Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts.

OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.

A 21-year-old man with systemic-onset juvenile rheumatoid arthritis, cough and progressive dyspnea.

Primary or nonobstructive, endogenous lipoid pneumonia is a rare clinical entity usually associated with an underlying systemic disease. The present report describes a case involving a 21-year-old man with systemic-onset juvenile rheumatoid arthritis who developed primary endogenous lipoid pneumonia. Multiple treatment regimens were attempted; however, definitive management was only achieved through double-lung transplantation.

[Salvage of a leg avulsion injury by vacuum negative pressure therapy: a case report]. / Sauvetage d'une avulsion cutanée de jambe grâce à la thérapie par pression négative (VAC) : à propos d'un cas.

We present the case of a 51-year-old woman who suffered an avulsion injury of the right leg in a car accident. In a first time, the simple suture with tiny debridement of the flaps is a failure and lead to a nearly complete necrosis. In a second time, a total avulsion of the devitalized skin is realised and a circumferential VAC system is placed on the wound. Four cycles of vacuum therapy and twelve days later, a split-thickness skin mesh-graft is applied on the leg. This one has a very good take and allows the patient to stand up one month after the initial accident. This example underlines the role of cleaning and pro-budding of the negative therapy after the salvage of a leg avulsion.

[Latissimus dorsi muscular flap in cosmetic sequelae of breast cancer conserving surgery: a case report]. / Le lambeau musculaire pur de Latissimus dorsi dans les séquelles de traitement conservateur du cancer du sein: à propos d'un cas.

The correction of type II sequelae of breast conservative surgery is a difficult problem to solve. The authors present the case of a 39 years old woman, in which the repair has been carried out in two steps. A latissimus dorsi muscular flap is first realised, then a breast implant and a double-opposing Z plasty on the areola finish the reconstruction. The final result is very satisfactory in a cosmetic point of view, with a little cost in terms of scars. This difficult case presents the muscular variant of the latissimus dorsi flap, as a technique of choice in the post-quadrantectomy sequelae.

A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma.

OBJECTIVE: Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc. METHODS: Seventy-one patients with diffuse SSc of <3 years' duration were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial. Thirty-five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment. RESULTS: At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLco), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. At study completion, results slightly favored the MTX group (mean +/- SEM modified Rodnan skin score 21.4+/-2.8 in the MTX group versus 26.3+/-2.1 in the placebo group [P < 0.17]; UCLA skin score 8.8+/-1.2 in the MTX group versus 11.0+/-0.9 in the placebo group [P < 0.15]; DLco in the MTX group 75.7+/-4.6 versus 61.8+/-3.4 in the placebo group [P < 0.2]). In addition, physician global assessment results favored MTX (P < 0.035), whereas patient global assessment did not differ significantly between groups. When between-group differences for changes in scores from baseline to 12 months were examined using intent-to-treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score -4.3 in the MTX group versus 1.8 in the placebo group [P < 0.009]; UCLA score -1.2 in the MTX group versus 1.2 in the placebo group [P < 0.02]), but differences in the degree of change in the DLco and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use. Dropout rates were similar in the 2 groups. CONCLUSION: Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between-group differences were small and the power to rule out false-negative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc.

The role of life events and childhood experiences in the development of rheumatoid arthritis.

OBJECTIVE: To evaluate the role of stressful life events, including negative childhood experiences on the development of rheumatoid arthritis (RA). METHODS: Retrospective, community based, case-control study founded upon 116 cases, aged 45 to 74 years, registered with the Norfolk Arthritis Register (NOAR), who were also participants in the Norfolk European Prospective Investigation of Cancer study (EPIC). Three controls, matched for age and sex, were selected for each of the cases from among EPIC participants not suffering from arthritis. Data on adverse experiences during childhood and adulthood were available from a self-report questionnaire. The 1987 American Rheumatism Association (ARA) criteria for RA were met by 55 NOAR cases and this subset provided the primary focus for analysis. RESULTS: The number and timing of occurrence of stressful life events, as well as their subjective immediate impact, did not differ between participants who developed RA and their matched controls. Termination of pregnancy was the only specific event individually associated with a higher risk of developing RA (OR 3.74; 95% CI 1.4-9.9). Negative childhood experiences were not associated with the risk of RA. However, RA cases reported significantly slower adaptation to the effects of adverse events than controls. CONCLUSION: The results of this study do not support the hypothesis that the rate of exposure or reported impact of stressful life events and of adverse childhood experiences play an etiologic role in the development of RA.

