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ID PMID Title PublicationDate abstract
28886085 Meibomian gland features in a Norwegian cohort of patients with primary Sjögren´s syndro 2017 PURPOSE: To assess the tear film and meibomian gland (MG) features in a Norwegian cohort of patients with primary Sjögren´s syndrome (pSS) and in age- and gender-matched control subjects. METHODS: Thirty-four female patients with pSS (age 52.9±11.9 years) and 32 female control subjects (age 49.0±11.5 years) were recruited. After completion of Ocular Surface Disease Index (OSDI) questionnaire and McMonnies Dry Eye Questionaire, participants underwent measurements of tear osmolarity, tear break-up time (TBUT), ocular surface and corneal staining, Schirmer I test, corneal sensitivity, MG expressibility evaluations, and lid margin morphology examination using slitlamp microscopy. Non-contact infrared meibography images were assessed by computer-assisted analysis. The MG loss, calculated as (tarsal area-MG area)/tarsal area, was evaluated in both upper (UL) and lower lids (LL). RESULTS: Compared to the control group, pSS patients demonstrated higher MG loss in both UL (33.8±13.2% vs. 24.4±8.5%, p< 0.01) and LL (52.5±15.7% vs. 43.0±9.6%, p<0.05), as well as higher lid abnormality score (0.8±0.8 vs. 0.2±0.6, p< 0.01). Furthermore, pSS patients showed higher OSDI and McMonnies questionnaire scores, elevated osmolarity, shorter TBUT, shorter blink interval, less wetting in Schirmer I test, more ocular surface staining and more corneal staining. MG loss in UL correlated negatively with TBUT (r = -0.386, p = 0.029) in the pSS group, whereas MG loss in LL correlated negatively with TBUT (r = -0.380, p = 0.035) in the control group. CONCLUSIONS: Significantly elevated dry eye symptoms and signs were found in the pSS group compared with the control group, which might be attributed to both decreased aqueous tear production and increased tear evaporation.
28789696 Long-term follow-up in primary Sjögren's syndrome reveals differences in clinical present 2017 Aug 8 BACKGROUND: Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjögren's syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS. METHODS: Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 ± 7.6 for women and 8.5 ± 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women. RESULTS: Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB (p = 0.02), and ANA (p = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease (p = 0.008), lymphadenopathy (p = 0.04) and lymphoma (p = 0.007). Conversely, concomitant hypothyroidism was more common among female patients (p = 0.009). CONCLUSIONS: We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS.
29244890 Prevalence and Predictors of Sjögren's Syndrome in Patients with Burning Mouth Symptoms. 2018 Winter AIMS: To investigate the prevalence and predictive factors of Sjögren's syndrome (SS) in a cohort of patients with burning mouth symptoms. METHODS: A total of 125 patients with burning mouth symptoms were enrolled in a prospective study and assessed for the presence of SS. The severity of oral symptoms was evaluated by using questionnaires. Salivary flow rates and salivary scintigraphy were used to evaluate salivary function. Patient laboratory work-ups were reviewed, and SS was diagnosed by a rheumatologist based on the American-European Consensus Group criteria. The differences between the SS patient group and the non-SS patient group were analyzed with chi-square test or t test. RESULTS: A total of 12 of the 125 enrolled patients (9.5%) had a positive autoimmune antibody test, and 6 (4.8% of the entire cohort) had SS (4 [3.2%] primary and 2 [1.6%] secondary). Patients with SS exhibited significantly decreased hemoglobin levels, an increased erythrocyte sedimentation rate, and an increased prevalence of autoantibody positive results compared to non-SS patients. Salivary scintigraphy showed that the uptake ratio of the submandibular gland in SS patients was decreased significantly. CONCLUSION: The prevalence of SS in patients with burning mouth symptoms was 4.8%. Therefore, clinicians who treat patients with burning mouth symptoms should evaluate laboratory findings and salivary functions to identify patients with SS.
