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ID PMID Title PublicationDate abstract
21789030 Prevalence of connective tissue diseases in egyptian patients presenting with Fever of unk 2011 OBJECTIVE: To estimate the prevalence of connective tissue diseases in patients presenting with fever of unknown origin (FUO). PATIENTS AND METHODS: In this study thirty patients diagnosed as FUO (Group 1), in 2008, were included in an observational study and diagnostic workup. Additionally, retrospective analysis of seventy patients' files (Group 2), for patients who presented with prolonged unexplained pyrexia to the same hospital in the previous two years, was performed. Patients were subjected to: full clinical assessment including full history taking, thorough clinical examination, laboratory investigations including the basic investigations for patients with prolonged fever, complete blood count, erythrocytes sedimentation rate, urine analysis and culture, blood culture, sputum culture and plain chest X ray. Further diagnostic work up and/or procedures were requested according to the potential diagnostic clues (PDC) present in every patient. RESULTS: Out of 100 FUO patients, 50% were found to have infectious diseases, 24% were found to have connective tissue diseases, 8% miscellaneous causes and 7% neoplastic diseases (P < 0.05). In 11 patients no definite cause for FUO could be identified. Connective tissue patients were: eight systemic lupus patients (33.3%), five patients with familial mediterranean fever (20.8%), four patients with rheumatoid arthritis (16.6%), three patients (12.5%) with Still's disease and Rheumatic fever and one patient with Behçet syndrome/Crohn's disease (4.3%), (P < 0.05). CONCLUSIONS: Despite the advanced technology, FUO remains a challenging medical problem. Infections were the most common cause of FUO in Egypt, confirming the trends found in other parts of the world. There was an increased prevalence of connective tissue patients presented with prolonged unexplained fever. A keen clinical eye, meticulous history taking and repeated physical examination remained the most important diagnostic tools in FUO patients.
21763467 Air pollution in autoimmune rheumatic diseases: a review. 2011 Nov Air pollution consists of a heterogeneous mixture of gasses and particles that include carbon monoxide, nitrates, sulfur dioxide, ozone, lead, toxic by-product of tobacco smoke and particulate matter. Oxidative stress and inflammation induced by inhaled pollutants may result in acute and chronic disorders in the respiratory system, as well as contribute to a state of systemic inflammation and autoimmunity. This paper reviews the mechanisms of air contaminants influencing the immune response and autoimmunity, and it focuses on studies of inhaled pollutants triggering and/or exacerbating rheumatic diseases in cities around the world. Remarkably, environmental factors contribute to the onset of autoimmune diseases, especially smoking and occupational exposure to silica in rheumatoid arthritis and systemic lupus erythematosus. Other diseases such as scleroderma may be triggered by the inhalation of chemical solvents, herbicides and silica. Likewise, primary vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) may be triggered by silica exposure. Only few studies showed that air pollutants could trigger or exacerbate juvenile idiopathic arthritis and systemic lupus erythematosus. In contrast, no studies of tropospheric pollution triggering inflammatory myopathies and spondyloarthropathies were carried out. In conclusion, air pollution is one of the environmental factors involved in systemic inflammation and autoimmunity. Further studies are needed in order to evaluate air pollutants and their potentially serious effects on autoimmune rheumatic diseases and the mechanisms involved in the onset and the exacerbation of these diseases.
21410426 Leflunomide-induced interstitial pneumonitis might be a representative of disease-modifyin 2011 Jul INTRODUCTION: Although disease-modifying antirheumatic drugs (DMARDs) are crucial for rheumatoid arthritis (RA) therapy, they have severe adverse events including interstitial pneumonitis (IP). DMARD-induced IP attracts attention because of its relatively high prevalence, occasionally fatal outcome and clinical features which are common to the IP caused by different DMARDs. AREAS COVERED: Immediately after the introduction of leflunomide (LEF) in Japan in 2003, IP frequently developed under its use and cases with a fatal outcome were reported. The data obtained by a registration system for all patients who were prescribed LEF are examined, and the features are compared to those of other DMARD-induced IP. The features included acute respiratory distress with severe inflammatory reaction; ground-glass opacities and/or consolidations in the upper, anterior and central lung fields on XP/CT; peripheral blood lymphopenia; and diffuse alveolar damage confirmed in autopsied cases. The most outstanding risk for LEF-induced lung injury was pre-existing IP with an odds ratio of 8.17. A good response to LEF in terms of arthritis remission was suggested. Similar cases have been reported in countries other than Japan, although fewer cases were in Western countries. EXPERT OPINION: LEF use should be avoided at least for Japanese RA patients with pre-existing IP. The pathogenesis of DMARD-induced lung injury may have common features that need to be clarified in the future.
