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To study the specific features of joint ultrasound readings in rheumatoid arthritis (RA) in relation to its duration. A total of 162 patients (mean age, 43.54±11.1 years) with a mean RA duration of 3.22±3.13 years were examined. Gray-scale ultrasound study (USS) of hand and ankle joints was performed using color Doppler energy imaging. Group 1 included 78 patients with a RA duration of less than 2 years; Group 2 consisted of 84 patients with a RA duration of more than 2 years. Joint USS diagnosed osteochondral erosions twice more frequently than conventional radiography. 82% of the patients with RA were found to have synovitis; 77% had thickening of the synovial membrane (SM) with hypervascularization, the vascularization intensity scores of 2-3 being predominant; and 54% had tenosynovitis of the carpal extensor tendon. Effusion into the joint cavity, SM hypervascularization scores of 2-3, and tenosynovitis were most common in Group 1. SM thickening and osteochondral erosions were prevalent in Group 2. Цель исследования. Изучить особенности ультразвуковых показателей суставов при ревматоидном артрите (РА) в зависимости от длительности заболевания. Материалы и методы. Обследованы 162 пациента, средний возраст 43,54±11,1 года, средняя продолжительность РА 3,22±3,13 года. Ультразвуковое исследование (УЗИ) суставов кистей и лучезапястных суставов выполняли в режиме серой шкалы и при использовании цветового и энергетического допплеровского исследования. В 1-ю группу включили 78 пациентов с длительностью РА до 2 лет, во 2-ю группу - 84 больных с длительностью РА более 2 лет. Результаты. У обследованных больных РА по сравнению со стандартным методом рентгенографии при УЗИ суставов в 2 раза чаще диагностировались костно-хрящевые эрозии. У 82% пациентов с РА установлен синовит, у 77% - утолщение синовиальной оболочки (СО) с гиперваскуляризацией, интенсивность васкуляризации преобладала с оценкой 2-3 балла, у 54% - теносиновиты сухожилий разгибателей кисти. В 1-й группе больных РА наиболее часто встречались выпот в полость сустава, гиперваскуляризация СО с оценкой 2-3 балла и теносиновиты. Во 2-й группе больных РА преобладали утолщение СО и наличие костно-хрящевых эрозий. Заключение. У пациентов с длительностью РА до 2 лет при УЗИ суставов преобладают процессы ангиогенеза и воспаления, а у пациентов с длительностью РА более 2 лет - пролиферативно-деструктивные процессы. Выявление преобладания патофизиологических процессов у каждого конкретного пациента с РА позволит индивидуализировать терапию и улучшить прогноз заболевания. Цель исследования. Изучить особенности ультразвуковых показателей суставов при ревматоидном артрите (РА) в зависимости от длительности заболевания. Материалы и методы. Обследованы 162 пациента, средний возраст 43,54±11,1 года, средняя продолжительность РА 3,22±3,13 года. Ультразвуковое исследование (УЗИ) суставов кистей и лучезапястных суставов выполняли в режиме серой шкалы и при использовании цветового и энергетического допплеровского исследования. В 1-ю группу включили 78 пациентов с длительностью РА до 2 лет, во 2-ю группу — 84 больных с длительностью РА более 2 лет. Результаты. У обследованных больных РА по сравнению со стандартным методом рентгенографии при УЗИ суставов в 2 раза чаще диагностировались костно-хрящевые эрозии. У 82% пациентов с РА установлен синовит, у 77% — утолщение синовиальной оболочки (СО) с гиперваскуляризацией, интенсивность васкуляризации преобладала с оценкой 2—3 балла, у 54% — теносиновиты сухожилий разгибателей кисти. В 1-й группе больных РА наиболее часто встречались выпот в полость сустава, гиперваскуляризация СО с оценкой 2—3 балла и теносиновиты. Во 2-й группе больных РА преобладали утолщение СО и наличие костно-хрящевых эрозий. Заключение. У пациентов с длительностью РА до 2 лет при УЗИ суставов преобладают процессы ангиогенеза и воспаления, а у пациентов с длительностью РА более 2 лет — пролиферативно-деструктивные процессы. Выявление преобладания патофизиологических процессов у каждого конкретного пациента с РА позволит индивидуализировать терапию и улучшить прогноз заболевания.

Joint USS revealed that angiogenesis and inflammation were dominant in the patients with a RA duration of less than 2 years and the proliferative-destructive processes were prevalent in those with a RA duration of more than 2 years. Identifying the predominance of pathophysiological processes in each specific patient with RA will be able to individualize therapy and to improve the prognosis of the disease.

The aim of this study was to evaluate the clinical and radiographic success of arthrolysis surgery and the risk of progression of osteoarthrosis at the ankle joint. In a retrospective clinical and radiological study, with a minimum follow-up of 24 months, the pain level and quality of living were evaluated. Following arthrolysis of the ankle joint, 16% of patients required ankle fusion within 2 years. Women had a higher quality-of-life in terms of Foot Function Index. Younger patients scored higher in both quality-of-life and function scores. Radiographic osteoarthrotic changes and the specific follow-up interval did not correlate with clinical outcome.

Fewer than 20% of patients required ankle fusion. Female gender and young age had a positive impact. Preoperative radiography and the postsurgical interval are poorly predictive for the progression of osteoarthrosis.

This study aimed to explore whether preoperative angiotensin II type 2 receptor (AT A total of 220 patients who had undergone unilateral TKA were enrolled from October 2019 to January 2020. Quantitative sensory testing (QST), PainDETECT questionnaires (PD-Q), the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), the hospital anxiety and depression (HAD) and serum AT The prevalence of CPSP was 13.6% (n = 30). Multiple logistic regression analysis showed that patients with higher AT

Our findings suggest that patients with higher preoperative AT

The aim of this study was to compare the early repair response of cartilage defects in trochlea (TR) and medial femoral condyle (MFC) at 2-3 weeks after bone marrow stimulation. Bilateral full-thickness cartilage defects were generated in central trochlear groove and MFC of skeletally mature rabbits. Four subchondral perforations were made on each defect, either by microfracture to 2 mm deep, or by drilling to 2 mm or 6 mm deep. Rabbits were sacrificed either on Day 14 post-operatively or on Day 21. Defects were analyzed by histology, stereology, histomorphometry and micro-computed tomography (CT). Intact femurs (N = 4) served as controls. Stromal cell density recruitment was similar in all defects, irrespective of defect location and surgical techniques used. There was a robust appearance of chondrocytes at Day 21 in TR defects with significantly higher volume fraction of chondrocytes in TR compared to MFC (P = 0.013). Chondrogenic foci were observed in marrow penetrating holes, with a significantly higher frequency and larger foci in TR vs MFC defects at Day 21 (P = 0.043 and P = 0.0014, respectively). Micro-CT analysis showed that deep drilling elicited significantly more mineralized bone fill compared to shallower perforations at 2 and 3 weeks repair (all at P ≤ 0.0008).

Bone marrow stimulation induced greater chondrogenesis in TR vs MFC defects in adult rabbits, with more chondrocytes and larger chondrogenic foci appearing in TR vs MFC on Day 21 post-operation.

To assess the incidence of abnormal internal rotation of the talus in the axial plane in patients with varus ankle osteoarthritis, and to determine whether this incidence differs from the severity of varus ankle osteoarthritis (moderate versus severe). We retrospectively evaluated weight-bearing computed tomography (CT) and plain radiographs of 52 ankles with no abnormalities (control group) and 96 ankles with varus osteoarthritis (varus-OA group), which were further stratified into a moderate-OA subgroup (50 ankles) and a severe-OA subgroup (46 ankles). A new radiographic parameter on weight-bearing CT, the talus rotation ratio, was used to assess the rotation of the talus in the axial plane. The normal range of the talus rotation ratio was defined as the 95% prediction interval for talus rotation ratio values in the control group. Abnormal internal rotation of the talus was defined for talus rotation ratio values above the normal range. We determined the incidence of abnormal internal rotation of the talus in the varus-OA group, moderate-OA subgroup, and severe-OA subgroup. In the varus-OA group, the incidence of abnormal internal rotation of the talus was 45% (43 ankles), which corresponded to an incidence of 32% (16 ankles) in the moderate-OA subgroup and 59% (27 ankles) in the severe-OA subgroup (p = 0.013).

Our study demonstrates that abnormal internal rotation of the talus occurs in patients with varus ankle osteoarthritis, and is more frequently noted in severe than in moderate varus ankle osteoarthritis.

Family factors and emotional functioning can play an important role in the ability of adolescents with juvenile primary fibromyalgia syndrome (JPFS) to cope with their condition and function in their everyday lives. The primary objectives of this study were to determine 1) whether adolescents with JPFS and their caregivers differed from healthy age-matched comparison peers and their caregivers in terms of emotional distress and functional impairment; 2) whether there were any differences in the family environment of adolescents with JPFS compared with healthy comparison peers; and 3) which individual-, caregiver-, and family-level variables were associated with functional impairment in adolescents with JPFS. Participants were 47 adolescents with JPFS recruited from a pediatric rheumatology clinic and 46 comparison peers without chronic illness matched for age, sex, and race. Participants and their caregivers (all mothers) completed a battery of standardized measures administered in their homes. Adolescents with JPFS had greater internalizing and externalizing symptoms than healthy comparison peers. Mothers of adolescents with JPFS reported twice as many pain conditions and significantly greater depressive symptoms than mothers of comparison peers. The JPFS group also had poorer overall family functioning and more conflicted family relationships. In adolescents with JPFS, maternal pain history was associated with significantly higher functional impairment.

Increased distress and chronic pain are evident in families of adolescents with JPFS, and family relationships are also impacted. Implications for child functional impairment and the need for inclusion of caregivers in treatment are discussed.

The aim of this study was to examine the quality of life (QoL) profiles of patients with early rheumatoid arthritis (RA) and to relate these to disease and impairment variables as indicated, respectively, by erythrocyte sedimentation rate (ESR) and by tender joint count (Ritchie Articular Index), fatigue, and pain. The present study uses part of the European Research on Incapacitating Disease and Social Support data of 573 patients with recently diagnosed RA (268 from the Netherlands, 216 from Norway, and 89 from France). A series of clinical and psychosocial data were collected on 4 (the Netherlands, France) and 3 (Norway) occasions, with 1-year intervals separating the waves of data collection. Of the disease activity (ESR) and impairment variables (tender joint count, fatigue, pain), fatigue was identified as the consequence of disease that differentiated best on a series of QoL aspects such as disability, psychological well-being, social support, and "overall evaluation of health." Next came pain and tender joint count, and ESR showed by far the least differentiating ability. A principal-component analysis on the QoL measures used in this study yielded one general factor measuring "overall QoL." After rotation, two separate factors were encountered, one referring to the physical domain and the other to the psychological and social domains of QoL. Again, the QoL of RA patients experiencing much fatigue appeared to decline the most.

Because of the highly variable nature of RA, impairments, activities of daily living (ADL) and instrumental ADL restrictions, and psychosocial distress can vary erratically. In particular, "fatigue" as measured over a period of 2 to 3 years distinguished best among RA patients as shown by their QoL profiles. Although the physical domain was most affected, the significant effect of RA on the psychosocial domain should not be underestimated.

The fibula is only indirectly involved in the composition of the human knee joint and has therefore been neglected in the research on knee osteoarthritis. Nonuniform settlement of the proximal tibia plateau is clinically defined as when the height of the medial tibial plateau is lower than that of the lateral side in medial compartment knee osteoarthritis (KOA). The non-uniform settlement of the proximal tibia plateau may be caused by fibular support on the lateral side. Orthopedic surgeons practice partial fibulectomy based on the clinical manifestation of nonuniform settlement, and this technique has been shown to reduce pain and improve function in patients with medial compartment KOA. However, this hypothesis of the mechanism of nonuniform settlement lacks an anatomical basis. The P45 polyester plastination technique was used to prepare sections of the proximal tibiofibular joint to investigate the distribution of the bone trabeculae in the region of the lateral tibial plateau. There was uneven distribution of trabeculae in the lateral condyle of the tibia and the head and neck of the fibula. The fibula and the posterolateral cortex of the shaft of the tibia united to form an arch beam via the tibiofibular joint. Many thick, dense trabeculae were present in a longitudinal direction above the tibiofibular arch.

The fibula supports the lateral tibial plateau, and the trabeculae were concentrated above the tibiofibular arch.

(1) To investigate the psychometric properties of a patient-reported numerical rating scale (NRS) for evaluating functional disability in osteoarthritis (OA), in comparison with the WOMAC function scale and with a physician-reported function NRS; (2) to estimate the patient acceptable symptomatic state (PASS) and the minimal clinically important improvement (MCII) values for treatment with non-steroidal anti-inflammatory drugs (NSAIDs). Data were extracted from a prospective multicentre study involving 1186 patients with knee or hip OA. The psychometric properties assessed were feasibility: percentage of responses, floor and ceiling effects; construct validity by examining the correlations with classically used OA outcomes measures; responsiveness by comparing the results of before and 1 month after treatment with NSAIDs using standardised response mean (SRM) and effect size (ES). The MCII and PASS values of each function scale were calculated by an anchoring method. No floor or ceiling effect was observed. High correlations were observed as expected between the patient NRS and WOMAC function, pain visual analogue scale and patient global assessment. The responsiveness was moderate to large, with SRM and ES ranging from 0.6 (hip OA) to 0.9 (knee OA) and higher than that of the WOMAC function scale. The PASS was close to 3 for the NRS scales. The MCII appears to be the change that makes the OA functional disability decrease from baseline to the PASS.

The patient-reported NRS demonstrated good psychometric properties, similar to the WOMAC function scale and can be regarded as a promising tool in therapeutic evaluation and decision-making in OA.

We explore the concept of "untimely diagnosis," where the onset of a long-term condition occurs at a life stage which does not conform to traditional expectations, focusing on two conditions (asthma and arthritis) typically associated with a particular life stage (childhood and older adulthood, respectively). Previous literature has focused on the meaning of chronic illness in terms of life history, and the biographical lens has been used in various ways to make sense of the experience. Less attention has been paid to the condition onset when it seems dissonant with chronological age. Secondary analysis of two qualitative data sets (total 58 interviews) exploring the experiences of people with adult-onset asthma and young people diagnosed with arthritis. Data from the original interview transcripts relating to diagnosis and symptom recognition were re-analysed using a "candidacy" framework to examine how age and diagnosis intersect. People did not always assert their candidacy for either condition because of pre-conceived expectations around age. Similarly, health professionals sometimes failed to recognize patients' candidacy, instead pursuing "age-plausible" possibilities. In some cases, participants were proactive in suggesting a diagnosis to the health professional where diagnosis was delayed.

The diagnosis of adult-onset asthma, and arthritis in young people, may be regarded as "untimely." We suggest that being diagnosed with what is perceived to be a "childhood" condition in adulthood, or "an older person's" condition in childhood, may be viewed as a "biographical paradox" and an "untimely breach" to the expected order.

Aggrecanase cleavage at the (392)Glu-(393)Ala bond in the interglobular domain (IGD) of aggrecan, releasing N-terminal (393)ARGS fragments, is an early key event in arthritis and joint injuries. We determined whether synovial fluid (SF) levels of ARGS-aggrecan distinguish subjects with progressive radiographic knee osteoarthritis (ROA) from those with stable or no ROA. We studied 141 subjects who, at examination A, had been given meniscectomies an average of 18 years earlier (range, 15 to 22 years). Seventeen individuals without surgery, and without known injury to the menisci or cruciate ligaments, were used as references. At examinations A and B, with a mean follow-up time of 7.5 years, we obtained SF and standing tibiofemoral and skyline patellofemoral radiographs. SF ARGS-aggrecan was measured with an electrochemiluminescence immunoassay, and we graded radiographs according to the OARSI atlas. The association between SF ARGS levels at examination A and progression of radiographic features of knee OA between examinations A and B was assessed by using logistic regression adjusted for age, gender, body mass index, and time between examinations, and stratified by ROA status at examination A. We found a weak negative association between SF ARGS concentrations and loss of joint space: the likelihood of progression of radiographic joint space narrowing decreased 0.9 times per picomole per milliliter increase in ARGS (odds ratio (OR) 0.89; 95% confidence interval (CI), 0.79 to 0.996). In subjects with and without preexisting ROA at examination A, the association was OR, 0.96; 0.81 to 1.13; and 0.77; 0.62 to 0.95, respectively. Average levels of SF ARGS 18 years after meniscectomy were no different from those of reference subjects and were not correlated to radiographic status at examination A.

In subjects with previous knee meniscectomy but without ROA, levels of SF ARGS-aggrecan were weakly and inversely associated with increased loss of joint space over a period of 7.5 years.