27346252 Expression of the calcium-sensing receptor in monocytes from synovial fluid is increased i 2017 Mar OBJECTIVES: We assessed calcium-sensing receptor (CaSR) expression in monocytes isolated from synovial fluid of patients with different types of rheumatisms and explored whether CaSR expression was related to the inflammatory nature of synovial fluid. METHODS: Forty-one patients were included: osteoarthritis (n=10), microcristallin rheumatisms (n=10), rheumatoid arthritis (n=12) and other inflammatory rheumatisms (n=9). Surface and total CaSR expressions in monocytes isolated from synovial fluid and blood were assessed by flow cytometry analysis. U937 cells were cultured during 24hours in presence of cell-free synovial fluids. RESULTS: Every monocyte population tested express the CaSR intra- and extracellularly. Whereas similar pattern of CaSR expression exist in monocyte isolated from blood or synovial fluids, our results indicate that higher CaSR expression levels can be observed in monocytes from synovial fluids than in circulating monocytes. In both populations of monocytes, surface and total CaSR expressions were found to be significantly increased in patients with osteoarthritis compared to rheumatoid arthritis. Similar data were obtained when U937 cells were incubated with cell-free synovial fluids from osteoarthritis patients. Still present, this effect was significantly lowered when "inflammatory" synovial fluids were introduced in culture. CONCLUSIONS: Our results indicate that CaSR expression in synovial derived monocytes is higher in osteoarthritis than in inflammatory rheumatisms and that CaSR expression is modulated by the nature of the synovial fluid. Given the role played by monocytes in the pathogenesis of chronic rheumatisms, monocytes could be interesting therapeutic targets via the CaSR.
29024866 Diclofenac but not celecoxib improves endothelial function in rheumatoid arthritis: A stud 2017 Nov BACKGROUND AND AIMS: We aimed at investigating the effect of celecoxib (COX-2 selective inhibitor) and diclofenac (non-selective COX inhibitor) on endothelial function, and at identifying the underlying mechanisms in adjuvant-induced arthritis (AIA). METHODS: At the first signs of AIA, diclofenac (5 mg/kg twice a day, i.p), celecoxib (3 mg/kg/day, i.p) or saline (Vehicle) was administered for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of NOS, arginase, EDHF and superoxide anions (O(2)(-°)) production. Aortic expression of eNOS, Ser1177-phospho-eNOS, COX-2, arginase-2, p22(phox) and p47(phox) was evaluated by Western blotting analysis. Arthritis scores, blood pressure, glycaemia and serum ADMA levels were measured. RESULTS: Diclofenac and celecoxib significantly reduced arthritis score to the same extent (p<0.05). As compared to vehicle-treated AIA, celecoxib did not change whereas diclofenac improved endothelial function (p<0.05) through increased EDHF production, decreased arginase activity and expression, decreased superoxide anions production and expression of p22(phox) and p47(phox). Diclofenac but not celecoxib significantly enhanced blood pressure and serum ADMA levels. Glycaemia was unchanged by both treatments. CONCLUSIONS: Our study reveals that the effect of NSAIDs on endothelial function cannot be extrapolated from their impact on arthritis severity and suggest that changes in blood pressure and plasma ADMA levels may not be useful to predict CV risk of NSAIDs in RA.
28879053 Efficacy of embedded nurse-led versus conventional physician-led follow-up in rheumatoid a 2017 OBJECTIVE: To compare the efficacy of embedded nurse-led versus conventional physician-led follow-up on disease activity in patients with rheumatoid arthritis (RA). METHODS: In a systematic literature search, we identified randomised controlled trials (RCTs) reporting on the efficacy of nurse-led follow-up on disease control in patients with RA compared with physician-led follow-up. Primary outcome was disease activity indicated by Disease Activity Score (DAS)-28. Secondary outcomes were: patient satisfaction, physical disability, fatigue, self-efficacy and quality of life. Outcomes were assessed after 1-year and 2 year follow-ups. RESULTS: Seven studies representing five RCTs, including a total of 723 participants, were included. All but one study included stable patients in low disease activity or remission at baseline. No difference in DAS-28 was found after 1 year (mean difference (MD) -0.07 (95% CI -0.23 to 0.09)). After 2 years, a statistically significant difference was seen in favour of nurse-led follow-up (MD -0.28 (95% CI -0.53 to -0.04)). However, the difference did not reach a clinically relevant level. No difference was found in patient satisfaction after 1 year (standard mean difference (SMD) -0.17 (95 % CI -1.0 to 0.67), whereas a statistical significant difference in favour of nurse-led follow-up was seen after 2 years (SMD: 0.6 (95% CI -0.00 to 1.20)). CONCLUSION: After 1 year no difference in disease activity, indicated by DAS-28, were found between embedded nurse-led follow-up compared with conventional physician-led follow-up, in RA patients with low disease activity or remission.