21253441 Anti-inflammatory and Anti-arthritic Effects of a Novel Leflunomide Analogue, UTL-5b (GBL- 2011 Jan 1 Rheumatoid arthritis (RA) is a common disease characterized by chronic inflammation and irreversible destruction of articular cartilage and bone. In this report, we examined the anti-inflammatory and anti-arthritic effects of a novel leflunomide analogue, UTL-5b (also known as GBL-5b), for potential RA treatment. Using a carrageenan-induced edema study in rats, UTL-5b exhibited a better anti-inflammatory effect as compared with leflunomide and its metabolite. The chronic efficacy of UTL-5b was examined using type II collagen-induced arthritis (CIA) mouse model. UTL-5b exerted an anti-arthritic effect in a dose-dependant manner with mice given 30 mg/kg exhibiting amelioration of disease early in the trial, but losing statistical significance over time. In contrast, mice treated with 60 mg/kg showed reduced clinical disease parameters early in the trial and these effects were sustained over the ten week trial period. Mechanistic studies indicate that UTL-5b is an inhibitor of TNF-α production in vivo. Oral administration of UTL-5b prior to i.p. injection with lethal dose of lipopolysaccharide (LPS)/D-galactosamine markedly reduced the levels of serum TNF-α and increased survival rates of animals from septic shock-induced death. Acute toxicity study using mice receiving increasing doses of UTL-5b showed that no animals were killed by UTL-5b at 2,000 mg/kg (LD(50) >2,000 mg/kg). Our studies show that UTL-5b represents a novel anti-inflammatory and anti-arthritic agent with potential therapeutic application for RA treatment.
20678963 The use of adjuvant high-dose-rate breast brachytherapy in patients with collagen vascular 2011 Mar PURPOSE: To analyze toxicity and cosmesis in patients with collagen vascular disease (CVD) treated with accelerated partial breast irradiation (APBI) via high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: This is a pooled analysis of patients with early stage and in situ breast cancer with CVD treated with adjuvant multicatheter or balloon brachytherapy. Physicians at multiple institutions were asked to review their experience and report data regarding toxicity and cosmesis in patients with CVD. All patients fit American Society of Breast Surgeons recommendations for APBI and were treated with HDR brachytherapy with ≥ 3 months followup. RESULTS: Nine cases from five institutions are the subject of this analysis. The median patient age was 54 years and median followup was 31 months. All patients had documented history and active signs/symptoms of rheumatoid arthritis, systemic lupus erythematosis, psoriatic arthritis, or scleroderma. All patients had received medical therapy for CVD in the past, and 78% were under active treatment at the time of brachytherapy. All the patients were treated with multicatheter or balloon (MammoSite [Hologic, Inc., Marlboro, MA], MammoSite ML [Hologic, Inc., Marlboro, MA], or Contura [Senorx, Irvine, CA]) brachytherapy with a median volume of 45.5 cc and a median skin distance of 7.5mm. Acute toxicity included Grade 1 skin erythema (5) and catheter-site wound dehiscence (1). Late toxicity included seroma (5), induration (5), pain (2), telangectasia (2), and superficial infection (1). Cosmesis was excellent or good for all the patients. CONCLUSIONS: Women with CVD have a toxicity and cosmesis profile consistent with other APBI series. Although confirmatory data is needed, it may not be necessary to exclude these patients from clinical trials of APBI.
21618940 Clinical benefits of intra-articular anakinra for persistent knee effusion. 2011 Mar Postoperative or postinjury inflammation after knee surgery is a significant clinical challenge. Cytokines, particularly interleukin-1 (IL-1), released by inflammatory cells have been shown to have a role in cartilage homeostasis and tissue repair and fibrosis. Anakinra, an IL-1 receptor antagonist (IL-1ra), has shown promising results from its use in treating rheumatoid arthritis, juvenile inflammatory arthritis, and autoimmune inflammatory syndromes. We hypothesized that intra-articular anakinra injection may result in sustained improvements of persistent effusion of the knee joint refractory to other modalities. We retrospectively reviewed 6 patients (3 female, 3 male), ranging in age from 17 to 50 years, who underwent injection of intra-articular anakinra, 200 mg, between November 15, 2007, and April 29, 2010, for persistent effusions of the postoperative knee. All of the patients treated with intra-articular anakinra for persistent effusions failed conservative treatment with physical therapy, oral anti-inflammatory medication, and 4 of 6 patients failed prior corticosteroid injections. After intra-articular anakinra, 66% had improvement in knee arc of motion (15 to 30 degrees) and pain, and 5 of 6 (83%) had improvement in swelling. All of these patients were able to return to sports. We found intra-articular anakinra to be safe and effective in this small group of patients with persistent effusions. There were no adverse clinical reactions or infections. These findings provide support for further study of IL-1 inhibition in the management of postsurgical inflammation.
