Objective. We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized antiinterleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs).Methods. This randomized, double-blind, placebo- Results. Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (؊2.3, ؊2.4, and ؊2.3, respectively) than in the placebo group (؊1.7) at week 10 (P < 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events.Conclusion. LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though synovitis is not affected. These findings indicate the potential utility of disrupting RANK signaling to preserve skeletal integrity in inflammatory arthritis.

Objective. To determine cancer risk in a cohort of 459 rheumatoid arthritis (RA) patients treated with methotrexate in community practice. Methods. All RA patients who started methotrexate prior to June 1986 and were attending 1 of 6 rheumatologists were studied. Demographic data were matched to the State Cancer Registry to identify all malignancies (except nonmelanoma skin cancer) for 1983-1998, and to the National Death Index to identify all deaths to the end of 1999. Followup started on the date when methotrexate was started and ended either on the last confirmed date on which the patient was seen by the rheumatologist or at death. Standardized incidence ratios (SIRs) were calculated using state population cancer rates stratified by sex, age (in 5-year groups), and calendar year. Results. There were 4,145 person-years of followup (average 9.3 years). Eighty-seven malignancies were identified (14 before, 64 during, and 9 after the followup period). There was an estimated 50% excess risk of malignancy among methotrexate-exposed RA patients relative to the general population (SIR 1.5, 95% confidence interval [95% CI] 1.2-1.9), with a 3-fold increase in melanoma (SIR 3.0, 95% CI 1.2-6.2), a 5-fold increase in non-Hodgkin's lymphoma (SIR 5.1, 95% CI 2.2-10.0), and an almost 3-fold increase in lung cancer (SIR 2.9, 95% CI 1.6 -4.8). Conclusion. Compared with the general population, methotrexate-treated RA patients have an increased incidence of melanoma, non-Hodgkin's lymphoma, and lung cancer. There may be a role for regular skin cancer screening for all RA patients, particularly those receiving immunosuppressive therapy.

This study investigated the tackling technique of high-performance, collision-sport athletes and documented the relationships between tackling technique and playing experience, playing level, game-specific tackling performance, and injury in these athletes. Twenty-two national rugby league (NRL) and 17 state-based rugby league (SRL) players underwent a standardized one-on-one tackling drill in a 10 m grid. Video footage was taken from the rear, side, and front of the defending player. Tackling technique was assessed using standardized technical criteria. A large difference (ES = 1.53, p <0.05) was detected between playing groups for tackling technique, with NRL players having better tackling technique than SRL players. Players who had at least 150 NRL matches experience had a significantly greater (ES = 1.1–1.6, p <0.05) tackling technique than players who had played up to 49 NRL matches, 50–99 NRL matches, or 100–149 NRL matches. Significant relationships (p <0.05) were detected between tackling technique and the proportion of tackles missed each game (r = −0.74) and the proportion of dominant tackles effected each game (r = 0.78). There was no relationship between tackling technique and the incidence of tackling injuries. The results of this study demonstrate that playing level and playing experience influence tackling technique in high-performance, collision sport athletes, with greater playing experience and playing level associated with greater tackling technique. Furthermore, significant relationships were detected between tackling technique and the proportion of tackles missed each game (negative) and the proportion of dominant tackles effected each game (positive). Identifying the factors that limit tackling proficiency may assist playing performance, but may have minimal effect on injury prevention in high-performance, collision-sport athletes.

Focal bone erosion in CIA is attributed to cells expressing definitive features of osteoclasts, including CTR. The expression of RANKL by cells within inflamed synovium suggests a mechanism for osteoclast differentiation and activation at sites of bone erosion. Inhibitors of RANKL may represent a novel approach to treatment of bone loss in rheumatoid arthritis.

Objective: To assess the intrarater and interrater reliability among rheumatologists of a standardised protocol for measurement of shoulder movements using a gravity inclinometer. Methods: After instruction, six rheumatologists independently assessed eight movements of the shoulder, including total and glenohumeral flexion, total and glenohumeral abduction, external rotation in neutral and in abduction, internal rotation in abduction and hand behind back, in random order in six patients with shoulder pain and stiffness according to a 6×6 Latin square design using a standardised protocol. These assessments were then repeated. Analysis of variance was used to partition total variability into components of variance in order to calculate intraclass correlation coefficients (ICCs). Results: The intrarater and interrater reliability of different shoulder movements varied widely. The movement of hand behind back and total shoulder flexion yielded the highest ICC scores for both intrarater reliability (0.91 and 0.83, respectively) and interrater reliability (0.80 and 0.72, respectively). Low ICC scores were found for the movements of glenohumeral abduction, external rotation in abduction, and internal rotation in abduction (intrarater ICCs 0.35, 0.43, and 0.32, respectively), and external rotation in neutral, external rotation in abduction, and internal rotation in abduction (interrater ICCs 0.29, 0.11, and 0.06, respectively). Conclusions: The measurement of shoulder movements using a standardised protocol by rheumatologists produced variable intrarater and interrater reliability. Reasonable reliability was obtained only for the movement of hand behind back and total shoulder flexion. Shoulder pain is common in the general population, its point prevalence averages between 7% and 51% and it is known to increase with age. Restricted range of motion and shoulder pain can interfere with activities in daily life and is associated with work absenteeism and use of medical services.1-5 Many patients receive some evaluation by a family doctor, rheumatologist, orthopaedic specialist, or physical therapist. 3A physical examination is often used for both diagnosis and evaluation of treatment success in patients with shoulder pain. One aspect of physical assessment of the shoulder is the evaluation of range of motion. No "gold standard" for the measurement of shoulder range of motion is yet available. Clinical trials that have assessed the efficacy of interventions for shoulder pain have commonly used range of motion of the shoulder as a measurement tool. 6 To be of value in clinical trials or routine care its reliability (that is, the repeated administration of an instrument to a stable population yielding the same results) should be established.Multiple methods for estimating shoulder range of motion have been used in the past, including visual estimation, the two armed goniometer, or a gravity referenced goniometer. [7][8][9][10][11][12][13][14][15][16] In many of these studies the methods are poorly described and most looked at...

