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ID PMID Title PublicationDate abstract
31470579 Importance of Virulence Factors for the Persistence of Oral Bacteria in the Inflamed Gingi 2019 Aug 29 Periodontitis is a chronic inflammation that develops due to a destructive tissue response to prolonged inflammation and a disturbed homeostasis (dysbiosis) in the interplay between the microorganisms of the dental biofilm and the host. The infectious nature of the microbes associated with periodontitis is unclear, as is the role of specific bacterial species and virulence factors that interfere with the host defense and tissue repair. This review highlights the impact of classical virulence factors, such as exotoxins, endotoxins, fimbriae and capsule, but also aims to emphasize the often-neglected cascade of metabolic products (e.g., those generated by anaerobic and proteolytic metabolism) that are produced by the bacterial phenotypes that survive and thrive in deep, inflamed periodontal pockets. This metabolic activity of the microbes aggravates the inflammatory response from a low-grade physiologic (homeostatic) inflammation (i.e., gingivitis) into more destructive or tissue remodeling processes in periodontitis. That bacteria associated with periodontitis are linked with a number of systemic diseases of importance in clinical medicine is highlighted and exemplified with rheumatoid arthritis, The unclear significance of a number of potential "virulence factors" that contribute to the pathogenicity of specific bacterial species in the complex biofilm-host interaction clinically is discussed in this review.
31172011 A Patient with KL-6 Elevation with Anti-TNFα Who Could Receive Long-Term Use without Inte 2019 May A 40-year-old man with refractory ulcerative colitis (UC) was treated with tumor necrosis factor α inhibitor (anti-TNFα), infliximab. One month later, the chest computed tomography and laboratory test showed noninfectious interstitial lung disease (ILD) and elevation of serum Krebs von den Lungen-6 (KL-6). Fortunately, ILD disappeared after the discontinuation with anti-TNFα. Two and a half years after his first UC treatment, he was treated again with another anti-TNFα, adalimumab, for relapse and he had a second ILD. This course suggested anti-TNFα induced ILD. The characteristics of anti-TNFα-induced ILD in inflammatory bowel disease (IBD) are not well understood. We summarized and investigated the characteristics of such patients based on a literature review including 15 cases. It suggested that anti-TNFα-induced ILD in IBD might be rare and tends to have a better outcome compared with ILD in rheumatoid arthritis.
30888954 Radiation and Hyperthermia Combination Therapy for Recalcitrant Verruca Vulgaris. 2019 A 47-year-old white woman presented to our clinic complaining of recalcitrant warts on her trunk and extremities. She had an extensive past medical history including immunodeficiency of unknown origin, pulmonary hypertension, rheumatoid arthritis, and systemic lupus erythematosus, for which she was being treated with chronic immunosuppressive therapy with methylprednisolone and belimumab. The patient had previously failed treatments at an outside facility with liquid nitrogen, trichloroacetic acid, topical cidofovir, imiquimod, topical 5-fluorouracil, intralesional candida antigen, pulsed-dye laser (Vbeam Perfecta), surgical excision, and photodynamic therapy. (SKINmed. 2019;17:68-71).
30710358 Upstream regulators of phosphoinositide 3-kinase and their role in diseases. 2019 Feb 2 Phosphoinositide 3-kinase (PI3K), a crucial signaling molecule, is regulated by various upstream regulators. Traditionally, receptor tyrosine kinases and G protein-coupled receptor are regarded as its principle upstream regulators; however, recent reports have indicated that spleen tyrosine kinase, β-arrestin2, Janus kinase, and RAS can also perform this role. Dysregulation of PI3K is common in the progression of various diseases, including, but not limited to, tumors, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, and acute myelogenous leukemia. The aim of this review is to provide a perspective on PI3K-related diseases examining both the classical and nonclassical upstream regulators of PI3K in detail.