Trauma and fibromyalgia: is there an association and what does it mean?

OBJECTIVES: The primary objective is to review current research with respect to the role of trauma in fibromyalgia (FM). A secondary objective is to hypothesize which steps need to be taken, first to determine whether such an association truly exists, and second to clarify what such an association might mean. METHODS: An extensive literature review was undertaken, including Medline from 1979 to the present. RESULTS: The strongest evidence supporting an association between trauma and FM is a recently published Israeli study in which adults with neck injuries had greater than a 10-fold increased risk of developing FM within 1 year of their injury, compared with adults with lower extremity fractures (P= .001). Several other studies provide a hypothetical construct for such an association. These include studies on (1) postinjury sleep abnormalities; (2) local injury sites as a source of chronic distant regional pain; and (3) the concept of neuroplasticity. There are, however, several primary arguments against such an association: (1) FM may not be a distinct clinical entity; (2) FM may be a psychological, rather than physical, disease; (3) the evidence supporting any association is limited and not definitive; (4) the Israeli study, itself, has some methodological limitations; and (5) other factors may be more important than the injurious event in determining chronic symptoms after an acute injury. CONCLUSIONS: Although there is some evidence supporting an association between trauma and FM, the evidence is not definitive. Further prospective studies are needed to confirm this association and to identify whether trauma has a causal role.

A placebo controlled crossover trial of subcutaneous salmon calcitonin in the treatment of patients with fibromyalgia.

The objective of this study was to evaluate the relative efficacy and tolerability of subcutaneously (s.c.) administered salmon calcitonin (sCT) in the treatment of patients with fibromyalgia. Eleven patients who fulfilled the American College of Rheumatology classification criteria for fibromyalgia were studied in a double-blind, crossover trial in which they alternatively received salmon calcitonin (100 IU s.c.) and isotonic saline (1 cc s.c.) for four weeks, with a four weeks wash-out period between the treatments. None of the 11 outcomes measures (seven analog scales, dolorimetry score, and three SIP scores) showed a significant improvement with sCT. The principal side effect observed with sCT was nausea in ten patients and erythema in four patients. These data suggest that sCT given at a dose of 100 IU daily for one month is not effective in the treatment of fibromyalgia.

Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus.

BACKGROUND: Although epidural corticosteroid injections are commonly used for sciatica, their efficacy has not been established. METHODS: In a randomized, double-blind trial, we administered up to three epidural injections of methylprednisolone acetate (80 mg in 8 ml of isotonic saline) or isotonic saline (1 ml) to 158 patients with sciatica due to a herniated nucleus pulposus. All patients had Oswestry disability scores higher than 20 (on a scale of 1 to 100, with scores of 20 or less indicating minimal disability, and higher scores greater disability). RESULTS: At three weeks, the Oswestry score had improved by a mean of -8.0 in the methylprednisolone group and -5.5 in the placebo group (95 percent confidence interval for the difference, -7.1 to 2.2). Differences in improvements between the groups were not significant, except for improvements in the finger-to-floor distance (P=0.006) and sensory deficits (P=0.03), which were greater in the methylprednisolone group. After six weeks, the only significant difference was the improvement in leg pain, which was greater in the methylprednisolone group (P=0.03). After three months, there were no significant differences between the groups. The Oswestry score had improved by a mean of -17.3 in the methylprednisolone group and -15.4 in the placebo group (95 percent confidence interval for the difference, -9.3 to 5.4). At 12 months, the cumulative probability of back surgery was 25.8 percent in the methylprednisolone group and 24.8 percent in the placebo group (P=0.90). CONCLUSIONS: Although epidural injections of methylprednisolone may afford short-term improvement in leg pain and sensory deficits in patients with sciatica due to a herniated nucleus pulposus, this treatment offers no significant functional benefit, nor does it reduce the need for surgery.