22302732 Cultural adaptation, validity, reliability and responsiveness of the Swedish version of th 2012 Mar BACKGROUND: Endorsed by the Outcome MEasures in Rheumatoid Arthritis in Clinical Trials (OMERACT) group, The Effective Consumer Scale (EC-17) was developed in English for patients with musculoskeletal diseases to assess the skills and perceptions important for participating in and managing health care. The objective of this study was culturally to adapt the questionnaire into Swedish and to study its psychometric properties. METHODS: After translation of the questionnaire into Swedish, two different groups of outpatients from two specialist rheumatology departments participated in the study. Face validity was assessed, together with internal consistency, test-retest and responsiveness of the questionnaire. Construct validity was assessed using the Arthritis Self-Efficacy Scale (ASES), and responsiveness to a five day educational intervention was analysed using the standardized response mean (SRM). RESULTS: Analyses were based on 124 patients with inflammatory rheumatic diseases, of whom 50 attended the intervention. Data quality met the requirements, with missing values <5%, and floor and ceiling effects <15%. Item total correlations were all >0.4, ranging from 0.49 to 0.88. Cronbach's alpha was 0.93 and 0.95 for the two groups. The test-retest correlation (ICC₂.₁) was 0.94, and there was a significant improvement as a result of the intervention, with an SRM of 0.43. However, the questionnaire had a higher construct validity with the ASES subscale 'other symptoms' than hypothesized a priori (r(s) 0.75). CONCLUSION: The Swedish version of the EC-17 met the required recommendations for face validity, internal consistency, test-retest reliability and responsiveness. Its construct validity needs to be further established, and the questionnaire needs further testing in different groups of patients and in different interventions.
22008049 Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic 2011 Oct Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis and is frequently used in the management of other forms of inflammatory arthritis. It is currently challenging to predict which patients will achieve adequate disease control and which patients will develop adverse effects while taking MTX. As an analog of dihydrofolic acid, MTX enters cells through the reduced folate carrier-1 protein, and is polyglutamated. MTX polyglutamates inhibit key enzymes in the folate pathway to produce an anti-inflammatory effect. It has been suggested that genetic polymorphisms in the folate pathway may influence intracellular folate and MTX polyglutamates pools, and thus MTX response. However, studies to identify genetic predictors have yielded inconclusive results. Nonreplication across studies has been attributed to insufficient statistical power as well as pharmacological and clinical confounders. Prospective studies, standardizing the definitions of response and toxicity, and application of genome-wide approaches may advance the search for genetic predictors of MTX response.
22243557 Misdiagnosis in fibromyalgia: a multicentre study. 2011 Nov BACKGROUND: Fibromyalgia (FM) is the second most common cause of visits to rheumatologists after osteoarthritis, and may be difficult to diagnose in many patients. It is associated with various rheumatic disorders such as rheumatoid arthritis, spondyloarthropathies (SpA) and connective tissue disease (CTD), and a late diagnosis or misdiagnosis is a common and underestimated problem. OBJECTIVES: The aim of this study was to investigate the 'underdiagnosis' of FM, and which rheumatic diseases tend to be confused with it. METHODS: The following data were collected at baseline: symptoms, disease duration, physical examination findings, previous and current investigations and management, laboratory tests, tender point count, tender and swollen joint counts, and spinal pain. The clinimetric evaluation included the Fibromyalgia Impact Questionnaire (FIQ) and Fibromyalgia Assessment Status (FAS). RESULTS: The study population consisted of 427 outpatients (418 females and 9 males; mean age 49.3 years; mean disease duration 8.5 years). Fifty-seven patients (13.3%) had been previously misdiagnosed as having other musculoskeletal disorders (MSDs); 370 patients had been previous correctly diagnosed as having FM, or were diagnosed as having it during the course of the study. The FM and MSD groups were comparable in terms of demographic data and referral patterns. Disease duration was longer and the erythrocyte sedimentation rate was higher in the MSD patients, who also had less severe FIQ and lower pain visual analogue scale scores. Moreover, the FIQ and FAS scores correlated in the MS group. CONCLUSIONS: The findings of this study suggest that, although FM is a wellknown clinical entity, differential diagnosis with SpA, CTD and inflammatory arthritis can still be a challenge for rheumatologists and general practitioners.
