Implementation of protocolized tight control and biological dose optimization in daily clinical practice: results of a pilot study.

OBJECTIVES: To assess the effects of education, guideline development, and individualized treatment advice on rheumatologist adherence to tight control-based treatment and biological dose optimization in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthropathy (SpA) patients. METHOD: This pilot study, among two rheumatologists and two specialized nurses in a general hospital, combined education, feedback, local guideline development, and individualized treatment advice. Outcomes (baseline and 1 year post-intervention) were the percentage of patients with a Disease Activity Score in 28 joints (DAS28) or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) measured during the visit, mean DAS28/BASDAI, and the percentage of patients using a reduced biological dose. DAS28 outcomes only applied to RA and PsA patients, BASDAI outcomes only applied to SpA patients whereas outcomes on biological dose applied to all patients. RESULTS: A total of 232 patients (67% RA, 15% PsA, 18% SpA; 58% female, mean age 56 ± 15 years) were included in the study. The percentage of DAS28 and BASDAI measurements performed increased after the intervention [DAS28 15-51%, odds ratio (OR) 3.3, 95% confidence interval (CI) 2.1-5.5; BASDAI 23-50%, OR 2.2, 95% CI 1.0-5.5], with mean DAS28 and BASDAI scores remaining similar (DAS28: mean difference 0.1, 95% CI -0.3 to 0.5; BASDAI: mean difference 0.03, 95% CI -1.8 to 1.9). Use of a reduced biological dose increased from 10% to 61% (OR 3.9, 95% CI 2.4-6.5). CONCLUSIONS: A multicomponent intervention strategy aimed at rheumatologists can lead to improved adherence to tight control-based treatment and a reduction in the use of biologicals in RA, SpA, and PsA patients.

EFSUMB minimum training requirements for rheumatologists performing musculoskeletal ultrasound.

In order to optimize and standardize musculoskeletal ultrasonography education for rheumatologists, there is a need for competency assessments addressing the required training and practical and theoretical skills. This paper describes how these competency assessments for rheumatologists were developed and what they contain.

The reliability of musculoskeletal ultrasound in the detection of cartilage abnormalities at the metacarpo-phalangeal joints.

OBJECTIVE: To assess the reliability of ultrasound (US) in detecting cartilage abnormalities at the metacarpo-phalangeal (MCP) joints in people with cartilage pathology. METHODS: Nine expert ultrasonographers initially achieved consensus on definitions and scanning protocols. They then examined the second to fifth MCP joints of the dominant hand of eight people with hand osteoarthritis (OA). US examinations were conducted in two rounds, with independent blinded evaluations of cartilage lesions. Global cartilage abnormalities were assessed by applying a dichotomous (presence/absence) score; in addition, the following lesions were evaluated using the same scoring system: loss of anechoic structure and/or thinning of the cartilage layer, and irregularities and/or loss of sharpness of at least one cartilage margin. Reliability was assessed using kappa (k) coefficients. RESULTS: Thirty-two joints were examined. Intra-observer k values ranged from 0.52 to 1 for global cartilage abnormalities; k values ranged from 0.54 to 0.94 for loss of anechoic structure and/or thinning of cartilage layer and from 0.59 to 1 for irregularities and/or loss of sharpness of at least one cartilage margin. Values of k for inter-observer reliability were 0.80 for global cartilage abnormalities, 0.62 for loss of anechoic structure and/or thinning of cartilage layer, and 0.39 for irregularities and/or loss of sharpness of at least one cartilage margin. CONCLUSION: US is a reliable imaging modality for the detection of cartilage abnormalities in patients with cartilage pathology in the MCP joints. The analysis of specific cartilage measures showed more variable results that may be improved by modifying definitions and further standardization of US techniques.

Which knee and probe position determines the final diagnosis of knee inflammation by ultrasound? Results from a European multicenter study.

