regression analysis to examine if these factors were associated with specific diagnoses.

  EFA resulted in four independent factors with minimal overlap of genes between factors explaining 51% of the variance. We labeled these factors by function as: 1) Purinergic and cellular modulators; 2) Neuronal growth and immune function; 3) Nociception and stress mediators; 4) Energy and mitochondrial function. Regression analysis predicting these biological factors using FMS, CFS, depression severity, age, and sex revealed that greater expression in Factors 1 and 3 was positively associated with CFS and negatively associated with depression severity (QIDS score), but not associated with FMS.

  Expression of candidate genes can be grouped into meaningful clusters, and CFS and depression are associated with the same 2 clusters but in opposite directions when controlling for co-morbid FMS. Given high co-morbid disease and interrelationships between biomarkers, EFA may help determine patient subgroups in this population based on gene expression.


Friday, July 24, 2015

Another clue that ME/CFS might be an autoimmune disease: Increased Risk of ME/CFS for people with allergies

  @ PubMed:

  Medicine (Baltimore). 2015 Jul;94(29):e1211. doi: 10.1097/MD.0000000000001211. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study.Yang TY1, Kuo HT, Chen HJ, Chen CS, Lin WM, Tsai SY, Kuo CN, Kao CH.

  Author information
  * 1From the Molecular and Genomic Epidemiology Center, China Medical University Hospital, China Medical University, Taichung (T-YY); Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua (T-YY); Department of Developmental and Behavioral Pediatrics, China Medical University Hospital (H-TK); School of Medicine, China Medical University (H-TK); Management Office for Health Data, China Medical University Hospital (H-JC); Department of Public Health, China Medical University; Asia University (H-JC); Division of Chinese Trauma, China Medical University Hospital, China Medical University, Taichung (C-SC); Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chiayi (W-ML); Chang Gung University, Taoyuan (W-ML); Department of Laboratory Medicine (Clinical Pathology), Mackay Memorial Hospital, Taipei (S-YT); Department of Health Policy and Management, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD (S-YT); Kau-Tang Traditional Medical Hospital (C-NK); Department of Nuclear Medicine and PET Center, China Medical University Hospital (C-HK); and Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan (C-HK).

  Several hypotheses have been proposed to explain the etiopathogenesis of chronic fatigue syndrome (CFS), including immune dysregulation. However, few population-based prospective cohort studies have been conducted on CFS and atopy. We investigated the relationship between atopy and CFS by using a population-based cohort study.

  In this prospective, population-based cohort study of the National Health Insurance Research Database, we identified 42,558 patients with atopy and 170,232 patients without atopy from 2005 to 2007 with follow-up to 2011. The incidence rates and risks for CFS were estimated using Cox proportion hazards regression.

  The overall incidence rate of CFS was higher in the atopy cohort compared with the nonatopy cohort (1.37 versus 0.87 per 1000 person-year), with an adjusted hazard ratio of 1.48 (95% confidence interval 1.30-1.69).

  The risk of CFS in the atopy cohort increased 1.47- to 1.50-fold for each nonexisting comorbidity. Patients with numerous atopic symptoms exhibited a biological gradient of increasing risk for CFS, and the risk changed significantly after adjustment for age, sex, and comorbidities, increasing from 1.46- to 2.59-fold.

  •   We revealed that atopy is associated with CFS, particularly in patients with numerous atopic syndromes. The actual mechanism for CFS development in patients with atopy remains unclear and requires further investigation. We recommend researching the subsequent fatigue symptom in patients with atopy, particularly those with multiple atopic syndromes.

Thursday, July 23, 2015

Research shows graded exercise therapy causes exercise intolerance and makes things worse in ME/CFS

@ PubMed:

  Dyn Med. 2005 Oct 28;4:10. Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Black CD1, McCully KK.

  Author information  * 1Department of Kinesiology, The University of Georgia, Athens, GA, USA.

In a previous study we demonstrated that while people with CFS had lower daily activity levels than control subjects, they were able to increase daily activity via a daily walking program.

  We reanalyzed our data to determine the time course of activity changes during the walking program. Daily activity assessed via an accelometer worn at the hip was divided into sleep, active, and walking periods. Over the first 4-10 days of walking the subjects with CFS were able to reach the prescribed activity goals each day. After this time, walking and total activity counts decreased.