Risk factors for adult Still's disease.

OBJECTIVE: To assess risk factors for adult Still's disease (ASD). METHODS: A matched case-control study of 60 patients with ASD and 60 same sex siblings closest in age was conducted. Subjects were recruited from cohorts in Eastern Canada, Pittsburgh, and the Arthritis, Rheumatism, and Aging, Medical Information Systems (ARAMIS). A questionnaire was used to obtain data on demographic characteristics, education, income, occupation, exposure to toxic substances, stress, and medical history. RESULTS: 116 patients with ASD were identified, of which 104 participated. 86 identified same sex siblings, of which 60 replied. When compared to same sex siblings, ASD patients were similar with respect to education and occupation but had a trend to higher median income. There were no significant associations of ASD with smoking, alcohol consumption, individual toxic substances, vaccination, blood transfusion, minor or major surgery, pregnancy, or diet in the year preceding disease onset. There were no significant associations with tonsillectomy or adenoidectomy, appendectomy, asthma, hay fever, allergy shots, or pregnancy at any time preceding the onset of disease. There was a statistically nonsignificant increase in a history of exposure to coal dust [odds ratio (OR) 3.0; 95% confidence interval (CI) 0.30 to 28.84], in allergy preceding the onset of disease (OR 2.67; 95% CI 0.71 to 10.05), and in oral contraceptive use in the year preceding onset (OR 2.00; 95% CI 0.18 to 22.06). Stressful life events (OR 2.56; 95% CI 1.18 to 5.52) in the year preceding onset was significantly associated with increased risk for ASD. This positive association should be treated with caution unless confirmed by a separate study. CONCLUSION: This exploratory study of risk factors for ASD draws attention to stress as a potentially important risk factor, while likely excluding a considerable number of others.

Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia.

OBJECTIVE: To determine the prevalence and clinical correlations of an anomaly consisting of electroencephalographic (EEG) waves within the alpha frequency band during non-rapid eye movement (NREM) sleep in patients with fibromyalgia, and to evaluate the alpha NREM sleep anomaly as a predictor of response to amitriptyline. METHODS: Twenty-two patients with fibromyalgia were studied in a 2-month, double-blind, crossover trial of amitriptyline (25 mg/day) versus placebo. Nocturnal EEGs were conducted on 2 consecutive nights at baseline and at the end of each 2-month treatment period. RESULTS: Six patients (27%) had a clinical response to amitriptyline, while none responded to placebo (P = 0.02). Treatment with amitriptyline or placebo did not result in any changes in the alpha ratings during NREM sleep. Only 8 patients (36%) exhibited the alpha NREM sleep anomaly at baseline. Those patients reported more sleep difficulty, but otherwise were clinically indistinguishable from those without this EEG sleep anomaly. Lower baseline alpha NREM sleep ratings were seen in responders to amitriptyline than in nonresponders, but these differences did not reach statistical significance. CONCLUSION: The alpha NREM sleep anomaly is present in only a small proportion of patients with fibromyalgia. It does not correlate with disease severity nor is it affected by treatment with amitriptyline. A larger sample size will be needed to adequately assess the value of this sleep anomaly in predicting the response to amitriptyline.

Variability of skin scores and clinical measurements in scleroderma.

OBJECTIVE: To determine the variability of several clinical outcome measurements commonly used in scleroderma clinical trials. METHODS: Ten researchers, members of a multicenter placebo controlled trial of methotrexate in early diffuse scleroderma, studied the intraobserver and interobserver variability of variables used to assess efficacy in scleroderma trials. RESULTS: For most measures, the variability within an observer was less than that found between observers, and therefore the intraobserver reliability was better than the interobserver reliability. The reliability of the modified Rodnan skin score exceeded the Rodnan skin score. Measures with inherent interpretation such as global assessments and skin scores had more variability than easily performed measurements such as grip strength and oral opening. CONCLUSION: Some of our variability was higher than variability previously reported; this could be due to the large number of examiners and patients in our study.