The beneficial effects of corticosteroid therapy in the treatment of rheumatic diseases may be offset by the occurrence of corticosteroid-related osteoporosis. This problem may be overcome by using low-dose corticosteroids; however, the dose of corticosteroids that is both efficacious and skeletal sparing is uncertain. Therefore, the aim of this study was to determine whether low-dose prednisolone treatment results in bone loss and modifies bone turnover. Nineteen patients (12 female, seven male) suffering from polymyalgia rheumatica received 10 mg or less daily, given in reducing dosage, with a range of 2.5-10 mg and an average of 6.0+/-0.2 mg daily (+/-S.E.M.). Prior to the commencement of therapy and at regular intervals during treatment, bone mineral density (BMD) using dual X-ray absorptiometry and circulating biochemical and hormonal determinants of bone turnover were measured. The patients were followed for 14.4+/-1.6 months (range 6-27). They were compared to 19 age-matched controls. Despite a mean exposure dose of 6 mg/day and disease remission, BMD decreased in the patients at the lumbar spine (2.6+/-0.8%, P < 0.01), femoral neck (2.9+/-1.5%, P=0.06), Ward's triangle (5.5+/-2.9%, P=0.06) and the trochanter (4.3+/-1.9%, P < 0.05). Total body bone mass decreased by 50+/-19 g in the first 6 months (P < 0.02), and by 39+/-30 g in the remaining 8 months of follow-up [not significant (NS)]. In the first 6 months, BMD decreased at the lumbar spine (1.7+/-0.9%, P = 0.06). From 6 months to the end of follow-up, BMD decreased by 8.5+/-3.5% at Ward's triangle (P < 0.05) and by 4.8+/-2.5% at the femoral neck (P=0.08). The fall in BMD correlated with the cumulative prednisolone dose at trabecular-rich regions (trunk r=-0.72, P < 0.001; ribs r=-0.53, P < 0.05). Bone resorption, assessed by urinary cross-laps, was 54.7% higher than controls before treatment was started (P < 0.05) and decreased by 23.5+/-7.1% in the first month of treatment when the mean prednisolone dose was 9.1 mg/day, range 5-10 (P < 0.0001). Serum osteocalcin was not suppressed by disease before treatment, decreased by 27.4+/-5.1% during the first month of treatment (P < 0.001), remained suppressed while the daily dose of prednisolone was > 5 mg/day, but returned to baseline below this dose. Serum parathyroid hormone was 19.3% lower in the patients than controls at baseline (NS), and increased by 46.1% (P < 0.05) but was no higher than controls at any time. Muscle strength increased by 20-60% (P < 0.05 to < 0.01). Prophylaxis should be considered in patients receiving > or = 5 mg/day prednisolone daily as bone loss is 2- to 3-fold expected rates. Earlier trabecular bone loss may predispose to spine and rib fracture; later cortical bone loss may predispose to hip fractures. Doses of prednisolone of < 5 mg daily may be skeletal sparing, but may not be efficacious.

Between 1987 and 1991 we performed Yttrium-90 (Y-90) silicate radionuclide synovectomies on 40 joints of 20 haemophiliac patients with haemophilic arthropathy. All were male, their mean age was 31 yr and 15 of the 20 (75%) were HIV antibody positive. The number of joint bleeds and amount of factor (VIII and IX) replacement given in the 6 months pre- and 6 and 12 months post-radionuclide synovectomy was compared. Y-90 silicate synovectomy was shown significantly to reduce both the number of joint bleeds (P < 0.001) and factor usage (P < 0.001) in the 6 months after the procedure, a result maintained up to 12 months. Depot methyl prednisolone was co-administered with Y-90 but thought unlikely to contribute to joint response beyond 6 months. The reduction of joint bleeds and factor usage was even more dramatic in the 6- to 12-month period post-synovectomy although this was not reflected by the P value (P < 0.001). The reduction of joint bleeds and factor consumption post-synovectomy was most obvious in elbow joints, although the other joints as a group showed a significant reduction. Patients who were HIV antibody positive showed considerable improvement up to 12 months post-treatment, both in reduction of joint bleeds and as a consequence factor consumption. This improvement was seen to a lesser extent in the smaller HIV-negative group.