PURPOSE: To investigate which knee and probe position best identifies knee inflammation and to determine a cut-off level for abnormal synovial effusion. MATERIALS AND METHODS: 18 experienced sonographers (all rheumatologists) performed ultrasound examinations of the knee joint in patients with knee symptoms and in healthy controls. Each sonographer performed longitudinal suprapatellar ultrasound scans using 9 different configurations at each knee: Midline, parapatallar lateral and parapatellar medial from midline in neutral position (0°) with and without quadriceps muscle contraction and in 30° flexion of the knee. The presence of synovial effusion (SE), the effusion measured in millimeters and the presence of synovial hypertrophy (SH) was noted. RESULTS: A total of 298 knees of 149 subjects (129 patients and 20 controls) were examined. The detection of SH is more sensitive and specific than the detection of SE, independently of the knee and probe position, for the final diagnosis of abnormality. The detection of both synovial hypertrophy and effusion in the knee in neutral position (0°) with quadriceps contraction and with the probe in the midline position, are the best independent predictors for knee abnormalities. Knee effusion > 3.2 mm measured with the probe in the lateral aspect of the knee is the best diagnostic characteristics for predicting pathological SE. CONCLUSION: The best combination for detecting SH and SE is obtained by placing the probe in the midline position with the knee in 0° with quadriceps contraction. A cut-off value for pathological effusion may be obtained in the lateral aspect of the knee.

The MCP2 and the wrist plus two extensor compartments are the most affected and responsive joints/tendons out of the US7 score in patients with rheumatoid arthritis-an observational study.

BACKGROUND: There is no international consensus on an optimal ultrasound score for monitoring of rheumatoid arthritis (RA) on patient-level yet. Our aim was to reassess the US7 score for the identification of the most frequently pathologic and responsive joint/tendon regions, to optimize it and contribute to an international consensus. Furthermore, we aimed to evaluate the impact of disease duration on the performance of the score. METHODS: RA patients were assessed at baseline and after 3 and 6 months of starting/changing DMARD therapy by the US7 score in greyscale (GS) and power Doppler (PD). The frequency of pathologic joint/tendon regions and their responsiveness to therapy were analyzed by Friedman test and Cochrane-Q test respectively, including the comparison of palmar vs. dorsal regions (chi-square test). The responsiveness of different reduced scores and the amount of information retained from the original US7 score were assessed by standardized response means (SRM)/linear regression. Analyses were also performed separately for early and established RA. RESULTS: A total of 435 patients (N = 138 early RA) were included (56.5 (SD 13.1) years old, 8.2 (9.1) years disease duration, 80% female). The dorsal wrist, palmar MCP2, extensor digitorum communis (EDC) and carpi ulnaris (ECU) tendons were most frequently affected by GS/PD synovitis/tenosynovitis (wrist: 45%/43%; MCP2: 35%/28%; EDC: 30%/11% and ECU: 25%/11%) and significantly changed within 6 months of therapy (all p ≤0.003 by GS/PD). The dorsal vs. palmar side of the wrist by GS/PD (p < 0.001) and the palmar side of the finger joints by PD (p < 0.001) were more frequently pathologic. The reduced US7 score (GS/PD: palmar MCP2, dorsal wrist, EDC and ECU, only PD: dorsal MCP2) showed therapy response (SRM 0.433) after 6 months and retained 76% of the full US7 score's information. No major differences between the groups of early and established RA could be detected. CONCLUSIONS: The wrist, MCP2, EDC, and ECU tendons were most frequently pathologic and responsive to therapy in both early and established RA and should therefore be included in a comprehensive score for monitoring RA patients on patient-level.

The relation between bone mineral density, bone turnover markers, and vitamin D status in ankylosing spondylitis patients with active disease: a cross-sectional analysis.

