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30742399 Flurbiprofen Therapy and CYP2C9 Genotype. 2012 Flurbiprofen (brand name Ansaid) is a nonsteroidal anti-inflammatory drug (NSAID). Tablets and skin patches are used in the management of osteoarthritis and rheumatoid arthritis. Flurbiprofen provides pain relief and reduces inflammation. Flurbiprofen eye drops (brand name Ocufen) may also be used to prevent miosis (excessive constriction of the pupil) during eye operations; e.g., cataract surgery. Flurbiprofen is primarily metabolized by CYP2C9. Individuals who lack CYP2C9 activity (CYP2C9 poor metabolizers) have an increased exposure to flurbiprofen, and an increased risk of side effects. Like all NSAIDs, flurbiprofen increases the risk of serious cardiovascular events, including myocardial infarction and stroke, and serious gastrointestinal (GI) adverse events such as bleeding, ulceration, and perforation, which may be fatal. The recommended starting dose of flurbiprofen tablets in adults is 200–300 mg per day, divided for administration 2, 3, or 4 times a day. But for all patients, the lowest effective dose of flurbiprofen should be used for the shortest length of time, consistent with the treatment goals of each individual. The FDA-approved drug label for flurbiprofen states that the dose of flurbiprofen should be reduced in “patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin)” (Table 1). This dose reduction is to avoid the abnormally high plasma levels of flurbiprofen in these patients caused by reduced metabolic clearance. However, specific dose reductions based on CYP2C9 phenotype are not provided (1). As for all NSAIDs, flurbiprofen is contraindicated in patients with a known hypersensitivity; a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or another NSAID; and for coronary artery bypass graft (CABG) surgery. Flurbiprofen should also be avoided by pregnant women starting at 30 weeks gestation (1).
30611908 Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-ter 2019 May Vitamin D3 is a secosteroid hormone produced in the skin in amounts estimated up to 25,000 international units (IUs) a day by the action of UVB radiation on 7-dehydrocholesterol. Vitamin D deficiency is common due to both lack of adequate sun exposure to the skin, and because vitamin D is present in very few food sources. Deficiency is strongly linked to increased risk for a multitude of diseases, several of which have historically been shown to improve dramatically with either adequate UVB exposure to the skin, or to oral or topical supplementation with vitamin D. These diseases include asthma, psoriasis, rheumatoid arthritis, rickets and tuberculosis. All patients in our hospital have been routinely screened on admission for vitamin D deficiency since July 2011, and offered supplementation to either correct or prevent deficiency. During this time, we have admitted over 4700 patients, the vast majority of whom agreed to supplementation with either 5000 or 10,000 IUs/day. Due to disease concerns, a few agreed to larger amounts, ranging from 20,000 to 50,000 IUs/day. There have been no cases of vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any patient. Three patients with psoriasis showed marked clinical improvement in their skin using 20,000 to 50,000 IUs/day. Analysis of 777 recently tested patients (new and long-term) not on D3 revealed 28.7% with 25-hydroxyvitaminD3 (25OHD3) blood levels < 20 ng/ml, 64.1% < 30 ng/ml, a mean 25OHD3 level of 27.1 ng/ml, with a range from 4.9 to 74.8 ng/ml. Analysis of 418 inpatients on D3 long enough to develop 25OHD3 blood levels > 74.4 ng/ml showed a mean 25OHD3 level of 118.9 ng/ml, with a range from 74.4 to 384.8 ng/ml. The average serum calcium level in these 2 groups was 9.5 (no D3) vs 9.6 (D3), with ranges of 8.4 to 10.7 (no D3) vs 8.6 to 10.7 mg/dl (D3), after excluding patients with other causes of hypercalcemia. The average intact parathyroid hormone levels were 24.2 pg/ml (D3) vs. 30.2 pg/ml (no D3). In summary, long-term supplementation with vitamin D3 in doses ranging from 5000 to 50,000 IUs/day appears to be safe.