30419221 Exosomes in inflammation and role as biomarkers. 2019 Jan Exosomes are endosomal-derived nano-vesicles. They are considered vehicles through which donor cells transfer proteins, lipids and nucleic acids to target cells thus influencing their metabolism. Exosomes are involved in inflammatory processes that play a pivotal role in a large number of pathologic states including cancer, inflammatory bowel diseases, type 2 diabetes, obesity, rheumatoid arthritis and neurodegenerative diseases. The association between inflammation and change in nature or expression level of some exosomal cargos is the fundamental step for identifying possible novel biomarkers of inflammatory-based diseases. A novel interesting exosome cargo is the SLC22A5 transport protein whose level in exosomes is regulated by the pro-inflammatory cytokine INF-γ. The advantage of using exosomes as a biomarker vehicle consists of their ease of collection from body fluids such as urine and saliva as they may represent a non-invasive means for screening human pathology.
31848497 [Significance of anti-carbamylated fibrinogen antibodies in systemic lupus erythematosus]. 2019 Dec 18 OBJECTIVE: Antibodies against carbamylated protein (anti-CarP) were found to be a promising marker to evaluate joint damage and disease activity in patients with rheumatoid arthritis (RA). However, whether anti-CarP antibodies were present in systemic lupus erythematosus (SLE) remained ambiguity. We have therefore undertaken this study to assess the levels of serum anti-CarP antibodies and to evaluate their clinical value in SLE. METHODS: Serum levels of antibodies against carbamylatedfibrinogen (anti-CarP) were measured by enzyme-linked immunosorbent assay (ELISA) in 105 SLE patients and 73 healthy controls. Other clinical and laboratory measurements of the SLE patients were collected from medical records. Data analyses between anti-CarP antibodies and other laboratory measurements were performed using SPSS software for Windows 24.0. RESULTS: The levels of serum anti-CarP antibodies in the patients with SLE were significantly higher than those in the healthy controls (P<0.05). There were significant differences between the anti-CarP-positive group and anti-CarP-negative group in many clinical features. The disease duration, values of ESR, CRP, RF, anti-cardiolipin, anti-dsDNA, D-dipolymer, IgA and IgG were significantly higher in the anti-CarP-positive group compared with the negative group (P<0.05). Conversely, the values of complement 3, complement 4, peripheral blood RBC, and hemoglobin were significantly lower in anti-CarP-positive group than in the negative group(P<0.05). Moreover, the incidence of increase of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), D-dipolymer, decrease of peripheral blood RBC, hemoglobin, complement 3, complement 4, and positive rate of anti-dsDNA were significant different between the two groups(P<0.05). The positive rate of anti-CarP (21.9%) was higher than that of anti-Sm (15.24%), and close to anti-ribosomal P protein (22.86%) in our SLE patients. In addition, anti-CarP antibody was present in the SLE patients lacking the disease specific antibodies, including anti-Sm (anti-CarP positive rate 20.2%, 18/89), anti-dsDNA (anti-CarP positive rate 9.3%, 4/43), anti-nucleosome (anti-CarP positive rate 12.5%, 6/48), and anti-ribosomal P protein antibody (anti-CarP positive rate 20.9%, 17/81). Moreover, the high levels of anti-CarP antibodies were correlated with short disease duration, low C3, C4, RBC, and hemoglobin (P<0.05), high ESR, CRP, IgA, IgG, RF, anti-cardiolipin, anti-dsDNA, and D-dipolymer (P<0.05). CONCLUSION: The level of anti-CarP antibody was increased in the serum of patients with SLE. There were correlations between anti-CarP antibodies and clinical and laboratory indicators of SLE patients.
