Fluge og Mella har tatt patent på behandling av ME/CFS med medikamenter som Rituximab som medfører en B-celle deplesjon

Fluge og Mella fra Haukeland Universitetssykehus har altså tatt patent i behandlingsmetodikken for bruk på ME/CFS pasienter ved bruk av Rituximab som medfører at B-celler som uttrykker CD20 dør. Patenten har tittel “B-cell depleting agents for the treatment of chronic fatigue syndrome”. Deler av patentsøknaden er verdt å oversette slik at dette kommer jeg tilbake til litt senere. I mellomtiden kan de som ønsker det se litt på deler av patentrapporten her.

Hele rapporten kan leses her

Informasjon om hva Rituximab er og pilotstudien kan du også lese i dette innlegget: Behandling: Effekt av Rituximab hos ME/CFS pasienter?

Vi publiserte nylig bruk av B-celle deplesjon som terapeutisk intervensjon ved kronisk tretthetssyndrom (KTS). Vi gjennomfører en dobbeltblind, randomisert, placebo-kontrollert fase II studie med det monoklonale antistoffet rituximab (Mabthera®) hos pasienter med KTS (KTS-1-2008). Etter avblinding febr. 2010 viser foreløpige resultater at Rituximab er assosiert med klar klinisk respons, 8 av 15 pasienter i rituximab-gruppen, versus 1 av 15 i placebogruppen (p=0.017). I tillegg har to pasient i rituximab-gruppen og en pasient i placebo-gruppen “moderat” respons (10/15 vs 2/15, p=0.009). Det er signifikant forskjell i favør av rituximab-gruppen ved 6, 7 og 8 mnd oppfølgning. Det primære endepunkt, effekt på symptombildet etter 3 mnd, er negativt. Det er ikke registrert alvorlig toksisitet. Hypotesen for KTS-3-2010 er at induksjon med rituximab og påfølgende vedlikeholdsinfusjoner til 15 mnd vil føre til klar respons hos pasienter med svært alvorlig KTS i funksjonsklasse III-IV. (kort prosjektbeskrivelse av forlengelse av fase 2 studien hentet fra REKs søk i offentlige journaler).

Patentrapporten: B-celle deplesjons medikamenter for behandling av ME/CFS


Nåværende oppfinnelse er relatert i en første aspekt til en B-celle reduserende anti-CD20 antistoffer eller en CD20-bindende antistoff fragmenter derav for behandling av kronisk utmattelsessyndrom og myalgic encephalomyelitis. Spesielt, er denne metoden relatert til bruken av anti-CD20 monoklonale antistoffer eller fragmenter av disse som fortrinnsvis er humanized for behandling av kronisk utmattelses syndrom/ myalgic encephalomyelitis i en pasient rammet av nevnte lidelse.


Mella, Olav (Olsvik, NO)
Fluge, Øystein (Morvik, NO)

Application Number:


Publication Date:


Filing Date:


Om ME/CFS – studien:

At the Department of Oncology and Medical Physics, Haukeland University Hospital, a striking symptomatic improvement after cytotoxic chemotherapy in a 43-year old female patient with stable CFS (debut in 1997, preceded by Epstein-Barr infection), was observed. She developed Hodgkin’s disease in 2003, and was treated with chemotherapy and radiation. She had a lymphoma relapse in 2004, and was treated with chemotherapy. Contrary to the expected (CFS patients generally tolerate all types of drugs and stress poorly), the patient experienced a marked decrease in CFS symptoms during and after this chemotherapy. The changes were not interpreted as related to lymphoma activity, and the effects lasted for approximately 5 months after chemotherapy initiation, with then gradual relapse of CFS-like symptoms. In addition to the cytotoxic effects, the chemotherapeutics given also had an immunomodulatory effect. It is assumed that the effects on CFS symptoms are mediated mainly through the drug Methotrexate administered during chemotherapy.

When reviewing the literature on CFS in an attempt to understand what our patient encountered during and after cancer chemotherapy, the conclusion was done that modification of the immune system seemed a likely explanation of the marked, but transient symptom improvement experienced. It may well be that chronic B-cell activation seen in CFS patients is important for the symptoms and also physiological changes reported, such as central nervous blood circulation alterations, and reports of lymphocyte infiltration in brain tissue, spinal nerve roots or cardiac muscle.

