History – Background
The general scientific strategy of the Gottfries Clinic has evolved from the seminal observation made by professor Gottfries, when he was a young physician in 1958-59. He then noticed that an increasing number of patients in his clinical practice presented with a syndrome like what is now called ME/CFS.
The patients had a status indicating ongoing mild infection after an influenza that was epidemic in Sweden in 1958 (the “Asian flu”). This observation led to treatment of the patients with antibiotics, with temporary effect, and to vaccinations aiming at stimulating the immune system. Improvements were noted in single individuals after prolonged treatment with a staphylococcus toxoid vaccine (Gottfries, 1999).
Based on this uncontrolled experience, such treatment was reuptaken in the 1990s, using Staphypan® manufactured by the Swiss Serum and Vaccine Institute Berne.
The use of staphylococcus vaccine
The first controlled double-blind study included 28 patients and lasted for three months (Andersson et al., 1998). Encouraged by the positive results, a second and larger controlled double-blind study was performed, lasting for eight months, on 100 women fulfilling the criteria of both FM and ME/CFS. The good results were evident (Zachrisson et al., 2002). Two thirds (65%) responded to treatment and wanted to continue after the trial was ended.
In summary, successful phase III clinical trials, performed at the Gottfries Clinic, have established Proof of Concept.
Moreover, long term study of n=160 patients for five years shows excellent adherence and clinical safety.
The clinical positive response to treatment is related to the response of the patient’s immune system. The greater the serologic response, as assessed by production of antibodies, the greater is the clinical effect (Zachrisson et al., 2004). In addition, by investigating serum samples before and after treatment, we found a significant relation between the capacity of serum to neutralise alpha-toxin and the clinical outcome of the treatment (Zachrisson et al., 2004).
Thus, deprived immunity at baseline was likely to predict poorer outcome of the treatment, at least within the first six months.
In summary, our controlled trials support the notion that patients with FM and ME/CFS are in a state of disrupted immune function, and the patients in general benefit substantially from immune-modulating therapy in the form of repeated subcutaneous injections of a staphylococcus toxoid vaccine every fourth week.
In October 2002, doctor Olof Zachrisson defended his doctoral thesis on ‘Fibromyalgia/Chronic Fatigue Syndrome’ (ISBN 91-628-5386-4), at the Göteborg University. This dissertation is based on research performed at the Gottfries Clinic, and is a good summary of the ‘State of the Art’ 2002 in this field of natural sciences.
The preparation of a staphylococcus toxoid vaccine, such as Staphypan®, was to be given subcutaneously in increasing doses at 7-day intervals over eight weeks, and then followed by monthly booster doses. Administered at these doses and intervals, the treatment is well tolerated and the side effects are few. The only important side effect seen in the trials (less than 5%) was related to allergy to salicylic acid, one of the components of the preservative (thiomersal). The need for continuous maintenance of the treatment, at least in adults, was conceived to be life-long.
The use of vitamin B12 and folic acid
At the Gottfries Clinic, we have put attention to the fact that efficacy of the treatment may be optimised, in some patients, by supplementing by somewhat high dosages of vitamin B12 (cobalamin) and folic acid. The rational basis for this treatment is supported by the finding of low vitamin B12 values and increased homocysteine levels in the cerebrospinal fluid of patients with FM (Regland et al., 1997). At present the research about the effect of this vitamin treatment in ME/CFS is continued by studying the cerebro spinal fluid of ME/CFS-patients.
In “A Primer for Clinical Practitioners” is said that a growing body of evidence indicates that energy metabolism and mitochondrial function are impaired in many patients with ME/CFS. The basis for such abnormalities remains undetermined, but chronic viral infection and chronic immune activation are both proven causes of such abnormalities.
Human Heat Shock Protein 60
In cooperation with professor Jonas Blomberg, Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University and co-workers the chaperonin human heat shock protein 60 (HSP60) was investigated. This protein occurs in mitochondria and in bacteria and is highly conserved, antigenic and a major auto antigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME/CFS-patients and 76 blood donors (BD) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array.
Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME/CFS-preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME/CFS and 399 non-ME/CFS samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumonia HSP60 detected IgM in 15 of 61 (24%) of ME/CFS, and in 1 of 399 non-ME/CFS at a high cutoff (p<0.0001).
IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME/CFS, compatible with infection-induced autoimmunity.
These findings may open a door for achieving a laboratory marker for ME/CFS and will of course also shed light on the ethology of ME/CFS. The findings if replicated will also definitely displace ME/CFS from being on the board of psychiatry.