Evidence for the improvement of fatigue in fibromyalgia: A 4-week left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation randomized-controlled trial.

BACKGROUND: Fibromyalgia is a complex chronic disorder with few effective treatments currently available. One promising treatment option is repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique that has shown promise in disorders effecting the central nervous system. METHODS: We assessed the efficacy of a course of high-frequency (10 Hz) left-hemisphere dorsolateral prefrontal cortex (DLPFC) rTMS in 26 patients (14 active; 12 sham) with a diagnosis of fibromyalgia. Participants underwent a double-blind stimulation protocol of daily (Monday-Friday) rTMS sessions over four consecutive weeks (total of 20 sessions; 75 × 4-s 10 Hz trains at 120% resting motor threshold). Assessments were conducted at baseline, 4 weeks and at 1-month follow-up. RESULTS: Using mixed-model analysis we did not identify a group difference for our primary outcome measures. However, we found that patients in the active group compared to sham treatment group had significantly greater improvement in the Physical Fatigue (p = 0.045) and General Fatigue (p = 0.023) scales of the Multidimensional Fatigue Inventory-20 at the 1 month follow-up. In a responder analysis, we also found the active group was significantly more likely (2.84 times) to achieve a minimum 30% improvement in pain intensity ratings. (p = 0.024). CONCLUSIONS: High-frequency rTMS applied daily for 4 weeks to the left DLPFC induces significant relief from fatigue and a greater chance of clinically meaningful improvement in pain intensity in patients with fibromyalgia. These results suggest DLPFC rTMS may be a relevant therapy for fibromyalgia. SIGNIFICANCE: This study provides evidence that 4-weeks of daily rTMS to the left DLPFC is able to improve fatigue in fibromyalgia. This novel finding provides impetus for the further investigation of the utility of TMS approaches for the relief of fatigue, an otherwise difficult-to-treat symptom, in fibromyalgia and related disorders.

Fibromyalgia onset has a high impact on work ability in Australians.

BACKGROUND: Although the disabling effects of fibromyalgia (FM) are well recognised, there are no published data regarding the impact of FM on work ability in Australians. The impact of the development of FM symptoms on ability to work in Australians was explored in a pilot survey project. METHOD: Members of the Fibromyalgia Support Network of Western Australia were invited to undertake an anonymous online survey. Information was gathered regarding demographics, symptom onset, the timing of diagnosis, employment status and changes in the ability to work. RESULTS: Two hundred and eighty-seven responses were analysed. Of the respondents, 90.6% were female, with a mean age of 51.1 ± 10.6 years and had experienced symptoms between 2 and 20 years; 52.8% were diagnosed less than 5 years previously. Of the participants, 54.2% were working full time and 21.5% working part time at symptom onset; however, only 15.6% were currently working full time, with 44.8% not currently working at all. Because of FM, 24.3% stopped and 32.6% reduced paid work directly within 5 years of symptom development, with 15.3% ceasing and an additional 17.4% reducing work because of symptoms before diagnosis. Due to FM symptoms, 35.1% currently received financial support because they were unable to work. While 24.3% reported FM medication increased their ability to work, 20.8% reported it reduced their ability to work. CONCLUSION: A community pilot survey of Australians with FM indicates a high impact on work ability. This occurs from symptom onset and often before diagnosis. Early diagnosis and intervention may provide a window of opportunity to prevent work disability in FM.

International travel in the immunocompromised patient: a cross-sectional survey of travel advice in 254 consecutive patients.

AIMS: Our primary aim was to determine the rate of overseas travel in immunocompromised individuals attending appropriate clinics at an Australian tertiary care hospital. We also aimed to characterise health-seeking behaviour prior to travel and investigated sources of pre-travel advice, compared travel patterns and activities between three specific immunosuppressed groups, and examined pre-immunosuppression patient serology. METHODS: We implemented a cross-sectional survey of patients between February and August 2012. This survey was implemented among three outpatient populations at Monash Medical Centre, an Australian tertiary care hospital. RESULTS: We recruited 254 immunosuppressed adults from three patient populations: human immunodeficiency virus-positive individuals, renal transplant patients and rheumatology patients requiring immunosuppressive therapy. No clinical intervention was performed. In the 10 years preceding the survey, 153 (60.2%) participants reported international travel. Of these, 105 (68.6%) were immunosuppressed at the time of travel. These patients were 47.6% male and 60% Australian born. Forty per cent were visiting friends and relatives as part of their travel. Fifty-four per cent of those immunocompromised at the time of travel were going to high-risk destinations. Pathology files indicated that serological screening was frequently not performed prior to immunosuppression in the renal transplant and rheumatology groups. CONCLUSIONS: Immunocompromised patients often travel to high-risk destinations with limited or inadequate pre-travel preparations. Doctors caring for the immunocompromised should be aware of travel risks, suitable vaccination protocols and when to refer to specialist travel clinics.