21470314 Strategies for improving the quality of care in psoriasis with the use of treatment goals- 2011 May Targeted treatment, early intervention and the use of treatment goals is a new approach in medicine that has been implemented across several disciplines (e.g. diabetes, pulmonary arterial hypertension and rheumatoid arthritis) over the last 5-10 years. As in other chronic diseases, well-defined treatment goals may be helpful in guiding physicians in their care of patients with psoriasis, thereby obviating poor outcomes. Individual treatment goals were recently developed for the first time in psoriasis by a European Consensus group of experts from 19 European countries to supplement guidelines and promote the consistent use of available therapies to improve patient care. Goal-oriented therapy involves treating according to a treatment algorithm, regularly monitoring therapeutic response and prompt modification of therapy if goals are not met. In the absence of hard outcomes in psoriasis (e.g. biomarkers or biomedical predictors of clinical response), the European Consensus group based their treatment goals on changes in Psoriasis Area Severity Index and Dermatology Life Quality Index scores. Further evidence generation is important to determine whether surrogate markers for disease progression (e.g. co-morbidities) or predictors of clinical response can be identified for psoriasis. Furthermore, psoriasis may have a potential cumulative effect on the life course of patients, the understanding of which is likely to provide the rationale for earlier treatment strategies in psoriasis. For the work of the European Consensus group to have an impact on clinical care, transmission of treatment goals into guidelines, along with implementation of treatment goals at both the regional and national level is needed. Thus, dermatology experts from Europe, the Middle East, Australia and Canada gathered in Frankfurt, 2010, for a 1.5 day educational meeting run by the Progressive Psoriasis Initiative to discuss how treatment goals in psoriasis might best be implemented in clinical practice. The meeting conclusions are presented here.
21898359 Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolut 2012 Jan OBJECTIVE: The mechanism responsible for persistent synovial inflammation in rheumatoid arthritis (RA) is unknown. Previously, we demonstrated that expression of the cyclin-dependent kinase inhibitor p21 is reduced in synovial tissue from RA patients compared to osteoarthritis patients and that p21 is a novel suppressor of the inflammatory response in macrophages. The present study was undertaken to investigate the role and mechanism of p21-mediated suppression of experimental inflammatory arthritis. METHODS: Experimental arthritis was induced in wild-type or p21-/- (C57BL/6) mice, using the K/BxN serum-transfer model. Mice were administered p21 peptide mimetics as a prophylactic for arthritis development. Lipopolysaccharide-induced cytokine and signal transduction pathways in macrophages that were treated with p21 peptide mimetics were examined by Luminex-based assay, flow cytometry, or enzyme-linked immunosorbent assay. RESULTS: Enhanced and sustained development of experimental inflammatory arthritis, associated with markedly increased numbers of macrophages and severe articular destruction, was observed in p21-/- mice. Administration of a p21 peptide mimetic suppressed activation of macrophages and reduced the severity of experimental arthritis in p21-intact mice only. Mechanistically, treatment with the p21 peptide mimetic led to activation of the serine/threonine kinase Akt and subsequent reduction of the activated isoform of p38 MAPK in macrophages. CONCLUSION: These are the first reported data to reveal that p21 has a key role in limiting the activation response of macrophages in an inflammatory disease such as RA. Thus, targeting p21 in macrophages may be crucial for suppressing the development and persistence of RA.
21210292 Enthesitis in seronegative spondyloarthropathies with special attention to the knee joint 2011 Mar Seronegative spondyloarthropathies are a unique group of disorders sharing similar clinical characteristics (e.g., inflammatory back pain, spondylitis, sacroiliitis, uveitis, inflammatory bowel disease, skin rashes, and enthesitis). Clinical and genetic similarities suggest that they also share similar causes or pathophysiologies. Rheumatoid factor (RF) is characteristically negative in this group of disorders, hence collectively termed seronegative spondyloarthropathies (SpA). They include psoriatic arthritis, ankylosing spondylitis, reactive arthritis, ulcerative colitis, and Crohn's disease. "Enthesitis", the term used to describe inflammation at tendon, ligament, or joint capsule insertions, is considered a common feature in this domain and was included in the European Spondyloarthropathy Study Group criteria for the classification of SpA. Evaluation of entheseal-related changes at different joints by MRI became an important item on the research agenda in both differentiated and undifferentiated arthritis. Most of the research focused on MRI findings in the hand and wrist joints among patients with RA and SpA and support two patterns of inflammation "RA" phenotype where synovial involvement is the primary target of inflammation and "SpA" pattern where enthesitis comes first followed by synovitis. In this review, we summarize the literature on enthesitis in SpA and focus on MRI findings in the knee joint in the SpA group of disorders and subclinical synovitis among patients with skin psoriasis.