Possible modes of action of B-cell depletion could be at several sites, such as interactions with the T-cell system, thus modifying inflammatory processes, and in influencing the levels of important pleiotropic players in the immune homeostasis, such as the vasoactive neuropeptides. These have a wide range of activities in the central nervous system.

Taking these existing data into account, together with the unexpected improvement of fatigue and pain in the CFS patient after immunomodulatory cytotoxic therapy, it is assumed that B-cell depletion as a concept could allow treatment of CFS.

At present, achievement of B-cell depletion is most readily achieved by the use of the monoclonal anti-CD20 antibody Rituximab. However, also new generation anti-CD20 antibodies are supposed to have at least a similar effect on CFS symptoms, due to a presumed more potent B-cell depletion achieved.


En: A method of treating chronic fatigue syndrome and, optionally, myalgic encephalomyelitis comprising the step of administering a B-cell depleting agent to a subject afflicted therewith, whereby said B-cell depleting agent is not a B-cell depleting CD-20 antibody or CD-20-binding antibody fragment thereof.


Chronic Fatigue Syndrome (CFS) is characterized by an unexplained, severe fatigue, persisting for at least six consecutive months, and with a substantial reduction of previous levels in occupational, social, or personal activities. Also, the patients often experience persistent or recurrent symptoms such as impairment of short-term memory or concentration, muscle pain, joint pain without evidence of arthritis, headache, sleep disturbances, and post-exercise exhaustion (Fukuda K, et al., 1994, Ann Intern Med 121:953-9 et al 1994). Although many studies have shown subtle alterations in blood tests or radiological investigations, no biomarker or diagnostic test exists.

The prevalence of CFS worldwide is thought to be at least 0.5%, and the female: male ratio is 3:1 (Wyller V B. 2007, Acta Neurol Scand Suppl 187:7-14).

The aetiology of CFS remains unclear. The various hypotheses include immunological, virological, neuroendocrinological, and psychological mechanisms. The pathogenesis of CFS is presumed to be multifactorial and to involve both host and environmental factors (Devanur & Kerr 2006).

In a recent review of November 2007, describing current research priorities in CFS, the urgent need to elucidate the pathogenesis is highlighted (Kerr J R et al., 2007, J Clin Pathol 60:113-6).

Many patients suffering from CFS have a history of an acute viral infection preceding the development of fatigue. Although research data indicate evidence of immune system activation, the disease mechanisms remain unknown. A collaborative study group was formed in 2001; to elucidate the molecular mechanisms of CFS, with the aims to develop a diagnostic test and also to guide the development of more specific treatment (Devanur L D, Kerr J R. 2006, J Clin Virol 37:139-50).

Several gene expression studies have been performed in CFS, indicating that there are specific but complex gene alterations in accordance with a dysfunction in immune response and in defense mechanisms. One microarray study showed differential expression of 16 genes in CFS, suggesting T-cell activation and a disturbance of neuronal and mitochondrial function (Kaushik N, et. Al., 2005, J Clin Pathol 58:826-32). Another microarray study using serial samples of peripheral blood mononuclear cells total RNA, from patients developing CFS after Epstein Barr virus (EBV) infection and also from subjects with EBV infection without development of fatigue, concluded that several genes affecting mitochondrial function and cell cycle were deregulated (Vernon S D, et. Al., 2006, BMC Infect Dis 6:15). Another gene expression study in CFS suggested disturbance of exercise responsive genes including several involved in membrane transport and ion channels (Whistler T, et. al., 2005, BMC Physiol 5:5). Recently, an analysis of gene networks in CFS revealed seven distinct genomic subtypes with differences in clinical presentation and severity (Kerr J, et. al., 2007, J Clin Pathol). Several other studies have addressed global gene expression in CFS (Fang H, et. al., 2006, Pharmacogenomics 7:429-40; Whistler T, et al., 2003, J Transl Med 1:10).

The gene expression data are not conclusive, but suggests that there are gene expression disturbances in CFS representing various cellular functions, and may indicate that the disease has a heterogeneous pathogenesis.