OPAL: a clinician driven point of care observational data management consortium.

A vast amount of important information on the various rheumatic diseases that the rheumatologist treats is available in the medical records derived from the patient consultation. Until recently, it has been difficult to assemble and interpret this data. Moreover, the 'everyday' rheumatologist seeing the 'everyday' patient often does not contribute data to better understanding of 'everyday' clinical issues. We discuss an approach to this problem by describing a blending of a customised electronic medical record with a consortium of like-minded clinicians. We feel that this approach demonstrates the powerful potential for targeted point of care data collection in rheumatology research and patient management.

Disease-modifying anti-rheumatic drug usage, prescribing patterns and disease activity in rheumatoid arthritis patients in community-based practice.

AIMS: Our aim was to examine the spectrum of disease activity and usage of disease-modifying anti-rheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients seen over a period of 12 months in community-based rheumatology practice. METHODS: Data were prospectively collected on 1059 consecutive RA patients who attended two private, community-based rheumatology clinics from 1 May 2007 to 1 May 2008. Information on patient demographics, medication history and disease activity was collected. Life table graphs were developed to track medication retention over time. Statistical significance was determined by log-rank tests. RESULTS: One thousand and fifty-nine patients with RA were entered into the database over a 12-month period. Eight hundred and twenty-six patients (85%) were treated with single or combination conventional DMARD compared with 159 patients (15%) on a biologic DMARD either alone or in combination. Methotrexate monotherapy was the most commonly prescribed DMARD, used in 41% of patients studied. Almost half (47%) were on combination DMARD therapy. Methotrexate and tumour necrosis factor inhibitors had the highest retention rate over 12 and 30 months since first prescription. A large proportion of patients (47%) had moderate disease activity. CONCLUSION: Rates of biologic DMARD usage were similar to other studies and the predominance of methotrexate use was also in keeping with current recommendations for management of RA. There appears to be a significant unmet need for improved disease control among RA patients with moderate disease activity, which requires further investigation.

Fibrosing alveolitis in systemic sclerosis: the need for early screening and treatment.

Abnormalities in lung function occur in 70% of patients with systemic sclerosis (SSc). Fibrosing alveolitis in SSc (FASSc) is more commonly seen in the diffuse cutaneous form of SSc, particularly in the presence of antitopoisomerase antibodies (Scl70), and with the decreasing incidence of scleroderma renal crisis it is now the major cause of mortality in this patient population. Screening of patients recently diagnosed with SSc by pulmonary function tests and the performance of high resolution computed tomography when physiological abnormalities are identified has resulted in the identification of significant numbers of patients with early, asymptomatic FASSc. Whether these patients should be further investigated with a surgical lung biopsy or receive immunosuppression is unclear, because it cannot yet be reliably predicted who will develop progressive disease and the evidence to support the efficacy of treatment is not strong. The objective of the present article was to review the evidence to support the use of immunosuppressive therapy in FASSc and, based on these data, to propose an algorithm for the investigation and management of this difficult clinical problem.

Fibromyalgia. What is it and how do we treat it?

BACKGROUND: Fibromyalgia is a chronic musculoskeletal disorder that is characterised by widespread pain, tenderness at multiple anatomical sites and other clinical manifestations such as fatigue and sleep disturbance. It occurs predominantly in women and affects approximately 2-4% of people in industrialised societies. OBJECTIVE: To discuss the syndrome of fibromyalgia and effective management strategies. DISCUSSION: Fibromyalgia is a disorder of pain amplification due to increased sensitivity of the pain system. Management of simple fibromyalgia involves education regarding the nature of the problem, an exercise program and advice on stress management. However, management needs to be flexible and holistic and may involve relaxation programs, physical therapies, cognitive behavioural therapy and analgesic medication.