30035379 Tissue-Resident Memory CD8+ T Cells Acting as Mediators of Salivary Gland Damage in a Mur 2019 Jan OBJECTIVE: Although a role for CD4+ T cells in the pathogenesis of Sjögren's syndrome (SS) has been documented, the pathogenic significance of CD8+ T cells is unclear. The aim of this study was to investigate the role of CD8+ T cells in the development of SS. METHODS: Flow cytometry and immunofluorescence analyses were utilized to detect T cell infiltration within the labial salivary glands of patients with primary SS. In parallel, p40(-/-) CD25(-/-) mice were used as a murine model of SS. In addition, mice with genetic knockout of CD4, CD8a, or interferon-γ (IFNγ) were crossed with p40(-/-) CD25(-/-) mice to study the pathogenic significance of specific lineage subpopulations, including functional salivary gland tests as well as histopathologic and serologic data. A CD8+ T cell-specific depletion antibody was used in this murine SS model to evaluate its potential as a therapeutic strategy. RESULTS: CD8+ T cells with a tissue-resident memory phenotype outnumbered CD4+ T cells in the labial salivary glands of patients with SS, and were primarily colocalized with salivary duct epithelial cells and acinar cells. Furthermore, infiltrating CD8+ T cells with a CD69+CD103+/- tissue-resident phenotype and with a significant elevation of IFNγ production were dominant in the submandibular glands of mice in this murine SS model. CD8a knockout abrogated the development of SS in these mice. Knockout of IFNγ decreased CD8+ T cell infiltration and gland destruction. More importantly, depletion of CD8+ T cells fully protected mice against the pathologic manifestations of SS, even after the onset of disease. CONCLUSION: These data reveal the pathogenic significance of CD8+ T cells in the development and progression of SS in the salivary glands. Treatment directed against CD8+ T cells may be a rational therapy for the management of SS in human subjects.
31735133 Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with 2020 Jul INTRODUCTION: Immune checkpoint inhibitors and angiogenesis inhibitors are novel treatment options for renal cell carcinoma and widely used in clinical practice. They are related with adverse events that occur as a consequence of immune system activation and inhibition of angiogenesis. Herein, we report a rare case of inflammatory arthritis seen in a patient treated with an anti Programmed cell death-1 pembrolizumab and an anti-vascular endothelial growth factor pazopanib. CASE REPORT: A 60-year-old Caucasian male presented to our clinic with inflammatory arthritis with pitting edema. He had been started on pembrolizumab therapy for metastatic renal cell carcinoma after enrolling in the KEYNOTE-679 study. After six cycles of treatment with pembrolizumab, metastasis had been determined in the lung. Then, the patient's therapy was changed to pazopanib. While the patient was on pazopanib treatment, he noticed a gradual swelling of both hands. Rheumatoid factor, anti-nuclear antibody and anti-cyclic citrullinated peptide were negative. Joint ultrasonography revealed acute tenosynovitis and soft tissue swelling with pitting edema, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. Management and outcome: He was started on 10 mg prednisolone daily. His symptoms dramatically responded to corticosteroid. He continued to take pazopanib. Then, the patient was discharged with 10 mg prednisolone daily. DISCUSSION: Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema can be among the rare rheumatic immune-related adverse events that clinicians may encounter as the immune check point inhibitors and anti-VEGF use increases. Corticosteroid therapy can relieve symptoms and cessation of therapy may not be necessary.
31463794 Canakinumab in Children with Familial Mediterranean Fever: A Single-Center, Retrospective 2019 Oct INTRODUCTION: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by interleukin (IL)-1 overproduction. Colchicine is the mainstay drug in the treatment of FMF; however, a minority of patients do not respond despite the highest tolerated doses. We aimed to share our experience with canakinumab, a human monoclonal antibody against IL-1β, in pediatric FMF patients. METHODS: This historical, single-cohort study retrospectively evaluated the disease characteristics, indications, and treatment responses of 14 pediatric FMF patients treated with canakinumab in our pediatric rheumatology department. RESULTS: The median age at onset and diagnosis of 14 FMF patients (9 females, 5 males), were 3.5 (range 0.5-10) years and 6 (range 3-16) years, respectively. Indications for canakinumab treatment were renal amyloidosis (n = 1), colchicine resistance (n = 11), and persistent arthritis (n = 2). Only two (14.3%) patients had colchicine intolerance. Complete response was obtained in 10/14 (71.5%) among all patients and 10/12 (86%) in patients with typical phenotype. The patient with chronic oligoarthritis had a complete response, whereas the patient with rheumatoid factor (RF)-positive polyarthritis demonstrated an initial partial response to canakinumab treatment. We found that attack frequency, proteinuria, and acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein, were significantly decreased after canakinumab treatment in children with FMF. CONCLUSION: Canakinumab may be an effective treatment option for pediatric FMF patients with colchicine resistance, renal amyloidosis, and chronic oligoarthritis. Further studies are needed to clarify the efficacy of canakinumab in patients with a second disease, RF-positive polyarticular juvenile idiopathic arthritis.