A prevailing theme in CFS research has been a sustained immune deregulation, following acute exogenous stimuli such as a viral infection. Among the microbial pathogens reported to be associated with CFS are Epstein-Barr virus (Lerner A M, et al., 2004, In Vivo 18:101-6), enterovirus (Chia J K, Chia A Y. 2007, J Clin Pathol), parvovirus B19 (Matano S, et al., 2003, Intern Med 42:903-5), cytomegalovirus (Lerner A M, et al., 2002, In Vivo 16:153-9), human herpes virus type 6 (Chapenko S, et al., 2006, J Clin Virol 37 Suppl 1:S47-51; Komaroff A L. 2006, J Clin Virol 37 Suppl 1:S39-46), Chlamydia pneumoniae (Nicolson G L, et al., 2003, Apmis 111:557-66). However, the data are not consistent (Soto N E, Straus S E., 2000,Herpes 7:46-50).

A recent study of postinfective fatigue syndrome found no differences in ex vivo cytokine production over a 12-month period, as compared to controls recovering promptly after infection (Vollmer-Conna U, et al., 2007, Clin Infect Dis 45:732-5). Others claim that despite evidence of immune activation, as demonstrated by increased number of activated T-cells and elevated levels of cytokines, the CFS patients may have a reduced immune cell function with a low NK-cell cytotoxicity and immunoglobulin deficiencies (Patarca R. 2001, Ann NY Acad Sci 933:185-200).

Others reported a high number of circulating B-lymphocytes, altered NK-cells subsets also with increased expression of adhesion molecules, as compared to controls (Tirelli U, et al., 1994, Scand J Immunol 40:601-8), while another study showed reduced CD56+ NK-cells, and reduced CD4+ and CD8+ T-Iymphocytes in CFS patients (Racciatti D, et al., 2004, Int J Immunopathol Pharmacol 17:57-62). Also, T- and NK-cells from CFS patients were found to express lower levels of the intracellular granule protein perforin, indicating a reduced ability to mediate cytotoxicity.

One study showed several abnormalities in laboratory markers associated with immune function in CFS patients (Klimas N G, et al., 1990, J Clin Microbiol 28:1403-10). The most consistent result was a low NK cell cytotoxicity, but also an increase in CD8+ T-cells, elevated number of CD20+ B-cells, and increase in the B-cell subset coexpressing CD20 and CD5 (Klimas et al 1990). These data were to some extent supported by a study reporting expansion of activated CD8+ cytotoxic T lymphocytes, along with a marked decrease in NK cell activity, in CFS patients (Barker E, et al., 1994. Clin Infect Dis 18 Suppl 1:S136-41).

A recent study comparing CFS patients and controls, reported decreased expression of CD69 on T-cells and NK-cells after mitogenic stimulation in vitro, indicating a disorder in the early activation of cellular immunity mediated by these cells (Mihaylova I, et al., 2007, Neuro Endocrinol Lett 28:477-83).

However, the data on immune deregulation in CFS are not consistent, and a study comparing lymphocyte subsets in CFS patients to those of patients with depression, multiple sclerosis and healthy controls, found no difference in T-, B-, or NK-cell subsets (Robertson M J, et al., 2005, Clin Exp Immunol 141:326-32). Similarly, a review of the immunology in CFS concluded that the studies performed in the research field had varying quality, and that no consistent pattern of immunological abnormalities could be identified (Lyall M, et al., 2003, J Psychosom Res 55:79-90).

Along with hypotheses of immune deregulation in CFS, autoimmunity to endogenous vasoactive neuropeptides has been proposed as a mechanism for the disease (Staines D R., 2005, Med Hypotheses 64:539-42), however not supported by scientific data. The author has also suggested a similar mechanisms in the aetiology of fibromyalgia, multiple sclerosis and amyotrophic lateral sclerosis, Parkinson’s disease, and sudden infant death syndrome hypothesizing that autoimmunity against vasoactive neuropeptides acting as hormones, neurotransmitters, immunmodulators and neurotrophes may explain the complex clinical pictures of these diseases. However, no autoantibodies to these neuropeptides have been documented in CFS.

One study investigated the presence of circulating anti-muscle and anti-CNS antibodies in CFS patients and controls, with no detected pathogenic antibodies. Another report of antinuclear autoantibodies in CFS concluded that there was no association (Skowera A, et al., 2002, Clin Exp Immunol 129:354-8), while another investigating common autoantibodies and antibodies to neuron specific antigens showed higher rates of antibodies to microtubule-associated protein 2 and ssDNA in CFS (Vernon S D, Reeves W C. 2005, J Autoimmune Dis 2:5). A single study showed the presence of autoantibodies to muscarinic cholinergic receptor in a subset of CFS patients (Tanaka S, et al., 2003, Int J Mol Med 12:225-30), and higher levels of autoantibodies to insoluble cellular antigens were reported in CFS as compared to controls (von Mikeecz A., et al., 1997, Arthritis Rheum 40: 295-305).