29992108 Anti-rheumatoid activity of ethanolic extract of Sesamum indicum seed extract in Freund's 2018 Jul Sesamum indicum, one of the first recorded plants used for its seeds, is reported to have analgesic, antioxidant, anticancer, anti-obesity as well as hepato and nephro protective activities. The current study evaluated the effects of two doses (400 and 800 mg/kg) of ethanolic extract of S. indicum seeds in Freund's complete adjuvant induced arthritis in rats in comparison with diclofenac and methotrexate by the changes produced in body weight, body temperature, paw volume and spontaneous activity, hemoglobin, erythrocyte sedimentation rate, total white blood cells, red blood cells, Interleukin-6 and Tumor necrosis factor-α as well as joint changes in X-ray and histological changes in joint tissue. Unlike the untreated group, the groups treated with S. indicum showed significant decrease in paw volume, body weight, white blood cell count, erythrocyte sedimentation rate, Interleukin-6 and Tumor necrosis factor-α and an increase in body weight, spontaneous activity, hemoglobin level, and red blood cell count. Histopathological examination showed gross reduction in synovial inflammation and cartilage damage. X-ray revealed significant improvement in joint space. The effect of ethanolic extract of S. indicum was found to be equivalent to methotrexate and greater than diclofenac.
28270934 Correction: Drug-specific risk and characteristics of lupus and vasculitis-like events in 2017 [This corrects the article DOI: 10.1136/rmdopen-2016-000314.].
28852846 Leveraging the electronic health record to improve quality and safety in rheumatology. 2017 Oct During the last two decades, improving the quality and safety of healthcare has become a focus in rheumatology. Widespread use of electronic health records (EHRs) and the availability of digital data have the potential to drive quality improvement, improve patient outcomes, and prevent adverse events. In the coming years, developing and leveraging tools within the EHR will be the key to making the next big strides in improving the health of patients with rheumatoid arthritis and other rheumatic diseases, including building EHR infrastructure to capture patient outcomes and developing automated methods to retrieve information from free text of clinical notes.
28382662 Successful targeted treatment of mast cell activation syndrome with tofacitinib. 2017 Aug Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile. For example, both activated KIT and numerous cytokine receptors activate the Janus kinases (JAKs). Thus, JAK-inhibiting therapies may be useful against the downstream inflammatory effects of MCAS. The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for rheumatoid arthritis and is in clinical trials for other chronic inflammatory disorders. Herein, we report two patients with MCAS who rapidly gained substantial symptomatic response to tofacitinib. Their improvement suggests need for further evaluation of this class of drugs in MCAS treatment.
29435359 Safety and maintenance of response for tofacitinib monotherapy and combination therapy in 2017 OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post hoc analysis evaluated patients receiving tofacitinib monotherapy or combination therapy, as well as those who switched from monotherapy to combination therapy (mono→combo) or vice versa (combo→mono) in long-term extension (LTE) studies. METHODS: Data were pooled from open-label LTE studies (ORAL Sequel (NCT00413699; ongoing; data collected 14 January 2016) and NCT00661661) involving patients who participated in qualifying index studies. Efficacy outcomes included American College of Rheumatology 20/50/70 rates, change from baseline in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index and DAS28-4(ESR) and CDAI low disease activity and remission. Safety was evaluated over 96 months. RESULTS: Of the 4967 patients treated, 35.4% initiated tofacitinib monotherapy, 64.6% initiated combination therapy, 2.6% were mono→combo switchers and 7.1% were combo→mono switchers. Patients who switched multiple times were excluded. Of those who initiated monotherapy and combination therapy, 87.8% (1543/1757) and 82.0% (2631/3210), respectively, remained on the same regimen throughout the study; efficacy was maintained. Incidence rates (IRs) for serious adverse events with tofacitinib 5 mg and 10 mg twice daily, respectively, were 9.42 and 8.41 with monotherapy and 8.36 and 10.75 with combination therapy; IRs for discontinuations due to AEs were 7.13 and 6.06 with monotherapy and 7.82 and 8.06 with combination therapy (overlapping CIs). For mono→combo and combo→mono switchers, discontinuations due to AEs were experienced by 0.8% and 0.9%, respectively, within 30 days of switching. CONCLUSION: Tofacitinib efficacy as monotherapy or combination therapy was maintained through month 48 and sustained to month 72, with minimal switching of treatment regimens. Safety was consistent over 96 months. CLINICAL TRIAL REGISTRATION: NCT00413699 (Pre-results) and NCT00661661 (Results).