31798442 Efficacy and Safety in the Continued Treatment With a Biosimilar Drug in Patients Receivin 2019 Introduction: Biological products, including infliximab (INF), are a therapeutic option for various medical conditions. In the Peruvian Social Security (EsSalud), infliximab is approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, ulcerative colitis and Crohn's disease (in cases refractory to conventional treatment). Biosimilars are a safe and effective alternative approved for these diseases in patients who start treatment with infliximab. Nevertheless, there are people in treatment with the biological reference product (BRP), in whom the continuing therapy with a biosimilar biological product (BBP) must be evaluated. Objectives: To synthesize the best available evidence, calculate a preliminary financial impact and conduct technical discussions about the interchangeability into biosimilar in patients receiving treatment with original infliximab for medical conditions approved in EsSalud. Methodology: We carried out a systematic review of controlled clinical trials. Primary search was performed in Pubmed- MEDLINE, SCOPUS, WOS, EMBASE, TRIPDATABASE, DARE, Cochrane Library, NICE, AHRQ, SMC, McMaster-PLUS, CADTH, and HSE until June-2018. We used the Cochrane Collaboration tool to assess the risk of bias. Also, we implemented a preliminary financial analysis about the impact of biosimilar introduction on institutional purchasing budget. Moreover, technical meetings with medical doctors specialized in rheumatology, gastroenterology and dermatology were held for discussing findings. Results: In primary search, 1136 records were identified, and 357 duplicates were removed. From 799 records, we excluded 765 after title and abstract evaluation. From 14 full-text appraised documents, we included five clinical trials in the risk of bias assessment: four studies evaluated CTP-13 and one tested SB2. Two double-blind clinical trials reported no differences in efficacy and safety profiles between maintenance group (INF/INF) and interchangeability group in all diseases included (INF/CTP-13) and rheumatoid arthritis (CTP13 and SB2). In the other three studies, open-label extension of primary clinical trials, no differences were founded in efficacy and safety profiles between CTP-13/CTP-13 and INF/CTP-13 groups. In financial analysis, the inclusion of biosimilars implied savings around S/7´642,780.00 (1USD=S/3.30) on purchasing budget of EsSalud. In technical meetings, beyond certain concerns, specialists agreed with the findings. Conclusions: Evidence from clinical trials support that there are no differences in efficacy or safety of continuing the treatment with Infliximab BRP or exchanging into its biosimilar in patients with medical conditions approved in EsSalud. Financial analysis shows that the biosimilar introduction produce savings in purchasing institutional budget. Therefore, based on cost-opportunity principle, exchanging into biosimilar in patients receiving the original Infliximab, is a valid therapeutic alternative in the Peruvian Social Security.
30988827 Aspects of exercise with person-centred guidance influencing the transition to independent 2019 BACKGROUND: Besides being health enhancing and disease preventing, exercise is also an important part of the management of chronic conditions, including the inflammatory joint disease rheumatoid arthritis (RA). However, older adults with RA present a lower level of physical activity than healthy older adults. The aim of this qualitative study was to explore aspects of participation in moderate- to high-intensity exercise with person-centred guidance influencing the transition to independent exercise for older adults with RA. METHODS: A qualitative interview study was conducted. In-depth interviews with 16 adults with RA aged between 68 and 75 years, who had taken part in the intervention arm of a randomized controlled trial performing moderate- to- high-intensity exercise with person-centred guidance, were analysed using qualitative content analysis. RESULTS: The analysis resulted in six main categories: A feasible opportunity to adopt exercise, Experiencing positive effects of exercise, Contextual factors affect the experience of exercise, Developing knowledge and thinking, Finding one's way, and Managing barriers for exercise. The exercise with person-centred guidance was described as a feasible opportunity to start exercising as a basis for the transition to independent exercise. They described developing knowledge and thinking about exercise during the intervention enabling them to manage the transition to independent exercise. Finding one's own way for exercise became important for sustaining independent exercise. Lastly, barriers for exercise and strategies for overcoming these were described. Reduced physical health, both temporary and permanent, was described as a considerable barrier for exercise. CONCLUSION: The participants described several aspects of participating in exercise that influenced and facilitated their transition to independent exercise. The exercise was experienced as manageable and positive, by a careful introduction and development of an individual exercise routine in partnership with a physiotherapist. This seems to have favored the development of self-efficacy, with importance for future independent exercise. Reduced physical health, both temporary and permanent, was described as a considerable barrier for exercise. The personal process of trying to make the exercise one's own, and developing knowledge about exercise and new thoughts about oneself, seemed to prepare the participants for managing independent exercise and overcoming barriers.