We undertook this study to determine whether thrombin-cleaved osteopontin (OPN) in synovial fluid (SF) represents a useful marker of osteoarthritis (OA) progression in the posterior cruciate ligament transection (PCLT) OA rabbit model. PCLT was performed on the right knee joints of 48 rabbits. The rabbits were then sacrificed separately at 4, 8, 16, and 24 weeks post-surgery, when the joint was harvested and macroscopic and histological assessments of articular cartilage were performed. Thrombin-cleaved OPN product in SF was determined using Western blotting and the levels were measured using an enzyme-linked immunoassay. The macroscopic and histological scores for PCLT knees were already elevated 4 weeks after surgery and increased with time. Western blotting showed the presence of thrombin-cleaved OPN in SF from PCLT knees. Thrombin-cleaved OPN levels in SF were elevated at 4 weeks (P < 0.001) and were elevated peaking at 24 weeks (P < 0.00001) after PCLT compared to baseline. A positive significant correlation was found between thrombin-cleaved OPN levels and the macroscopic scores (8 weeks: ρ = 0.695, P = 0.012; 16 weeks: ρ = 0.751, P = 0.005; 24 weeks: ρ = 0.660, P = 0.020). Furthermore, the same correlation was noted between thrombin-cleaved OPN levels and the histological scores (4 weeks: ρ = 0.609, P = 0.036; 8 weeks: ρ = 0.662, P = 0.019; 16 weeks: ρ = 0.827, P = 0.001; 24 weeks: ρ = 0.813, P = 0.001).

In this rabbit model of PCLT, thrombin-cleaved OPN levels in SF appear to provide a useful marker of OA disease severity and progression.

To review the clinical evidence on subcutaneous (sc) abatacept and to formulate recommendations in order to clear up points related to its use in rheumatology. An expert panel of rheumatologists objectively summarized the evidence on the mechanism of action, practicality, effectiveness, and safety of abatacept sc and formulated recommendations after a literature review. The efficacy and safety of abatacept sc was studied in 7 clinical trials, 3 double-blind, 3 open, and one mixed, with the following endpoints: comparison against abatacept iv, impact on immunogenicity, effect of replacing iv by sc, abatacept sc in monotherapy, and non-inferiority to adalimumab. No significant differences were found between sc and iv abatacept on efficacy or safety. The development of sc abatacept has allowed a complementary study to the iv, formulation, thus making the abatacept profile better defined.

This is a practical document to supplement the summary of product characteristics. In summary, abatacept sc is presented as an effective and safe drug and, therefore, as an alternative for use within the broad armamentarium the rheumatologist has to treat RA. It also has the advantage of being the only biological agent that can be administered iv and sc which can facilitate its use in certain patients.

The goal of this study was to investigate the usefulness of a short ultrasound (US) assessment in gout. Patients with gout, confirmed by urate crystal identification, and having at least one symptomatic flare in the last three months were included. Standardised US examinations of sixteen joints and eight tendons in the lower limbs were carried out. Six lesions were studied: hyperechoic spots in the synovial fluid, hyperechoic cloudy areas (HCA), bright stippled aggregates (BSA), the double contour sign (DCS), erosions and the Doppler signal. For reliability, inter-reader analyses were performed by five rheumatologists. With the results, a short US assessment was created. Twenty-nine consecutive patients were included (93% men). The Doppler signal, HCAs and BSAs appeared in 100%, 97% and 93% of the patients, respectively. The DCS was found in 69% of patients. The locations that were most affected were the first metatarsophalangeal joint (MTP) and the knee joints, both of which are in 93% of patients. Reliability analyses showed consistent results for erosions, the Doppler signal, HCAs and the DCS in the 1st MTP (k=0.818, k=0.958, k=0.739 and k= 0.697, respectively) and for the DCS in the knees (k=0.779). A six-minute US examination of four joints (knees and the 1st MTPs) detected HCAs or DCS in 97% of cases.

A US examination of four joints for two elemental lesions (the DCS and HCAs) is feasible, reliable and has face and content validity as a diagnostic test in patients with crystal-proven gout.

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease characterized by the production of various autoantibodies. The aim of this study was to investigate the presence of anti-ficolin-2 antibodies in SLE patients and to evaluate the association between the levels of these autoantibodies, clinical manifestations, and disease activity. This is a comparative study using a cohort of 165 SLE patients and 48 healthy subjects. SLE patients were further divided into 2 groups (low disease activity [SLE Disease Activity Index (SLEDAI) score ≤4, n = 88] and high disease activity [SLEDAI score >4, n = 77]). Clinical manifestations were defined according to the physician in charge. Active lupus nephritis (LN) was documented by kidney biopsy. Detection of anti-ficolin-2 antibodies was performed by enzyme-linked immunosorbent assay. Levels of anti-ficolin-2 autoantibodies were significantly higher in SLE patients as compared to healthy subjects and associated with SLEDAI score. They were found to be positive in 61 of 165 SLE patients (37%). The presence of anti-ficolin-2 antibodies was significantly related only to renal involvement, with a very high prevalence (86%) of anti-ficolin-2 antibodies in SLE patients with active LN. Patients with active proliferative LN had significantly more positive anti-ficolin-2 antibodies than those with nonproliferative LN. The combination of anti-ficolin-2, anti-ficolin-3, and anti-C1q demonstrated a very high specificity (98%) for the diagnosis of active LN.

Our results support the usefulness of anti-ficolin-2 as a complementary serologic biomarker for the diagnosis of active lupus with renal manifestations.

Chemokines are a family of low molecular weight proteins that induce chemotaxis of inflammatory cells, which mainly depends on the recognition of a chemo-attractant gradient and interaction with the substratum. In Rheumatoid Arthritis (RA), abundant chemokines are expressed in synovial tissue, cause inflammatory cells migration into the inflamed joint that necessitates the formation of new blood vessels i.e. angiogenesis. Over the decades, studies showed that continuous inflammation may lead to the loss of tissue architecture and function, causing severe disability and cartilage destruction. In spite of the advancement of modern drug therapy, thousands of arthritic patients suffer mortality and morbidity globally. Thus, there is an urgent need for the development of novel therapeutic agents for the treatment of RA. This review is carried out throughout a non-systematic search of the accessible literature, will provide an overview of the current information of chemokine in RA and also exploring the future perspective of the vital role of targeting chemokine in RA treatment. Since, chemokines are associated with inflammatory cells/leucocyte migration at the site of inflammation in chronic inflammatory diseases and hence, blockade or interference with chemokines activity showing a potential approach for the development of new anti-inflammatory agents. Currently, results obtained from both preclinical and clinical studies showed significant improvement in arthritis.

This review summarizes the role of chemokines and their receptors in the pathogenesis of RA and also indicates possible interactions of chemokines/receptors with various synthetic and natural compounds that may be used as a potential therapeutic target in the future for the treatment of RA.

To compare the sensitivity of Sharp's and Larsen's radiographic scoring methods for detecting change in rheumatoid arthritis (RA) over time. Radiographs of the hands and wrists were taken at the beginning and at the end of a 2-year followup period, in 42 patients with active RA. Films were scored blindly using both scoring methods. Patients were under treatment with methotrexate (intramuscular injections). Radiographic evidence of progression or amelioration was detected in 25 patients by Larsen's method and in 35 patients by Sharp's method. The relative sensitivity to change over time was greater for Sharp's method (0.01 less than P less than 0.025).

Sharp's radiographic scoring method seems to be more sensitive to change over time than is Larsen's method. The clinical importance of the change needs to be definitively established.

To prospectively evaluate patient related outcome measures after total wrist arthroplasty (TWA) using four different total wrist implants operated at a single referral center in Sweden. 206 primary TWAs were assessed preoperatively and after one year postoperatively with respect to the following eight outcome measures: Range of motion (flexion/extension, radial/ulnar deviation, pronation/supination), hand grip strength, Canadian Occupational Performance Measure (COPM), performance and satisfaction, Visual Analog Scale (VAS) pain scores at rest and in activity. The Maestro TWA had a significantly greater improvement of radial/ulnar deviation than the Biax and Remotion TWAs. COPM performance and satisfaction improved more for the Maestro and Universal 2 prostheses than the Biax and Remotion.

All four TWAs offer reduced VAS-scores and improved COPM-scores with preserved hand grip strength and somewhat improved range of motion. The Maestro TWA performed favorably compared to the Remotion TWA. Implant design may affect patient related outcome.

The pro-inflammatory calcium-binding protein S100A12 has been recently ascribed to the novel group of damage associated molecular pattern (DAMP) molecules. Serum levels of S100A12 reflect neutrophil activation during synovial inflammation. The aim of this project was to analyse the effect of intra-articular corticosteroids or systemic anti-TNF treatment on synovial expression and serum levels of S100A12 in rheumatoid arthritis (RA). Serum and synovial tissue was obtained from 19 RA patients prior to and 2 weeks after intra-articular corticosteroid therapy. Serum was collected for 34 other patients, and in 14 of these patients synovial tissue was additionally obtained prior to and after 8 weeks of infliximab treatment. The expression of S100A12 was analysed by immunohistochemistry on frozen sections. Levels of S100A12 in serum were determined by ELISA. S100A12 serum levels were elevated in patients with active RA prior to therapy and decreased significantly in patients who responded to treatment in both patient groups, but not in non-responders. The synovial expression of S100A12 was reduced 2 weeks after successful intra-articular corticosteroid treatment. A similar decrease in local expression was found after 8 weeks of successful infliximab treatment.

Successful treatment of RA leads to downregulation of the DAMP protein S100A12. Expression and secretion of S100A12 is rapidly diminished after therapy with intra-articular corticosteroids or infliximab. Taking these findings together, decreasing serum concentrations of S100A12 could reflect alleviated synovial neutrophil activation during successful anti-inflammatory therapy in RA.

Osteoarthritis (OA), which increases knee loading, muscle co-contraction, and pain, is a mechanical disease that requires biomechanical exploration to reduce pain in the knee. Therefore, this article aims to investigate the effectiveness of an exercise programme on the aforementioned outcomes in people with medial knee OA. Cohort pilot study design. A total of 19 patients with knee OA attended a six-week group exercise programme integrated with self-management education. The following outcomes were assessed before and after the exercise programme: external knee adduction moment (EKAM), knee adduction angular impulse (KAAI), knee antagonist muscle co-contraction, and pain subscale of the knee injury and osteoarthritis outcome score (KOOS). Of the 19 patients, 14 completed the study. The EKAM and KAAI did not show statistical significance post-exercise intervention (p=0.21-0.7 and 0.56, respectively). Muscle co-contraction between vastus lateralis and biceps femoris muscles decreased in early-stance (64.78 (44.35) compared with 38.10 (23.10), p=0.01) and mid-stance (27.62 (32.12) compared with 14.94 (17.40), p=0.04). A corresponding significant pain reduction was observed (p=0.00) with a median (range) of 51.50 (47.00 to 62.50) at week 6 compared with 34.50 (29.25 to 41.25) at baseline.

This is the first known study to explore the effect of an exercise programme on knee loading and muscle co-contraction in patients with OA. Although the value of EKAM did not change, the findings suggest that the reduction in vastus lateralis and biceps femoris co-contraction might be the mechanism behind the reduction of pain.

The aims of this study were to develop recommendations for occupational therapy assessment and design of hand exercise programmes in patients with hand osteoarthritis. An expert group followed a Delphi procedure to reach consensus for up to 10 recommendations for assessment and exercises, respectively. Thereafter, an evidence-based approach was used to identify and appraise research evidence supporting each recommendation, before the recommendations were validated by the expert group. The process resulted in 10 recommendations for assessment and eight for design of exercise programmes. The literature search revealed that there is a paucity of clinical trials to guide recommendations for hand osteoarthritis, and the evidence for the majority of the recommendations was based on expert opinions. Also, even if a systematic review demonstrates some evidence for the efficacy of strength training exercises in hand OA, the evidence for any specific exercise is limited to expert opinions.

A first set of recommendations for assessment and exercise in hand osteoarthritis has been developed. For many of the recommendations there is a paucity of research evidence. High-quality studies are therefore needed to establish a high level of evidence concerning functional assessment and the effect of hand exercises in hand osteoarthritis.

Rheumatoid arthritis (RA) is an inflammatory disease associated with accelerated atherosclerosis and high risk of cardiovascular (CV) disease. Angiopoietin-2 (Angpt-2), a marker of endothelial cell activation, has been proposed as a mediator of angiogenesis, which might play an important role in the regulation of endothelial integrity and inflammation. Therefore, the aim of this study was to determine whether Angpt-2 is related to severity and CV disease in RA patients. Angpt-2 serum levels were measured by enzyme linked immunosorbent assay (ELISA) in 290 patients with RA. A control group of 100 individuals frequency matched by age and sex and classic CV risk factors and CV disease was also assessed. Eighty-four patients with RA (28.9%) had experienced CV events. Also, extra-articular manifestations were present in 41 (14%) of these patients. Although there were not significant differences between patients and controls, a correlation between age at the time of disease onset and Angpt-2 was observed in RA patients (r=-0.31; p=0.02). Angpt-2 serum levels also correlated positively with extra-articular disease (mean±standard deviation in RA patients with and without extra-articular manifestations were 2476±1716 pg/ml and 1897±1228 pg/ml, respectively; p=0.01). Moreover, after adjustment for sex, age at RA diagnosis and CV risk factors, Angpt-2 levels were higher in RA patients with CV disease than in RA patients without CV complications (2472±1826 pg/ml vs. 1875±1101 pg/ml; p=0.05). Angpt-2 serum levels remained significantly higher in RA patients with CV disease compared to those without CV disease after additional adjustment for extra-articular manifestations (p=0.04).

Our results show that Angpt-2 serum levels correlate with disease severity, early onset and CV disease in RA patients.

To study the expression of chemokine receptors CCR5 and CXCR3 and the Th1/Th2 cytokine balance in children with oligoarticular or polyarticular juvenile idiopathic arthritis (JIA). Using 3-color immunofluorescence, we studied the expression of CCR5 and CXCR3 on, and T cell cytokine production by, paired samples of synovial fluid (SF) and peripheral blood (PB) T cells from 20 patients with oligoarticular- or polyarticular-onset JIA. Chemokine and cytokine phenotypes were also compared within the CD45RO+,CD3+ subsets. CCR5 genotypes were confirmed by polymerase chain reaction typing and sequencing. In the majority of samples, the number of T cells that were CCR5+ and CXCR3+ was higher in SF than in PB, and this difference was significant. One child was homozygous for the null A32 CCR5 allele; 4 others had lower expression of CXCR3 in SF than in blood. All samples showed strongly Th1-type cytokine production by synovial T cells compared with that by PB T cells. Both features were also markedly polarized within the synovial CD45RO+ subset compared with PB CD45RO+ T cells.

The high expression of CCR5 and CXCR3 and high interferon-gamma:interleukin-4 ratios suggest a type 1 phenotype of SF T cells in JIA. The difference between CD45RO+ T cells from SF and from PB suggests that specific activation events have occurred in synovial T cells. We suggest that the highly activated, Th1-type phenotype of T cells within the chronically inflamed joints of children with JIA may reflect specific recruitment events that contribute to the polarization of these cells.

Corticosteroids have long been used to effectively treat rheumatic disorders, but adverse effects associated with extended-duration regimens generate disagreement among clinicians regarding optimal tapering strategies. The objective of this systematic review was to assess clinical outcomes of differing tapering regimens after corticosteroid monotherapy in adults with rheumatic disorders. A systematic review of Medline/PubMed, Embase, Cochrane, International Pharmaceutical Abstracts, Web of Science, Scopus, Global Index Medicus, American College of Rheumatology, gray literature, and reference lists up to June 27, 2018, was conducted by 2 authors. Randomized controlled trials, case-control studies, and prospective observational studies comparing at least 2 tapering strategies of medium- to high-dose (>7.5 mg but ≤100 mg oral prednisone equivalent daily), extended-duration (≥10 days) corticosteroids were included if they reported at least 1 efficacy and 1 adverse effect parameter. Two studies met criteria for the review, which included 62 patients. One study examined a prednisolone versus a modified release prednisone taper for giant cell arteritis and suggested 80% (n = 4) and 85.7% (n = 6) remission rates, respectively, at 26 weeks. The other study examined a methylprednisolone versus a prednisone taper for polymyalgia rheumatica and reported 100% and 89% remission rates, respectively, at 26 weeks. Adverse effects reported between the 2 studies included sleep, hyperglycemia, infection, and fractures. However, the studies were not powered to detect differences in these outcomes.

There is no high-level evidence to guide tapering until discontinuation after extended courses of medium- to high-dose treatment regimens, as current guidelines rely heavily on expert opinion and small case series with a trial-and-error approach. This review supports the need for additional research to shift tapering recommendations to a more evidence-based practice.

