Selwyn Richards

Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome

Background: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. Aims: To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. Methods: To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Control criteria and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression ⩾ 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples. Results: Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively. Conclusion: These results suggest that patients with CFS have reproducible alterations in gene regulation.

Gene Expression Subtypes in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. We set out to determine the precise abnormalities of gene expression in the blood of patients with CFS/ME. We analyzed gene expression in peripheral blood from 25 patients with CFS/ME diagnosed according to the Centers for Disease Control and Prevention diagnostic criteria and 50 healthy blood donors, using a microarray with a cutoff fold difference of expression of >or=2.5. Genes showing differential expression were further analyzed in 55 patients with CFS/ME and 75 healthy blood donors, using quantitative polymerase chain reaction. Differential expression was confirmed for 88 genes; 85 were upregulated, and 3 were downregulated. Highly represented functions were hematological disease and function, immunological disease and function, cancer, cell death, immune response, and infection. Clustering of quantitative polymerase chain reaction data from patients with CFS/ME revealed 7 subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes, and severity.

Emotional expression, self-silencing, and distress tolerance in anorexia nervosa and chronic fatigue syndrome

OBJECTIVES. Difficulties in processing emotional states are implicated in the aetiology and maintenance of diverse health conditions, including anorexia nervosa (AN) and chronic fatigue syndrome (CFS). This study sought to explore distress tolerance, self-silencing, and beliefs regarding the experience and expression of emotions in individuals diagnosed with AN and CFS. These conditions were chosen for this study because their clinical presentation is characterized by physical symptoms, yet cognitive behavioural models suggest that emotional processing difficulties contribute to the aetiology and maintenance of both. DESIGN. A between-subjects cross-sectional design was employed. METHODS. Forty people with AN, 45 with CFS, and 48 healthy controls (HCs) completed the Distress Tolerance Scale (DTS), Silencing the Self Scale (STSS), Beliefs about Emotions Scale (BES), and measures of clinical symptomatology. RESULTS. Initial group comparisons found that both AN and CFS participants scored higher than HCs on a subscale measuring difficulties in distress tolerance. AN and CFS participants were also more likely to judge themselves by external standards, endorse statements reflecting a tendency to put the needs of others before themselves, and present an outwardly socially compliant image of themselves whilst feeling hostile within. Relative to HCs, AN participants reported more maladaptive beliefs regarding the experience of having negative thoughts and feelings and revealing these emotions to others, with CFS participants showing a non-significant trend in the same direction. After controlling for differences in age, anxiety, and depression the only significant difference to remain was that observed for the STSS care as self-sacrifice subscale. More maladaptive beliefs about the experience and expression of emotions were associated with greater degree of eating disorder symptomatology in the AN group. CONCLUSIONS. Differences in emotional processing are present in AN and CFS compared to HCs, with some disorder-specific variation, and may be associated with greater clinical symptomatology. These findings support current explanatory models of both AN and CFS, and suggest that emotional processing should be addressed in the assessment and treatment of individuals with these illnesses.

Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis: disease mechanisms, a diagnostic test and specific treatments.

Chronic fatigue syndrome (CFS) is an illness characterised by disabling fatigue of at least 6 months duration, which is accompanied by various rheumatological, infectious and neuropsychiatric symptoms. A collaborative study group has been formed to deal with the current areas for development in CFS research—namely, to develop an understanding of the molecular pathogenesis of CFS, to develop a diagnostic test and to develop specific and curative treatments. Various groups have studied the gene expression in peripheral blood of patients with CFS, and from those studies that have been confirmed using polymerase chain reaction (PCR), clearly, the most predominant functional theme is that of immunity and defence. However, we do not yet know the precise gene signature and metabolic pathways involved. Currently, this is being dealt with using a microarray representing 47 000 human genes and variants, massive parallel signature sequencing and real-time PCR. It will be important to ensure that once a gene signature has been identified, it is specific to CFS and does not occur in other diseases and infections. A diagnostic test is being developed using surface-enhanced, laser-desorption and ionisation-time-of-flight mass spectrometry based on a pilot study in which putative biomarkers were identified. Finally, clinical trials are being planned; novel treatments that we believe are important to trial in patients with CFS are interferon-β and one of the anti-tumour necrosis factor-α drugs.

Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a neuro-immune disease of uncertain pathogenesis. Human parvovirus B19 infection has been shown to occur just prior to development of the onset of CFS/ME in several cases, although B19 seroprevalence studies do not show any significant differences between CFS/ME and controls. In this study, we analysed parvovirus B19 markers in CFS/ME patients (n=200), diagnosed according to Fukuda CDC criteria, and normal blood donors (n=200). Serum from each subject was tested for anti-B19 VP2 IgM and IgG (by Biotrin ELISA), anti-B19 NS1 IgM and IgG (by immunofluorescence), and B19 DNA (by real-time PCR). CFS/ME patients and normal blood donors had a similar B19 seroprevalence (75 % versus 78 %, respectively). Eighty-three CFS patients (41.5 %) as compared with fourteen (7 %) normal blood donors tested positive for anti-B19 NS1 IgG (chi(2)=64.8; P<0.0001; odds ratio=9.42, CI 5.11-17.38). Of these 83 patients, 61 complained of chronic joint pain, while 22 did not. Parvovirus B19 DNA was detected in serum of 11 CFS patients and none of the controls by Taqman real-time PCR (chi(2)=9.35, P<0.002). Positivity for anti-B19 NS1 IgG was associated with higher expression levels of the human CFS-associated genes NHLH1 and GABPA. As NS1 antibodies are thought to indicate chronic or severe courses of B19 infection, these findings suggest that although the seroprevalence of B19 in CFS patients is similar to controls, the immune control of the virus in these patients may not be efficient.