29359131 Serum Protein N-Glycosylation Changes with Rheumatoid Arthritis Disease Activity during an 2017 Symptoms of rheumatoid arthritis (RA) improve during pregnancy, a phenomenon that was found to be associated with N-glycosylation changes of immunoglobulin G. Recent advances in high-throughput glycosylation analysis allow the assessment of the N-glycome of human sera as well. The aim of this study was to identify new protein N-glycosylation properties that associate with changes in RA disease activity during and after pregnancy. A longitudinal cohort of serum samples was collected during 285 pregnancies (32 control individuals and 253 RA patients). Per individual one sample was collected before conception, three during pregnancy, and three after delivery. Released serum protein N-glycans were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) after employing chemical modification of the sialic acids to allow discrimination of sialic acid linkage isomers. Serum protein N-glycosylation showed strongly modified during pregnancy, with similar changes visible in control individuals and RA pregnancies. Namely, a decrease in bisection and an increase in galactosylation in diantennary glycans were found, as well as an increase in tri- and tetraantennary species and α2,3-linked sialylation thereof. The change in RA disease activity [DAS28(3)-CRP] proved negatively associated with the galactosylation of diantennary N-glycans, and positively with the sialylation of triantennary fucosylated species (A3FGS). While the protein source of the novel finding A3FGS is thus far unknown, its further study may improve our understanding of the etiology of RA disease severity.
28581157 Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD 2017 Dec Protein arginine deiminase type IV (PAD4) is responsible for the posttranslational conversion of peptidylarginine to peptidylcitrulline. Citrullinated protein is the autoantigen in rheumatoid arthritis, and therefore, PAD4 is currently a promising therapeutic target for the disease. Recently, we reported the importance of the furan ring in the structure of PAD4 inhibitors. In this study, the furan ring was incorporated into peptides to act as the "warhead" of the inhibitors for PAD4. IC(50) studies showed that the furan-containing peptide-based inhibitors were able to inhibit PAD4 to a better extent than the furan-containing small molecules that were previously reported. The best peptide-based inhibitor inhibited PAD4 reversibly and competitively with an IC(50) value of 243.2 ± 2.4 μm. NMR spectroscopy and NMR-restrained molecular dynamic simulations revealed that the peptide-based inhibitor had a random structure. Molecular docking studies showed that the peptide-based inhibitor entered the binding site and interacted with the essential amino acids involved in the catalytic activity. The peptide-based inhibitor could be further developed into a therapeutic drug for rheumatoid arthritis.
28123778 Factors influencing the use of tocilizumab as monotherapy in patients with rheumatoid arth 2017 INTRODUCTION: Using a biologic disease-modifying antirheumatic drug (bDMARD) as monotherapy in clinical practice for patients with rheumatoid arthritis (RA) is common and recognised by health authorities although current guidelines recommend to combine them with conventional synthetic (cs)DMARDs. This study mainly aimed to search for real-life factors influencing the use of tocilizumab as MONO or in combination (COMBO). METHODS: In this non-interventional, prospective, national, multicentre study, data were collected every 3 months over a 12-month period in RA patients starting tocilizumab. The proportion of monotherapy patients was described, together with significant explicative factors. RESULTS: Among the 577 analysed patients recruited from January 2012 to August 2013 (228 monotherapy patients; 40%), 79% were women, mean RA duration was 11±9 years, previous RA treatments included bDMARDs and csDMARDs in 75% of cases and mean Disease Activity Score 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) was 5.2±1.3 at inclusion. Explicative factors for monotherapy were at least 65 years (OR=1.47, p=0.0485), no methotrexate within the two last years (OR=5.96, p<0.0001), past severe infection (OR=1.99, p=0.0272) and higher baseline DAS28-ESR (OR=1.22, p=0.0086). Regarding clinical results (DAS28-ESR, Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) low disease activity and remission; ACR20/50/70 and European League Against Rheumatism (EULAR) response; Health Assessment Questionnaire Disability Index (HAQ-DI) score), no relevant differences between monotherapy and combination patients were observed at 1 year. A total of 23 tocilizumab-treated patients (4%) experienced serious infections; no new safety signals were noted with no differences between groups. CONCLUSIONS: ACT-SOLO confirms the high proportion of RA patients receiving tocilizumab as MONO in clinical practice. The study also showed that clinical results at 1 year were similar between MONO and COMBO patients in a real-life setting. TRIAL REGISTRATION NUMBER: NCT01474291.