30762274 Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from origi 2019 Jun BACKGROUND AND OBJECTIVES: The 52-week, randomized, double-blind, noninferiority, government-funded NOR-SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar CT-P13 was not inferior to continued treatment with infliximab originator. The NOR-SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT-P13 throughout the 78-week study period (maintenance group) versus patients switched to CT-P13 at week 52 (switch group). The primary outcome was disease worsening during follow-up based on disease-specific composite measures. METHODS: Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis. RESULTS: Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per-protocol set). Adjusted risk difference was 5.9% (95% CI -1.1 to 12.9). Frequency of adverse events, anti-drug antibodies, changes in generic disease variables and disease-specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases. CONCLUSION: The NOR-SWITCH extension showed no difference in safety and efficacy between patients who maintained CT-P13 and patients who switched from originator infliximab to CT-P13, supporting that switching from originator infliximab to CT-P13 is safe and efficacious.
31517725 Prevalence of Novel Candidate Sjögren Syndrome Autoantibodies in the Penn Sjögren's Inte 2019 Dec PURPOSE: To evaluate the prevalence of novel candidate autoantibodies associated with Sjögren syndrome (SS) and their ability to identify those with SS among participants with dry eye enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) study at the University of Pennsylvania (Penn). METHODS: All participants previously underwent a full ocular and systemic evaluation for possible SS as part of the SICCA study. An enzyme-linked immunosorbent assay was used to detect IgG, IgA, and IgM autoantibodies to salivary protein 1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase 6 from previously banked baseline serum samples from SICCA study participants enrolled at Penn. The prevalence rate of each autoantibody, calculated by considering the presence of any isotype as antibody positive, was compared between participants with dry eye with SS (n = 81) or without SS (n = 129) using the Fisher exact test. RESULTS: The prevalence of SP-1 IgM autoantibodies was higher in those with SS compared with those without SS (14% vs. 5%; P = 0.03). Similarly, the prevalence of PSP IgA autoantibodies was higher in those with SS compared with non-SS dry eye participants (21% vs. 11%; P = 0.048). There was no statistically significant difference in the prevalence of carbonic anhydrase 6 autoantibodies between those with or without SS (15% vs. 20%; P = 0.36). CONCLUSIONS: In the Penn SICCA cohort, SP-1 IgM and PSP IgA autoantibodies were more prevalent in the serum of SS-related dry eye participants compared with those without SS. Further longitudinal studies are needed to determine the clinical significance of these findings.
29316023 Sjögren's syndrome X-chromosome dose effect: An epigenetic perspective. 2019 Mar Sjögren's syndrome (SS) is a chronic autoimmune disease affecting exocrine glands leading to mouth and eyes dryness. The extent to which epigenetic DNA methylation changes are responsible for an X-chromosome dose effect has yet to be determined. Our objectives were to (i) describe how epigenetic DNA methylation changes could explain an X-chromosome dose effect in SS for women with normal 46,XX genotype and (ii) determine the relevant relationships to this dose effect, between X-linked genes, genes controlling X-chromosome inactivation (XCI) and genes encoding associated transcription factors, all of which are differentially expressed and/or differentially methylated in the salivary glands of patients with SS. We identified 58 upregulated X-chromosome genes, including 22 genes previously shown to escape XCI, based on the analysis of SS patient salivary gland GEO2R gene expression datasets. Moreover, we found XIST and its cis regulators RLIM, FTX, and CHIC1, and polycomb repressor genes of the PRC1/2 complexes to be upregulated. Many of the X-chromosome genes implicated in SS pathogenesis can be regulated by transcription factors which we found to be overexpressed and/or differentially methylated in patients with SS. Determination of the mechanisms underlying methylation-dependent gene expression and impaired XCI is needed to further elucidate the etiopathogenesis of SS.