Cost effectiveness of pregabalin in the treatment of fibromyalgia from a UK perspective

Abstract Background: Fibromyalgia is a chronic condition associated with widespread pain, sleep disturbance and disability. Disease related costs are high and effective treatment options few. Objectives: To evaluate the cost effectiveness of pregabalin in the treatment of fibromyalgia. Methods: A decision-analytic model was developed comparing pregabalin 300 mg or 450 mg against placebo, duloxetine 60 mg or 120 mg, gabapentin, tramadol and amitriptyline. After a 12 week treatment phase patients who responded to treatment entered an ongoing treatment phase using a Markov model in which patients maintained response, lost response or dropped out. The base case considered patients with severe fibromyalgia defined as a Fibromyalgia Impact Questionnaire score of ≥59 and a pain score of ≥6.5 at baseline. Response rates for pregabalin and placebo were taken from three randomised trials, and a 1 year open-label extension study was used for long-term parameters. Response was defined as a ≥30% improvement over baseline in pain score and a patient global impression of change rating of much improved or very much improved. Relative rates of response for other comparators over placebo were extracted from a systematic review of published randomised controlled studies. The primary effectiveness endpoint was Quality Adjusted Life Years (QALYs). Utilities gained over baseline were estimated by applying the SF-6D utility algorithm to SF-36 data collected in the pregabalin trials. Resource use associated with fibromyalgia management was estimated from published studies and costs were estimated from the UK NHS perspective at 2008 prices. Costs and QALYs were discounted at 3.5%. Non-parametric bootstrapping analysis was used to generate confidence intervals. Results: In the base case, pregabalin 300 mg and 450 mg increased cost per patient by £601 (95% CI: 532, 669) and £653 (587, 727) and improved QALYs per patient by 0.03 (−0.03, 0.06) and 0.03 (−0.04, 0.08) respectively compared to placebo. The cost per QALY gained (CQG) was £23,166 and £22,533. In the base case population CQG for pregabalin 450 mg against duloxetine 60 mg and 120 mg was £19,224 and £14,096, against gabapentin £35,737, against tramadol £98,072, and was dominated by amitriptyline. Sensitivity analysis found the cost effectiveness of pregabalin to be most sensitive to drug price and response rates. Limitations of the analysis include different definitions of response used and lack of subgroup data reported in the published studies synthesised, and limited data on long-term effect of therapies in fibromyalgia. Although the analysis was based on the best available evidence, the comparisons against amitriptyline and tramadol rely on old studies that were not designed to meet current quality criteria. Conclusion: This model found pregabalin 300 mg and 450 mg to be cost effective compared with placebo and, within the limits of available evidence, against duloxetine using standard UK criteria in patients with fibromyalgia experiencing severe pain.

497 FACTORS TO HELP PRIMARY CARE PHYSICIANS DETECTING FIBROMYALGIA IN ROUTINE PRACTICE

The incidence of complex regional pain syndrome (CRPS) type I after surgery of the trapeziometacarpal joint varies from 8% to 19%. We investigated prospectively our results after arthroplasty under vitamin C prophylaxis. In patients with trapeziometacarpal arthritis a cementless total semiconstrained prosthesis [type Roseland, Depuy International Ltd, Leeds, England] was implanted. Visual analogue scale (VAS) scores for pain, activities of daily living (ADL) and satisfaction were taken preand postoperatively, together with first web opening. Vitamin C 500mg daily was started two days prior to surgery during 50 days. We operated 39 hands in 33 patients (mean age 61 years; 26 females and 7 males). In 15 cases there was stage II osteoarthritis according to Dell, 23 times stage III, and in one case there was a traumatic trapeziometacarpal dislocation. There were no cases of CRPS according to the IASP, Bruehl or Veldkamp criteria. First web opening increased 16 degrees and there was a significant improvement for pain, ADL and satisfaction as well (p = 0.000). Patient satisfaction was strongly associated with the amount of pain reduction. In this study the postoperative treatment was functional. Torrededia et al. used a neoprene splint for one month and reported CRPS in 5 patients (13%) after 38 operations with the same implant. The difference is significant [Relative Risk (RR) = 0.87 (Confidence interval 0.77–0.98), p = 0.03]. We advise our patients for hand surgery to use vitamin C to diminish the chance on the occurrence of CRPS.