SUMMARY: Osteoporosis is a well recognized complication of ankylosing spondylitis (AS). This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis, and that bone turnover markers (BTM) are valuable markers to detect bone loss in AS. INTRODUCTION: The aim of this study was to elucidate the pathophysiology of AS-related osteoporosis by investigating the relation between bone mineral density (BMD), BTM, vitamin D, and clinical assessments of disease activity and physical function, as well as to identify parameters that are related to low BMD (osteopenia or osteoporosis) in AS patients with active disease. METHODS: One hundred twenty-eight consecutive Dutch AS outpatients were included in this cross-sectional study. Bath AS Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR), C-reactive protein, ASAS-endorsed disease activity score (ASDAS), Bath AS Functional Index (BASFI), bone formation markers procollagen type 1 N-terminal peptide (PINP) and osteocalcin (OC), bone resorption marker serum C-telopeptides of type I collagen (sCTX), 25-hydroxyvitamin D (25OHvitD), lumbar spine and hip BMD, and vertebral fractures were assessed. Z-scores of BTM were calculated using matched 10-year cohorts of a Dutch reference group to correct for the normal influence that age and gender have on bone turnover. RESULTS: sCTX Z-score, OC Z-score, BASDAI, age, and gender were independently related to low BMD. In addition, PINP Z-score, ESR, 25OHvitD, age, and gender were independently related to sCTX and/or OC Z-score. CONCLUSIONS: This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis. Furthermore, sCTX and OC Z-scores seem to be valuable markers to detect bone loss in AS patients in daily clinical practice where BMD of the lumbar spine, measured by DXA, may be overestimated due to osteoproliferation in patients with advanced AS.

Reliability of ultrasonography in detecting shoulder disease in patients with rheumatoid arthritis.

OBJECTIVE: To assess the intra and interobserver reproducibility of musculoskeletal ultrasonography (US) among rheumatologists in detecting destructive and inflammatory shoulder abnormalities in patients with rheumatoid arthritis (RA) and to determine the overall agreement between US and MRI. METHODS: A total of 14 observers examined 5 patients in 2 rounds independently and blindly of each other. US results were compared with MRI. Overall agreement of all findings, of positive findings on MRI, as well as intra and interobserver reliabilities, were calculated. RESULTS: Overall agreement between US and MRI was seen in 79% with regard to humeral head erosions (HHE), in 64% with regard to posterior recess synovitis (PRS), in 31% with regard to axillary recess synovitis (ARS), in 64% with regard to bursitis, in 50% with regard to biceps tenosynovitis (BT), and in 84% for complete cuff tear (CCT). Intraobserver and interobserver kappa was 0.69 and 0.43 for HHE, 0.29 and 0.49 for PRS, 0.57 and 1.00 for ARS, -0.17 and 0.51 for bursitis, 0.17 and 0.46 for BT and 0.52 and 0.6 for CCT, respectively. The intraobserver and interobserver kappa for power Doppler (PD) was 0.90 and 0.70 for glenohumeral signals and 0.60 and 0.51 for bursal signals, respectively. CONCLUSIONS: US is a reliable imaging technique for most shoulder pathology in RA especially with regard to PD. Standardisation of scanning technique and definitions of particular lesions may further enhance the reliability of US investigation of the shoulder.

Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study.

OBJECTIVES: Everolimus, a proliferation signal inhibitor with disease-modifying properties, may be useful in treating rheumatoid arthritis (RA). This proof-of-concept study assessed efficacy and safety of everolimus in combination with methotrexate (MTX) in patients with refractory RA. METHODS: A multi-centre, randomised, double-blind, placebo-controlled trial was performed in 121 patients with active RA receiving MTX. Patients were randomised to receive everolimus (6 mg/day) or placebo. The primary endpoint was the American College of Rheumatology criteria for a 20% improvement in measures of disease activity (ACR20) at 12 weeks. RESULTS: There was a rapid onset of action and at 12 weeks the ACR20 response rate was significantly higher in the everolimus group (36.1%) than in the placebo group (16.7%; p = 0.022). Improvements from baseline in tender and swollen joint counts, patient's assessment of pain, and patient's and physician's global assessment of disease activity were significantly greater after treatment with everolimus. The most common adverse events (AEs) in the everolimus group were gastrointestinal (52.5% vs 31.7% in the placebo group), skin (29.5% vs 8.3%), and nervous system disorders (21.3% vs 10.0%); AEs leading to treatment discontinuation were reported for 16.4% and 10.0% of patients, respectively. Changes in haematological parameters, liver function tests, and lipid levels occurred more frequently with everolimus compared to placebo, but were mild and reversible. CONCLUSIONS: The study indicates that everolimus plus MTX provides clinical benefit with an acceptable safety and tolerability profile. It may offer a new treatment option in RA patients with inadequate response to MTX.