However, there is no direct evidence with consistent data for the presence of pathogenic autoantibodies, or for T-lymphocyte-mediated autoimmunity. No indirect evidence has recreated the CFS disease in an animal model by immunization with antigens analogous to (putative) human autoantigens.

CFS is at present not defined as an autoimmune disease, and a recent protocol for a Cochrane review of pharmacological treatment in CFS states the aetiology as unknown. (Rawson K M, et al., 2007. Pharmacological treatments for chronic fatigue syndrome in adults. (Protocol) Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD006813.)

Other hypotheses for CFS pathogenesis are blood platelet dysfunction (Kennedy G, et al., 2006, Blood Coagul Fibrinolysis 17:89-92), neurological (Natelson B H, et al., 2005, Clin Diagn Lab Immunol 12:52-5), neuroendocrine (Van Den Eede F, et al., 2007, Neuropsychobiology 55:112-20), metabolic or autonomic disturbances, ion channel dysfunction (Chaudhuri A, et al., 2000,Med Hypotheses 54:59-63), zinc deficiency (Maes M, et al., 2006, J Affect Disord 90:141-7), toxin exposure or prior vaccinations (Appel S, et al., 2007, Autoimmunity 40:48-53). Others have focused on an abnormal response to exercise with intracellular immune deregulation as a possible mechanism in CFS pathogenesis (Nijs J, et al., 2004, Med Hypotheses 62:759-65). Also, post-infective impairment of the ability to synthesise n-3 and n-6 long-chain polyunsaturated fatty acids has been proposed as important in the pathophysiology of CFS (Puri B K. 2007, J Clin Pathol 60:122-4).

Hence, recent reviews on CFS in renown journals state that the disease at present has an unknown cause (Hampton T. 2006, Jama 296:2915; Hooper M. 2007, J Clin Pathol 60:466-71; Prins J B, et al., 2006, Lancet 367:346-55). Thus, no consistent picture has emerged for the aetiology and pathogenesis of CFS.

Nåværende behandling:

Due to the lack of knowledge of the exact pathogenesis, and with no known causal mechanism, there is no current standard specific treatment for CFS. A systematic review concluded that CFS should be associated with a “biopsychosocial model” with emphasis on progressive muscular rehabilitation, combined with behavioural and cognitive treatment (Maquet et al, 2006, Ann Readapt Med Phys 49:337-47, 418-27).

The unknown aetiology of CFS is probably the reason for the remarkably few studies performed, evaluating therapy based upon a biological hypothesis.

As the majority of evidence suggests an immune system deregulation, perhaps precipitated by an exogenous stimulus, two studies have assessed use of intravenous gammaglobulin for CFS. One was a case report in three patients with CFS following an acute parvovirus B19 infection, treated with 5-days intravenous immunoglobulin, with improvement of clinical symptoms and resolution of cytokine dysregulation (Kerr et al , 2003., Clin Infect Dis 36:e100-6). In a double-blind, placebo-controlled, randomized study of 71 adolescents with CFS, three infusions of gammaglobulin were given one month apart, with functional improvement in the gammaglobulin-treated group at six-month follow-up with average duration 18 months. In the first six months of the trial, both the placebo group and the gammaglobulin-treated group reported improvement (Rowe 1997, J Psychiatr Res 31:133-47).

In a pilot study reported in abstract form (Lamprecht 2001, Meeting of the American association of chronic fatigue syndrome (AACFS). Seattle) six patients with CFS were given etanercept (Enbrel , i.e. human tumor necrosis factor receptor p75 Fc fusion protein, which is a soluble competitive TNF-receptor acting to inhibit the TNF-mediated cellular response) and a clinical benefit was reported.

Among other therapeutic strategies, valganciclovir was used to treat 12 patients with long-standing fatigue and elevated antibody-titres to Epstein-Barr virus or human herpes virus-6, and nine had improvement of the symptoms, however with uncertainty as to whether the effects were mediated through anti-viral effect or through immunomodulation (Kogelnik A M,. 2006., J Clin Virol 37 Suppl 1:S33-8). Treatment with azithromycin, an antibiotic with immunomodulating properties, gave improvement in 59% of 99 CFS patients (Vermeulen & Scholte 2006, J Transl Med 4:34).