30642862 Autoimmune myelofibrosis: a rare haematological involvement in systemic lupus erythematosu 2019 Jan 14 Autoimmune myelofibrosis is a distinct clinicopathological entity that occurs with autoimmune disorders. We report the case of a 44-year-old woman admitted with pancytopenia and clinical features of systemic lupus erythematosus, Sjogren's syndrome and antiphospholipid antibodies syndrome. Bone marrow biopsy showed decreased global cells and an increase of reticulin fibres on argentic coloration, consistent with myelofibrosis. The JAK2 V617, Myeloproliferative leukemia (MPL) and calreticulin mutations were negative. The patient's condition improved after treatment with hydroxychloroquine, vitamin K antagonists and prednisone.
31708547 Thrombotic Thrombocytopenic Purpura Treated with Rituximab Associated with Primary Sjögre 2020 Mar 1 A 47-year-old man was admitted to our hospital because of thrombocytopenia and consciousness disturbance. As his laboratory data showed undetectable activity of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) and the presence of ADAMTS13 inhibitor, he was diagnosed with acquired thrombotic thrombocytopenic purpura (TTP). Asymptomatic primary Sjögren's syndrome (SS) and primary hypothyroidism were incidentally diagnosed on screening. After initial plasma exchange therapy and pulse corticosteroid therapy, the patient received rituximab therapy for refractory TTP with "inhibitor boosting" and recovered. TTP secondary to primary SS is rare but can trigger refractory TTP. Treatment with rituximab, which is considered "inhibitor boosting," should be considered when re-exacerbation occurs.
30809091 Emodin induces apoptosis and autophagy of fibroblasts obtained from patient with ankylosin 2019 BACKGROUND: Ankylosing spondylitis (AS) is a type of rheumatoid disease, which has been reported to be associated with the excessive proliferation of fibroblasts recently. Emodin, a single component from a traditional Chinese medicine Rheum palmatum, exerts anti-inflammation and antirheumatic arthritis activities. However, could emodin be used to treat AS remains unclear? Thus, this study aimed to investigate the effect of emodin on AS. METHODS: Fibroblasts obtained from patients with AS were used in the current study. In addition, multiple cellular and molecular biology techniques such as Cell Counting Kit-8, Western blotting, flow cytometry, monodansylcadaverine staining, and immunofluorescence assay were applied as well. RESULTS: Emodin-induced apoptosis of fibroblasts obtained from patient with AS via increasing active caspase-9, active caspase-3, and Bax levels and downregulating Bcl-2. Meanwhile, emodin enhanced autophagy in fibroblasts via upregulation of the expression of Atg12, Atg5, and Beclin 1, which was further confirmed by monodansylcadaverine staining. As expected, autophagy inhibitor 3-methyladenine (3MA) completely reversed emodin-induced autophagy in fibroblasts. Moreover, 3MA significantly increased emodin-induced apoptosis of fibroblasts obtained from patient with AS by increasing the levels of γH2AX, active caspase-9, active caspase-3, and cleaved poly ADP-ribose polymerase. CONCLUSION: Our results indicated that emodin effectively induced apoptosis and autophagy of fibroblasts obtained from patient with AS. In addition, suppression of autophagy enhanced emodin-induced apoptosis in fibroblasts. Therefore, we proposed that combination of emodin with autophagy inhibitor might be a potent strategy for improving the symptoms of AS in the future.