30877063 Properties of FDA-approved small molecule protein kinase inhibitors. 2019 Jun Because mutations, overexpression, and dysregulation of protein kinases play essential roles in the pathogenesis of many illnesses, this enzyme family has become one of the most important drug targets in the past 20 years. The US FDA has approved 48 small molecule protein kinase inhibitors, nearly all of which are orally effective with the exceptions of netarsudil (which is given as an eye drop) and temsirolimus (which is given intravenously). Of the 48 approved drugs, the majority (25) target receptor protein-tyrosine kinases, ten target non-receptor protein-tyrosine kinases, and 13 target protein-serine/threonine protein kinases. The data indicate that 43 of these drugs are used in the treatment of malignancies (36 against solid tumors including lymphomas and seven against non-solid tumors, e.g., leukemias). Seven drugs are used in the treatment of non-malignancies: baricitinib, rheumatoid arthritis; fostamatinib, chronic immune thrombocytopenia; ruxolitinib, myelofibrosis and polycythemia vera; nintedanib, idiopathic pulmonary fibrosis; sirolimus, renal graft vs. host disease; netarsudil, glaucoma; tofacitinib, rheumatoid arthritis, Crohn disease, and ulcerative colitis. Moreover, ibrutinib and sirolimus are used for the treatment of both malignant and non-malignant diseases. The most common drug targets include ALK, B-Raf, BCR-Abl, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor (VEGFR). Most of the small molecule inhibitors (45) interact directly with the protein kinase domain. In contrast, sirolimus, temsirolimus, and everolimus are larger molecules (MW ≈ 1000) that bind to FKBP-12 to generate a complex that inhibits mTOR (mammalian target of rapamycin). This review presents the available drug-enzyme X-ray crystal structures for 27 of the approved drugs as well as the chemical structures and physicochemical properties of all of the FDA-approved small molecule protein kinase antagonists. Six of the drugs bind covalently and irreversibly to their target. Twenty of the 48 drugs have molecular weights greater than 500, exceeding a Lipinski rule of five criterion. Excluding the macrolides (everolimus, sirolimus, temsirolimus), the average molecular weight of drugs is 480 with a range of 306 (ruxolitinib) to 615 (trametinib). Nearly half of the antagonists (23) have a lipophilic efficiency with values of less than five while the recommended optima range from 5-10. One of the vexing problems is the near universal development of resistance that is associated with the use of small molecule protein kinase inhibitors for the treatment of cancer.
30370485 Autoimmune disease-associated non-Hodgkin's lymphoma-a large retrospective study from Chin 2019 Feb The incidence and clinical implications of autoimmune diseases (ADs) in patients with non-Hodgkin's lymphoma(NHL) remain unclear. The aim of this study was to examine the prevalence of ADs in NHL and define the clinical characteristics and prognosis of AD-associated NHL patients. Patients diagnosed with NHL in our institute between 1995 and 2017 were retrospectively reviewed to assess the incidence of ADs. Of 4880 patients with NHL, 140 (2.9%) presented with autoimmunity, with a total of 24 ADs. The most common AD was Sjögren syndrome, followed by autoimmune cytopenia, psoriasis, rheumatoid arthritis, etc. Psoriasis and rheumatoid arthritis were significantly associated with pre-existing ADs, whereas autoimmune cytopenia was significantly associated with secondary AD. Sjögren syndrome was significantly associated with B-cell lymphoma, and systemic vasculitis was significantly associated with T-cell lymphoma. Patients with AD-associated NHL had a high frequency of extranodal involvement(87%), with significant associations between specific extranodal sites of lymphoma and subtypes of ADs. Among patients with available data on pre-treatment peripheral blood Epstein-Barr virus (EBV) DNA(n = 68), elevated EBV-DNA load was observed in a variety of NHL subtypes, including 20% of marginal zone lymphoma and 14.3% of follicular lymphoma patients. In a matched-pair analysis, survival did not differ significantly between NHL patients with and without ADs. However, for NHL patients with pre-existing ADs, a prior history of systemic corticosteroids therapy was significantly associated with worse survival (HR = 7.33, P = 0.006). Taken together, our data suggest that a broad spectrum of ADs is associated with NHL, and AD-associated NHL has distinct features with regard to clinical manifestations and prognosis.