The objective of this study was to evaluate the long-term safety and efficacy of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor, in rheumatoid arthritis (RA) patients. Patients with RA who completed one of two 24-week randomized controlled trials (RCTs) participated in this 52-week, flexible-dose, open-label extension study. Patients in RCT1 received intravenous placebo, 30-mg tabalumab or 80-mg tabalumab every 3 weeks, and patients in RCT2 received subcutaneous placebo or 1-, 3-, 10-, 30-, 60- or 120-mg tabalumab every 4 weeks (Q4W). Regardless of prior treatment, all patients in this study received subcutaneous 60-mg tabalumab Q4W for the first 3 months, then a one-time increase to 120-mg tabalumab Q4W (60-mg/120-mg group) and a one-time decrease to 60-mg tabalumab Q4W per patient was allowed (60-mg/120-mg/60-mg group). There were 182 patients enrolled: 60 mg (n = 60), 60/120 mg (n = 121) and 60/120/60 mg (n = 1). Pretabalumab baseline disease activity was generally higher in the 60-mg/120-mg group. There was a higher frequency of serious adverse events and treatment-emergent adverse events, as well as infections and injection-site reactions, in the 60-mg/120-mg group. One death unrelated to the study drug occurred (60-mg/120-mg group). In both groups, total B-cell counts decreased by approximately 40% from the baseline level in the RCT originating study. Both groups demonstrated efficacy through 52 weeks of treatment relative to baseline pretabalumab disease activity based on American College of Rheumatology criteria improvement ≥20%, ≥50% and ≥70%; European League against Rheumatism Responder Index in 28 joints; Disease Activity Score in 28 joints-C-reactive protein; and Health Assessment Questionnaire-Disability Index. ClinicalTrials.gov Identifier: NCT00837811 (registered 3 February 2009).

With long-term, open-label tabalumab treatment, no unexpected safety signals were observed, and B-cell reductions were consistent with previous findings. Despite differences in RCT originating studies, both groups demonstrated an efficacy response through the 52-week extension.

To elucidate how mechanical stresses that are applied to the whole organism are transmitted to individual cells and transduced into a biochemical response. In this article, we describe fundamental design principles that are used to stabilize the musculoskeletal system at many different size scales and show that these design features are embodied in one particular form of architecture that is known as tensegrity. Tensegrity structures are characterized by use of continuous tension and local compression; architecture, prestress (internal stress prior to application of external force), and triangulation play the most critical roles in terms of determining their mechanical stability. In living organisms, use of a hierarchy of tensegrity networks both optimizes structural efficiency and provides a mechanism to mechanically couple the parts with the whole: mechanical stresses applied at the macroscale result in structural rearrangements at the cell and molecular level.

Due to use of tensegrity architecture, mechanical stress is concentrated and focused on signal transducing molecules that physically associate with cell surface molecules that anchor cells to extracellular matrix, such as integrins, and with load-bearing elements within the internal cytoskeleton and nucleus. Mechanochemical transduction may then proceed through local stress-dependent changes in molecular mechanics, thermodynamics, and kinetics within the cell. In this manner, the entire cellular response to stress may be orchestrated and tuned by altering the prestress in the cell, just as changing muscular tone can alter mechanical stability and structural coordination throughout the whole musculoskeletal system.

To use clinical measures and biochemical markers of bone turnover to investigate mechanisms of generalized bone loss in early rheumatoid arthritis (RA). We studied 232 patients with RA of less than 2 years' duration and 72 healthy controls using serial dual x-ray absorptiometry scanning of lumbar spine and hips. Patients attended the clinic for clinical and laboratory assessment with storage of serum, urine, and plasma at each visit. Change in bone mineral density (BMD) was calculated for patients and controls and compared with baseline and mean serial values of bone markers over the same intervals. Serum was assayed for procollagen I carboxyterminal propeptide (PICP) and skeletal alkaline phosphatase (sALP); urine for pyridinoline and deoxypyridinoline corrected for creatinine; and plasma for interleukin 1 (IL-1) and IL-6. Patients lost bone significantly faster than controls at all sites (p < 0.01 for all). At first visit patients had significantly lower PICP levels than controls (p < 0.05) and sALP correlated with initial BMD in both patients (p < 0.01, r > 0.35, all sites) and controls (p < 0.0001, r > 0.50, all sites). We rescanned 167 patients at one year and 121 patients at 2 years. Mean urinary pyridinoline and deoxypyridinoline levels correlated strongly with BMD change at all sites, were increased in patients with active disease (p < 0.005), and correlated closely with mean C-reactive protein (CRP) (p < 0.005, r > 0.41 for both).

This study suggests that osteoclastic activation, rather than suppression of bone formation, is the dominant process leading to bone loss in early RA. Although urinary pyridinoline and deoxypyridinoline were excellent markers of BMD change, CRP was found to be best overall. This provides a rational approach for selecting and treating patients with RA to reduce their established longterm risk of osteoporotic fracture.

Systemic juvenile idiopathic arthritis (sJIA) is an auto-inflammatory disease characterized by fever, arthritis, and ≥1 of rash, generalized lymphadenopathy, hepato/splenomegaly, and serositis. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the initial treatments of sJIA, but there is currently no evidence indicating which children should undergo a trial of NSAID monotherapy and which should not. Our objective is to identify presentation characteristics which are associated with response and lack of response to a trial of NSAID monotherapy. This is a retrospective single-center cohort study of children diagnosed with sJIA from 2000 to 2014. Patient demographics and disease characteristics were investigated to identify predictors of response to NSAID monotherapy. Eighty-seven children were newly diagnosed with sJIA 2000-2014. Thirteen of the 51 children who received NSAID monotherapy achieved clinically inactive disease (CID) without other medications. Age at presentation (≤8 years old), initial joint count (≤5), and C-reactive protein (CRP) (≤13 mg/dL) at diagnosis were associated with achievement of CID on NSAIDs alone. Physicians were less likely to trial NSAID monotherapy if the patient had either serositis or macrophage activation syndrome (MAS) at diagnosis. Ultimate achievement of CID and time to CID were not significantly affected by whether the patient received a trial of NSAID monotherapy.

While a subset of children with sJIA can achieve CID with NSAID monotherapy, we recommend against a trial in patients who are >8 years old, with >5 joints involved, or with CRP > 13 mg/dL. Patients who undergo a trial of NSAID monotherapy should follow up within 2-4 weeks to evaluate for possible need for drug escalation. Clinical trials are necessary to confirm these findings.

There has been a recent interest in custom-made partial knee arthroplasties to provide patient-specific instrumentation and better fit of the prosthesis. While unicondylar knee arthroplasties (UKAs) have demonstrated good outcomes and durable results in many studies, there is little evidence on outcomes of these custom-made implants. We performed a retrospective review of all custom-made UKAs performed at our institution by one surgeon from 2008 to 2015. We analyzed preoperative demographics, clinical follow-up evaluations, and radiographs and performed an analysis of risk factors including age, gender, height, weight, body mass index, and tibial insert thickness. The incidence of revision surgery, radiographic failures indicating component loosening, and symptomatic clinically failed implants was calculated at an average of 54.0 months of follow-up. We analyzed 115 consecutive custom-made medial UKAs from a single surgeon at our institution and found 29 (25.2%) UKAs had failed at an average of 33.1 months after surgery. Reasons for failure included aseptic femoral loosening (10), aseptic tibial loosening (8), loosening of both components (4), infection (3), progression of osteoarthritis (2), pain (1), and dislodged polyethylene insert (1). We found a significant relationship between implant failure and body mass index; no other study variables were statistically significant.

We found a relatively high rate of aseptic loosening and particularly femoral component loosening in the short- to intermediate-term follow-up period. While further study of larger numbers of custom-made UKA from multiple institutions may help verify these findings, we recommend careful consideration of the use of this implant.

We aimed to ascertain the feasibility of crowdsourcing via Facebook for medical research purposes; by investigating surgical, oncological and functional outcome and quality-of-life (QOL) in patients with pigmented villonodular synovitis (PVNS) enrolled in a Facebook community (1112 members). Patients completed online open surveys on demographics, surgery and clinical outcomes (group 1); and patient-reported outcome measures (PROMs) including knee-injury osteoarthritis outcome score (KOOS), hip-disability osteoarthritis outcome score (HOOS), Toronto extremity salvage score (TESS) and SF-36 (group 2). Mean follow-up was 70 months (12-374). Consistency checks were performed with Cohen's kappa statistic for intra-rater agreement. The first survey was completed by 272 patients (group 1) and 72 patients completed the second (group 2). In group 1, recurrence-rate was 58 % (69/118) after arthroscopic, 36 % (35/97) after open and 50 % (5/10) after combined synovectomy (p = 0.003). In group 2, recurrence-rate was 67 % (26/39) after arthroscopic and 51 % (17/33) after open synovectomy (p = 0.19). Recurrence-risk was increased for diffuse disease (OR = 16; 95%CI = 3.2-85; p < 0.001). Mean function and QOL did not differ after arthroscopic or open synovectomy: KOOS 49 vs. 58 (p = 0.24), HOOS 62 vs. 53 (p = 0.56), TESS 78 vs. 82 (p = 0.86), SF-36 61 vs. 66 (p = 0.41). Cohen's kappa statistic for intra-rater agreement was good to outstanding (κ = 0.68-0.95; p < 0.001).

Local recurrence-risk was higher for diffuse-type disease and arthroscopic synovectomy. Functional outcome and QOL were comparable for both types of surgery. Gathering data via crowdsourcing seems a promising and innovative way of evaluating rare diseases including PVNS.

To study the effect of intracellular reactive oxygen species (ROS) levels on T cell activation and apoptosis of synovial cells in collagen induced arthritis (CIA) rats, and to explore the mechanism of Fengshining Capsule (FSN) in the treatment of rheumatoid arthritis (RA). Sixty rats were randomly divided into the normal control group, the CIA model group, the Tripterygium Poly-glycoside Tablet (TPT) group, the low dose FSN group (at the daily dose of 0.33 g/kg), the middle dose FSN group (at the daily dose of 0.66 g/kg), and the high dose FSN group (at the daily dose of 1.32 g/kg), 10 in each group. T lymphocyte subsets were detected by flow cytometry. The content of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in plasma of rats were detected by ELISA. Its expression of hydroxyl radicals was detected by ultraviolet spectrophotometry. Caspase-3 and Caspase-9 protein expressions were measured by Western blot. Compared with the CIA model group, the levels of ROS were elevated in each dose FSN group (P < 0.01). The level of CD4+ / CD8 was significantly reduced in the middle dose FSN group (P < 0.01). The content of IFN-gamma was obviously lowered in each dose FSN group (P < 0.01), while that of IL-4 was obviously elevated in the high dose FSN group (P < 0.01). Meanwhile, the expression of Caspase-9 and Caspase-3 significantly increased in each dose FSN group (P < 0.05). Besides, the average gray scale of Caspase-9 was significantly higher in the low and middle FSN groups than in the TPT group (P < 0.05, P < 0.01).

The mechanism of FSN for regulating the immune hyperfunction and inhibiting the proliferation of synovial cells in CIA rats might be associated with up-regulating in vivo ROS levels.

Despite increasing evidence regarding the significance of sex hormones in rheumatoid arthritis (RA), their etiopathological role and potential longterm effect on joint destruction remain unclear. We hypothesized that estrogen receptors (ER-alpha) are present in fibroblast-like synoviocytes, and 17beta-estradiol can modulate the production and activity of matrix degrading enzymes produced by these cells. Thus, depending on the endocrine balance, fibroblast-like synoviocyte activity can be suppressed or enhanced, leading to amelioration or exacerbation of the disease process, respectively. By utilizing an in vitro cartilage invasion model, in combination with the molecular analyses of hormone receptors, matrix metalloproteinases (MMP) and their respective inhibitors, we investigated the effect of hormones (i.e., estrogen and progesterone) on fibroblast-like synoviocyte phenotypic changes, with particular emphasis on their functional interactions with cartilage. Our studies reveal the presence of functional ER-alpha in fibroblast-like synoviocytes. The findings indicate that estrogen exerts a stimulatory effect, while progesterone has an inhibitory effect on the expression of MMP, their tissue inhibitors (TIMP), and enzymatic activity of MMP produced by these cells. Furthermore, transfection of fibroblast-like synoviocytes with the ER-alpha gene resulted in the increased degradation and invasion of cartilage.

We identified the presence of functional ER-alpha in fibroblast-like synoviocytes. This renders fibroblast-like synoviocytes as target cells for hormonal regulation. The regulatory effect of estrogen is partly targeted to the MMP and their respective inhibitors associated with fibroblast-like synoviocytes. Such studies provide a link between hormonal status and disease activity in RA and open new venues for future therapeutic intervention to combat this debilitating disease.

There is limited literature concerning the outcomes and role of THA as a surgical option for amputee patients. The aim of this study is to determine the mid-to long-term survival and complication rates of cementless total hip arthroplasty (THA) in patients with contralateral below knee amputations. A retrospective review of 54 patients with below knee amputation were perfomed who underwent THA for osteoarthritis of the contralateral hip over a 5-year period between 1999 and 2014. Patients were monitored for at least 5 years and assessed with the Harris Hip Score and activities of daily living scale and by evaluating migration or osteolysis around the acetabular cup and femoral stems (amputee group). The amputee group was compared with a control group (non-amputee group) with the same number of patients. Differences in the Harris Hip Score (p = 0.021) and activities of daily living scale (p = 0.043) between the two groups were statistically significant lower in the amputee group at 3 months after surgery. However, no differences were found between the groups from 6 months postoperatively to the last follow-up (Harris Hip Score p = 0.812, activities of daily living scale p = 0.885). Radiologically, any cups or stems showed no signs of migration or osteolysis. In the amputee group, dislocation was found in 1 patient 2 months after arthroplasty (p = 0.315) and long stem revision surgery were performed on two patients due to periprosthetic fracture (p = 0.153). Level IV, therapeutic study.

THA performed on the contralateral side of patients with below knee amputation is considered to be an effective treatment with good clinical and radiological results at mid-to long-term follow-up.

To examine the in vivo effects of carboxymethylated chitin (CMC), intra-articularly administered, on cartilage degradation and the level and distribution of cartilage matrix metalloproteinase-1 (MMP-1). Osteoarthritis (OA) was induced in 20 rabbits by unilateral anterior cruciate ligament transection (ACLT). The experimental group, comprising 10 rabbits randomly selected, was given an intra-articular injection of 0.3 ml of 2% CMC solution at 1, 3, and 5 weeks after ACLT. A further 10 rabbits that received an intra-articular injection of 0.3 ml normal saline at the same time served as controls. All knees were harvested at 6 weeks after surgery. Cartilage degradation of femoral condyles was evaluated at two levels: macroscopic and light microscopic. Tissue level and distribution of MMP-1 was documented by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Cartilage degradation in the control group was significantly more severe than that in the experimental group both on the macroscopic grading scale and on Mankin's grading scale. In RT-PCR the amount of MMP-1 was significantly reduced by the treatment of CMC. Immunohistochemical study showed that in the experimental group MMP-1 was predominantly expressed in the superficial and upper intermediate layers of cartilage, and the amount of MMP-1 in the experimental group was also lower than that in control group.

CMC significantly reduces the severity of cartilage degradation and reduces the expression of MMP-1 in cartilage, both at the mRNA and the protein level, and thus may be a potential drug for the treatment of OA.

About 12% of patients who have undergone primary anterior cruciate ligament (ACL) reconstruction sustain a contralateral ACL injury within 5 years. To investigate patient-reported knee function, quality of life, and activity level in patients with bilateral ACL injuries. Cohort study; Level of evidence, 3. A search of hospital records identified 147 patients, aged 18 to 45 years, with bilateral ACL injuries. Of these, 83 met the inclusion criteria, having had their first ACL injury up to 12 years ago with no other major injuries to the knee joint. Sixty-six of these patients (80% of total; 47% female; mean age, 29.1 ± 7.2 years) answered a questionnaire packet. Patients who had undergone unilateral ACL reconstruction (n = 182) were used for comparison. Patients with bilateral ACL injuries had a median Lysholm knee score of 82 (range, 34-100). The mean EuroQol index (EQ-5D) score of the overall health status was 0.77 ± 0.22, and the mean EQ-5D visual analog scale score was 75.5 ± 17.6. The median Tegner activity level was 9 (range, 1-9) before any injuries, 7 (range, 1-9) before the second ACL injury, and 4 (range, 1-9) at the time of follow-up. The activity level before the second injury was higher compared with the follow-up for patients who had undergone unilateral ACL reconstruction. At follow-up, 23% of the patients with bilateral ACL injuries returned to their previous activity, and 12% of patients returned to the same level as before their injuries compared with 43% (P = .004) and 28% (P = .01) in patients who had undergone unilateral ACL reconstruction, respectively. Patients with bilateral ACL injuries had significantly lower values in the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales for pain, function in sports and recreation, and knee-related quality of life as well as the ACL Deficiency Quality of Life (ACL-QOL) score compared with patients who had undergone unilateral ACL reconstruction.

Patients with bilateral ACL injuries reported poorer knee function and quality of life compared with those who had undergone unilateral ACL reconstruction. Their activities had changed, and they were dissatisfied with their current activity level. They had a high activity level before their first and second ACL injuries but an impaired activity level after their contralateral injury at follow-up.

Tumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LTα) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin- alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LTα. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR). Patients (n = 214) with active RA (≥ 6 swollen and tender joints, C-reactive protein ≥ 10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed. Pateclizumab reduced the DAS28(4)-ESR response (-1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (-1.54), while adalimumab (-2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AEs) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients. ClinicalTrials.gov NCT01225393, Registered 18 October 2010.

Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients.