27900570 Concomitant Use of Statins in Tocilizumab-Treated Patients with Rheumatoid Arthritis: A Po 2017 Jun INTRODUCTION: Patients with rheumatoid arthritis (RA) have decreased survival because of increased cardiovascular risk compared with the general population, and treatment with tocilizumab (TCZ) has been shown to increase lipid levels; however, the relationship between lipids and cardiovascular risk is unknown. This post hoc analysis expanded on previously reported 24-week results by characterizing statin use and subsequent changes in lipid parameters in patients with RA treated with intravenous or subcutaneous TCZ (TCZ-IV or TCZ-SC) over 2 years of treatment. METHODS: Data were collected from patients with moderate to severe active RA who received ≥1 dose of the study drug in seven international, randomized, double-blind, controlled phase 3 and 4 clinical trials of TCZ-IV or TCZ-SC. Lipid levels and safety events were assessed over 2 years of treatment. Data were summarized for all pooled treatment groups of the intention-to-treat populations in the TCZ-IV and TCZ-SC studies, and results were stratified by concomitant statin use. RESULTS: Data from this descriptive, retrospective, pooled analysis indicated that statins can stabilize lipid levels without a clinically significant increase in adverse events. Approximately 30% of patients in the TCZ treatment arms who never received a statin demonstrated a shift in low-density-lipoprotein cholesterol (LDL-C) from <130 mg/dl at baseline to ≥130 mg/dl at 2 years. However, despite the increased potential cardiovascular risk, <15% of patients with LDL-C ≥100 mg/dl and <35% of patients with a total cholesterol:high-density-lipoprotein cholesterol ratio >5 at 2 years were receiving concomitant statins. CONCLUSION: Concomitant statin use attenuated TCZ-mediated lipid increases; however, a large proportion of TCZ-treated patients potentially at risk of cardiovascular disease were untreated. These findings highlight the need for better understanding of potential risk associated with TCZ-mediated lipid elevations as well as implementation of RA-specific guidelines on the recognition and management of elevated risk of cardiovascular events in patients with RA. FUNDING: F. Hoffmann-La Roche, Ltd.
27774824 Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1. 2017 Feb Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts. The authors have ordered recent patents according to the primary applicant's name, with part 1 covering A through to I. Expert opinion: Inhibition of JAK-family kinases is an area of growing interest, catalysed by the maturity of data on marketed inhibitors ruxolitinib and tofacitinib in late stage clinical trials. Many applicants are pursuing traditional fast-follower strategies around these inhibitors, with a range of chemical strategies adopted. The challenge will be to show sufficient differentiation to the originator compounds, since dose limiting toxicities with such agents appear to be on target and mechanism-related and also considering that such agents may be available as generic compounds by the time follower agents reach market.
29358919 The Calcium-Induced Regulation in the Molecular and Transcriptional Circuitry of Human Inf 2017 Rheumatoid arthritis synovial fibroblasts (RASFs) are fundamental effector cells in RA driving the joint inflammation and deformities. Celastrol is a natural compound that exhibits a potent anti-arthritic effect promoting endoplasmic reticulum (ER) stress mediated by intracellular calcium (Ca(2+)) mobilization. Ca(2+) is a second messenger regulating a variety of cellular processes. We hypothesized that the compound, celastrol, affecting cytosolic Ca(2+) mobilization could serve as a novel strategy to combat RA. To address this issue, celastrol was used as a molecular tool to assay the inflammatory gene expression profile regulated by Ca(2+). We confirmed that celastrol treatment mobilized cytosolic Ca(2+) in patient-derived RASFs. It was found that 23 genes out of 370 were manipulated by Ca(2+) mobilization using an inflammatory and autoimmunity PCR array following independent quantitative PCR validation. Most of the identified genes were downregulated and categorized into five groups corresponding to their cellular responses participating in RA pathogenesis. Accordingly, a signaling network map demonstrating the possible molecular circuitry connecting the functions of the products of these genes was generated based on literature review. In addition, a bioinformatics analysis revealed that celastrol-induced Ca(2+) mobilization gene expression profile showed a novel mode of action compared with three FDA-approved rheumatic drugs (methotrexate, rituximab and tocilizumab). To the best of our knowledge, this is a pioneer work charting the Ca(2+) signaling network on the regulation of RA-associated inflammatory gene expression.