21360520 Extra domain A of fibronectin primes leukotriene biosynthesis and stimulates neutrophil mi 2011 Jun OBJECTIVE: There is increasing evidence of a role for Toll-like receptors (TLRs) in inflammatory arthritis. The extra domain A (ED-A)-containing isoform of fibronectin is generated under pathologic conditions such as rheumatoid arthritis, and ED-A has been identified as an endogenous TLR-4 ligand. Leukotriene B4 (LTB4) and polymorphonuclear neutrophils (PMNs) play a critical role in murine models of inflammatory arthritis. The aim of this study was therefore to investigate the putative effects of ED-A on leukotriene biosynthesis and PMN migration through TLR signaling. METHODS: The effect of recombinant human ED-A (rhED-A) on leukotriene biosynthesis was evaluated in isolated human blood PMNs and monocytes by high-performance liquid chromatography. The capacity of rhED-A to stimulate PMN migration was evaluated using a transendothelial/matrix migration assay in vitro and the mouse air-pouch model in vivo. RESULTS: Recombinant human ED-A efficiently primed the biosynthesis of LTB4 in PMN and monocyte suspensions. This priming effect was dependent on TLR-4 activation, since the TLR-4-signaling inhibitor CLI-095 completely blocked the effect of rhED-A but not that of other TLR ligands (R-848, Pam2 CSK4) or cytokines. Moreover, rhED-A stimulated transendothelial migration of PMNs in vitro, which was inhibited by 50-60% with the LTB4 receptor 1 (BLT1) antagonist CP105,696 or the cytosolic phospholipase A2 α inhibitor pyrrophenone. In vivo, rhED-A induced a significant PMN recruitment into the air pouch of C3H/HeOuJ mice (expressing functional TLR-4), but not in C3H/HeJ mice (expressing nonsignaling TLR-4). CONCLUSION: These results demonstrate the ability of rhED-A to promote LTB4 biosynthesis and PMN migration through TLR-4 activation, thus providing new insights on TLR-dependent mechanisms of regulation of LTB4 biosynthesis and PMN infiltration in inflammatory joint diseases.
22802946 Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast fo 2012 A major therapeutic challenge is how to replace bone once it is lost. Bone loss is a characteristic of chronic inflammatory and degenerative diseases such as rheumatoid arthritis and osteoporosis. Cells and cytokines of the immune system are known to regulate bone turnover by controlling the differentiation and activity of osteoclasts, the bone resorbing cells. However, less is known about the regulation of osteoblasts (OB), the bone forming cells. This study aimed to investigate whether immune cells also regulate OB differentiation. Using in vitro cell cultures of human bone marrow-derived mesenchymal stem cells (MSC), it was shown that monocytes/macrophages potently induced MSC differentiation into OBs. This was evident by increased alkaline phosphatase (ALP) after 7 days and the formation of mineralised bone nodules at 21 days. This monocyte-induced osteogenic effect was mediated by cell contact with MSCs leading to the production of soluble factor(s) by the monocytes. As a consequence of these interactions we observed a rapid activation of STAT3 in the MSCs. Gene profiling of STAT3 constitutively active (STAT3C) infected MSCs using Illumina whole human genome arrays showed that Runx2 and ALP were up-regulated whilst DKK1 was down-regulated in response to STAT3 signalling. STAT3C also led to the up-regulation of the oncostatin M (OSM) and LIF receptors. In the co-cultures, OSM that was produced by monocytes activated STAT3 in MSCs, and neutralising antibodies to OSM reduced ALP by 50%. These data indicate that OSM, in conjunction with other mediators, can drive MSC differentiation into OB. This study establishes a role for monocyte/macrophages as critical regulators of osteogenic differentiation via OSM production and the induction of STAT3 signalling in MSCs. Inducing the local activation of STAT3 in bone cells may be a valuable tool to increase bone formation in osteoporosis and arthritis, and in localised bone remodelling during fracture repair.