31571337 Preterm birth phenotypes in women with autoimmune rheumatic diseases: a population-based c 2020 Jan OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort. DESIGN: Retrospective cohort study. SETTING: California, USA. POPULATION: All live singleton births in California between 2007 and 2011 were analysed. Patients with autoimmune disease at delivery were identified by International Classification of Diseases, Ninth Revision , Clinical Modification (ICD-9-CM), codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA). METHODS: Maternally linked hospital and birth certificate records of 2 481 516 deliveries were assessed (SLE n = 2272, RA n = 1501, SSc n = 88, JIA n = 187, DM/PM n = 38). Multivariable Poisson regression models estimated the risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared with the general obstetric population, adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care. MAIN OUTCOME MEASURES: Preterm birth (PTB) was assessed overall (20-36 weeks of gestation) and by subphenotype: preterm prelabour rupture of membranes (PPROM), spontaneous birth, or medically indicated PTB. The risk of PTB overall and for each phenotype was partitioned by gestational age: early (20-31 weeks of gestation) and late (32-36 weeks of gestation). RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27, 95% CI 3.01-3.56), RA (RR 2.04, 95% CI 1.79-2.33), SSc (RR 3.74, 95% CI 2.51-5.58), JIA (RR 2.23, 95% CI 1.54-3.23), and DM/PM (RR 5.26, 95% CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well. CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counselling and close monitoring during pregnancy is crucial. TWEETABLE ABSTRACT: This study found that women with systemic autoimmune diseases have an elevated risk of preterm birth phenotypes.
31206593 AURIEL-PsO: a randomized, double-blind phase III equivalence trial to demonstrate the clin 2020 Feb BACKGROUND: MSB11022 is a proposed adalimumab biosimilar. OBJECTIVES: To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab. METHODS: AURIEL-PsO was a double-blind randomized controlled equivalence trial, in which patients with moderate-to-severe chronic plaque-type psoriasis were randomized 1 : 1 to MSB11022 or reference adalimumab. The primary end point was ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with a prespecified equivalence interval of ± 18%. Patients with a ≥50% improvement in PASI at week 16 were eligible to enter a double-blind extension period: patients receiving MSB11022 continued treatment, and patients receiving reference adalimumab were rerandomized 1 : 1 either to continue reference adalimumab or to switch to MSB11022. Other efficacy end points and safety, immunogenicity and pharmacokinetic parameters were evaluated at scheduled visits up to weeks 52 (efficacy and immunogenicity), 54 and 66 (safety). RESULTS: In total, 443 patients were randomized. The difference in PASI 75 response rates at week 16 between the treatment arms was -1·9%, and the 95% confidence interval (-7·8% to 4·1%) was within the prespecified equivalence interval. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the trial, and no new safety signals were observed. Following treatment switch at week 16, no clinically meaningful differences in safety or immunogenicity were seen between treatment arms through to the end of the observation period. CONCLUSIONS: Therapeutic equivalence between MSB11022 and reference adalimumab was demonstrated. AURIEL-PsO provides evidence to support the similarity of both products with regard to efficacy, safety and immunogenicity. What's already known about this topic? Adalimumab is a fully human antitumour necrosis factor-α monoclonal antibody, indicated for the treatment of multiple inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases and ankylosing spondylitis. MSB11022 is a proposed adalimumab biosimilar that has shown structural and functional similarity to the reference product in an extensive analytical comparability exercise. MSB11022 has demonstrated bioequivalence and comparable safety and immunogenicity profiles in a phase I study in healthy volunteers. What does this study add? This phase III study confirmed equivalent efficacy for MSB11022 and reference adalimumab in patients without any immunomodulation comedication in moderate-to-severe chronic plaque-type psoriasis at week 16. The efficacy, safety and immunogenicity of MSB11022 and reference adalimumab were similar over the respective observation periods (week 52 for efficacy and immunogenicity, week 66 for safety). A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity.
30704507 IgG4:IgG RNA ratio differentiates active disease from remission in granulomatosis with pol 2019 Jan 31 OBJECTIVES: An important limitation in granulomatosis with polyangiitis (GPA) is the lack of disease activity markers. Immunoglobulin G4-positive (IgG4(+)) B cells and plasma cells are implicated in the pathogenesis of GPA. We hypothesized that the presence of these cells in peripheral blood could serve as disease activity parameter in GPA. METHODS: We included 35 proteinase 3-antineutrophil cytoplasmic antibodies-positive patients with GPA in a cross-sectional study. Active disease was defined as Birmingham Vasculitis Activity Score (BVAS) ≥ 3 (n = 15), remission as BVAS of 0 (n = 17), and low disease activity (LDA) as BVAS of 1-2 and clinical remission (n = 3). Healthy subjects (n = 10), patients with systemic lupus erythematosus (n = 24), and patients with rheumatoid arthritis (n = 19) functioned as control subjects. An additional longitudinal study was performed in ten patients with GPA. Using a validated qPCR test, we measured the IgG4:IgG RNA ratio in all groups and compared the results with known biomarkers. RESULTS: The median qPCR score was higher in active GPA (21.4; IQR 12.1-29.6) than in remission/LDA (3.3; IQR 1.6-5.6) (Mann-Whitney U test, p < 0.0001) and outperformed other known disease activity parameters in detecting activity. A cutoff qPCR score of 11.2% differentiated active disease from remission/LDA accurately (AUC 0.993). The qPCR test correlated well with the BVAS (Spearman r = 0.77, p < 0.0001). In the longitudinal study, a decrease in BVAS correlated with qPCR score reduction (paired t test, p < 0.05). CONCLUSIONS: The IgG4:IgG RNA ratio in GPA accurately distinguishes active disease from remission and correlates well with disease activity in these single-center studies. If these results are confirmed in larger longitudinal studies, this test might help to steer treatment decisions in patients with GPA.