In a recent review of current research priorities in CFS (Kerr et al 2007, J Clin Pathol 60:113-6), new studies are encouraged to focus on the understanding of the molecular pathogenesis of the disease, to test useful biomarkers, and to aid in the development of specific treatment. Various molecular techniques are available and have been used for this purpose, including global gene expression analyses using microarrays.



Det må jo sies at det er fint at Norge tar patent i behandling av ME/CFS pasienter. Av det vi kan tolke så er det også meget lovende behandlingsresultater som kommer i publikasjonen om studien av fase 2. Publikasjonen er forventet å komme i disse dager.

«Etter avblinding febr. 2010 viser foreløpige resultater at Rituximab er assosiert med klar klinisk respons, 8 av 15 pasienter i rituximab-gruppen, versus 1 av 15 i placebogruppen (p=0.017).«

Som sagt vil denne publikasjonen komme til å ha stor betydning for behandling og forståelse for det neuroimmunologiske patofysologiske prosessene og endringene som er funnet i ME/CFS pasienter.

Om vi tidligere i dag publiserte ett svar fra Helseministeren, så må denne publikasjonen få betydning for utredning av pasienter, slik at en kan se hvem som kan egne seg til denne type behandling.

For at dette skal være mulig må helsemyndighetene sende ut ett mer presis oppfordring til fastleger om at det finnes veiledere og kriterier for bruk på de pasientene de mistenker kan være rammet av ME/CFS.

Prøver å få dette innlegget oversatt i de nærmeste dagene, og der funker ikke google.


4 kommentarer om “Fluge og Mella har tatt patent på behandling av ME/CFS med medikamenter som Rituximab som medfører en B-celle deplesjon

  1. Hei Ronny og velkommen til bloggs 😀

    Takk for oversettelsen. Gjorde ett forsøk på det i går, men tiden det tar for å korrigere google-oversettelsen riktig, eller til grei norsk ble litt mye og forvirrende. Da er alternativet at det må gjennom manuell fri oversettelse med kapasitetsreduksjon og kognitiv svikt hau hihi – da går noen dager… tid men ikke så forvirrende iallefall!!

    ME-saken! Jo vi er mange som gjør så godt vi kan – mye gode krefter i det miljøet. Æ blir veldig imponert og gla’ for de som skriver brev og virkelig setter «trøkk». Veldig takknemmelig for det 😀

    Vi har nok fått nok. denne tilstanden er så alvorlig at vi er nødt til å bli hørt og vi har rett å få vite hva vi feiler!

    😉 ikke sant? Folket får kose seg med oversettelsen til så lenge!!!

  2. Omega

    Flott bloggpost. Den aller siste greien, med hvordan azithromycin hadde hatt effekt på over halvparten av ME-pasietene kjente jeg ikke til. Trist at LHK får problemer nå for antibiotikabehandling.

    1. Hei Omega og velkommen til bloggs 😀

      Antibiotikaen du refererer til her og studien som ligger bak er http://www.translational-medicine.com/content/4/1/34 denne.

      det som fremkommer her er at antibiotikaen brukes fordi den da viser seg til å ha immunmoddelerende effekt ved kroniske lidelser og kan virke inflammasjonsdempene. rett og slett som tiltak mot forhøyet oksidativt stress som jepp forekommer i denne tilstanden.

      Vel der har vi også en hel del andre tiltak, som diett og b12, glutation og C-vitaminer med mer.

      hvorvidt LHK har denne i sin protokoll vet jeg ikke – jeg har ikke brukt denne.

      Denne antibiotikaen vil i såtilfelle gå under bruk hvor der ikke er objektive funn som patogener.

      Antibiotikaen er mye brukt mot bakterielle infeksjoner som halsbetennelse, steptokokkinfeksjon i hals etc. Link: http://en.wikipedia.org/wiki/Azithromycin

      Det LHK har fått stopp på er bruk av antibiotika for mage/tarm, og ellers bruk som ikke er veiledende i norske protokoller for behandling.

      Så ja det går ut over behandling av dysbiose i mage/tarm og håper inderlig at denne behandlingen blir akseptert av helsetilsynet – fordi det er nødvendig.

      Men kommer du der og har opplagt infeksjon som krever antibiotika så får du foreskrevet dette på LHK som på alle andre legekontorer….

      😉 jepp vi får bare håpe at det ordner seg……

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