30168281 Biologics and risk of tuberculosis in autoimmune rheumatic diseases: A real-world clinical 2019 Feb AIM: Tuberculosis (TB) is one of the major adverse events of concern associated with the use of biologics for managing autoimmune inflammatory rheumatic diseases (AIRDs). The study presents the data on incidence of TB in relation to biologic used, screening test and TB prophylaxis in a real-world setting. METHODS: The cross-sectional, observational, retrospective study was conducted across 12 centres in Karnataka, India. The study included patients receiving biologics therapy for AIRDs, established based on the respective diagnostic criteria. The development of TB after receiving biologic therapy and other clinical variables and the predictability of the test performed for latent TB were evaluated. RESULTS: One hundred and ninety-five AIRDs patients with an average age of 41 years were initiated on biologic therapy. Twenty-one patients were latent TB positive and were given antitubercular prophylaxis, prior to biologics treatment. During follow-up, seven patients belonging to the negative test group (n = 174) developed TB. The negative predictive values noted for Mantoux test (n = 120) and quantiFERON TB gold test (n = 178) were 96.52% and 96.25%, respectively. Patients on anti-tumor necrosis factor were more likely to develop TB. Presence of comorbidities and steroid use increased the likelihood of developing TB by 1.5 and 4.6 times, respectively. CONCLUSION: Close monitoring of patients receiving biologics is essential for early identification of adverse events, especially in test negative patients. Prophylaxis can effectively reduce the risk of developing TB in patients positive for screening.
31037459 Cross-cultural adaptation of the connective tissue disease screening questionnaire and dev 2019 Sep OBJECTIVES: To cross-culturally adapt the Connective Tissue Disease (CTD) Screening Questionnaire (CSQ) in a multi-ethnic Asian population in Singapore. METHODS: An expert panel of accredited rheumatologists evaluated the content validity of the original CSQ. Consenting participants newly referred from primary care to a rheumatology specialist outpatient clinic for evaluation of possible CTDs were studied. Cognitive debriefing interviews (CDIs) using the original CSQ were conducted with English-speaking participants, with modifications made based on their inputs and in discussion with a second expert panel (rheumatologists and the CSQ developers). Forward and back translations of the adapted English version were reviewed by the second expert panel. The common translation produced was tested in CDIs with Chinese-speaking participants. Adapted English and Chinese versions were pilot tested in a separate group of newly referred patients. RESULTS: Content validity of the original CSQ was confirmed by the expert panel. A total of 30 and 15 participants were recruited for English and Chinese CDIs, respectively. Alternative terms and explanatory notes were added to difficult medical terms in the adapted English CSQ. A further explanatory note was added to one difficult item, and English medical terms were retained in the Chinese version. Pilot testing of the adapted CSQ was performed on 116 participants, which exhibited an overall sensitivity and specificity of 71% and 58%, respectively, in identifying CTDs. CONCLUSIONS: The adapted CSQ demonstrated satisfactory sensitivity in the pilot testing and appears to be a promising tool for facilitating early identification of CTDs in the multi-ethnic Asian population. KEY POINTS: • Early identification and management of patients with CTDs is crucial given their high disease burden and short "windows of opportunity." • High reliability and validity of original CSQ and its cross-culturally adapted versions have been reported; however, the CSQ has not been validated in Southeast Asia where CTDs are associated with higher morbidity and mortality compared to other countries. • Our cross-culturally adapted CSQ demonstrated satisfactory sensitivity in identifying CTDs in the multi-ethnic Asian population.