Small studies have shown an improvement in disease activity in patients with RA who have switched between anti-TNF therapies for reasons of inefficacy. However, it is not clear whether switching improves longer term outcomes, such as disability. This analysis compares changes in HAQ scores 1 yr following lack of response to a first anti-TNF based on subsequent treatment during that year. Analysis was limited to RA patients with inefficacy to a first anti-TNF based on (i) clinician opinion and/or (ii) disease activity score in 28 joints and had an HAQ measured at time of non-response and 12 months later. Patients were classified into three groups based on treatment during the next 12 months: (i) continued anti-TNF despite non-response; (ii) stopped anti-TNF with no further biologics; and (iii) switched to a second anti-TNF. Mean improvement in HAQ was compared among the groups using multivariable linear regression models. As of July 2006, 868 patients met the inclusion for this analysis. Four hundred and seventy-nine patients stopped anti-TNF of whom 331 switched to a second anti-TNF. Three hundred and eighty-nine continued treatment. Patients who continued and those who switched had improvements in HAQ over the 12 months, unlike patients who discontinued all biologic therapy. The best improvement was seen in those who switched [adjusted mean improvement in HAQ 0.15 (95% CI 0.26, 0.05)].

There is a significant improvement in HAQ in patients who switch to a second anti-TNF, providing an effective next choice of therapy for some patients who fail to respond to their first anti-TNF.

To investigate the expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in cells from synovial fluid (SF) of patients with acute or chronic arthritis. SF was obtained from eight patients with acute crystal-induced arthritis, nine with rheumatoid arthritis and four with psoriatic arthritis. COX-1 and COX-2 gene expression was studied by reverse transcriptase-polymerase chain reaction (RT-PCR). Protein expression was detected by Western blotting and immunocytochemistry. There was expression of COX-1 mRNA in all and COX-2 mRNA in most of the SF samples from acute or chronic arthritis. By immunocytochemistry, both COX-1 and COX-2 immunoreactivity was restricted to a variable fraction of mononuclear cells. COX-1 staining was observed in 10-fold more cells than COX-2. By Western blotting, COX-1 protein was detected in 60% of the SF samples and COX-2 in none. There were no differences in the pattern of COX-1 and COX-2 expression between chronic and acute SF samples.

In arthritis, both COX-1 and COX-2 isoforms are expressed by SF cells. COX-1 is the most abundant isoform. Since the strong COX-1 immunostaining observed in a fraction of mononuclear SF cells is not observed in peripheral blood leucocytes, it may be the result of either the activation or recruitment of a subset of mononuclear cells with a high COX-1 expression level.

Namilumab (AMG203) is an immunoglobulin G1 monoclonal antibody that binds with high affinity to the GM-CSF ligand. This was a phase 1b, randomized, double-blind study (PRIORA) to assess namilumab in active, mild-to-moderate rheumatoid arthritis (RA). The primary outcome was the safety and tolerability of repeated subcutaneous injections of namilumab in patients with mild-to-moderate RA. Adults with mild-to-moderate RA on stable methotrexate doses for ≥12 weeks were eligible. Patients received three subcutaneous injections of namilumab 150 or 300 mg, or placebo on days 1, 15, and 29, with 12 weeks' follow-up. Primary objective was safety/tolerability. Patients in cohort 1 were randomized to namilumab 150 mg (n = 8) or placebo (n = 5). In cohort 2, patients were randomized to namilumab 300 mg (n = 7) or placebo (n = 4). Incidence of treatment-emergent adverse events (TEAEs) was similar across the three groups (namilumab 150 mg: 63%; namilumab 300 mg: 57%; placebo: 56%). TEAEs in ≥10% of patients were nasopharyngitis (17%) and exacerbation/worsening of RA (13%). No anti-namilumab antibodies were detected. The pharmacokinetics of namilumab were linear and typical of a monoclonal antibody with subcutaneous administration. In a post hoc efficacy, per protocol analysis (n = 21), patients randomized to namilumab showed greater improvement in Disease Activity Score 28 (erythrocyte sedimentation rate and C-reactive protein [CRP]), swelling joint counts and tender joint counts compared with placebo. Difference in mean DAS28-CRP changes from baseline between namilumab and placebo favored namilumab at both doses and at all time points. In addition area under the curve for DAS28-CRP was analyzed as time-adjusted mean change from baseline. A significant improvement in DAS28-CRP was shown with namilumab (150 and 300 mg groups combined) compared with placebo at day 43 (p = 0.0117) and also 8 weeks after last dosing at day 99 (p = 0.0154). ClinicalTrials.gov, NCT01317797 . Registered 18 February 2011.

Subcutaneous namilumab was generally well tolerated. Although namilumab demonstrated preliminary evidence of efficacy, patient numbers were small; phase 2 studies are ongoing.

To determine the performance of different tear and salivary tests applied in Sjögren's syndrome (SS) and to disclose how these tests relate to common serologic tests in SS. In addition to the routine ocular and oral tests for diagnosing SS (Schirmer test, rose bengal score, unstimulated whole saliva flow, and parotid sialography), tear breakup time and flow rate of glandular saliva (parotid and submandibular-sublingual [SM/SL]) were evaluated in patients referred for diagnosis of SS. Patients were categorized into primary SS, secondary SS, and non-SS groups according to the revised European classification criteria for SS. Referral center. Referred sample of 80 consecutive patients. Correlation between ocular and salivary measures. Breakup time performed insufficiently in diagnosing SS, as opposed to the rose bengal score. In patients with primary and secondary SS, a clear correlation was noted between tear and saliva quality and secretion rate, and between the rose bengal score and parotid sialography. Increased rose bengal scores also correlated significantly with hyperglobulinemia and presence of SS-B antibodies in serum, with duration of subjective eye dryness, and with decreased tear-gland function. With regard to the oral tests, whole, parotid, and SM/SL salivary flow decreased significantly with increasing duration of oral complaints, with the stimulated SM/SL flow rate showing the strongest decrease and being more specific in diagnosing SS. Also, parotid sialography was more specific in excluding patients without SS than the commonly applied diagnostic criterion of secretion of unstimulated whole saliva.

The rose bengal score remains the eye test of choice, as it has the highest specificity for SS. Hyperglobulinemia and especially positive serologic findings for SS-B may warrant close monitoring of the eyes, since these serum findings appear to relate to the severity of ocular surface damage. Parotid sialography and stimulated secretion of SM/SL saliva are more specific in diagnosing SS than unstimulated secretion of whole saliva.

The health state classifier EQ-5D of the EuroQoL group has been expanded to a 5-level instrument (EQ-5D-5L), but studies on psychometric properties of this new instrument, applied to the general population, are rare. A sample of 2,469 subjects, representatively selected from the German general population, was asked to fill in the EQ-5D-5L and several other questionnaires. Crude sum scores of the EQ-5D-5L were calculated and compared with scores derived from two sets of utilities, one from a German and one from a UK sample. The mean sum score (0-100 scale) was 91.5. Males reported better health states than females, and there was a nearly linear age trend. The list of the 45 most frequent health patterns (those with at least 0.2 % of the respondents) showed that almost half of the participants (47.5 %) responded being in the optimal health state, indicating a ceiling effect. Correlations between EQ-5D-5L scores and other questionnaires were very similar for all three scoring systems of the EQ-5D-5L. Finally, normative scores are given on the basis of sum scores.

The applicability of the EQ-5D-5L in the general population is limited because of the skewness. Sum scores are useful because of their simplicity, international generalizability, and construct validity.

To determine the association between radiographic osteoarthritis (OA) and pre-operative function in patients undergoing primary knee replacement. Single centre study examining pre-operative outcomes in a consecutive series of 525 patients who underwent primary knee replacement for OA between January 2006 and December 2007. Pre-operative data included: demographics, American Society of Anaesthesiologists (ASA) status and OA in the contralateral knee. The International Knee Society (IKS) rating and Short Form-12 (SF-12) were recorded for each patient. Pre-operative radiographs were read by a single observer for Kellgren and Lawrence (K&L) grading and Osteoarthritis Research Society International (OARSI) atlas features. Multiple linear regression was used to assess the strength of associations between radiographic OA severity and function, adjusting for clinically relevant variables. Lateral tibiofemoral osteophyte grade was an independent predictor of pre-operative function as determined by the functional sub-scale of the IKS in patients undergoing primary knee replacement (coefficient=2.58, p=0.033). No associations were evident between pre-operative function and modified K&L, joint space narrowing, Ahlbäck attrition and coronal plane deformity. Other statistically significant predictors of poorer pre-operative function included: advancing age, female gender, knee pain and poorer SF-12 mental component summary scores which including osteophyte grade accounted for 24.6% of the variation in functional scores, (r=0.496).

Osteophytes in the lateral compartment of the knee were associated with pre-operative function in patients with advanced knee OA. Further studies are required which examine individual radiographic features specifically in patients with advanced knee OA to determine their relationship to pre-operative pain and function.

The RhoA/Rho kinase pathway plays a pivotal role in cold-induced vasoconstriction, vascular smooth muscle cells function, and vascular homeostasis. This study evaluates the efficacy of fasudil, a RhoA/Rho kinase inhibitor, to reverse cold-induced vasospasm in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc; scleroderma). This is a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of oral fasudil (40 mg or 80 mg) or placebo administered 2 hours before a standardized cold challenge. The fall in skin temperature after the cold challenge and time to recover 50% and 70% of prechallenge digital skin temperature were used as primary outcomes. Digital blood flow assessed by laser Doppler, time to minimum skin temperature, and rate of skin cooling were also measured. A total of 17 patients with SSc and RP completed the study. After the cold challenge, skin temperatures and the average time (minutes) to recover 50% (7.9 minutes for placebo, 7.5 minutes for fasudil 40 mg, and 8.2 minutes for fasudil 80 mg; P = 0.791) and 70% (18.2 minutes for placebo, 15.0 minutes for fasudil 40 mg, and 17.1 minutes for fasudil 80 mg; P = 0.654) of prechallenge skin temperature were not significantly different across the 3 groups. The digital blood flow measurements were higher in fasudil-treated groups than placebo, but differences were not significant (P = 0.693).

Fasudil administered at a single oral dose of 40 mg or 80 mg was not associated with significant benefit in terms of the skin temperature recovery time and the digital blood flow after the cold challenge.

People with osteoarthritis (OA) of the knee who have pain generally exhibit decreased activity and physical deconditioning. This study investigated the effects of mechanical unweighting on knee pain and exercise responses in people with OA of the knee who have pain. Four men and 23 women, with a mean age of 67.9 years (SD = 11.3, range = 50-88) and having a 12-year average duration of knee OA, participated. A mechanical unloading device enabled subjects to perform a modified Naughton treadmill exercise test at 0%, 20%, and 40% of body weight support (BWS). Oxygen consumption (VO2), heart rate (HR), and perceived pain were measured during the last minute of each exercise stage. Mechanical unweighting at 20% and 40% BWS decreased the Vo2 and HR responses to treadmill exercise but did not decrease knee pain during walking in this sample.

These findings indicate that treadmill exercise accompanied by BWS permits recommended training intensities to be obtained in elderly people with OA, but may not provide pain relief in this group.

Blood transfusion is often necessary in operations for total hip replacement (THR). This study was done to investigate the efficacy of three different methods of autologous blood conservation and transfusion in patients undergoing primary THR without cement. One hundred fifty-five patients with osteoarthritis underwent unilateral cementless THR using normotensive general anesthesia performed by a single surgeon. The patients were divided into four groups depending on which conservation method was used. Ten different demographic and hematologic parameters were recorded and analyzed by using analysis of the variance and multiple regression methods. All three methods were effective in reducing the need for homologous blood transfusions. The greatest benefit was realized when both preoperative autologous blood donation and intraoperative salvage using the Cell Saver were combined. The addition of postoperative salvage and retransfusion of wound drainage blood using the Solcotrans System did not significantly reduce further the chance of homologous blood transfusions.

The data from this study were similar to previously published reports. Regression analysis confirmed the correlation among the different variables studied. We currently offer preoperative donation and intraoperative salvage with the Cell Saver to patients undergoing cementless total hip replacement.

To evaluate the role of magnetic resonance imaging (MRI) in the diagnosis, staging, and follow-up of the rheumatoid wrist. A Medline search was performed to identify all publications from the years 1985 to 1999 concerning MRI of the wrist in patients with rheumatoid arthritis (RA). Additional papers were retrieved by scanning the references to the Medline-listed articles. Details of the MRI technique, as well as clinical data, were analyzed and compared. A total of 55 papers were identified. There were considerable variations in imaging sequence, section type, and slice thickness. Erosions and synovitis were the conditions that mostly profited from the adoption of MRI. Although the visualization of erosions was better detailed with MRI than with conventional radiography, erosions were only rarely related to clinical and laboratory parameters. Another advantage was that synovitis imaging, which can be enhanced by contrast agents, was amenable to quantitation. The extent of the synovial surface and the rate of contrast enhancement in a series of consecutive, rapidly acquired images were the most common measures.

MRI of the rheumatoid wrist is a useful technique to ascertain the criteria for diagnosis and progression of RA, and to monitor the effects of treatment. Implementation of a standardized protocol could further increase its value.

Pain sensitization and the related secretion of neuropeptides from sensory nerve terminals are proinflammatory in osteoarthritis (OA), rheumatoid arthritis (RA), and adjuvant-induced polyarthritis. In contrast, endogenous opioids such as the recently discovered endomorphins (EMs) are antiinflammatory. However, the role of endogenous EMs such as EM-1 and EM-2 has never been investigated in OA and RA. We established a highly sensitive radioimmunoassay to detect EM-1 and EM-2. In patients with RA and patients with OA, immunohistochemistry for EM-1 and EM-2 was performed, and double-staining was used to identify EM-positive cells. The effects of EM-1 and EM-2 on the secretion of interleukin-6 (IL-6) and IL-8 from human synovial tissue were studied by tissue superfusion, and the therapeutic effects of EM-1 were tested in a rat model of adjuvant-induced polyarthritis. EM-positive cells were located in the sublining area and vessel walls but were particularly evident in the highly inflamed lining area. Human macrophages, T cells, and fibroblasts stained positive for EMs. The synovial density of EM-positive cells was higher in patients with OA than in those with RA. EM-1 inhibited synovial secretion of IL-6 in patients with RA and secretion of IL-8 in patients with RA and those with OA (maximum 10(-10)M). EM-2 inhibited IL-8 secretion only from RA tissue (maximum 10(-10)M). In rats with adjuvant-induced polyarthritis, thymus, spleen, and synovial tissue contained significantly more EM-1 than was observed in controls. Rats with adjuvant-induced polyarthritis benefited from EM-1 treatment.

EM-1 had antiinflammatory effects in patients with OA or RA and in a model of adjuvant-induced polyarthritis. Local enhancement of EM-1 might be an interesting therapeutic option in different forms of arthritis.

To determine ethnic variations of large-joint osteoarthritis (OA) in past populations. One thousand two hundred and nine adult skeletons, excavated from archaeological sites in Japan, China and France were assessed for OA as defined by the presence of eburnation. Within Asian skeletal populations, elbow OA and patellofemoral joint OA were more common in hunter-gatherers than in agriculturalists. Compared with Caucasians, the Asian skeletal population had a higher prevalence of tibiofemoral joint OA.

The relative frequencies of OA within and between ethnic groups at certain joint sites have changed over time from the past to the present.

To analyse the clinical features and pathogenesis of overlapping features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), termed 'Rhupus syndrome'. Twenty-four patients with Rhupus syndrome were identified over the last two decades. The clinical features of these patients were described and the literatures about this disease were reviewed. Twenty-four patients (twenty-three women, one man) were enrolled with an average age of 45.5 years. The mean age at presentation was 36.8 years. Nineteen of the patients initially present with erosive RA and developed SLE over about 7.7 years. In 14 patients who had convincing personal histories, 4 had pregnancies, 2 had dysmenorrhea and one had ovary cyst before poly arthritis developed. Ten of these patients were associated with menopause during transitions from RA to SLE. Expression frequencies of RA associated antibodies were similar as other RA patients. SLE associated manifestations were moderate in Rhupus syndrome especially severe renal damage. Hematopoietic system manifestations were prominent in this population.

Most of the Rhupus syndrome patients firstly presented with RA and showed less SLE associated severe damages. Sex hormone factor might be associated with the incidence of the disease.

To investigate the seroprevalence of A total of 205 cases with definitive diagnosis of rheumatoid arthritis, 257 cases with definitive diagnosis of malignant tumors and 235 cases with definitive diagnosis of schizophrenia were recruited, while 250 healthy volunteers served as controls. The demographic features were captured from the study subjects and serum samples were collected. The serum IgG and IgM antibodies against The seroprevalence of the anti-

The patients with rheumatoid arthritis, malignant tumors and schizophrenia present with higher seroprevalence of the anti-T.

To analyze the clinical course and duration of therapy in 28 patients with polymyalgia rheumatica (PMR) and/or temporal arteritis (TA) for identifying factors that influence prolonged steroid use and relapses. 28 cases of PMR and/or TA diagnosed from 1992 to 2001 were retrospectively studied in PUMC hospital. Patients were grouped according to the absence or presence of corticosteroid resistant and relapses. Of 28 patients, 22 had pure PMR, 3 had both PMR and TA and 3 had pure TA. 15 patients received corticosteroid therapy and 13 had both corticosteroid and immunosuppressor therapy. The median duration was (25.5 +/- 24.0) months. Increase of white blood cell level and higher baseline erythrocyte sedimentation rate (ESR) were significant risk factors associated with corticosteroid resistant (P < 0.01). Quicker reduction of corticosteroid dose was associated with relapse (P < 0.05).