Longterm methotrexate use in rheumatoid arthritis: 12 year followup of 460 patients treated in community practice.

OBJECTIVE: To extend our observations on the longterm tolerability of methotrexate (MTX) and reasons for discontinuation in a cohort of 460 patients with rheumatoid arthritis (RA). METHODS: We studied all patients with RA who started MTX before June 1986 and attended the community based private practices of 6 rheumatologists in Melbourne. Information to at least April 1, 1995, or within one year of death was updated from the patient's medical records to include MTX discontinuation and reasons for discontinuation. Addition of disease modifying antirheumatic drugs (DMARD) concomitant with MTX was noted. Survival analyses based upon life table methods were used with MTX discontinuation as the observable endpoint. Three different definitions of MTX discontinuation were used (1) according to whether the patient was taking the drug at last followup irrespective of any periods of temporary discontinuation; (2) MTX discontinuation for > 3 months considered to be a treatment endpoint; and (3) addition of concomitant DMARD considered to be only partial success of MTX (as a need for additional therapy to meet treatment goals). RESULTS: At 12 years, 53% of patients were continuing to take MTX (irrespective of any periods of temporary discontinuation). If discontinuation of the drug for 3 or more months was considered a treatment termination then 38% were still taking the drug at 12 years, and if addition of concomitant DMARD was regarded as a treatment endpoint only 17% of patients were continuing MTX at 12 years. Withdrawal for gastrointestinal toxicity declined over time but the risk of other adverse effects appeared to persist over time. CONCLUSION: MTX in RA is well tolerated over the longer term, with > 50% of patients starting MTX in a community based rheumatology private practice continuing to take it 12 years later. However, a substantial number of patients had 2nd line therapies added over this time. Monitoring for toxicity should continue throughout the course of therapy.

Clinical experience with combination disease-modifying antirheumatic drug therapy with cyclosporine.

OBJECTIVES: We previously reported on the clinical use of cyclosporine (Neoral), alone or in combination with methotrexate (MTX), in the first 46 refractory rheumatoid arthritis (RA) patients treated at our centre between March 1996 and November 1997. Thirty of the 46 patients remained on cyclosporine at study completion (mean dose 2.98 mg/kg/day) with efficacy inferred by significant reductions in the prednisolone and MTX doses and creatinine maintained in an acceptable range. Early discontinuation was primarily related to non-serious side effects. METHODS: The 30 patients continuing cyclosporine were reviewed 12 months later in November 1998. Analysis included life-table techniques. RESULTS: 21 of the original 46 patients (46%) continued at a mean dose of 2.59 mg/kg/day after a mean of 23.4 months. Nine patients discontinued cyclosporine during this 12-month period: 3 due to inactive disease, 2 due to hypertension, 2 due to elevated creatinine, and 1 due to mononeuritis multiplex secondary to rheumatoid vasculitis, and 1 due to inefficacy. Patients continuing cyclosporine had a shorter disease duration (9.85 versus 15.5 years [P = 0.05]). The prednisolone dose decreased from a baseline value of 10.57 mg/day to 6.78 mg/day (P = 0.007) and the MTX dose from 15.6 mg/week to 13.1 mg/week (P = 0.02). The mean serum creatinine level increased from a baseline of 73.86 mumol/l to 85.8 mumol/l (16%). 21/30 patients on combination therapy with MTX showed no difference in discontinuation rates compared with those on cyclosporine alone. Life-table analysis showed a bimodal distribution with significantly increased cyclosporine discontinuation in the first 12 months (principally due to non-renal/hypertensive causes) versus the subsequent period. CONCLUSION: This follow-up study indicates that the use of cyclosporine in refractory RA allows a reduction in the prednisolone and MTX doses. Utilization is longer in earlier disease and is unaffected by combination with MTX. Renal function is maintained within an acceptable range. The bimodal discontinuation curve reflects early patient/physician concern about minor side effects, while renal/hypertension changes resulted in later discontinuation.

Stress system response and rheumatoid arthritis: a multilevel approach.