  Sedentary controls subjects were able to maintain their daily walking and total activity goals throughout the 4 weeks.

  Unlike our previous interpretation of the data, we feel this new analysis suggests that CFS patients may develop exercise intolerance as demonstrated by reduced total activity after 4-10 days.

  The inability to sustain target activity levels, associated with pronounced worsening of symptomology, suggests the subjects with CFS had reached their activity limit.

  FREE PMC article


Wednesday, July 22, 2015

The putative role of viruses, bacteria, and  mold in CFS

@ PubMed:

  Mol Neurobiol. 2015 Jun 17. [Epub ahead of print]

  The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability.

  Morris G 1, Berk M 2,3, Walder K 4, Maes M 5,6.



  Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge.

  The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation.

  Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms.

  More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi.

  Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased.

  The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

Saturday, July 18, 2015

Frederick Douglass about harmful CBT and GET for ME/CFS: Power concedes nothing without a demand

"Power concedes nothing without a demand. It never did, and it never will. 

  Find out just what people will submit to, and you have found out the exact amount of injustice and wrong which will be imposed upon them; and these will continue until they are resisted with either words or blows, or with both. 

  The limits of tyrants are prescribed by the endurance of those whom they oppress." 

  -- Frederick Douglass, August 4, 1857 

  Born a slave, Frederick Douglass was the most important black American leader of the 19th century.

Thursday, July 16, 2015

Remembering the Outbreak of ME in the Royal Free Hospital on the 13th of July 1955


  Sixty years ago on this very day, July 13th 1955, a resident doctor and a ward sister became ill in the Royal Free Hospital. It was the start of the outbreak of a mysterious disease, which would become known as the Royal Free Disease, one of the most famous and well-documented outbreaks of Myalgic Encephalomyelitis(ME).

  What follows is an excerpt from the book “Myalgic Encephalomyelitis and Postviral Fatigue States – The saga of Royal Free Disease” by Melvin Ramsay.

  On July 13th 1955 a resident doctor and a ward sister on the staff of the Royal Free Hospital were admitted to the wards with an obscure illness.

  By July 25th more than 70 members of the staff were similarly affected and it was plain that there was in the hospital an epidemic of a highly infectious nature producing, among other things, manifestations in the central nervous system. Because of the threat to the health of patients, and because of the large number of nurses involved, the hospital closed on that date and remained closed until October 5th. By that time the epidemic was almost over although sporadic cases appeared up to November 24th.

  Between July 13th and November 24th, 292 members of the medical, nursing, auxiliary medical, ancillary and administrative staff were affected by the illness and of these, 255 were admitted to hospital; 37 nurses were looked after at home or admitted to other hospitals from their home.

  It is remarkable that, although the hospital was full at the time of the epidemic, only 12 patients who were already there developed the disease.


Friday, July 10, 2015

My response to the medically unexplained nonsense from Professor Moss Morris

  Dear Professor Moss Morris,

  as a doctor who has been bedridden for more than a decade with ME/CFS, the result of a major Relapse caused by harmful graded exercise therapy, which breaches the do No Harm principle of the GMC, I'm always amazed that doctors and other medical professionals in this day and age of the computer, where you can read up on all the evidence sitting behind your computer using PubMed, totally ignore all the evidence that what they say is wrong. On the other hand I shouldn't be so surprised as in the first part of your post you write that you are from Kings College and that's where the top dog of Pinocchio psychiatry resides who has been deliberately ignoring clinical evidence for decades that what he says is wrong, to the detriment of people with severely disabling neuro immune diseases.

  In Good Medical Practice, duties of a doctor, the GMC makes it's perfectly perfectly clear that not keeping up to date with the current evidence is unacceptable, unfortunately that is what you and the Pinocchio Psychiatrists are doing when you ignore all the evidence that ME/CFS is a debilitating physical disease and call it a medically unexplained disease instead.

  What is medically unexplained is that people like yourself totally ignore evidence. Or as Dr Shepherd, the honorary medical adviser of the ME Association recently wrote: "Failure to keep up with the research on ME/CFS is 'inexcusable'"

  As professor Hooper wrote a few years ago when does ignoring evidence become serious professional misconduct ? It's clear that the Pinocchio Psychiatrists have crossed that line a long time ago. Please do keep in mind that evidence that something is psychosomatic or all in the mind, because that's basically what you say when you call a disease medically unexplained, does not exist.