A controlled study of the long-term prognosis of adult Still's disease.

PURPOSE: To assess the long-term prognosis of patients with adult Still's disease for physical and psychological disability, pain, social functioning, social support, medication use, formal education, occupation, time lost from work, and family income, and to contrast these results with those of same-sex sibling controls. PATIENTS AND METHODS: Patients were recruited from medical center-based cohorts in Pittsburgh and Eastern Canada and from a national survey of rheumatologists. Patients and same-sex sibling controls completed the Health Assessment Questionnaire for physical disability, the psychological and social function domains of the Arthritis Impact Measurement Scales, and the Interpersonal Skills Evaluation List questionnaire for social support, and replied to questions on medication use, formal education, occupation, time lost from work, and family income. RESULTS: One hundred four of 111 eligible adult Still's patients (94%) provided data. They identified 86 same-sex sibling controls, of whom 60 (70%) participated. The mean duration of adult Still's disease was 10 years. Approximately half of patients continued to require medication even 10 years after diagnosis. Patients had significantly higher levels of pain, physical disability, and psychological disability when compared with the controls. However, the levels of pain and physical disability were low compared to patients with other rheumatic diseases. Educational achievement, occupational prestige, social functioning and support, time lost from work, and family income were similar for both patients and controls. CONCLUSIONS: Despite causing disability, pain, and, in many, the need for long-term medication, patients with adult Still's disease are resilient. The disease did not interfere with educational attainment, occupational prestige, social functioning and support, time lost from work, or family income.

Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial.

OBJECTIVE: To compare the relative efficacy and tolerability of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia, and to identify predictors of response to amitriptyline and cyclobenzaprine. METHODS: Two hundred eight patients who fulfilled the American College of Rheumatology criteria for the classification of fibromyalgia were entered into a 6-month prospective, double-blind, multicenter trial and were randomized to 1 of 3 treatment groups: amitriptyline, cyclobenzaprine, or placebo. RESULTS: After 1 month, 21%, 12%, and 0% of the amitriptyline, cyclobenzaprine, and placebo patients, respectively, had significant clinical improvement (amitriptyline versus placebo P = 0.002, cyclobenzaprine versus placebo P = 0.02, amitriptyline versus cyclobenzaprine P not significant). These percentages increased to 36%, 33%, and 19%, respectively, at the 6-month assessment (P not significant). The nature and frequency of side effects reported by patients treated with amitriptyline and those reported by patients treated with cyclobenzaprine were similar. A normal Minnesota Multiphasic Personality Inventory (MMPI) profile at baseline was predictive of clinical improvement at the 1-month evaluation (odds ratio 3.3, 95% confidence interval 1.2-9.0). However, neither the MMPI profile nor any of the demographic, clinical, or functional parameters evaluated at baseline predicted long-term response. CONCLUSION: Our data confirm the short-term efficacy of amitriptyline and cyclobenzaprine in a small percentage of patients with fibromyalgia. Long-term efficacy could not be demonstrated because of a higher-than-expected placebo response. Predictors of response to these drugs could not be determined.

Osteoarthritis antirheumatic drug trials. I. Effects of standardization procedures on observer dependent outcome measures.

We designed a study to assess the effects of standardization procedures on reducing interobserver variability for outcome measures given in the current Food and Drug Administration and European League Against Rheumatism guidelines and others selected from the rheumatology literature. Over 2 days, 6 rheumatologists independently examined 6 patients with osteoarthritis (OA) in predetermined order before and after standardizing their examination techniques. An important and beneficial effect of the standardization procedure was observed on the majority of outcome variables. Such reductions in observer variability have the potential to diminish sample size requirements for OA antirheumatic drug studies.