Patients with increase of white blood cell level and higher baseline erythrocyte sedimentation rate (ESR) are more likely to be resistant to corticosteroid therapy. Quicker reduction in corticosteroid is more likely to relapse. Immunosuppressor therapy should be added to patients who has corticosteroid resistant, and relapse or PMR associated with TA.

To measure adherence and persistence with methotrexate (MTX) and injectable tumor necrosis factor-α (iTNF-α) inhibitors (etanercept, adalimumab) among children prescribed these medications by a rheumatologist. Data were obtained from a US pharmacy benefits management firm. Children were included if they were < 18 years of age, had ≥ 1 prescription claim between January 2009 and December 2010 for MTX or an iTNF-α inhibitor that was prescribed by an adult or pediatric rheumatologist. The medication possession ratio (MPR) was calculated for each medication, with MPR ≥ 80% indicating good adherence. MPR were compared by route of administration, age, and by new users versus continuing users. Persistence was measured for new users of each medication from initiation until discontinuation, or for a maximum of 1 year. A total of 1964 children were included. The majority of children had MPR < 80%. Children taking subcutaneous MTX had the lowest mean MPR [46.9%; median 44.9%; interquartile range (IQR) 23%-69.6%] and the lowest persistence, with 26% of children continuing the medication at 1 year. Mean MPR was highest for iTNF-α (65.7%; median 70.1%; IQR 46%-89.3%), as was persistence, with 52% of children continuing the medication at 1 year. Children age < 13 years tended to have higher MPR, but this was statistically significant only for oral MTX (61.1% vs 54.9% in children age ≥ 13 yrs; p = 0.02).

Adherence and persistence in this cohort varied by medication and route of administration. Both outcomes are important considerations for physicians prescribing these medications in routine clinical care and for the assessment of treatment effectiveness in the research setting.

To determine the effect of two different weekly doses of folic acid on the toxicity and efficacy of low-dose methotrexate therapy for rheumatoid arthritis. Randomized, double-blind, placebo-controlled study. 79 persons between 19 and 78 years of age who fulfilled the American Rheumatism Association's criteria for rheumatoid arthritis. Participants were randomly assigned to visually identical placebo or to 5 mg or 27.5 mg of folic acid each week. Duration, intensity, and clinical severity of toxic events; efficacy (indices of joint tenderness and swelling and grip strength); plasma and erythrocyte folate levels; and other laboratory variables. Folic acid supplementation at either dose did not affect the efficacy of methotrexate therapy as judged by joint indices and patient and physician assessments of disease. Patients given folic acid supplements had lower toxicity scores than did participants given placebo (P < or = 0.001). Low blood folate levels and increased mean corpuscular volumes were associated with substantial methotrexate toxicity, whereas daily dietary intakes of more than 900 nmol (400 micrograms) of folic acid were associated with little methotrexate toxicity.

Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.

Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on this disease remain scarce. This study was undertaken to describe patient characteristics and disease evolution, identify prognostic factors, and define different clinical phenotypes of RP. We performed a retrospective study of 142 patients with RP who were seen between 2000 and 2012 in a single center. Of the 142 patients, 86 (61%) were women. The mean ± SD age at first symptoms was 43.5 ± 15 years. Patients had the following chondritis types: auricular (89%; n = 127), nasal (63%; n = 89), laryngeal (43%; n = 61), tracheobronchial (22%; n = 32), and/orcostochondritis (40%; n = 57). The main other manifestations were articular (69%; n = 98), ophthalmologic (56%; n = 80), audiovestibular (34%; n = 48), cardiac (27%; n = 38), and cutaneous (28%; n = 40). At a mean ± SD followup of 13 ± 9 years, the 5- and 10-year survival rates were 95 ± 2% and 91 ± 3%, respectively. Factors associated with death on multivariable analysis were male sex (P = 0.01), cardiac abnormalities (P = 0.03), and concomitant myelodysplastic syndrome (MDS) (P = 0.004) or another hematologic malignancy (P = 0.01). Cluster analysis revealed that separating patients into 3 groups was clinically relevant, thereby separating patients with associated MDS, those with tracheobronchial involvement, and those without the 2 features in terms of clinical characteristics, therapeutic management, and prognosis.

This large series of patients with definite RP revealed an improvement in survival as compared with previous studies. Factors associated with death were male sex, cardiac involvement, and concomitant hematologic malignancy. We identified 3 distinct phenotypes.

The aim of the present study was to investigate the participation of TRPV1 in an acute gout attack model. Experiments were conducted to evaluate the participation of TRPV1 in the nociceptive and inflammatory responses (oedema, plasma extravasation, leucocyte infiltration and also IL-1β production) triggered by IA (ankle) administration of monosodium urate (MSU) in rats using selective antagonist TRPV1 receptor, defunctionalization of sensory fibres and increased immunoreactivity. We have also analysed the inflammatory response. The participation of mast cells in the MSU-induced nociception and inflammation was evaluated using a mast cell stabilizer and a mast cell degranulator compound. We observed that MSU (1.25 mg/site) injected into the rat ankle joint elicited ongoing pain-like behaviour, hyperalgesia, allodynia and articular oedema as well as plasma extravasation, leucocyte infiltration and IL-1β production in lavage fluid. All of these events were inhibited by the co-administration of the selective TRPV1 receptor antagonist SB366791 (10 nmol/site). MSU crystals also increased the immunoreactivity of the TRPV1 receptor in the articular tissue of injected animals. Furthermore, the defunctionalization of TRPV1-positive sensory neurons also significantly reduced MSU-induced ongoing pain-like behaviour, hyperalgesia and oedema.

Thus we demonstrate that TRPV1 acts on sensory neurons and plays a relevant role in the nociception and inflammation induced by IA MSU, indicating it as a potential target to treat acute gout attacks.

Cementation of tibial implants in total knee arthroplasty is the gold standard considering the high loosening rates of cementless implants. In contrast, only sparse data exist regarding unicondylar arthroplasty due to its lesser use. In this study, we compare cemented with cementless unicondylar knee arthroplasty and aim to define both clinical and radiological differences in treatment outcome. In a retrospective study, 106 patients who had undergone a medial unicondylar replacement were examined after a mean postoperative period of 8 years. Of these, 42 patients (median age 81 +/- 7 years) had received a cemented and 64 (median age 73 +/- 7 years) a cementless knee arthroplasty by the same surgeon while 7 patients were deceased or could not be reached. Well-established clinical (VAS, HSS, KSS, UCLA, WOMAC) and quality of life (SF-36) scores were used to evaluate treatment outcome. X-rays were performed to evaluate periprosthetic loosening zones, according to Ewald's criteria. The cementless patient group presented significantly better clinical scores (HSS, KSS, UCLA, WOMAC), except in the visual analogue scale (VAS) for pain assessment. The quality of life was significantly better in the cementless group except in the subgroups for physical function, vitality and social role, in that it resembles the normal population. Moreover, radiographic analysis using antero-posterior X-rays revealed significantly more and larger periprosthetic loosening areas in tibial zone 2 in the cementless group.

The inferior clinical results characterising the cemented group could be attributed to the higher mean age. Regarding the radiological loosening zones, we did not detect any differences in the techniques of fixation, although physical activity and accordingly mechanical stresses were higher in the cementless group.

Nonsteroidal antiinflammatory drugs (NSAIDs) increase blood pressure and potentially cardiovascular burden, which may limit their use in ankylosing spondylitis (AS). Our objective was to determine the association of NSAID use with incident hypertension in a longitudinal AS cohort. Adults with AS were enrolled in a prospective cohort study of patient outcomes and examined every 4-6 months. Hypertension was defined by patient-reported hypertension; antihypertensive medication use; or, on 2 consecutive visits, systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. Continuous NSAID use was dichotomized based on the validated NSAID index. We assessed the association of NSAID use as a time-varying exposure with the incidence of hypertension using Cox proportional hazards models. Of the 1,282 patients in the cohort, 628 patients without baseline hypertension had at least 1 year of follow-up and were included in the analysis. Of these, 72% were male, the mean age at baseline was 39 ± 13 years, and 200 patients used NSAIDs continuously. On follow-up, 129 developed incident hypertension. After controlling for other variables, continuous NSAID use was associated with a hazard ratio of 1.12 for incident hypertension (95% confidence interval 1.04-1.20), compared to noncontinuous or no use. The association did not differ in subgroups defined by age, body mass index, biologic use, or disease activity.

In our prospective, longitudinal AS cohort, continuous NSAID use was associated with a 12% increased risk for the development of incident hypertension, as compared to noncontinuous or no NSAID use.

To determine whether antibodies to double stranded DNA (anti-dsDNA) have a pathogenic role in systemic lupus erythematosus (SLE). IgG was purified from 17 patients with SLE (median anti-dsDNA titre 1212 IU/ml) and nine healthy controls (median titre 40 IU/ml). Anti-dsDNA depleted polyclonal IgG (median anti-dsDNA titre 17 IU/ml) was also prepared from sera of the 17 patients by affinity chromatography on a DNA cellulose column. Binding to antiendothelial cell antibodies (AECA) and expression of von Willebrand factor (VWF) antigen by cultured human umbilical vein endothelial cells (HUVECs) were studied by flow cytometry. The percentage of HUVECs binding to AECA or expressing VWF was greater for cells incubated with IgG from patients with SLE than for cells incubated with control IgG, though values did not reach statistical significance; nevertheless, HUVECs incubated with IgG from patients expressed a greater mean fluorescence intensity with AECA (p = 0.0001) and greater VWF expression (p = 0.019). Both the fluorescence intensity and percentage of HUVECs binding to AECA or expressing VWF were significantly greater in HUVEC incubated with IgG containing anti-dsDNA than in those incubated with anti-dsDNA depleted IgG. The concentration of VWF in the supernatant was significantly increased in HUVECs incubated with IgG containing anti-dsDNA compared with control IgG or anti-dsDNA depleted IgG. Pretreatment of HUVECs with native DNA before incubation with IgG from lupus patients did not increase binding to AECA, or expression or release of VWF.

Our study provides in vitro evidence that antibodies to DNA have a pathogenic role in the induction of inflammatory injury of the vascular endothelium in SLE.

To evaluate whether change in fixed-location measures of radiographic joint space width (JSW) and cartilage thickness by MRI predict knee replacement. Knees replaced between 36 and 60 months' follow-up in the Osteoarthritis Initiative were each matched with one control by age, sex and radiographic status. Radiographic JSW was determined from fixed flexion radiographs and subregional femorotibial cartilage thickness from 3 T MRI. Changes between the annual visit before replacement (T0) and 2 years before T0 (T-2) were compared using conditional logistic regression. One hundred and nineteen knees from 102 participants (55.5 % women; age 64.2 ± 8.7 [mean ± SD] years) were studied. Fixed-location JSW change at 22.5 % from medial to lateral differed more between replaced and control knees (case-control [cc] OR = 1.57; 95 % CI: 1.23-2.01) than minimum medial JSW change (ccOR = 1.38; 95 % CI: 1.11-1.71). Medial femorotibial cartilage loss displayed discrimination similar to minimum JSW, and central tibial cartilage loss similar to fixed-location JSW. Location-independent thinning and thickening scores were elevated prior to knee replacement. • Fixed-location JSW predicts surgical knee replacement more strongly than minimum JSW. • MRI predicts knee replacement with similar accuracy to radiographic JSW. • MRI reveals greater cartilage thinning and thickening prior to knee replacement.

Discrimination of structural progression between knee pre-placement cases versus controls was stronger for fixed-location than minimum radiographic JSW. MRI displayed similar discrimination to radiography and suggested greater simultaneous cartilage thickening and loss prior to knee replacement.

The aim of this study was to evaluate the effects of an exercise training protocol and low-level laser therapy (and the association of both treatments) on musculoskeletal atrophy using an experimental model of knee osteoarthritis (OA). Fifty male Wistar rats were randomly divided into five groups: control group, knee OA control group, OA plus exercise training group, OA plus low-level laser therapy group, and OA plus exercise training associated with low-level laser therapy group. The exercise training and the laser irradiation started 4 wks after the surgery, 3 days per week for 8 wks. The exercise was performed at a speed of 16 m/min, 3 days per week, 50 mins per day, for 8 wks. Laser irradiation was applied at two points of the left knee joint (medial and lateral), for 24 sessions. The results showed that both trained groups (irradiated or not) presented a significant increase in the muscle cross-sectional area and a decrease in muscle fiber density compared with the knee OA control group. Moreover, both trained and laser-irradiated groups demonstrated decreased muscle-specific ring-finger protein 1 and atrogin-1 immunoexpression.

These results suggest that exercise training and low-level laser therapy were effective in preventing musculoskeletal alterations related to atrophy caused by the degenerative process induced by knee OA.

Methotrexate (MTX) is a first-line disease-modifying agent and anchor drug for biologic therapy used in rheumatoid arthritis and other inflammatory rheumatic disorders. Adverse effects are a common cause of drug discontinuation and include preventable serious incidents that may result in patient harm or death. The objective of this study was to audit adherence by health professionals to national and international guidelines for patient education and risk reduction in patients prescribed MTX for inflammatory rheumatic diseases. A combination of interviews, case record reviews, and self-administered patient knowledge questionnaires with individual patient feedback was used. The setting was the rheumatology outpatient department of a district general hospital. Fifty-one patients participated in the audit. The mean age was 58.6 (SD, 13.1) years and median duration of disease was 3.7 years (interquartile range, 1.7-7.6 years). Nurse-led patient education was documented at baseline for 94.1% of participants. Despite this, only 11.8% of participants recognized the potentially lethal drug-drug interaction with trimethoprim/Septrin (co-trimoxazole), and less than 60.8% recognized possible major adverse effects related to MTX. Although lifestyle implications relating to alcohol consumption and pregnancy/breast-feeding were recognized by the majority, only 52.9% of males were aware of recommendations in relation to conception. Univariable and multivariable analyses identified male sex, not speaking English as a first language, and a longer duration of therapy as predictors of lower levels of patient knowledge.

Despite consistent baseline patient education, end-user knowledge and awareness pertinent to MTX safety are limited. Good-quality written information in the most appropriate language, patient feedback on educational programs, follow-up testing of patient knowledge, and targeted reeducation are recommended to address individual deficiencies in core knowledge.

Frailty is defined as the degradation of physical and cognitive function in older adults. The relationship between frailty and disease activity in patients with rheumatoid arthritis is unclear. Factors related to frailty in Japanese rheumatoid arthritis patients were investigated in a cross-sectional analysis. Of 100 patients who entered the prospective, observational Correlation research of sarcopenia, skeletal muscle and disease activity in rheumatoid arthritis (CHIKARA) study, 95 completed a frailty check list (maximal score 25), and were classified as frail (8-25 points), pre-frail (4-7 points) and normal (0-3 points). The relationship with disease activity was investigated in the frailty, pre-frailty and normal groups. Relationships between clinical variables and frailty were evaluated by univariate and multiple logistic regression analyses. The prevalences of frailty, pre-frailty and normal were 18.9%, 38.9% and 42.2%, respectively. The disease activity score 28 erythrocyte sedimentation rate, matrix metalloproteinase 3 and modified health assessment questionnaire were higher in the frailty group. In remission, 66.6% were normal and 6.7% had frailty, but with moderate and high disease activity, 13.3% were normal and 46.7% had frailty. On univariate analysis, factors positively related to frailty were age, locomotive syndrome, disease activity score 28 erythrocyte sedimentation rate, matrix metalloproteinase 3, use of biological disease-modifying antirheumatic drugs or targeted synthetic disease-modifying antirheumatic drugs, Steinbrocker class and modified health assessment questionnaire; and the leg muscle score and grip strength were negatively related. Matrix metalloproteinase 3 was the only independent factor on multivariate logistic analysis. In patients aged >60 years, this tendency was similar.

Frailty was found to be related to disease activity and physical function in rheumatoid arthritis. Control of disease activity appears important to prevent frailty. Geriatr Gerontol Int 2019; 19: 1220-1225.