Recommendations for the content and conduct of European League Against Rheumatism (EULAR) musculoskeletal ultrasound courses.

OBJECTIVE: To develop education guidelines for the conduct of future European League Against Rheumatism (EULAR) musculoskeletal ultrasound (MSUS) courses. METHODS: We undertook a consensus-based, iterative process using two consecutive questionnaires sent to 29 senior ultrasonographer rheumatologists who comprised the faculty of the 14th EULAR ultrasound course (June 2007). The first questionnaire encompassed the following issues: type of MSUS educational model; course timing; course curriculum; course duration; number of participants per teacher in practical sessions; time spent on hands-on sessions; and the requirements and/or restrictions for attendance at the courses. The second questionnaire consisted of questions related to areas where consensus had not been achieved in the first questionnaire, and to the topics and pathologies to be assigned to different educational levels. RESULTS: The response rate was 82.7% from the first questionnaire and 87.5% from the second questionnaire. The respondents were from 11 European countries. The group consensus on guidelines and curriculum was for a three-level education model (basic, intermediate and advanced) with timing and location related to the annual EULAR Congresses. The topics and pathologies to be included in each course were agreed. The course duration will be 20 h. There will be a maximum of six participants per teacher and 50-60% of total time will be spent on practical sessions. There was also agreement on prerequisite experience before attending the intermediate and advanced courses. CONCLUSION: We have developed European agreed guidelines for the content and conduct of EULAR ultrasound courses, which may also be recommended to national and local MSUS training programmes.

Systematic review of trends in prophylaxis of corticosteroid-induced osteoporosis: the need for standard audit guidelines.

UNLABELLED: Corticosteroid-induced osteoporosis (CIOP) is currently undertreated. Systematic review of the literature revealed that the percentage of patients treated adequately is dependent on study quality. Therefore, it remains unknown whether adherence to the guidelines is really so poor. Five major quality criteria provide the standard for future studies on this scope. INTRODUCTION: It has recently been stated that the degree of prophylaxis of corticosteroid-induced osteoporosis (CIOP) is low and effort should be put into determining reasons for non-prescribing of preventive agents. The aim of this study was to identify: how many studies adequately audit the prevalent guideline; the longitudinal trends in prevention of CIOP; which patient groups appear to be most undertreated; and which intervention strategies are effective. METHODS: We performed a comprehensive search of MEDLINE and systematically recorded the outcomes and quality of published studies, using five major criteria. RESULTS: Twenty-four studies were included in the analysis. The quality of the included studies was poor (31%) or moderate (37%). There was a longitudinal increase in quality of the studies and percentage of prevention. Multivariable linear regression showed that the quality of the study was the only independent predictor of the prevention rate reported in the study. CONCLUSIONS: The results show undertreatment of CIOP might be due to insufficient quality of the studies rather than poor practice or failure to recognise the right patients. Future interventions should comply with five major quality criteria, and a multifaceted approach is required in order to make an impact on the underprescribing of CIOP prophylaxis.

Amendment of the OMERACT ultrasound definitions of joints' features in healthy children when using the DOPPLER technique.

BACKGROUND: Recently preliminary ultrasonography (US) definitions, in B mode, for normal components of pediatric joints have been developed by the OMERACT US group. The aim of the current study was to include Doppler findings in the evaluation and definition of normal joint features that can be visualized in healthy children at different age groups. METHODS: A multistep approach was used. Firstly, new additional definitions of joint components were proposed during an expert meeting. In the second step, these definitions, along with the preliminary B-mode-US definitions, were tested for feasibility in an exercise in healthy children at different age groups. In the last step, a larger panel of US experts were invited to join a web-based consensus process in order to approve the developed definitions using the Delphi methodology. A Likert scale of 1-5 was used to assess agreement. RESULTS: Physiological vascularity and fat pad tissue were identified and tested as two additional joint components in healthy children. Since physiological vascularity changes over the time in the growing skeleton, the final definition of Doppler findings comprised separate statements instead of a single full definition. A total of seven statements was developed and included in a written Delphi questionnaire to define and validate the new components. The final definitions for fat pad and physiological vascularity agreed by the group of experts reached 92.9% and 100% agreement respectively in a web survey. CONCLUSION: The inclusion of these two additional joints components which are linked to detection of Doppler signal in pediatric healthy joints will improve the identification of abnormalities in children with joint pathologies.