31263071 Chronic Joint Pain 3 Years after Chikungunya Virus Infection Largely Characterized by Rela 2020 Aug 1 OBJECTIVE: To determine the frequency of chronic joint pain and stiffness 3 years after infection with chikungunya virus (CHIKV) in a Latin American cohort. METHODS: A cross-sectional followup of 120 patients from an initial cohort of 500 patients who reported joint pain 2 years after infection from the Atlántico Department, Colombia. Patients were clinically diagnosed as having CHIKV during the 2014-2015 epidemic, and baseline and followup symptoms at 40 months were evaluated in serologically confirmed cases. RESULTS: Of the initial 500 patients enrolled in the study, 482 had serologically confirmed chikungunya infection. From this group, 123 patients reported joint pain 20 months after infection, and 54% of those patients reported continued joint pain 40 months after infection. Therefore, 1 out of every 8 people who tested serologically positive for CHIKV infection had persistent joint pain 3 years after infection. Participants who followed up in person were predominantly adult (mean ± SD age 51 ± 14 yrs) and female (86%). The most common type of pain reported in these patients at 40 months post-infection was pain with periods of relief and subsequent reoccurrence, and over 75% reported stiffness after immobility, with 39% experiencing morning stiffness. CONCLUSION: To our knowledge, this is the first report to describe persistent joint pain and stiffness 40 months after viral infection. The high frequency of chronic disease highlights the need to develop prevention and treatment methods. Further studies should be conducted to understand the similarities between post-chikungunya joint pain and rheumatoid arthritis.
31848433 Conformational exchange in the potassium channel blocker ShK. 2019 Dec 17 ShK is a 35-residue disulfide-linked polypeptide produced by the sea anemone Stichodactyla helianthus, which blocks the potassium channels Kv1.1 and Kv1.3 with pM affinity. An analogue of ShK has been developed that blocks Kv1.3 > 100 times more potently than Kv1.1, and has completed Phase 1b clinical trials for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. Previous studies have indicated that ShK undergoes a conformational exchange that is critical to its function, but this has proved difficult to characterise. Here, we have used high hydrostatic pressure as a tool to increase the population of the alternative state, which is likely to resemble the active form that binds to the Kv1.3 channel. By following changes in chemical shift with pressure, we have derived the chemical shift values of the low- and high-pressure states, and thus characterised the locations of structural changes. The main difference is in the conformation of the Cys17-Cys32 disulfide, which is likely to affect the positions of the critical Lys22-Tyr23 pair by twisting the 21-24 helix and increasing the solvent exposure of the Lys22 sidechain, as indicated by molecular dynamics simulations.