A growing body of research indicates that the stress system, and its interactions with the immune system, play a pivotal role in the aetiology and progression of rheumatoid arthritis (RA). The stress system has multiple levels and comprises physiological, psychological and environmental components. However, most investigations in RA that involve the stress system tend to focus on the interrelationships between neuroendocrine and immune function, and related disease activity, with little regard for the role of other aspects of stress system activation, including psychological variables. This is despite the fact that psychological stressors, and related psychological variables, are known to influence RA disease activity. This article aims to explore the multiple levels of stress system activation and how they may ultimately influence disease-related outcomes in RA. Some measurement issues of psychological stress will also be examined.

Primary care and specialist management options.

Fibromyalgia syndrome varies from being a mild intermittent disorder to one that is severe and protracted. Much of the management of the more common milder type is best done at the primary care level with the expectancy of improvement in key symptoms and a generally good prognosis. Careful appraisal of the dimensions of fibromyalgia is needed with an individualized management strategy. Critical to good outcome is the need for an understandable explanation of the mechanism of fibromyalgia and introduction to self-management skills that include exercise and techniques that minimize aberrant responses to psychosocial stressors. The primary care practitioner is well placed to identify risk factors that associate with fibromyalgia in order to minimize emotional distress accompanying illness or psychosocial predicaments. Little formal research has been done on these important areas. In contrast, there is much information on management of fibromyalgia when it presents to specialist practice. More complex and expensive approaches result in variable changes in the outcome of fibromyalgia.

The safety and efficacy of cyclosporine (Neoral) in rheumatoid arthritis.

OBJECTIVE: To assess the safety and efficacy of cyclosporine (Neoral), its steroid sparing effect, and its usefulness in combination therapy with methotrexate (MTX) in the treatment of refractory rheumatoid arthritis (RA). METHODS: All patients given cyclosporine for refractory RA over a 21 month period were included in an open, prospective study. Patients were reviewed initially fortnightly then monthly with clinical evaluation and serum creatinine. There were no restrictions on the use of other disease modifying agents, nonsteroidal antiinflammatory drugs, or corticosteroids. RESULTS: Forty-six patients with severe RA were included in the study, 33 (72%) female and 13 (28%) male, with a mean age of 54.8 years (range 20-74). At the completion of the study 30 (65%) were still taking cyclosporine at a mean dose of 2.94 mg/kg/day for a mean duration of 10.5 months. Thirteen patients discontinued cyclosporine due to side effects, most commonly gastrointestinal, and 3 due to inefficacy. Thirty-seven of the 46 patients were taking prednisolone at the start of the study at a mean dose of 10.36 mg/day, which decreased to 7.068 mg/day at the end of the study (p < 0.001). Thirty patients used cyclosporine in combination with MTX. The mean dose of MTX decreased from 15.08 to 13.67 mg/wk (p = 0.02). The mean serum creatinine increased by 13% from 74 to 83.7 micromol/l. Patients who continued therapy had a shorter duration of disease, with a mean of 9.93 years compared to 15.73 years in those who stopped therapy (p = 0.004). CONCLUSION: Cyclosporine (Neoral) was a safe and effective therapy in this population of patients with RA refractory to standard therapy. We observed a significant steroid sparing effect and have shown that combination therapy with MTX does not increase side effects and allows for a decrease in MTX dose. Renal function is not adversely affected if guidelines are followed.

Three year follow-up of body composition changes in pre-menopausal women with systemic lupus erythematosus.