To analyze the gross features of articular cartilage wear in varus knee osteoarthritis, and discuss the risk factors for lateral compartmental cartilage erosion. Data prospectively collected from the dissection of 286 total knee arthroplasties (223 patients) with varus knee osteoarthritis from January 2013 to December 2013 were analyzed. At the operation, the gross assessments of articular cartilage, ligament and meniscus were recorded, and then the slices were evaluated for histologic analysis. Parameters of the patients with lateral compartmental cartilage erosion were compared with those without lateral compartmental cartilage erosion using the univariate analysis. Logistic regression analysis was used to analyze the risk factors associated with lateral compartmental cartilage erosion. There were 223 patients with 286 knees were included,including 37 male patients (47 knees) and 189 female patients (239 knees), with an average age of (66±8) years (range 50-86 years), body mass index (BMI) was (27±5) kg/m2 (18.0-40.0 kg/m2). Varus degree was 8°±4° (1°-34°). Range of motion was 103°±21° (0°-143°), and Hospital for Special Surgery (HSS) score was 53±12 (29-76). Seventy-five knees (60 patients) showed lateral compartmental cartilage wear (26.2%). Environmental factors showed no differences in age, side, gender, BMI, range of motion,and HSS score (P>0.05). Factors significantly increasing the risk of lateral compartmental cartilage wear by univariate analysis included varus degree, activity level, duration of onset, meniscus, Weidow grade, Kellgren-Lawrence grade, collateral ligament and anterior cruciate ligament (P<0.05). Multiple Logistic regression analysis revealed the factors most highly associated with the increase risk for lateral compartmental wear were high activity level (OR=2.843, 95% CI: 1.010-8.002) and longer duration of onset (OR=1.216, 95% CI: 1.115-1.325). However, intact lateral meniscus (OR=0.012, 95% CI: 0.003-0.048) and anterior cruciate ligament (OR=0.406, 95% CI: 0.192-0.857) were associated with the protection of lateral compartmental.

In varus knee osteoarthritis, the wear incidence of lateral compartmental is low. High activity and increased duration of onset are risk factors of lateral compartmental wear, and intact meniscus and anterior cruciate ligament are protective factors.

The relative safety of long-term use of nonsteroidal anti-inflammatory drugs is unclear. Patients and providers are interested in an integrated view of risk . We examined the risk of major nonsteroidal anti-inflammatory drug toxicity in the PRECISION trial. We conducted a post hoc analysis of a double-blind, randomized, controlled, multicenter trial enrolling 24,081 patients with osteoarthritis or rheumatoid arthritis at moderate or high cardiovascular risk. Patients were randomized to receive celecoxib 100 to 200 mg twice daily, ibuprofen 600 to 800 mg thrice daily, or naproxen 375 to 500 mg twice daily. All patients were provided with a proton pump inhibitor. The outcome was major nonsteroidal anti-inflammatory drug toxicity, including time to first occurrence of major adverse cardiovascular events, important gastrointestinal events, renal events, and all-cause mortality. During follow-up, 4.1% of subjects sustained any major toxicity in the celecoxib arm, 4.8% in the naproxen arm, and 5.3% in the ibuprofen arm. Analyses adjusted for aspirin use and geographic region found that subjects in the naproxen arm had a 20% (95% CI 4-39) higher risk of major toxicity than celecoxib users and that 38% (95% CI 19-59) higher risk. These risks translate into numbers needed to harm of 135 (95% CI, 72-971) for naproxen and 82 (95% CI, 53-173) for ibuprofen, both compared with celecoxib.

Among patients with symptomatic arthritis who had moderate to high risk of cardiovascular events, approximately 1 in 20 experienced a major toxicity over 1 to 2 years. Patients using naproxen or ibuprofen experienced significantly higher risk of major toxicity than those using celecoxib.

Laparoscopic cholecystectomy is one of the most frequently performed surgical interventions nowadays in developed countries. While lost gallstones during the procedure represent a commonly encountered issue, there is an ongoing debate whether split gallstones imperatively need to be extracted during the same procedure. The reported case of a wall abscess several years after follow-up lights up this debate. A 75-year-old male Caucasian with a history of rheumatoid arthritis and congestive heart failure presented with a recurrent subcutaneous abdominal wall abscess with occasional, spontaneous drainage of pus. He underwent laparoscopic cholecystectomy for acute calculous cholecystitis 3 years ago with uneventful and prompt recovery. A computed tomography scan showed a cavity in the periumbilical abdominal wall with peripheral contrast-enhancing, next to a calcified foreign body between the rectus muscle sheets. Wound exploration under general anaesthesia was performed with drainage of the cavity, extraction of the foreign body and closure of the anterior rectus sheet over a drainage catheter. The foreign body turned out to be a gallstone lost in the periumbilical port site during the procedure. Antibiotic treatment with co-amoxiclav was continued for 14 days. The patient was discharged 9 days postoperatively with a clean wound.

This case and short review of the literature is a reminder of the importance of careful extraction of split gallstones during cholecystectomy in order to avoid early or late complications. This is especially important in the light of one of the most commonly performed surgical procedures in developed countries with generally low morbidity.

Study of prevalence of gout with concomitant diseases. Study population included all living persons in Stockholm County, Sweden, on January 1st 2013 (N=2,124,959). A diagnosis of gout was identified during 2013-2014, with information of diabetes mellitus and insulin resistance, hypertension, chronic heart failure, chronic kidney disease, alcohol abuse, and malignancies. Age-adjusted odds ratios (ORs) with 95% confidence intervals (95% CI) for women and men with gout, using individuals without gout as referents, were calculated. Age-adjusted odds of co-morbidities among individuals with gout vs. those without gout were: diabetes mellitus and insulin resistance 3.97 (95% CI 3.65-4.31) in women and 1.88 (95% CI 1.78-1.99) in men; hypertension 4.02 (95% CI 3.69-4.37) in women and 3.21 (95% CI 3.06-3.37) in men; chronic heart failure 4.72 (95% CI 4.31-5.19) in women and 2.84 (95% CI 2.66-3.04) in men; chronic kidney disease 2.08 (95% CI 1.50-2.87) in women and 2.39 (95% CI 2.15-2.66) in men; alcohol abuse 8.98 (95% CI 8.15-9.80) in women and 4.38 (95% CI 4.10-4.69) in men; and malignancies 1.32 (95% CI 1.17-1.48) in women and 1.13 (95% CI 1.06-1.21) men.

Gout is a warning sign for concomitant diseases, e.g. alcoholism, diabetes, cardiovascular diseases, and cancer. KEY MESSAGES.

The objective of this study was to compare the two-year migration pattern and clinical outcomes of a total knee arthroplasty (TKA) with an asymmetrical tibial design (Persona PS) and a well-proven TKA with a symmetrical tibial design (NexGen LPS). A randomized controlled radiostereometric analysis (RSA) trial was conducted including 75 cemented posterior-stabilized TKAs. Implant migration was measured with RSA. Maximum total point motion (MTPM), translations, rotations, clinical outcomes, and patient-reported outcome measures (PROMs) were assessed at one week postoperatively and at three, six, 12, and 24 months postoperatively. A linear mixed-effect model using RSA data of 31 asymmetrical and 38 symmetrical TKAs did not show a difference in mean MTPM migration pattern of the tibial or femoral components. Mean tibial component MTPM at two years postoperative of the asymmetrical TKA design was 0.93 mm and 1.00 mm for the symmetrical design. For the femoral component these values were 1.04 mm and 1.14 mm, respectively. No significant differences were observed in other migration parameters or in clinical and PROM measurements.

The TKA design with an asymmetrical tibial component has comparable component migration with the proven TKA with a symmetrical tibial component. This suggests the risk of long-term aseptic loosening of the two designs is comparable. Cite this article:

Calcium pyrophosphate dihydrate (CPPD) crystals are commonly observed in osteoarthritic joints. The aim of our study was to investigate the efficacy of a dual-energy computed tomography (DECT) for detecting CPPD crystals in knee meniscus. Twenty-six patients undergoing primary total knee arthroplasty were included in the study. Radiographs of knee joint and synovial fluid specimens were analyzed for the presence of CPPD crystals. Meniscus extracted during surgery was scanned using DECT. Sensitivity and specificity of DECT and radiograph for detecting CPPD crystals were calculated against a reference standard (polarizing light microscopy of synovial fluid aspirate). Meniscus in which CPPD crystals were suspected with DECT was further examined to confirm the crystals using a polarized microscopy. CPPD crystals in synovial fluid were observed in 9 (36%) patients. The sensitivity and specificity of DECT in the detection of CPPD crystals, against microscopic identification, were 77.8 and 93.8%, respectively. The sensitivity and specificity of conventional radiography in the detection of CPPD crystals were 44.4 and 100%, respectively. DECT was able to detect the area where CPPD crystals were deposited in the meniscus.

DECT provides good diagnostic sensitivity and specificity for detection of CPPD crystals in knee meniscus as well as spatial information about CPPD crystals. DECT is currently a research tool, but we believe that DECT can be a useful instrument to diagnose CPPD deposition disease, especially for the regions where aspiration is difficult to be performed such as pubic symphysis, atlantoaxial joint, interphalangeal joint.

There is no standardized approach to the initial treatment of polyarticular juvenile idiopathic arthritis (JIA) among pediatric rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available will result in better health outcomes for polyarticular JIA. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for use in clinical practice to facilitate such studies. A case-based survey was administered to CARRA members to identify the common treatment approaches for new-onset polyarticular JIA. Two face-to-face consensus conferences employed modified nominal group technique to identify treatment strategies, operational case definition, end points, and data elements to be collected. A core workgroup reviewed the relevant literature, refined plans, and developed medication dosing and monitoring recommendations. The initial case-based survey identified significant variability among treatment approaches for new-onset polyarticular JIA. We developed 3 CTPs based on treatment strategies for the first 12 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The CTPs include a step-up plan (nonbiologic disease-modifying antirheumatic drug [DMARD] followed by a biologic DMARD), an early combination plan (nonbiologic and biologic DMARD combined within a month of treatment initiation), and a biologic only plan. This approach was approved by 96% of the CARRA JIA Research Committee members attending the 2013 CARRA face-to-face meeting.

Three standardized CTPs were developed for new-onset polyarticular JIA. Coupled with data collection at defined intervals, use of these CTPs will enable the study of their comparative effectiveness in an observational setting to optimize initial management of polyarticular JIA.

To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA). Human aortic endothelial cells (HAECs) were treated with lipopolysaccharide (LPS), OxPAPC, and free fatty acids (FFA) at baseline and after incubation with the TLR4 antagonist eritoran (E5564). Cytokine expression was assessed by quantitative real-time PCR. In vivo endothelial function was assessed as brachial artery flow-mediated dilation (FMD) in RA patients with the wild type gene (aa) and with the Asp299Gly TLR4 polymorphic variant (ag). In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFα, CCL-2, VCAM and ICAM (P<0.05 for all) and inhibited Ox-PAPC-induced mRNA expression of IL-8 (P<0.05) and IL-6, albeit not to a statistically significant level (p = 0.07). In contrast, eritoran did not affect FFA-induced mRNA expression of IL-6 (P>0.05). In 30 patients with RA (15 with the ag allele) undergoing measurement of FMD, no differences in FMD and plasma levels of IL-6, IL-8, VCAM, and ICAM were found between the aa and the ag phenotype (P>0.05 for all).

TLR4 signaling in endothelial cells may be triggered by LPS and oxidized phospholipids, leading to endothelial activation and inflammation, which are inhibited by eritoran. Our in vivo investigation, however, does not support an association between the Asp299Gly TLR4 polymorphism and improved endothelium-dependent vasodilator function in patients with RA. Further study is needed to better understand the potential role of TLR4 on endothelial dysfunction in this and other patient populations.

The distribution and function of lymphatic vessels in normal and diseased human knees are understood incompletely. This study aimed to investigate whether lymphatic density is associated with clinical, histological or radiographic parameters in osteoarthritis (OA). Sections of synovium from 60 knees from patients with OA were compared with 60 post mortem control knees (from 37 individuals). Lymphatic vessels were identified using immunohistochemistry for podoplanin, and quantified as lymphatic vessel density (LVD) and lymphatic endothelial cell (LEC) fractional area. Effusion status was determined by clinical examination, radiographs were scored for OA changes, and inflammation grading used haematoxylin and eosin stained sections of synovium. Lymphatic vessels were present in synovia from both disease groups, but were not identified in subchondral bone. Synovial lymphatic densities were independent of radiological severity and age. Synovia from patients with OA displayed lower LVD (z=-3.4, P=0.001) and lower LEC fractional areas (z=-4.5, P<0.0005) than non-arthritic controls. In patients with OA, low LVD was associated with clinically detectable effusion (z=-2.2, P=0.027), but not with histological evidence of synovitis. The negative associations between lymphatics and OA/effusion appeared to be independent of other measured confounders.

Lymphatic vessels are present in lower densities in OA synovia. Abnormalities of synovial fluid drainage may confound the value of effusion as a clinical sign of synovitis in OA.

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology characterized by cartilage and bone destruction. The main genetic determinant to RA, the shared epitope, maps to the HLA-DR locus, although this is not the only risk factor. The osteopontin (OPN) gene, with pleiotropic functions in inflammatory and immune responses, has been implicated in the pathogenesis of RA. We studied the association of polymorphisms in the OPN gene and predisposition to RA. Analysis was performed in a case-control study with 263 patients and 478 controls. Four single nucleotide polymorphisms (SNP), 327T/C, 795C/T, 1128A/G, and 1284A/C, of the OPN gene were genotyped by primer-specific amplification in the presence of SYBR Green. Distorted transmission of these polymorphisms was studied in 58 RA trios and 61 affected sibling pairs. These SNP demonstrated strong linkage disequilibrium. No statistically significant association was observed (80% power to exclude a genotypic relative risk of 1.49 at the 5% significance level, with minor allele frequencies of 28%). This lack of association with RA was found after stratification for the shared epitope as well.

Our data suggest that, unlike the reported effect of the OPN SNP conferring predisposition to common diseases such as multiple sclerosis or systemic lupus erythematosus, these OPN gene polymorphisms do not contribute to RA susceptibility in the Spanish population we studied.

The overexpression of B-cell activating factor (BAFF) in mucosa-associated lymphoid tissue (MALT) may decrease the efficacy of rituximab treatment in Sjögren's syndrome (SS). Anti-CD20 therapy was effective on marginal zone B cells, in the murine model for human CD20 expression only when preceded by anti-BAFF therapy. The possible efficacy of a sequential anti-BAFF/anti-CD20 therapy in SS was investigated. We treated with belimumab, a monoclonal anti-BAFF antibody, and soon after with rituximab a patient with severe, refractory SS, parotid low-grade B-cell MALT lymphoma and cryoglobulinaemic vasculitis. Previous treatments with rituximab and with rituximab plus high dose glucocorticoids, as well as with cyclophosphamide, azathioprine, plasma exchange, hyperbaric therapy, VAC therapy, prostacyclin, mycophenolate mofetil and surgery, had previously failed. Treatment with belimumab was then given, but it also failed. A new course of rituximab (375 mg/m2; four weekly infusions) was started 49 days after the last infusion of belimumab. This sequential belimumab-rituximab treatment was followed by a marked amelioration, with the complete and persistent regression of lymphoma and healing of a refractory skin ulcer. A full cycle of rituximab was then repeated 6 and 12 months later; no further treatment was given in the following 22 months up to now. Serum cryoglobulins and rheumatoid factor became persistently negative and serum BAFF and C4 persistently normal. No relevant side effects were noticed, except for a marked decrease in serum IgM. The follow up after belimumab-rituximab sequential therapy is now three and a half years.

Therapy with belimumab followed by rituximab may be effective for SS-related B-cell lymphoproliferation. The efficacy and safety of the sequential or concomitant targeting of BAFF and CD20 deserves further evaluation in SS.

Assessor-based disease activity measures such as the Disease Activity Score in 28 joints (DAS28), although widely used in rheumatoid arthritis (RA), have high interobserver variability. We developed and validated a patient-based disease activity score (PDAS) as an alternative assessment. Patients' assessments of swollen or tender joints, visual analog scales for pain and general health, the Health Assessment Questionnaire, and erythrocyte sedimentation rate (ESR) were used to develop the PDAS. In a developmental cohort (204 patients), regression analyses determined the best fit with the DAS28. A validation cohort (322 patients) subsequently evaluated criterion and construct validity against a range of outcome measures, including the Nottingham Health Profile (NHP) and Short Form 36 (SF-36). Sensitivity to change was assessed in 56 patients after 6 months of treatment with disease-modifying antirheumatic drugs or biologics. In the developmental cohort, the PDAS with ESR (PDAS1) and without ESR (PDAS2) achieved excellent fit with the DAS28 (r = 0.88 and 0.74, respectively). In the validation cohort, the PDAS showed high criterion validity by correlation with the DAS28 (PDAS1: r = 0.89, PDAS2: r = 0.76). Construct validity was demonstrated by high correlations with a range of disease activity measures (r > or = 0.45), whereas low correlations (r < 0.45) with mental and social components of the SF-36 and NHP indicated divergent validity. The PDAS and DAS28 had similar sensitivity to change, determined using effect sizes (DAS28 = 1.03, PDAS1 = 1.02, PDAS2 = 0.77) or standardized response means (DAS28 = 0.79, PDAS1 = 0.77, PDAS2 = 0.73).

The PDAS1 and PDAS2 are valid and sensitive tools to assess disease activity in RA. They appear suitable for clinical decision making, epidemiologic research, and clinical trials.