The role of PET/CT in Cogan's syndrome.

We report on the case of a 60-year-old woman with complaints of fatigue, coughing, anorexia, atypical chest pain, recurrent fever, and also ear pain and hearing loss. A test for anti-neutrophil cytoplasmic antibody (ANCA) was myeloperoxidase positive with p-ANCA specificity. Laboratory acute phase parameters were increased. A 2-deoxy-2-[(18)F]fluoro-D: -glucose positron emission tomography/computed tomography investigation showed pathological uptake in the aorta ascendens, with no other involvement of the large vessels. After therapy with methylprednisolon intravenously and later prednisolon orally with methothrexate, her general condition and hearing loss improved both subjectively and objectively. "Atypical" Cogan's syndrome was diagnosed on the basis of sensorineural deafness with improvement on steroids and large-vessel vasculitis of the aortic arch.

[Alendronate more effective than alfacalcidol in the prevention of osteoporosis in patients with rheumatic disease who are starting glucocorticoid therapy]. / Alendroninezuur effectiever dan alfacalcidol voor preventie van osteoporose bij patiënten met een reumatische ziekte die starten met glucocorticoïdtherapie.

OBJECTIVE: To compare the effects of alendronate and alfacalcidol in the prevention ofglucocorticoid-related osteoporosis in patients with a rheumatic disease. DESIGN: Randomised, double-blind, double-placebo clinical trial (www. clinicaltrials.gov; number: NCT00138983). METHODS: A total of 201 patients with rheumatic disease who were starting glucocorticoid treatment at a daily dose that was equivalent to at least 7.5 mg of prednisone were randomised to alendronate (10 mg) and a placebo capsule ofalfacalcidol daily (n = 100) or alfacalcidol (1 microg) and a placebo tablet ofalendronate daily (n = 101) for 18 months. Primary outcome was change in lumbar spine bone mineral density at 18 months. The main secondary outcome was the incidence of morphometrically confirmed vertebral deformities. RESULTS: Overall, 163 patients completed the study. The bone mineral density of the lumbar spine increased by 2.1% (95% CI: 1.1-3.1) in the alendronate group and decreased by 1.9% (95% CI: -3.I--0.7) in the alfacalcidol group. At 18 months the mean difference in change in bone mineral density between the two groups was 4.0% (95% CI: 2.4-5-5). Three patients in the alendronate group had a new vertebral deformity, compared with 8 patients in the alfacalcidol group, including 5 symptomatic vertebral fractures in 3 patients; the hazard ratio was 0.4 (95% CI: 0.1-1.4). CONCLUSION: Alendronate was more effective than alfacalcidol in preventing glucocorticoid-induced bone loss during this 18-month trial in patients with rheumatic diseases who were starting glucocorticoid treatment.

Back pain and condensation of the eighth thoracic vertebra: is it always a metastatic disease?

The case of a 55-year-old female patient with discogenic sclerosis of a thoracic vertebra is illuminated by a radiologic vignette. The clinical and radiologic features, including those of conventional radiography, computed tomography scanning and magnetic resonance imaging are hallmarked in this portrait. The importance of differentiating the condition particularly from infectious spondylodiscitis and metastatic disease to the spine is underpinned.

Educational recommendations for the conduct, content and format of EULAR musculoskeletal ultrasound Teaching the Teachers Courses.

OBJECTIVE: To produce educational guidelines for the conduct, content and format of theoretical and practical teaching at EULAR musculoskeletal ultrasound (MSUS) Teaching the Teachers (TTT) Courses. METHODS: A Delphi-based procedure with 24 recommendations covering five main areas (Duration and place of the course; Faculty members; Content of the course; Evaluation of the teaching skills; TTT competency assessment) was distributed among a group of experts involved in MSUS teaching, in addition to an advisory educational expert being present. Consensus for each recommendation was considered achieved when the percentage of agreement was >75%. RESULTS: 21 of 24 invited participants responded to the first Delphi questionnaire (88% response rate). All 21 participants also responded to the second round. Agreement on 19 statements was obtained after two rounds. CONCLUSIONS: This project has led to the development of guidelines for the conduct, content and format of teaching at the EULAR MSUS TTT Courses that are organised annually, with the aim of training future teachers of EULAR MSUS Courses, EULAR Endorsed MSUS Courses, as well as national and local MSUS Courses. The presented work gives indications on how to homogenise the teaching at the MSUS TTT Courses, thus resolving current discrepancies in the field.