  Or to use the words of exercise physiologist professor Keller: "Given what we have learned in the past eight years about this illness, it is intellectually embarrassing to suggest that ME is a psychological illness."

  A Danish study showed a few days ago that the quality of life for people with this disease is the worst when compared with 20 other diseases, including a number of cancers, chronic renal failure, ischaemic heart disease etc. This also makes it perfectly clear that the current "treatments", ie CBT and GET, are at best totally useless.

  It would be "nice" if you change your post in line with all the current evidence that ME/CFS is a debilitating physical disease, and not a psychological or psychiatric disease, as the prestigious American Institute the IOM recently concluded after an extensive review of the literature.

  Instead of ridiculing and belittling us with psychosomatic nonsense it's more than time that we get proper treatment so we get our health and independence back, can come off benefits and go back to work.

  For your information Prof Mella, a Norwegian oncologist and his team recently published their latest study which not only suggests that ME/CFS is an autoimmune disease but also shows that two thirds of responders to the cancer drug Rituximab, are still in remission at the 36-month follow-up.

  So not medically unexplained but a debilitating neuro immune disease. More than time that you and Kings College get up to date with the current evidence instead of ignoring it, which is inexcusable, breaches the GMC guidance and constitutes Bad Medical Practice.

  Kind regards,

  Dr Maik Speedy


  #     Exercise physiologist Prof Keller: "Given what we have learned in the past eight years about this illness, it is intellectually embarrassing to suggest that ME is a psychological illness."

  #     Professor Hooper: When does ignoring evidence by doctors become serious professional misconduct ?

  #     Prof Edward Shorter and the psychic epidemic of ignoring clinical evidence

  #     Evidence that a disease is psychosomatic doesn't exist

  #     Massachusetts Medical Society's NEJM Journal Watch: "There is still no cure, or even any reliably effective treatment, for CFS"

  #     Editorial in Jacobs Journal of Physiotherapy and Exercise: it is essential to protect ME patients against harm by exercise regimes

  #     Rituximab maintenance infusions leads to prolonged disease remission in ME/CFS

  #     Immunological Similarities between Cancer and Chronic Fatigue Syndrome

  #     Danish study finds patients with MEcfs have the lowest health-related quality of life of 21 conditions looked at which means / confirms that CBT and GET are at best totally useless 


Thursday, July 9, 2015

Dr O'Sullivan, Pinocchio Psychiatry and breaching the GMC's Guidance on Good Medical Practice, Duties of a Doctor

"The duties of a doctor registered with the General Medical Council Patients must be able to trust doctors with their lives and health. To justify that trust you must show respect for human life and make sure your practice meets the standards expected of you in four domains.

Knowledge, skills and performance
 * Make the care of your patient your first concern.
 * Provide a good standard of practice and care.
 * Keep your professional knowledge and skills up to date.
 * Recognise and work within the limits of your competence."

Calling ME a psychosomatic disease, ignoring all the evidence that ME is a physical disease is not Keeping your professional knowledge up to date. That normally should mean that doctors who do not do that, land themselves in heavy Waters with the GMC.

It's also interesting if you look at the other domains. For example:

"Maintaining trust"
 * "Never abuse your patients' trust in you or the public's trust in the profession."

Calling a physical disease psychosomatic as Dr O'Sullivan is doing or all in the mind, SSD etc as the Pinocchio Psychiatrists have been doing for decades is severely abusing the public's trust in the profession.

And what about the following one:

"Communication, partnership and teamwork 
* Treat patients as individuals and respect their dignity.
 * Treat patients politely and considerately."

It is that this is a very debilitating disease otherwise it would make you laugh if you know how bad people with this disease are being treated thanks to the Pinocchio Psychiatrists and now Dr O'Sullivan who wants to have a piece of the Pinocchio cake.

If you want to read up on the GMC's Guidance on Good Medical Practice, Duties of a Doctor, you can do it @ the GMC's own website

# Exercise physiologist Prof Keller: "Given what we have learned in the past eight years about this illness, it is intellectually embarrassing to suggest that ME is a psychological illness."