Combined anteversion in total hip arthroplasty influences both dislocation risk and range of motion. One of its components, stem version (SV), could be dictated by many factors, from native femoral anatomy to stem geometry and surgeon's choice. In the present multicenter study, robotic technology was used to assess the influence of native femoral version on final SV and combined anteversion using a straight, uncemented stem. Three hundred sixty-two patients undergoing total hip arthroplasty were enrolled from 3 different orthopedic centers from 2012 and 2016. All patients underwent computed tomography planning with measurement of femoral neck version (FNV) and intraoperative measurement of stem version (SV), acetabular component version (AV), and combined version (CV) with robotic instrumentation. Mean FNV was 5.0° ± 9.6°, and SV was 6.4° ± 9.7°. The average difference between FNV and SV was 1.6° ± 9.8°. A moderate correlation was found between FNV and SV (R = 0.48, P < .001). SV was between 5° and 20° in 174 patients (48%). Mean CV was 28.2° ± 7.9°. A strong correlation was found between SV and CV (R = 0.89, P < .001). A significant difference in SV was found between the 3 centers (P < .001). CV was <25° in 109 patients (30.1%). Relative risk of CV < 25° was 8.6 times greater with SV < 5° (P < .001).

With the use of an uncemented, single-wedge, straight stem, SV is highly variable. Despite being moderately correlated with native FNV, SV can be partially influenced by the surgeon. A low SV could be hardly corrected, bringing high risk of low CV.

In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti-citrullinated protein antibody (ACPA), CCP-Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP-Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA. The target protein of CCP-Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline-reverted (GL-rev) CCP-Ab1 was generated, and its reactivity was compared to that of mature CCP-Ab1. The functions of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis-prone SKG mice. CCP-Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL-rev CCP-Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL-rev CCP-Ab1 binding to a citrullinated peptide, cfc1-cyc, were almost identical to those implicated in CCP-Ab1 binding. In arthritis-prone SKG mice, CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin-6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP-Ab1 compared to those treated with GL-rev CCP-Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP-Ab1 (P < 0.05 versus control treatment groups).

These data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.

Immunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. In contrast, IgG anti-MDA are increased in chronic inflammation and autoimmunity and may instead have pathogenic properties. Herein, we investigated serum IgG anti-MDA levels by enzyme-linked immunosorbent assay (ELISA) in 398 systemic lupus erythematosus (SLE) patients in the Swedish Karolinska SLE cohort and compared these to findings in 225 US SLE patients from New York University and Johns Hopkins University. In two independent cohorts, IgG anti-MDA levels correlated positively with disease activity by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; p < 0.0001, Spearman R = 0.3). Meta-analysis found an odds ratio of 2.7 (confidence interval (CI) 1.9-3.9; p < 0.0001) for high anti-MDA IgG levels with active disease (SLEDAI ≥ 6). Furthermore, IgG anti-MDA correlated directly with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2), and vascular cell adhesion molecule 1 (VCAM-1) measurements, and inversely with complement factors (C1q, C2, C3, C4). Importantly, IgG anti-MDA levels were significantly elevated in SLE patients with active nephritis (p = 0.0005) and correlated with cystatin C estimated glomerular filtration rate and albuminuria.

Elevated IgG anti-MDA in SLE patients was associated with high disease activity, with active lupus nephritis, and with biomarkers of systemic inflammation. This natural antibody reactivity may have potential prognostic utility, and may also actively contribute to pathogenesis.

To investigate the impact of deleting Suppressor of Cytokine Signaling (SOCS)-3 (SOCS3) in chondrocytes during murine skeletal development. Mice with a conditional Socs3 allele (Socs3 Socs3

Our results suggest a potential role for SOCS3 in GP chondrocyte proliferation by regulating FGFR3-dependent MAPK signaling in response to FGF18.

By using machine learning, our study aimed to build a model to predict risk and time to total knee replacement (TKR) of an osteoarthritic knee. Features were from the Osteoarthritis Initiative (OAI) cohort at baseline. Using the lasso method for variable selection in the Cox regression model, we identified the 10 most important characteristics among 1,107 features. The prognostic power of the selected features was assessed by the Kaplan-Meier method and applied to 7 machine learning methods: Cox, DeepSurv, random forests algorithm, linear/kernel support vector machine (SVM), and linear/neural multi-task logistic regression models. As some of the 10 first-found features included similar radiographic measurements, we further looked at using the least number of features without compromising the accuracy of the model. Prediction performance was assessed by the concordance index, Brier score, and time-dependent area under the curve (AUC). Ten features were identified and included radiographs, bone marrow lesions of the medial condyle on magnetic resonance imaging, hyaluronic acid injection, performance measure, medical history, and knee-related symptoms. The methodologies Cox, DeepSurv, and linear SVM demonstrated the highest accuracy (concordance index scores of 0.85, Brier score of 0.02, and an AUC of 0.87). DeepSurv was chosen to build the prediction model to estimate the time to TKR for a given knee. Moreover, we were able to decrease the features to only 3 and maintain the high accuracy (concordance index of 0.85, Brier score of 0.02, and AUC of 0.86), which included bone marrow lesions, Kellgren/Lawrence grade, and knee-related symptoms, to predict risk and time of a TKR event.

For the first time, we developed a model using the OAI cohort to predict with high accuracy if a given osteoarthritic knee would require TKR, when a TKR would be required, and who would likely progress fast toward this event.

Pain, fatigue and functional disability are common key outcomes in most rheumatologic disorders. While many studies have assessed the outcomes of specific disease states, few have compared the outcomes of various rheumatic diseases. To assess how the intensity and rating of pain, fatigue and functional disability vary among groups of patients with various rheumatic disorders receiving standard care. In a cross-sectional study conducted in a hospital-based rheumatology unit, standard clinical and laboratory data were obtained and all patients filled out questionnaires on pain, fatigue and daily function. The analysis concentrated on visual analogue scales (VAS) using specific statistical methods. A total of 618 visits of 383 patients with inflammatory as well as non-inflammatory rheumatic disorders were analyzed. Fibromyalgia patients had significantly higher VAS scores compared to all other groups. On the other hand, patients with polymyalgia rheumatica demonstrated significantly lower VAS scores compared to all other groups of patients. Patients with psoriatic arthritis also demonstrated relatively low VAS scores. VAS scores were lower in patients with inflammatory disorders as compared to patients with non-inflammatory disorders.

Our results suggest a spectrum of outcome intensity in various rheumatic disorders receiving standard care, ranging from fibromyalgia patients who report distinctive severity to patients with inflammatory disorders who are doing relatively well as compared to patients with non-inflammatory disorders. The findings emphasize the need to explore the underlying mechanisms of pain and fatigue in patients with non-inflammatory rheumatic disorders.

To study the effects of lipopolysaccharide (LPS), the supernatant of U937 cells stimulated with LPS and dexamethasone on matrix metalloproteinase-9 (MMP-9) expression in the synoviocyte from patients with rheumatoid arthritis(RA). Fibroblast-like cells (FLS) from the joint tissue of patients with rheumatoid arthritis were cultured and incubated for 24 h with LPS (1 mg.L-1) or the supernatant of U937 cells stimulated with LPS (1 mg.L-1) for 24 h. Dexamethasone was added to the supernatant of U937 cells and FLS was incubated for 24 h. The activity of MMP-9 was analyzed by gelatin zymography. Protein expression of MMP-9 was detected by Western blot using special polyclonal antibodies. The mRNA expression of MMP-9 was detected by RT-PCR. The expression of MMP-9 was not markedly changed in FLS treated with LPS. The MMP-9 activity, MMP-9 secretion and MMP-9 mRNA expression were significantly increased in FLS cultured with the supernatant from U937 cell treated with LPS. Dexamethasone markedly inhibited the activity, protein secretion and mRNA expression of MMP-9 in FLS cultured with the supernatant from U937 cell stimulated with LPS, and the inhibitory effects were increased as the concentration of dexamethasone increased.

LPS did not directly affect the expression of MMP-9 in FLS, but it was found to indirectly cause the increase of MMP-9 expression in FLS by stimulating U937 cell. Dexamethasone was found to inhibit this increase of MMP-9 expression.

In 2012, a European initiative called To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists). In total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations.

The SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe.

A higher mortality rate in patients with RA than in the general population has been reported in most series. Treatment strategies for RA have improved dramatically over the last decades, resulting in less inflammation and joint damage. We investigated whether this change in treatment corresponds to reversal of excess mortality by studying a large inception cohort of early RA patients exposed to different treatment strategies. Six hundred and eighty-four RA patients included in the Leiden Early Arthritis Clinic between 1993 and 2008 were studied. Treatment was different for three inclusion periods. From 1993 to 1995 patients were treated with NSAIDs and only late in their disease with DMARDs. From 1996 to 1998 patients were promptly treated with HCQ or SSZ. From 1999 to 2008 patients were immediately treated with MTX monotherapy or in combination with other disease-modifying drugs. Life/death status was tracked nationally using the civic registries. Mortality rates were compared with the general Dutch population. In Periods 1 and 2, increased standardized mortality rates were found, 1.35 (95% CI 0.94, 1.93) and 1.23 (95% CI 0.91, 1.67), respectively, while a decreased standardized mortality rate was found for patients included in 1999-2006 [0.49 (95% CI 0.31, 0.77)]. Age of onset [hazard ratio (HR) 1.10 (95% CI 1.07, 1.13)], erosive disease [HR 2.03 (95% CI 1.22, 3.37)], high CRP level [HR 1.09 (95% CI 1.01, 1.18)], smoking [HR 2.39 (95% CI 1.31, 4.38)] and higher baseline HAQ score [HR 1.53 (95% CI 1.06, 2.20)] associated with mortality.

Current treatment strategies for early RA, such as that given in inclusion Period 3, might contribute to the reversal of excess mortality in RA.

The purpose of the present study was to examine the current prevalence of mood and anxiety disorders, and factors related to mood and anxiety disorders in patients with rheumatoid arthritis (RA). The study sample included 83 consecutive patients with RA who were admitted to a rheumatology outpatient clinic. Diagnoses of psychiatric disorders were determined using the Structured Clinical Interview for DSM-IV (SCID-I). To assess physical disability and disease activity, the Health Assessment Questionnaire and the Disease Activity Score, respectively, were used. The prevalence of any mood or any anxiety disorder was 43.4%. The two most common psychiatric diagnoses were major depression (21.7%) and generalized anxiety disorder (16.9%). Mood and anxiety disorders were unrelated to sociodemographic features, disease-related factors, and medications for RA except anti-tumor necrosis factor-alpha (TNF-alpha). These disorders, however, were identified less frequently in patients with RA receiving anti-TNF-alpha drugs compared to patients who did not receive such medications.

Patients with RA frequently have mood and anxiety disorders, and anti-TNF-alpha drugs may be useful for the mental status of these patients.

To determine the effect of c-fos on human chondrocytes and to examine the role of c-fos in cartilage destruction in rheumatoid arthritis (RA). We examined changes in collagen synthesis by transfecting human c-fos into cultured human chondrocytes and evaluated expression of c-fos mRNA and localization of Type II collagen, matrix metalloproteinases-1 (MMP-1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in articular cartilage samples from patients with RA or osteoarthritis (OA) by in situ hybridization and immunohistochemistry. Introduction of c-fos in the chondrocytes decreased endogenous transcription of Type II collagen and TIMP-1, and increased that of MMP-1. The effect of the activating protein-1 protein on the MMP-1 and TIMP-1 promoters in human articular chondrocytes was analyzed by chloramphenicol acetyltransferase activity assay. MMP-1 promoter was clearly activated by Jun related proteins as well as Fos/Jun related protein heterocomplex. On the other hand, c-fos combined with any of the Jun related proteins failed to stimulate the TIMP-1 promoter, although it was activated by Fra-1 or Fra-2/Jun related protein heterocomplexes. Expression of c-fos mRNA was detected in chondrocytes in the mid and deep layers of cartilage in 11/15 patients (73%) with RA, but only in the superficial layer of cartilage from 2/10 patients (20%) with OA. Although TIMP-1 staining exceeded that of MMP-1 in OA cartilage, it appeared to be less intense than MMP-1 staining in RA cartilage.

These results suggest that activation of c-fos may be involved in cartilage metabolism and hence play a crucial role in the pathogenesis of arthritic destruction in RA.

To develop and validate an extensive radiographic scoring system for ankylosing spondylitis (AS). The Stoke Ankylosing Spondylitis Spinal Score (SASSS) was modified by adding a score for the cervical spine and defining squaring. This modified SASSS (mSASSS) is the sum of the lumbar and cervical spine score (range 0-72). 370 lateral views of the lumbar and cervical spine were used for development of the mSASSS, standardisation of observers, and for studying reliability. In a 48 week NSAID study of 57 patients, change over time and construct validity were studied. Interobserver correlations of the lumbar and cervical spine scores were good (r>0.95). The interobserver duplicate error was 0.55 in a range from 0 to 36. The mean change in the cervical and lumbar spine scores between weeks 0 and 48 of all patients was 1.45 (range 0-6.0) and 1.06 (0-5.0), respectively (paired t testing, p<0.001). Change in radiological score was seen in 36/57 (63%) patients (lumbar and cervical spine 11, cervical spine 12, lumbar spine 13 patients).

The mSASSS is useful for assessing extensive radiographic damage in AS. It is reliable, detects changes over 48 weeks, and shows a satisfactory face and construct validity.

To assess the prevalence of generalized soft tissue rheumatism (GSTR) in medical students in Izmir, Turkey. Medical students from each grade of Medical School of Ege University, Izmir, Turkey, were evaluated by a survey and physical examination for GSTR including fibromyalgia (FM) syndrome, myofascial pain syndrome (MPS), benign joint hypermobility syndrome (BJHS), and chronic fatigue syndrome. FM Impact Questionnaire was assessed in FM diagnosed students. Short Form-36 (SF-36) was obtained from each student to determine the quality of life. Among the participants (n = 306), 191 were women (62.4%) and 115 were men (37.6%) and mean age was 20.23 +/- 1.56. Fifty-eight students (19%) were diagnosed with a GSTR. The distributions of the diagnoses were: 6 (2%) FM, 21 (6.9%) MPS, 28 (9.2%) BJHS, 1 (0.3%) chronic fatigue syndrome, and 2 students (0.7%) had both BJHS and MPS. Fifty-three (27.7%) women and 5 (4.3%) men were diagnosed with a GSTR (P < 0.01). Mean FM Impact Questionnaire score was 50.8 in FM diagnosed students. Physical role, vitality, and mental subscores of SF-36 were significantly lower in the students having a GSTR (P < 0.05).

This is the first study performed in medical students to find out the prevalence of generalized soft tissue rheumatic conditions. Although medical students are under high stress due to hard training, the prevalence of GSTR in medical students was found similar to previous reports in the general population.

To understand the impact of ankylosing spondylitis (AS) on work disability (WD) over 12 years compared with the general population, and explore factors predicting adverse work outcome, defined as new partial WD or reduction in working hours. Source of data was the Outcome Assessments in Ankylosing Spondylitis International Study, which includes patients from The Netherlands, France, and Belgium. Standardized WD rates over time compared to the general population were calculated using indirect standardization (Dutch patients only). Cox survival analyses identified baseline predictors as well as time-varying factors influencing adverse work outcome over 12 years. Of 215 patients, 55 (26%) were full WD at baseline and 139 (65%) were at risk for adverse work outcome during followup. When compared to the general population, WD over 12 years continued to be increased in Dutch men (incidence rate [IR] 2.9 [95% confidence interval (95% CI) 1.2, 4.6]), but less clearly for women (IR 1.2 [95% CI -0.4, 2.9]). Within the entire sample, baseline predictors of adverse work outcome over 12 years were residence in The Netherlands (versus France or Belgium) (hazard ratio [HR] 3.4 [95% CI 1.4, 8.4]) and worse Bath Ankylosing Spondylitis Functional Index (BASFI) (HR 1.2 [95% CI 1.0, 1.4]). Time-varying predictors over 12 years were residence in The Netherlands, uveitis, and either BASFI or Bath Ankylosing Spondylitis Disease Activity Index with age and inflammatory bowel disease.

Although WD was already prevalent at inclusion in the cohort, a substantial proportion of patients incurred further adverse work outcome over 12 years. In addition to country of residence, uveitis, age, and self-reported physical function or disease activity predicted long-term adverse work outcome.

The health-related quality of life (HRQOL) of people with HIV is lower than in the general population, but it is unknown how it compares with that of persons with other chronic medical conditions. We compared HRQOL in HIV with HRQOL in diabetes mellitus type 1, diabetes mellitus type 2 and rheumatoid arthritis (RA). In addition, we investigated factors associated with HRQOL in HIV. Cross-sectional study. HRQOL was measured with the Medical Outcomes Study Short Form 36-item Health Survey in a nationwide sample of people with HIV in care in the Netherlands and on combination antiretroviral therapy for at least 6 months. We added data from studies in diabetes mellitus types 1 and 2, and RA. Logistic regression analysis was used to examine: the association between disease group and a poor HRQOL, and patient factors associated with poor HRQOL in HIV. The odds of a poor physical HRQOL in the HIV group were comparable with the odds in diabetes mellitus types 1 and 2, but lower than in RA patients. The odds of a poor mental HRQOL in HIV were higher than in the other groups. In HIV, a history of AIDS, longer duration of combination antiretroviral therapy and severe comorbidity were associated with a poor physical HRQOL. Sub-Saharan African descent and CD4 cell count of less than 350 cells/μl were associated with poor mental HRQOL.