OBJECTIVES: To measure the change in body composition in a pre-menopausal female systemic lupus erythematosus (SLE) population over 3 yr, and to identify predictors of change in body composition including the effects of disease-, corticosteroid (CS)- and patient-related variables. METHODS: All 55 pre-menopausal females with SLE who participated in a cross-sectional study of body composition in 1994 were invited to undergo interview, examination, medical record review, and body composition assessment by dual-energy X-ray absorptiometry (DXA). RESULTS: Twenty-eight subjects participated with a mean (S.E.M.) age of 34.4 (1.6) yr, duration of SLE of 6.8 (0.8) yr and mean (range) time to follow-up of 3.2 (2.9-3.4) yr. Seventeen subjects were exposed to CS during the study period with a mean (range) daily dose of prednisolone of 12.0 (2.8-22.9) mg. There was a significant increase in body mass index (BMI) (24.53+/-0.83 vs 25.37+/-1.04, P = 0.03) and fat-free mass (41.04+/-0.83 vs 41.53+/-0.92, P = 0.05) over the 3 yr period. Univariate analysis revealed that change in fat-free mass was significantly associated with change in total body bone mineral density (BMD) (P = 0.03). Stepwise multiple linear regression analysis revealed a significant independent association of disease activity with increases in both BMI (r2 = 0.41, P = 0.006) and fat mass (r2 = 0.39, P = 0.007), and of exercise and Modified Health Assessment Questionnaire with an increase in fat-free mass (r2 = 0.51, P = 0.007). Age at SLE diagnosis and smoking were significant independent predictors for loss of total body BMD, while CS duration was predictive of an increase in total body BMD (r2 = 0.80, P < 0.0001). CONCLUSION: In this SLE population, disease activity was predictive of deleterious changes in body composition, including increases in BMI and fat mass. Patient-related variables were also important predictors of body composition change with exercise independently predicting an increase in fat-free mass, and smoking predictive of loss of total body BMD. In contrast, CS-related variables were not found to have harmful effects on body composition. Change in fat-free mass, and not fat mass, was predictive of change in total body BMD.

Three year followup of bone mineral density change in premenopausal women with systemic lupus erythematosus.

OBJECTIVE: To measure the change in bone mineral density (BMD, g/cm2) in a female population with systemic lupus erythematosus (SLE) over 3 years, to identify factors predictive of bone loss, including the role of corticosteroid and disease related variables, and to determine the predictive value of urinary collagen crosslinks for bone loss. METHODS: All premenopausal women with SLE who participated in a cross sectional study of BMD in 1994 were invited to undergo a standardized interview, examination, medical record review, and BMD measurement of the lumbar spine and femoral neck by dual energy x-ray absorptiometry. RESULTS: Thirty-two women participated with a mean (SEM) age of 35.2 (1.5) years, duration of SLE of 7.0 (0.8) years, and mean (range) time to followup of 3.2 (2.9-3.4) years. Twenty-one subjects were exposed to corticosteroids during the study period with a mean (range) daily dose of prednisolone of 11.1 (2.8-22.9) mg. There was no significant change over the 3 years in BMD at the lumbar spine (1.161+/-0.122 vs. 1.169+/-0.022; p = 0.39) or femoral neck (0.944+/-0.023 vs. 0.955+/-0.020; p = 0.47) for the group as a whole, or when subjects were divided according to corticosteroid exposure. However, in the corticosteroid exposed subgroup, patients treated with > or = 7.5 mg/day (n = 14) lost lumbar spine BMD (-0.50%/yr) in contrast to those receiving <7.5 mg/day, who gained 1.06%/yr (p = 0.02). Furthermore, no participant receiving <7.5 mg/day lost lumbar spine BMD, while 57% of patients receiving > or =7.5 mg/day lost lumbar spine BMD (p = 0.01). In the corticosteroid exposed subgroup only, subjects who did not exercise regularly lost femoral neck BMD, while those who did gained femoral neck BMD (-0.54%/yr vs. 1.39%/yr; p = 0.02). Disease related variables (disease severity, activity, duration, functional capacity) and baseline urinary collagen crosslink levels were not predictive of BMD change. CONCLUSION: Loss of lumbar spine and femoral neck BMD in this premenopausal female SLE population was minimal for the group as a whole; however, a daily dose of prednisolone of > or =7.5 mg was associated with loss of lumbar spine BMD. In corticosteroid exposed patients, regular exercise was protective of femoral neck BMD loss. A single baseline measurement of urinary collagen crosslinks was not predictive of bone loss.

The value of clinical signs in rheumatology.

BACKGROUND: Eliciting and interpreting clinical signs is essential in diagnosing many rheumatic disorders but the sensitivity and specificity of many of these signs for any given disorder remains poorly categorised. OBJECTIVE: To discuss important clinical signs in rheumatological disease and to assess their clinical significance. DISCUSSION: Physical examination forms a vital part of the assessment of musculoskeletal and rheumatic disorders but there remains a need for studies to assess the clinical usefulness of a number of the clinical signs elicited. The patterns of presentation of groups of clinical signs are of more diagnostic significance than individual clinical signs.

Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment.

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain (P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.01% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P < 0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may in part reflect the preferential COX-2 selectivity of meloxicam, although the dose and other aspects of tolerability may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.