A randomised trial evaluating anakinra in early active rheumatoid arthritis.

OBJECTIVES: The effectiveness of anakinra (interleukin-1 receptor antagonist) in early rheumatoid arthritis (RA) is unknown. We evaluated the efficacy of anakinra (combined with methotrexate) in a randomised clinical trial of early active RA patients. METHODS: The Combination Anti-Rheumatic Drugs in Early RA-2 (CARDERA-2) trial was a randomised trial of early (duration <1 year) active RA. Patients were randomised to 12 months of: (1) methotrexate or (2) anakinra-methotrexate. Follow-up lasted 2 years. The primary outcome was erosive progression (changes from baseline in modified Larsen scores). Secondary outcomes were changes from baseline in disease activity score on a 28-joint count (DAS28), health assessment questionnaire (HAQ), and quality of life (EQ-5D) scores alongside ACR responder rates. RESULTS: 154 patients received the allocated intervention (from 259 screened). Similar Larsen score progression was seen at 12 and 24 months in patients receiving anakinra-methotrexate (mean changes from baseline of 2.50 and 5.10, respectively) and methotrexate monotherapy (mean changes from baseline of 4.16 and 5.20, respectively). Lower improvements in DAS28 and HAQ scores were seen at all time-points in anakinra-methotrexate treated patients; these were significantly less at 24 months (DAS28 p=0.04; HAQ P=0.02). Significantly lower EQ-5D score increases were seen at 12 months with anakinra-methotrexate (p=0.03). Anakinra-methotrexate was associated with more serious adverse events compared with methotrexate monotherapy (11 vs. 6 patients), although this was not significant (p=0.59). CONCLUSIONS: Anakinra (combined with methotrexate) is not effective in early, active RA. It provided no clinical benefits beyond methotrexate monotherapy.

Improving the primary care physicians' decision making for fibromyalgia in clinical practice: development and validation of the Fibromyalgia Detection (FibroDetect®) screening tool.

BACKGROUND: Fibromyalgia diagnosis is a challenging and long process, especially among primary care physicians (PCPs), because of symptom heterogeneity, co-morbidities and clinical overlap with other disorders. The purpose was to develop and validate a screening tool in French (FR), German (DE) and English (UK) to help PCPs identify patients with fibromyalgia. METHODS: The FibroDetect questionnaire was simultaneously developed in FR, DE and UK based on information obtained from a literature review, focus groups conducted with clinicians, and face-to-face interviews with fibromyalgia patients (FR, DE and UK, n = 23). The resulting tool was comprehension-tested in patients with diagnosed or suspected fibromyalgia (n = 3 and n = 2 in each country, respectively). Acceptability and applicability were assessed and the tool modified accordingly, then assessed in clinical practice. A scoring method was created using an iterative process based on statistical and clinical considerations with American College of Rheumatology + (ACR+) patients and ACR- patients (n = 276), and validated with fibromyalgia and non-fibromyalgia patients (n = 312). RESULTS: The FibroDetect included 14 questions assessing patients' pain and fatigue, personal history and attitudes, symptoms and impact on lives. Six questions were retained in the final scoring, demonstrating satisfactory discriminative power between ACR + and ACR- patients with area under the Receiver Operating Characteristic curve of 0.74. The predictive accuracy of the tool increased to 0.86 for fibromyalgia and non-fibromyalgia patient detection, with a sensitivity of 90% and a specificity of 67% for a cut-off of 6 on the score. CONCLUSIONS: The FibroDetect is a self-administered tool that can be used as a screening classification surrogate to the ACR criteria in primary care settings to help PCPs detect potential fibromyalgia patients among a population complaining of chronic widespread pain.

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.

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.

Evidence-based clinical guidelines: a new system to better determine true strength of recommendation.

RATIONALE, AIMS AND OBJECTIVES: Clinical practice guidelines often grade the 'strength' of their recommendations according to the robustness of the supporting research evidence. The existing methodology does not allow the strength of recommendation (SOR) to be upgraded for recommendations for which randomized controlled trials are impractical or unethical. The purpose of this study was to develop a new method of determining SOR, incorporating both research evidence and expert opinion. METHODS: A Delphi technique was employed to produce 10 recommendations for the role of exercise therapy in the management of osteoarthritis of the hip or knee. The SOR for each recommendation was determined by the traditional method, closely linked to the category of research evidence found on a systematic literature search, and on a visual analogue scale (VAS). Recommendations were grouped A-D according to the traditional SOR allocated and the mean VAS calculated. Difference across the groups was assessed by one-way ANOVA variance analysis. RESULTS: Mean VAS scores for the traditional SOR groups A-D and one proposition which was 'not recommended' showed significant linearity on one-way ANOVA. However, certain recommendations which, for practical reasons, could not assessed in randomized controlled trials and therefore could not be recommended strongly by the traditional methodology, were allocated a strong recommendation by VAS. CONCLUSIONS: This new system of grading strength of SOR is less constrained than the traditional methodology and offers the advantage of allowing SOR for procedures which cannot be assessed in RCTs for practical or ethical reasons to be upgraded according to expert opinion.