23269082 Epstein-Barr virus-negative, CD5-positive diffuse large B-cell lymphoma developing after t 2012 A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration.
21521773 Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-i 2011 Jul Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation, and proliferation of B-lineage cells, making it an attractive target for the treatment of rheumatoid arthritis. The objective of this study was to evaluate the antiarthritis effect of GDC-0834 [R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], a potent and selective BTK inhibitor, and characterize the relationship between inhibition of BTK phosphorylation (pBTK) and efficacy. GDC-0834 inhibited BTK with an in vitro IC(50) of 5.9 and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC(50) of 1.1 and 5.6 μM in mouse and rat, respectively. Administration of GDC-0834 (30-100 mg/kg) in a rat collagen-induced arthritis (CIA) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology. An integrated disease progression pharmacokinetic/pharmacodynamic model where efficacy is driven by pBTK inhibition was fit to ankle-diameter time-course data. This model incorporated a transit model to characterize nondrug-related decreases in ankle swelling occurring at later stages of disease progression in CIA rats. The time course of ankle swelling in vehicle animals was described well by the base model. Simultaneous fitting of data from vehicle- and GDC-0834-treated groups showed that overall 73% inhibition of pBTK was needed to decrease the rate constant describing the ankle swelling increase (k(in)) by half. These findings suggest a high degree of pBTK inhibition is required for maximal activity of the pathway on inflammatory arthritis in rats.
21561397 Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 rando 2011 Jul BACKGROUND: Gastrointestinal (GI) tolerability is an important treatment consideration for physicians when choosing a nonselective nonsteroidal anti-inflammatory drug (NSAID) for their elderly arthritis patients. The objective of this study was to compare the GI tolerability of the cyclooxygenase-2 selective NSAID celecoxib and nonselective NSAIDs in elderly patients with arthritis aged 65 years or older. METHODS: This was a retrospective, pooled analysis of patients aged 65 years or older with osteoarthritis (OA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS) from randomized, parallel-group trials. Selected trials had a duration of ≥2 weeks and at least one celecoxib 200-400 mg/day and one nonselective NSAID (naproxen, ibuprofen, or diclofenac) arm. Patient-level data from the safety populations of the trials were pooled. Analysis included the combined incidence of the GI intolerability adverse events (AEs) (abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea) and incidence and time to trial discontinuation due to these intolerability AEs. RESULTS: A total of 21 trials were selected involving 9461 elderly patients (mean age 71.9 years). Of these, 5872 received celecoxib, 1104 naproxen, 151 ibuprofen, and 2334 diclofenac. The combined incidence of GI intolerability AEs were reported by significantly fewer patients treated with celecoxib (16.7%) than naproxen (29.4%; p < 0.0001), ibuprofen (26.5%; p = 0.0016), or diclofenac (21.0%; p < 0.0001). The discontinuation rate due to GI intolerability AEs was significantly lower for celecoxib (4.0%) versus naproxen (8.1%; p < 0.0001) and ibuprofen (7.3%; p < 0.05), but not diclofenac (4.2%; p = 0.75). CONCLUSIONS: Among elderly arthritis patients, the incidence of GI intolerability AEs was lower with celecoxib than with naproxen, ibuprofen, or diclofenac. Fewer elderly patients discontinued due to GI intolerability AEs with celecoxib than with either naproxen or ibuprofen.
22937072 The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activi 2012 BACKGROUND: The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis. METHODOLOGY AND RESULTS: We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5' allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype. CONCLUSIONS: Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability.
21510342 [The differential diagnosis of tenosynovitis]. 2011 Mar 16 Etymologically a ténosynovites means inflammation of a tendon sheath. We recognize two separate presentations: exsudative and stenosing. The wide differential diagnosis includes infections, most of chronic inflammatory joint diseases, mainly connective tissue disorders, rheumatoid and psoriatic arthritis, pathology related to mechanical stress as De Quervain's tenosynovitis or trigger finger and unusually tumor. Diabetes is a risk factor for most of them and is related to poor prognosis. Musculoskeletal ultrasound is useful for diagnosis and to guide procedure as fluid aspiration or steroid injection.
23190644 Common and specific signatures of gene expression and protein-protein interactions in auto 2013 Mar The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/β-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the diagnoses and understanding of autoimmunity and/or specific autoimmune diseases.