31694743 Long-term survival of lung transplantation for interstitial lung disease associated with c 2020 Jul OBJECTIVES: Interstitial lung disease (ILD) is a leading cause of mortality in patients with connective tissue diseases (CTD). Lung transplantation has become a viable option for patients with end-stage CTD-ILD. However, patients with CTD are often considered suboptimal candidates for lung transplantation because of concerns of worse outcomes. We assessed post-transplant survival of patients with CTD-ILD compared to patients with idiopathic pulmonary fibrosis (IPF). METHODS: Medical records of patients who underwent lung transplantation for CTD-ILD at a single referral centre for lung transplantation in Northern Spain between 1998 and 2018 were reviewed. This cohort was compared with patients with IPF (group-matched for age ±3.3 years, transplant year and use of basiliximab induction previous to transplant). Cumulative survival rates after transplantation were estimated by the Kaplan-Meier method and compared between groups using the log-rank test. RESULTS: We studied 26 patients with CTD-ILD and 26 patients with IPF. The underlying diseases of CTD-ILD patients were rheumatoid arthritis (n=9), scleroderma (n=6), Sjögren's syndrome (n=4), ANCA-associated vasculitis (n=3), anti-synthetase syndrome (n=2), and dermatomyositis, systemic lupus erythematosus (1 each). Baseline characteristics were similar in both groups. CTD-ILD patients experienced acute graft rejection less commonly than those with IPF (32.0% vs. 62.5%; p=0.032). However, a non-statistically significant increased frequency of chronic graft rejection was observed in CTD-ILD patients (20.0% vs. 8.3%; p=0.417). In this regard, the 5-year cumulative survival rates after transplantation was reduced in CTD-ILD (42.4% vs. 65.8%) but the difference did not achieve statistical significance (p=0.075). CONCLUSIONS: Long-term post-transplant survival in Northern Spanish patients with CTD-ILD is reduced compared with IPF.
31639851 Comparison of Patient Demographics and Utilization Trends of Robotic-Assisted and Non-Robo 2021 May Robotic-assisted unicompartmental knee arthroplasty (RAUKA) is an emerging area of interest. The purpose of this study was to compare (1) different patient demographic profiles; (2) annual primary and revision utilization rates; (3) risk factors for revision procedures; and (4) survivorship between RAUKA and manual UKA (MUKA). Using the PearlDiver database, patients who underwent RAUKA or MUKA between 2005 and 2014 within the Medicare database were identified, yielding a total of 35,061 patients (RAUKA = 13,617; manual = 21,444). Patient demographics (age, gender, comorbidities, Charlson-Comorbidity Index, and geographic region) were compared between cohorts. Annual primary and revision utilization rates as well as risk factors for revision procedures were also compared. Kaplan-Meier survivorship was also calculated. The Pearson χ(2) test was used to test for significance in patient demographics, whereas the Welch t-test was used to compare the incidence of revisions as well as the revision burden (proportion of revisions to total sum of primary and revision procedures). Multivariate binomial logistic regression analysis was performed to compare risk factors for revision procedures. There were statistically significant differences in RAUKA versus MUKA patients with respect to age (p < 0.001), gender (p < 0.001), and region (p < 0.001). RAUKA procedures performed increased over 12-fold compared with manual, which increased only 4.5-fold. RAUKA procedures had significantly lower revision incidence (0.99 vs. 4.24%, p = 0.003) and revision burden (0.91 vs. 4.23%, p = 0.005) compared with manuals. For patients undergoing RAUKA, normal (19-24 kg/m(2)) and obese (30-39 kg/m(2)) body mass index (p < 0.05), congestive heart failure (p = 0.004), hypothyroidism (p < 0.001), opioid dependency (p = 0.002), and rheumatoid arthritis (p < 0.001) were risk factors for a revision procedure. Kaplan-Meier survival curve 3 years following the index procedure to all-cause revisions demonstrated that RAUKA patients maintained nearly 100% survivorship compared with manual patients who had 97.5% survivorship. The data demonstrate increased utilization of RAUKA in the United States. The current data indicated that RAUKA has significantly lower revision rates and improved survivorship compared with patients undergoing non-RAUKA within Medicare patients.