# Professor Hooper: When does ignoring evidence by doctors become serious professional misconduct ?

# Prof Edward Shorter and the psychic epidemic of ignoring clinical evidence

# Evidence that a disease is psychosomatic doesn't exist

# Massachusetts Medical Society's NEJM Journal Watch: "There is still no cure, or even any reliably effective treatment, for CFS"

# Editorial in Jacobs Journal of Physiotherapy and Exercise: it is essential to protect ME patients against harm by exercise regimes

# Rituximab maintenance infusions leads to prolonged disease remission in ME/CFS

# Immunological Similarities between Cancer and Chronic Fatigue Syndrome

# Danish study finds patients with MEcfs have the lowest health-related quality of life of 21 conditions looked at which means / confirms that CBT and GET are at best totally useless

Tuesday, July 7, 2015

Danish study finds patients with ME/CFS have the lowest health-related quality of life of 21 conditions looked at

  Published July 6, 2015 @ plosone:

  * Conclusion
The study provides the first Danish EQ-5D-3L preference scores for ME/CFS patients as well as the newest EQ-5D-3L estimates for use internationally in health economics, health-care planning and research. It is found that ME/CFS in this study has a major impact on the patients’ HRQoL. In conclusion, the EQ-5D-3L-based HRQoL of ME/CFS is significantly lower than the population mean.

  In fact, the ME/CFS HRQoL in this study was the lowest of all the compared conditions in both the unadjusted analysis and in the adjusted regression analysis.

  My conclusion: so basically this study confirms that CBT and GET are at best totally useless and that it's more than time that we get proper medication / treatment which is what patients have been saying for decades.


Sunday, July 5, 2015

Immunological Similarities between Cancer and Chronic Fatigue Syndrome


  Immunological Similarities between Cancer and Chronic Fatigue Syndrome: The Common Link to Fatigue?


  Author Affiliations  * 1Division of Musculoskeletal Physiotherapy, Department of Health Sciences, Artesis University College Antwerp (AHA), Antwerp  * 2Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel (VUB), Brussel  * 3Private Practice for Internal Medicine, Ghent & Aalst;  * 4CVS Contactgroep, Belgium  * Correspondence to: Jo Nijs, Artesis Hogeschool Antwerpen (AHA), Department of Health Sciences, Division of Musculoskeletal Physiotherapy, Van Aertselaerstraat 31, 2170 Merksem, Belgium. Tel: +32 36418205, e-mail:  or

  Abstract Cancer and chronic fatigue syndrome (CFS) are both characterised by fatigue and severe disability. Besides fatigue, certain aspects of immune dysfunctions appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunctions in CFS and cancer is provided. Special emphasis is given to the relationship between immune dysfunctions and fatigue.

  Abnormalities in ribonuclease (RNase) L and hyperactivation of nuclear factor kappa beta (NF-κB) are present in CFS and in prostate cancer. Malfunctioning of natural killer (NK) cells has long been recognised as an important factor in the development and reoccurrence of cancer, and has been documented repeatedly in CFS patients.

  The dysregulation of the RNase L pathway, hyperactive NF-κB leading to disturbed apoptotic mechanisms and oxidative stress or excessive nitric oxide, and low NK activity may play a role in the two diseases and in the physiopathology of the common symptom fatigue. However, in cancer the relation between the immune dysfunctions and fatigue has been poorly studied.

  Immunological abnormalities to such as a dysregulated RNase L pathway, hyperactive NF-κB, increased oxidative stress and reduced NK cytotoxicity, among others, are present in both diseases. These anomalies may be part of the physiopathology of some of the common complaints, such as fatigue. Further studies to confirm the hypotheses given here are warranted.


Thursday, July 2, 2015

Rituximab maintenance infusions leads to prolonged disease remission in ME/CFS

@ Plosone:


  Background Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.

  Methods In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.

  Findings Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8–66). 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 demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

  Trial registration NCT01156909

  Citation: Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, et al. (2015) B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS ONE 10(7): e0129898. doi:10.1371/journal.pone.0129898

  Academic Editor: Christina van der Feltz-Cornelis, Tilburg University, NETHERLANDS

  Received: February 13, 2015; Accepted:May 14, 2015; Published: July 1, 2015



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