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

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 >or=59 and a pain score of >or=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 >or=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 pound601 (95% CI: 532, 669) and pound653 (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 pound23,166 and pound22,533. In the base case population CQG for pregabalin 450 mg against duloxetine 60 mg and 120 mg was pound19,224 and pound14,096, against gabapentin pound35,737, against tramadol pound98,072, 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.

Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis.

BACKGROUND: The authors have previously reported genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) based on expression of 88 human genes. AIM: To attempt to reproduce these findings, determine the specificity of this signature to CFS/ME, and test for associations between CFS/ME subtype and infection. METHODS: Expression levels of 88 human genes were determined in blood of 62 new patients with idiopathic CFS/ME (according to Fukuda criteria), six patients with Q-fever-associated CFS/ME from the Birmingham Q-fever outbreak (according to Fukuda criteria), 14 patients with endogenous depression (according to DSM-IV criteria) and 29 normal blood donors. RESULTS: In patients with CFS/ME, differential expression was confirmed for all 88 genes. Q-CFS/ME had similar patterns of gene expression to idiopathic CFS/ME. Gene expression in patients with endogenous depression was similar to that in the normal controls, except for upregulation of five genes (APP, CREBBP, GNAS, PDCD2 and PDCD6). Clustering of combined gene data in CFS/ME patients for this and the authors' previous study (117 CFS/ME patients) revealed genomic subtypes with distinct differences in SF36 scores, clinical phenotypes, severity and geographical distribution. Antibody testing for Epstein-Barr virus, enterovirus, Coxiella burnetii and parvovirus B19 revealed evidence of subtype-specific relationships for Epstein-Barr virus and enterovirus, the two most common infectious triggers of CFS/ME. CONCLUSIONS: This study confirms the involvement of these genes in CFS/ME.

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.

Creatine supplements in patients with idiopathic inflammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six-month, double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To test the hypothesis that oral creatine supplements with exercise are more effective than exercise alone in improving muscle function in patients with established dermatomyositis or polymyositis receiving chronic medical therapies who are clinically weak yet stable. METHODS: In a 6-month, 2-center, double-blind, randomized controlled trial, patients were randomized to receive oral creatine supplements (8 days, 20 gm/day then 3 gm/day) or placebo. All patients followed a home exercise program. The primary outcome was aggregate functional performance time (AFPT), reflecting the ability to undertake high-intensity exercise. Secondary outcomes included a functional index measuring endurance and muscle bioenergetics on (31)P magnetic resonance spectroscopy ((31)P MRS). Patients were receiving stable immunosuppressive treatment and/or corticosteroids. RESULTS: A total of 37 patients with polymyositis or dermatomyositis were randomized (19 to creatine, 18 to placebo); 29 completed 6 months. Intent-to-treat analyses demonstrated that AFPT improved significantly at 6 months with creatine (median decrease 13%, range -32-8%) compared with placebo (median decrease 3%, range -13-16%; P = 0.029 by Mann-Whitney U test). A completer analysis also showed significant benefits from creatine (P = 0.014). The functional index improved significantly with both creatine and placebo (P < 0.05 by paired Wilcoxon's rank sum test), with a significant benefit between groups in the completer analysis only. Phosphocreatine/beta-nucleoside triphosphate ratios using MRS increased significantly in the creatine group (P < 0.05) but not in the control group. No clinically relevant adverse events were associated with creatine. CONCLUSION: Oral creatine supplements combined with home exercises improve functional performance without significant adverse effects in patients with polymyositis or dermatomyositis. They appear safe, effective, and inexpensive.

Prescribed exercise in people with fibromyalgia: parallel group randomised controlled trial.

OBJECTIVES: To evaluate cardiovascular fitness exercise in people with fibromyalgia. DESIGN: Randomised controlled trial. SETTING: Hospital rheumatology outpatients. Group based classes took place at a "healthy living centre." PARTICIPANTS: 132 patients with fibromyalgia. INTERVENTIONS: Prescribed graded aerobic exercise (active treatment) and relaxation and flexibility (control treatment). MAIN OUTCOME MEASURES: Participants' self assessment of improvement, tender point count, impact of condition measured by fibromyalgia impact questionnaire, and short form McGill pain questionnaire. RESULTS: Compared with relaxation exercise led to significantly more participants rating themselves as much or very much better at three months: 24/69 (35%) v 12/67 (18%), P=0.03. Benefits were maintained or improved at one year follow up when fewer participants in the exercise group fulfilled the criteria for fibromyalgia (31/69 v 44/67, P=0.01). People in the exercise group also had greater reductions in tender point counts (4.2 v 2.0, P=0.02) and in scores on the fibromyalgia impact questionnaire (4.0 v 0.6, P=0.07). CONCLUSIONS: Prescribed graded aerobic exercise is a simple, cheap, effective, and potentially widely available treatment for fibromyalgia.