Risk assessment for osteoporosis by quantitative ultrasound of the heel in ankylosing spondylitis.

OBJECTIVE: The aim of this cross-sectional cohort study is to assess the potential of quantitative ultrasound (QUS) of the calcaneus in pre-screening for vertebral/non-vertebral fractures, and in discriminating osteoporotic from normal bone density in patients with ankylosing spondylitis (AS); a second objective is to determine the prevalence of osteoporosis using dual-energy X-ray absorptiometry (DEXA) in this patient group. RESULTS: Included are 50 consecutive AS patients with no history of osteoporosis: mean (SD) age 52 (12) yrs, range 26-75 yr; female/male ratio 15/35. The mean (SD) DEXA T score in the lumbar spine (AP view) was -0.82 (1.73), mean (SD) DEXA T score in femoral neck -1.46 (1.12). The mean (SD) calcaneal QUS T score was -0.73 (0.95). In our population of AS patients the prevalence of femoral neck osteoporosis according to the WHO definition (DEXA T < -2.5) was 20%. Osteoporosis criteria were met at the femoral neck in 10 (20%) patients, and 7 of them (70%) were correctly diagnosed using QUS, with T < -1.0 as cut-off value; normal bone density at the femoral neck was found in 15 AS patients (30%), yet in 2 of them the calcaneal QUS T was < -1.0. In AS the 20% pretest probability of having femoral neck osteoporosis increased using calcaneal QUS, with a cut-off level T < -1.0 (70% sensitivity, 68% specificity), and then rose to 35% as the predictive value of a positive test, yielding a net result of QUS testing of +15%. The predictive value of a negative QUS test result was 90%, which makes QUS applicable to exclude severe osteoporosis. Vertebral and/or non-vertebral fractures occurred in 12 out of 50 AS patients (24%); 5 of them (10%) were associated with osteoporosis as defined by WHO criteria measured via DEXA. CONCLUSION: The performance of QUS is similar to DEXA in finding patients with osteoporosis-associated fractures: the sensitivity of QUS T < -1.0 in finding the fracture is 80%, and the sensitivity of femoral neck DEXA T < -2.5 in finding fractured patients is 60%. We conclude that both osteoporosis and fractures are common sequelae in AS. Calcaneal QUS offers a promising approach to screen for osteoporosis, and may be applied to exclude osteoporosis-associated high fracture risk in AS.

Thalidomide Celgene Corp.