People with HIV were more likely to have a poor mental HRQOL than patients with other chronic conditions. Addressing mental health should be an integral part of outpatient HIV care.

Rifampin is known to influence the pharmacokinetics of tofacitinib owing to drug interactions. The aim of this study was to determine the efficacy of tofacitinib on co-administration with rifampin in rheumatoid arthritis (RA) patients. Biologic-naïve RA patients treated with tofacitinib were selected, and electronic medical reports were reviewed retrospectively. All patients underwent screening for latent tuberculosis infection (LTBI) before starting tofacitinib, and patients with positive results were treated to prevent progression to active tuberculosis. To evaluate the efficacy of tofacitinib with or without rifampin, the discontinuation rates of tofacitinib were examined during the first 6 months. Kaplan-Meier analysis was used to construct cumulative discontinuation curves, and comparisons were performed using the log-rank test. Among 81 patients who starting tofacitinib, 21 were LTBI-positive and 18 were administered rifampin concomitantly with tofacitinib. Additionally, 14 of the 81 patients (17.3%) discontinued tofacitinib during the follow-up, and 7 patients discontinued tofacitinib because of uncontrolled RA activity. The discontinuation rates of tofacitinib within the first 6 months were significantly higher in patients treated with rifampin for LTBI than in those not treated with rifampin (lack of efficacy: 24.7% vs. 5.1%, P<0.01; all causes: 38.9% vs. 11.2%, P<0.01).

Discontinuation rates were higher in RA patients who started tofacitinib during chemoprophylaxis involving rifampin than in those who did not receive rifampin. Physicians should be aware that the efficacy of tofacitinib could be decreased by chemoprophylactic regimens for tuberculosis.

To explore the effect of mucosal administration of alpha-fodrin in inhibition of autoimmunity in Sjögren's syndrome (SS). Thirty-four 4-week-old NOD mice were randomly divided into 4 equal groups: to be immunized by nasal administration of alpha-fodrin 1 microg/dose and 10 microg/dose respectively every two days (experimental groups), and phosphate-buffered saline (PBS) or glutathion2 S-tansferase4 (GST) (control groups). The weekly volume of water drinking was calculated. The salivary flow was maintained. Serum samples were obtained to detect the anti-SSA, anti-SSB, RF, ANA, anti- -fodrin and anti-type 3 muscarinic acetylcholine receptor polypeptide (M3RP) by immunofluorescence or ELISA. The cytokines of IFN-gamma and IL-10 were measured with ELISA. The salivary glands were examined by HE staining and immunohistochemical analysis. Flow cytometry was used to detect the proportion of Foxp3+ CD4+ CD25+ T cells. The titers of anti- -fodrin antibody and M3RP antibody of the mice immunized with-fodrin were lower than those of the 2 control groups (all P < 0.05), however, there was not significant differences between these two a-fodrin immunized groups. Five of the 8 mice in the GST group, 5 mice in the PBS group, 2 mice in the alpha-fodrin 1 microg/dose group, and 3 mice in the alpha-fodrin 10 microg/dose showed ANA positive. The serum IFN-gamma levels in the mice of alpha-fodrin 1 microg/dose and 10 microg/dose groups, PBS group, and GST group were (42 +/- 16), (37 +/- 15), (87 +/- 18), and (72 +/- 11) pg/ml respectively, those of the fodrin groups being significantly lower than those of the control groups (all P < 0.05). There were not significant differences in the level of serum IL-10 among these four groups. The numbers of Foxp3+ CD4 CD25+ regulatory T cells were higher in the fodrin groups than in the PBS and GST control groups (all P < 0.05). The lymphocytic infiltration and expression of alpha-fodrin were decreased in the alpha-fodrin administrated groups. The volume of water drinking of the alpha-fodrin 1 microg/dose group, alpha-fodrin 10 microg/dose group, PBS group, and GST group were (39.2 +/- 2.1), (40.4 +/- 2.5), (49.3 +/- 3.1), and (51.6 +/- 2.8) ml respectively.

Mucosal administration of alpha-fodrin effectively inhibits the progression of experimental Sjögren's syndrome autoimmunity.

Patients with gout are encountered frequently in clinical practice. Previous studies have suggested that hyperuricemia and gout may represent risk factors for coronary heart disease (CHD), the most common cause of death in American men. Prospectively collected data from 2 longitudinal cohort studies of former medical students--371 black men in the Meharry Cohort Study and 1181 white men in the Johns Hopkins Precursors Study--were analyzed. The development of gout and of CHD was determined by physician self-report, and validated by using published criteria. The risk for CHD associated with gout was evaluated using Cox proportional hazards analysis. During a median follow-up of 30 years, there were 38 gout cases and 44 CHD events among the Meharry men, and 68 gout cases and 138 CHD events among the Hopkins men. Prior gout was not associated with an increased risk for incident CHD (relative risk = 1.20; 95% confidence interval, 0.37-3.92) among the Meharry men or among the Hopkins men (relative risk = 0.66; 95% confidence interval, 0.24-1.79). Multivariate analysis adjusted for known CHD risk factors did not alter these findings.

These results, in black and white male physicians, do not suggest a role in men for targeting gout identification in the primary prevention of CHD.

To compare the reproducibility of the standing extended view (SEV) (also known as the standing anteroposterior view) with the semiflexed, postero-anterior view [the 'metatarsophalangeal' (MTP)] view for assessing joint space width (JSW) and osteophytes in osteoarthritis of the knee when used in a busy routine X-ray department. Forty-seven patients (24 men) had both SEV and MTP views taken on the same day in a busy National Health Service radiography department. Repeat views were taken as entirely separate procedures some time over the following 2 weeks, in the same department and with no special arrangements for the selection of radiographers, time of day, or X-ray machine. The first 24 patients had second views in the SEV position whilst the remaining 23 had second MTP views. Radiographs were read independently by two experienced observers who measured JSW with a transparent ruler to the nearest 0.5 mm at the narrowest point in both medial and lateral compartments of the tibiofemoral joint in both knees. Osteophytes were graded 0-2 according to a standard atlas. Ten SEV and 10 MTP radiographs selected randomly were re-read by one observer. Mean (95% confidence interval) JSW in the medial compartment measured on SEV radiographs was 3.54 mm (3.08, 3.99) and on MTP radiographs it was 2.80 mm (2.37, 3.23); in the lateral compartment it was 6.04 mm (5.71, 6.37) when measured on SEV radiographs and 5.47 mm (5.09, 5.85) on MTP radiographs. The estimated variances for the medial compartment were 2.0 mm2 for SEV and 0.2 mm2 for MTP (P < 0.001) and for the lateral compartment 1.4 mm2 for SEV and 0.5 mm2 for MTP (P < 0.001). The proportion of radiographs for which there was disagreement between observers regarding osteophyte grade was not statistically different between SEV and MTP views (SEV, medial 40%, lateral 44%; MTP, medial 39%, lateral 39%).

Even when radiographs are taken in a busy National Health Service radiography department, measurement of JSW from the MTP view is more reproducible than from the SEV view, the MTP view gives a slightly lower measurement of JSW, and there is no advantage in using either view in recording osteophyte grade. We recommend the wider adoption of the MTP method.

To highlight the opportunities and challenges of developing and implementing performance outcome measures in rheumatology for accountability purposes. We constructed a hypothetical performance outcome measure to demonstrate the benefits and challenges of designing quality measures that assess patient outcomes. We defined the data source, measure cohort, reporting period, period at risk, measure outcome, outcome attribution, risk adjustment, reliability and validity, and reporting approach. We discussed outcome measure challenges specific to rheumatology and to fields where patients have predominantly chronic, complex, ambulatory care-sensitive conditions. Our hypothetical outcome measure was a measure of rheumatoid arthritis disease activity intended for evaluating Accountable Care Organization performance. We summarized the components, benefits, challenges, and tradeoffs between feasibility and usability. We highlighted how different measure applications, such as for rapid cycle quality improvement efforts versus pay for performance programs, require different approaches to measure development and testing. We provided a summary table of key take-home points for clinicians and policymakers.

Performance outcome measures are coming to rheumatology, and the most effective and meaningful measures can only be created through the close collaboration of patients, providers, measure developers, and policymakers. This study provides an overview of key issues and is intended to stimulate a productive dialogue between patients, practitioners, insurers, and government agencies regarding optimal performance outcome measure development.

Serum levels of lipoprotein(a) [Lp(a)] are determined largely by genetic variation in the gene encoding for apolipoprotein(a) [apo(a)], the specific protein component of Lp(a) that is very homologous to plasminogen. High plasma levels of Lp(a) increase the risk for premature atherosclerotic vessel diseases. We investigated the little-characterized role of Lp(a) as a risk factor for venous thromboembolic diseases, alone and in conjunction with established thrombophilic risk factors of proteins regulating blood coagulation and fibrinolysis. Serum levels of Lp(a) and lipids, protein C, protein S, and antithrombin, as well as the size of apo(a) isoforms and the presence of the factor V:Q(506) mutation, were determined in 186 consecutively admitted children from neonates to 18 years old with a history of venous thrombosis and in 186 age- and disease-matched control subjects. Children with a history of venous thrombosis had a significantly higher median Lp(a) level (19 versus 4.4 mg/dL) than control subjects. The risk for thromboembolic events in children with Lp(a) levels in the upper quartile, ie, >30 mg/dL, was 7.2 (95% CI, 3.7 to 14.5). The size of apo(a) isoforms was inversely related to Lp(a) levels and to the risk for thromboembolic events. Compared with the highest quartile of the apo(a) size distribution, the lowest quartile was associated with a risk of 8.2. In addition, multivariate statistical analysis gives evidence that the factor V:Q(506) mutation (OR/CI, 2.8/1.6 to 4.9), protein C (OR/CI, 6.5/2.1 to 19), and antithrombin deficiency (OR/CI, 10.4/1.2 to 90) were independent risk factors of childhood venous thrombosis. Coincidence of elevated Lp(a) with factor V:Q(506) mutation or deficiencies of protein C or antithrombin further increased the risk for thromboembolic events to 8.4.

Lp(a) >30 mg/dL is a risk factor for venous thromboembolism in childhood. Lp(a) measurements should be included in the screening of causal factors in children with venous thromboembolic events.

Dorsal capsulodesis and triscaphe arthrodesis are possible treatment modalities for patients with scapholunate dissociation. In light of overlapping indications for either operation for patients with carpal instability, it is important to compare the postoperative results. From 1998 until 2002, we operated on 87 patients suffering from scapholunate dissociation. 52 patients were treated by dorsal capsulodesis after R. Berger and 35 patients were treated by triscaphe arthrodesis as published by Watson. Of these 87 patients, we managed to follow-up 77 patients (47 dorsal capsulodesis und 30 triscaphe arthrodesis) with a physical examination, X-ray of the wrists and Krimmer Score. In terms of grip-strength, range of motion, functional outcome (Krimmer Score), duration of the operation and hospitalisation, the dorsal capsulodesis group performed better (p < 0.05) than the triscaphe arthrodesis group at the time of follow-up. At follow-up, pain reduction was significant in both groups (p < 0.05). Krimmer Score (functional outcome) and the rate of complication was clearly better for the dorsal capsulodesis group as compared to the triscaphe arthrodesis group.

In case of non-static scapholunate dissociation, dorsal capsulodesis should be the first choice treatment. In case of a young manually working man with static scapholunate dissociation, it should be a case-to-case decision whether performing a triscaphe arthrodesis or a dorsal capsulodesis. With this investigation we wanted to discuss and demonstrate the difficulties with the differential-indication for the two operations. Generally speaking the postoperative results did not depend on the type of scapholunate dissociation (dynamic versus static) but rather on the chosen surgical procedure.

To evaluate the relationship between systemic inflammation and skin microcirculation in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). We assessed skin microcirculation flux (laser Doppler flowmetry), classical cardiovascular risk factors, inflammatory markers and disease activity (Disease Activity Score 28, Bath Ankylosing Spondylitis Disease Activity Index) in 75 patients with arthritis with a median disease duration of 4 years, and in 26 healthy subjects. In patients with arthritis inflammatory markers (C-reactive protein, interleukin 6, fibrinogen) were increased, peak flux velocity after the occlusion at the temperature of 36.6°C and maximal heat flux velocity after the heating were significantly lower. These findings were accompanied by the slower increase in the flux rate during local heating. There were positive correlations between inflammatory markers and microcirculation parameters in patients with RA and AS, but only for RA patients between peak flux velocity and disease activity. There were no significant intergroup differences when the classical cardiovascular risk factors were compared except for the lower HDL cholesterol in arthritis patients.

Patients with chronic systemic inflammatory arthritis presented altered microvascular function and reduced vasodilator capacity of the forearm skin microcirculation.

To describe the prevalence of self-reported diabetes and undiagnosed diabetes using new fasting plasma glucose (FPG) criteria, and vascular associations with diabetes history in a representative sample of older Australians attending the population-based Blue Mountains Eye Study. 3654 people aged 49 years or older, representing 88% of permanent residents in two postcode areas west of Sydney, underwent a detailed medical and eye examination. This included history of diabetes, vascular events and vascular risk factors. Fasting pathology tests, including glucose, were obtained for 88% of these subjects. A diabetes history was given by 217 people (5.9%), including 7.0% of men and 5.2% of women. Elevated FPG (> or = 7.0 mmol/l) was found in a further 66 people (2.2% of persons who had FPG performed) and Impaired Fasting Glucose (FPG > or = 6.1 mmol/l and < 7.0 mmol/l) was found in a further 127 people (4.2%). History of diabetes was associated with an increased prevalence of obesity, elevated mean blood pressure and serum triglycerides, and lower mean serum cholesterol and HDL-cholesterol. Statistically significant associations were found between diabetes history and history of angina, acute myocardial infarction, stroke, gout and thyroid disease, after adjusting for age and sex using logistic regression. The vascular relationships with diabetes were stronger among people who currently smoked.

This study has found similar diabetes prevalence to recently published Australian National Health Survey findings. Strong cross-sectional associations between diabetes history and vascular events and increased prevalence of vascular risk factors among older subjects with diabetes emphasise the need to address vascular risk factors in this group.

Our aim was to summarize key aspects of the pathomechanism and the ocular involvements of rheumatic and systemic autoimmune diseases. Apart from a paper in French (Morax V, Ann Oculist 109:368-370, 1893), all papers referred to in this article were published in English. All the materials were peer-reviewed full-text papers, letters, reviews, or book chapters obtained through a literature search of the PubMed database using the keywords ocular manifestations; pathogenesis; systemic inflammatory rheumatic diseases; rheumatoid arthritis; osteoarthritis; fibromyalgia; systemic lupus erythematosus; seronegative spondyloarthritis; ankylosing spondylitis; reactive arthritis; enteropathic arthritis; psoriatic arthritis; systemic sclerosis; polymyalgia rheumatica and covering all years available. Some statements articulated in this paper reflect the clinical experience of the authors in their tertiary-referral center. Ophthalmic disorders are categorized by anatomical subgroups in all rheumatic diseases. The most common ocular manifestations are diverse types of inflammations of different tissues and dry eye disease (DED).

The eye could be a responsive marker for the onset or aggravation of an immune reactivation in many rheumatic diseases, furthermore, ocular findings can antedate the diagnosis of the underlying rheumatic disease. By recognizing ocular manifestations of systemic rheumatic diseases it might be possible to avoid or at least delay many long term sequelae.

With the advent of more wear-resistant bearings, there is renewed interest in resurfacing total hip arthroplasty. However, there is a paucity of information on the biomechanical results of this type of arthroplasty compared with those of contemporary total hip arthroplasty. Using standardized radiographs, we measured and compared the biomechanical parameters that affect the hip joint reactive forces in fifty hips that had a metal-metal surface replacement with those parameters in forty hips that had a contemporary cementless total hip replacement performed during the same time-period by the same surgeon. On the average, the arthritic hips that were treated with metal-metal surface replacement had had a more valgus preoperative neck-shaft angle and less horizontal femoral offset than the normal, contralateral hips (p = 0.0003). After both the metal-metal surface replacements and the cementless total hip replacements, the hip center of rotation was medialized by approximately 6 mm. Both procedures were associated with an average increase in limb length of approximately 3 or 4 mm. After the metal-metal surface replacements, the horizontal femoral offset was essentially equal to the preoperative value, but both values averaged about 8 mm less than those on the normal, contralateral side (p < 0.00001). In the hips with a conventional total hip replacement, the horizontal femoral offset increased an average of 9.5 mm compared with the preoperative value and was an average of 5 mm more than that for the normal, contralateral hip (p = 0.001). Therapeutic study, Level III-1 (case-control study). See Instructions to Authors for a complete description of levels of evidence.

The biomechanical results of total hip resurfacing depend on the preoperative anatomy of the proximal part of the femur. Limb lengthening of 1 cm can be achieved, but horizontal femoral offset is essentially unchanged by hip resurfacing. Horizontal femoral offset can be increased reliably with a contemporary total hip replacement. Arthritic hips of limbs that are more than 1 cm shorter than the contralateral limb or that have a comparatively low horizontal femoral offset may be better served by a contemporary total hip replacement. These biomechanical limitations should be considered in the selection of hips for resurfacing.