29694270 Higher Incidence Rates of Comorbidities in Patients with Psoriatic Arthritis Compared with 2019 Jan BACKGROUND: Psoriatic arthritis (PsA) is associated with multiple comorbid conditions, including cardiovascular (CV) comorbidities that impose a considerable burden on patients. Effective management of PsA requires an understanding of comorbidity profiles. OBJECTIVE: To compare the frequency and incidence rates of comorbidities and hospitalizations among newly diagnosed PsA patients and a matched general population without PsA, using large national claims databases in the United States. METHODS: This retrospective observational study used MarketScan databases from January 1, 2008, to September 30, 2015, to identify adult patients with newly diagnosed PsA (i.e., no PsA diagnosis during the 1 year before the first observed PsA diagnosis). The earliest date of PsA diagnosis was defined as the index date. Patients with no PsA diagnosis any time during the study period (controls) were directly matched to PsA patients with demographic characteristics. All patients had ≥ 2 years of medical and pharmacy coverage before the index date and ≥ 1 year of follow-up. Incident rates per 100 person-years for comorbidities of interest were evaluated. The hazard ratios of having various comorbid conditions for PsA patients were estimated by Cox proportional hazards models. All-cause and CV-related hospitalizations during the follow-up period were evaluated. RESULTS: A total of 14,898 PsA patients and 35,037 matched controls met the study criteria. Compared with controls, PsA patients had a higher risk of CV disorders (incidence rate = 6.5 vs. 5.8; HR = 1.46; 95% CI = 1.37-1.56) and a higher risk of the majority of the specific CV disorders (hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, peripheral vascular disease). PsA patients also had a higher risk for any autoimmune disease (incidence rate = 8.4 vs. 1.6; HR = 18.26; 95% CI = 17.18-19.40) and most autoimmune categories (psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, and other autoimmune disorders). Rates of other PsA-related comorbidities (diabetes, anxiety, fatigue, smoking, alcohol use, obesity or overweight, depression, osteoporosis, uveitis, eczema, and gout) were also significantly higher for PsA patients. The all-cause hospitalization rate was higher among PsA patients than controls (24.9% vs. 16.2%; P < 0.001). The CV-related hospitalization rate varied depending on whether the CV condition was the primary discharge diagnosis only or was any diagnosis on the inpatient claims. The rates of coronary artery disease hospitalizations were significantly higher in PsA patients than in controls with both methods of analysis (primary diagnosis: 0.8% vs. 0.5%; P < 0.001; nonprimary diagnosis: 3.2% vs. 2.2%; P < 0.001). CONCLUSIONS: This retrospective U.S.-based claims study found that PsA patients had a high comorbidity burden. Compared with the non-PsA population, PsA patients were associated with a higher incidence of CV comorbidities, autoimmune diseases, and other PsA-related comorbidities and a higher rate of all-cause and CV-related hospitalizations. Understanding these comorbidity profiles may provide insight on the effect of comorbid conditions on disease management and health care utilization associated with PsA. DISCLOSURES: This study was funded by Novartis. Kaine is a paid consultant for Novatis. Hur and Palmer are Novartis employees and stockowners. Song and Kim work for Truven Health Analytics, which received funding from Novartis to conduct this study.