35528582 Inhibition of miR-16 enhances the sensitivity of fibroblast-like synovial cells to methotr 2019 Aug 23 MicroRNAs (miRNAs) are demonstrated to contribute to the regulation of drug resistance in a number of diseases. Nevertheless, little is known about the role and the underlying mechanism of miR-16 in rheumatoid arthritis (RA) methotrexate resistance. In this study, we firstly examined the miR-16 expression in the serum and synovial fluid from RA patients who were unresponsive to methotrexate monotherapy (UR-MTX patients) and responsive RA patients (R-MTX patients). Secondly, the miR-16 expression was measured in both fibroblast-like synovial cells (FLS) and methotrexate resistance RA-FLS cells (FLS-MTX). FLS cells used in this study were isolated from synovial tissue specimens obtained from patients with RA who underwent total joint replacement. FLS-MTX cells were conducted by gradually increasing the concentration of methotrexate in the medium. The construction of FLS-MTX cells was confirmed by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay. Thirdly, in order to further investigate the role of miR-16 in FLS-MTX cells, we introduced miR-16 inhibitor into FLS-MTX cells to knockdown the expression of miR-16, used fluorescence quantitative PCR to detect the inhibition efficiency. The effects of miR-16 inhibition on cell viability, cell cycle arrest and apoptosis in FLS-MTX cells were monitored with MTT and flow cytometry analysis, respectively. And the regulation of miR-16 on P-glycoprotein (P-gp) was performed using qRT-PCR, western blotting, and immunofluorescence staining. Fourthly, ammonium pyrrolidinedithiocarbamate (PDTC), a NF-κB pathway inhibitor, was applied to verify the mechanism by which miR-16 involved in to regulate the P-gp expression, and thus contributing to the methotrexate resistance in FLS-MTX cells. MiR-16 was upregulated in the in serum and synovial fluid from UR-MTX patients as well as in FLS-MTX cells. Inhibition of miR-16 re-sensitized the FLS-MTX cells to methotrexate by suppressing the cell viability, cell promoting cycle arrest at G0/G1 phase and enhancing apoptosis. Knockdown of miR-16 significantly reduced MDR1 mRNA expression and P-gp protein expression in FLS-MTX cells. Furthermore, inhibition of NF-κB pathway by PDTC reinforced the effect of miR-16 knockdown on P-gp expression, cell viability, cell cycle arrest and apoptosis. In conclusion, our study illustrated that inhibition of miR-16 in FLS-MTX cells alleviated methotrexate resistance by inhibiting MDR1/P-gp expression through inactivation of the NF-κB pathway.
31396837 Investigation of anti-DFS70 antibody in patients with systemic autoimmune rheumatic diseas 2019 Dec INTRODUCTION: Dense fine-speckled 70 (DFS70) antibody is defined as an antinuclear antibody (ANA) pattern in indirect immunofluorescence (IIF). The presence of anti-DFS70 antibody has been shown as a potential marker for the exclusion of systemic autoimmune rheumatic diseases (SARD) (without any other SARD-associated autoantibodies). We aimed to investigate the frequency of anti-DFS70 antibodies in patients with SARD and in the blood bank donors (BD). MATERIALS AND METHODS: The study group consists of 418 rheumatoid arthritis (RA), 101 systemic lupus erythematosus (SLE), 71 Sjogren's syndrome (SS), 43 ankylosing spondylitis (AS), 36 systemic sclerosis-scleroderma (SSc), 2555 undifferentiated connective tissue disease (UCTD), and 507 BD. All samples were tested on the HEp-2 IIF-ANA assay. Samples that showed DFS70 pattern in IIF were confirmed by a specific DFS70 antibody enzyme-linked immunosorbent assay (ELISA). RESULTS: The DFS70 pattern was detected in 43 (1.33%) in SARD and four (0.78%) in BD. The anti-DFS70 antibody was detected in three (0.59%) in BD, six (1.43%) in RA, three (2.97%) in SLE, one (1.40%) in SS, and 25 (0.97%) in UCTD, however, it was not detected in AS and SSc by ELISA. There was no significant difference between BD and SARD (p = 0.28). Distinctly, the frequency of anti-DFS70 was significantly different for SLE in SARD (p = 0.02). CONCLUSION: Anti-DFS70 antibody was more prevalent in the subsets of SARD than BD. This result may be related to the demographic formation of study groups and individual immunological status. More comprehensive studies are needed to investigate the importance of the anti-DFS70 antibody for SARD.Key Points• This study draws attention to the importance of anti-DFS70 antibodies in the diagnostic algorithm in systemic autoimmune rheumatic diseases.• This study emphasizes the further investigation of anti-DFS70 antibodies in undifferentiated connective tissue diseases.• This study emphasizes the need to verify the DFS70 pattern detected in IIF-ANA test for definitive diagnosis with additional confirmation methods.