29137228 A native-like bispecific antibody suppresses the inflammatory cytokine response by simulta 2017 Oct 10 Anti-tumor necrosis factor (TNF) therapies are successful in the treatment of inflammatory disorders. However, some patients with rheumatoid arthritis (RA) fail to response anti-TNF drugs due to the compensation of other inflammatory signals. In this study, to reduce compensatory responses of interleukin-17A (IL-17A) during TNF-α inhibition, we generated an IgG-like bispecific antibodiy (bsAb) against TNF-α and IL-17A through a combination method of electrostatic Fc pairing and light chain crossover. This bsAb exhibited relatively high stability comparable to natural IgG antibodies, and retained the unaltered affinities to both of two targets. BsAb significantly decreased not only the expression level of neutrophil or Th17 chemokines, but also the secretion of IL-6/IL-8 on fibroblast-like synoviocytes (FLS) from a patient with RA. Meanwhile, TNF-α-mediated cellular cytotoxicity of fibroblasts was neutralized by bsAb. Importantly, we demonstrate that the combined blockade of TNF-α and IL-17A is more efficient than inhibition of either factor alone. Our results suggest the IgG-like anti-TNF-α/IL-17A bispecific molecule overcome the limited therapeutic responses using anti-TNF drugs. It may be a promising therapeutic agent for the treatment of autoimmune diseases.
28819927 Switching From Immediate-Release to Delayed-Release Prednisone in Moderate to Severe Rheum 2017 Dec INTRODUCTION: Rheumatoid arthritis (RA) produces debilitating morning stiffness. Exogenous glucocorticoids can help with these symptoms when timed appropriately. Bedtime dosing of delayed-release prednisone (DR-prednisone) matches the rise of inflammatory cytokines before awakening and can improve stiffness and other RA symptoms. A prospective open-label study was conducted in patients currently on stable doses of immediate-release prednisone (IR-prednisone) who were switched to DR-prednisone to analyze the incremental benefit of better timed and lower dose glucocorticoid therapy. METHODS: Twelve US sites enrolled patients with moderate-severe RA into a 12-week prospective study. Patients were switched from IR- to DR-prednisone while maintaining other existing background therapies. Change from baseline in morning stiffness severity, morning stiffness duration, swollen and tender joint counts (S-TJC), 28 joint disease activity score (DAS28), and patient/physician global assessment (PGA/PhGA), among others, were measured. Post-hoc analyses were performed on those completing 10 weeks of treatment and those with >60 min of morning stiffness at baseline. RESULTS: Fifty-six patients had at least one follow-up visit and were similar in demographics to previous controlled trials with DR-prednisone with regard to baseline age and DAS28-CRP but had lower morning stiffness and RA duration. DR-prednisone produced a trend toward lower morning stiffness severity and duration with a reduction in daily prednisone dose of almost 1 mg. Patients treated with DR-prednisone for ≥10 weeks demonstrated significant reductions in morning stiffness duration, SJC, TJC, DAS28-CRP, and PhGA (all p ≤ 0.04). Patients treated for ≥10 weeks with >60 min of baseline morning stiffness produced similar results in these measures as well as a 21% reduction in morning stiffness severity (p = 0.02). CONCLUSION: Patients switched to DR-prednisone from IR-prednisone in this practice-based study maintained or improved their outcomes across a variety of domains, and results were comparable to previous controlled trials in which patients completed at least 10 weeks of treatment. FUNDING: Horizon Pharma USA, Inc. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02287610.
29340042 Identification of potential genetic causal variants for rheumatoid arthritis by whole-exom 2017 Dec 19 Rheumatoid arthritis (RA) is a highly prevalent chronic autoimmune disease. However, genetic and environmental factors involved in RA pathogenesis are still remained largely unknown. To identify the genetic causal variants underlying pathogenesis and disease progression of RA patients, we undertook the first comprehensive whole-exome sequencing (WES) study in a total of 124 subjects including 58 RA cases and 66 healthy controls in Han Chinese population. We identified 378 novel genes that were enriched with deleterious variants in RA patients using a gene burden test. The further functional effects of associated genetic genes were classified and assessed, including 21 newly identified genes that were involved in the extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, focal adhesion and glycerophospholipid metabolism pathways relevant to RA pathogenesis. Moreover, six pathogenic variants were investigated and structural analysis predicted their potentially functional alteration by homology modeling. Importantly, five novel and rare homozygous variants (NCR3LG1, RAP1GAP, CHCHD5, HIPK2 and DIAPH2) were identified, which may exhibit more functional impact on RA pathogenesis. Notably, 7 genes involved in the olfactory transduction pathway were enriched and associated with RA disease progression. Therefore, we performed an efficient and powerful technique WES in Chinese RA patients and identified novel, rare and common disease causing genes that alter innate immunity pathways and contribute to the risk of RA. Findings in this study may provide potential diagnostic tools and therapeutic strategies for RA patients.