Thalidomide, in development by Celgene, inhibits the effects of elevated TNFalpha and may consequently be of use in a range of diseases including cachexia, bacterial meningitis, rheumatoid arthritis, septic shock, AIDS, tuberculosis, multiple sclerosis, ulcerative colitis, graft-versus-host disease and systemic lupus erythematosus. In July 1998, Celgene received clearance from the US FDA to market and sell Thalomid (thalidomide) for the treatment of erythema nodosum leprosum (a severe and debilitating condition associated with leprosy) [291919], following a recommendation for approval by the FDA advisory committee in September 1997 [261846,263970]. In that same month, Celgene filed an IND for the treatment of the chronic autoimmune disorders Behcet's disease, and aphthosis [264366]. The trial will be conducted by investigators at the Mayo Clinic and Bowman Gray School of Medicine. It will be divided into two phases, the first phase lasting 4 weeks in which patients will receive 100 mg thalidomide or placebo, and a second open-label phase which will call back all patients to receive the same dose of thalidomide over a 24-week period. It will be determined whether the drug significantly reduces existing ulcerations and inhibits the formation of new lesions. Positive results of a National Institute of Allergy and Infectious Diseases trial for aphthous ulceration of the mouth in HIV-infected patients prompted Celgene to commence a pivotal trial for the same indication. A total of 84 patients will be randomized to 100 mg, 200 mg or 400 mg thalidomide/day for 4 weeks. Patients achieving a full response after 4 weeks will be re-randomized on 100 mg thalidomide or placebo for up to another year [248356]. The company has also completed the pivotal phase III trial for AIDS-related cachexia [225437]. Results from a pivotal phase II/III trial showed that the drug significantly increased body weight in AIDS patients, but also increased viral load initially. A total of 99 patients, who had lost more than 10% of their body weight due to HIV infection, received either 100 or 200 mg/day of thalidomide or placebo orally for 8 weeks. Although there was a significant increase in body weight associated with the 100 mg dose (p = 0.025), there was no difference in body weight changes between patients treated with 200 mg doses and those on placebo. There was a 55% dropout rate at the higher dose due to side-effects such as somnolence, rash, neutropenia, neuropathy and dizziness. Viral load was significantly increased after 4 weeks of treatment. However, there was no further increase in viral load at 8 weeks, and patients were not receiving triple combination antiviral therapy [243943]. In April 1996, Celgene initiated a phase II trial of thalidomide in London for the treatment of chronic intractable diarrhea in HIV positive patients. The double-blind, placebo-controlled trial will involve up to 120 patients, aged 18 to 65 inclusive, at three centers for 28 days of therapy; those on drugs will be orally dosed with 100 mg of thalidomide daily at bedtime. The primary endpoint is reduction in the occurrence of diarrhea [205006,206218]. The trial will be conducted in the US, the UK and Mexico [210069]. The company expanded its clinical trial program in June 1996, for use of thalidomide in graft versus host disease and AIDS complications, such as debilitating ulcers of the digestive system [212461]. A phase II trial for the treatment of cachexia in cancer patients was carried out at St George's Hospital, London. Ten patients received thalidomide (100 mg) orally for 8 weeks and ten received placebo. The study was structured to determine the ability of thalidomide to reduce or stabilize the symptoms of cachexia. Quality of life and levels of disease markers will also be assessed. Results showed that after a 3-week treatment period, patients who received thalidomide gained an average 4.5% in overall body weight versus 0.9% with placebo [190161]. Results from a 65 patient multicenter phase II/III trial for cachexia are still awaited [221227]. Celgene is also conducting a double-blind, placebo-controlled pivotal trial for the treatment of rheumatoid arthritis at New York University's Hospital of Joint Diseases. Levels of TNFalpha are increased in patients with rheumatoid arthritis. Indicators for the trial will be joint swelling and pain and levels of serological markers [177618]. A separate study is being conducted by the US National Institute for Allergy and Infectious Diseases, of thalidomide in combination with Chiron's IL-2 for the treatment of HIV infection [192218]. In vitro evidence suggests that thalidomide can inhibit the replication of HIV type 1 [169245]. In addition to the associated patent, WO-09214455, which discloses the use of thalidomide in TNF-related diseases, another Celgene patent, US-05463063, discloses a scaleable process to make high purity thalidomide [194937].

Severe neutropenia due to naproxen therapy in rheumatoid arthritis: a case report and review of literature.

Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the joints and is often treated with non-steroidal anti-inflammatory drugs (NSAIDs) on demand and disease-modifying antirheumatic drugs (DMARDs), with a relatively low risk of side effects. Although an infrequent side effect, neutropenia has been described as a sequel of NSAIDs. We report a case of neutropenia proven (by rechallenge) to be due to naproxen therapy. The literature on neutropenia during treatment with NSAIDs and DMARDs is briefly reviewed.

Sweet's syndrome.

Two women are reported both of whom exhibited, after an episode of an upper respiratory tract infection, painful, erythematous, sharply demarcated plaque-like lesions on the extremities, in combination with fever. In addition, one woman also had acute polyarthritis and episcleritis. The histological features of the lesions showed a perivascular neutrophilic infiltration in the dermis without signs of vasculitis, pathognomonic of Sweet's syndrome. One patient was successfully treated, initially with aspirin and later prednisone, the other with potassium iodide. Recognition of this syndrome is important in view of the dramatic response to treatment, particularly corticosteroids.