31670893 Secukinumab-induced paradoxical hidradenitis suppurativa. 2020 Jan Paradoxical reactions during treatment with biological agents may be defined as an appearance or exacerbation of a pathological condition that usually responds to this class of drug. Typical examples of paradoxical adverse effect are, among others, palmoplantar pustular and psoriasiform reactions or HS, in patients during a treatment of rheumatoid arthitis or IBD mainly. A few reports have been described an exacerbation of psoriasis1, palmoplantar pustular, or pustular psoriasis eruption with secukinumab. Marasca et al. highlights the immunological complexity that surrounds autoinflammatory diseases showing the potential double pathogenetic face of secukinumab in HS, describing a case of secukinumab-induced HS and a case of HS caused by adalimumab treatment and controlled by secukinumab therapy. Real world evidence and results from clinical trials with secukinumab for HS, will possibly show the real role that anti-IL-17 drugs play in this complex disease.
31639706 Transition of Methotrexate Polyglutamate Drug Monitoring Assay from Venipuncture to Capill 2019 Jul OBJECTIVE: Methotrexate (MTX) polyglutamate (MTXPG(3)) levels from isolated red blood cells (RBCs) collected by venipuncture have clinical utility in guiding MTX dosing for patients with rheumatoid arthritis (RA). Our objective was to transition this RBC-based therapeutic drug monitoring (TDM) assay to dried capillary blood collected by fingerstick. METHODS: Patients with RA treated with MTX were enrolled. Specimens were collected by fingerstick (volumetric absorptive microsampler) and venipuncture to measure MTXPG(3) from dried capillary blood, total venous blood, and isolated RBCs. MTXPG(3) levels from dried capillary blood were measured using LC-MS/MS, converted to RBC equivalent (nmol/L), and compared with those from isolated RBCs (reference method). Following transition to fingerstick collection, comparability in the distributions of dried capillary and venipuncture-based RBC MTXPG(3) levels was assessed using the Kolmogorov-Smirnov (K-S) test. RESULTS: Intraday and interday precision ranged from 2.0% to 10.9% and 3.1% to 10.8%, respectively, at MTXPG(3) concentrations ranging from 5 to 100 nmol/L. In 106 participants treated with MTX, MTXPG(3) levels from total venous and dried capillary blood were comparable [slope = 0.97 (95% CI, 0.92-1.03); R (2) = 0.92]. Dried capillary blood MTXPG(3) converted to RBC equivalent was similar to levels from isolated RBCs (30 ± 18 nmol/L vs 33 ± 19 nmol/L; n = 106). After implementation in the clinical laboratory, RBC equivalents MTXPG(3) from the fingerstick method were similar to levels from venipuncture [39 ± 22 nmol/L (n = 825) vs 39 ± 24 nmol/L (n = 47935)] (K-S test P = 0.09). Underexposure to MTX (MTXPG(3) ≤5 nmol/L RBCs) was detected in 7.0% and 8.5% patient specimens collected using the fingerstick and venipuncture methods, respectively. CONCLUSION: Capillary blood MTXPG(3) levels can be used to guide MTX dosing in TDM practice.
31004743 Citrullination of fibronectin alters integrin clustering and focal adhesion stability prom 2019 Sep The extracellular matrix (ECM) microenvironment is increasingly implicated in the instruction of pathologically relevant cell behaviors, from aberrant transdifferentation to invasion and beyond. Indeed, pathologic ECMs possess a panoply of alterations that provide deleterious instructions to resident cells. Here we demonstrate the precise manner in which the ECM protein fibronectin (FN) undergoes the posttranslational modification citrullination in response to peptidyl-arginine deiminase (PAD), an enzyme associated with innate immune cell activity and implicated in systemic ECM-centric diseases, like cancer, fibrosis and rheumatoid arthritis. FN can be citrullinated in at least 24 locations, 5 of which reside in FN's primary cell-binding domain. Citrullination of FN alters integrin clustering and focal adhesion stability with a concomitant enhancement in force-triggered integrin signaling along the FAK-Src and ILK-Parvin pathways within fibroblasts. In vitro migration and in vivo wound healing studies demonstrate the ability of citrullinated FN to support a more migratory/invasive phenotype that enables more rapid wound closure. These findings highlight the potential of ECM, particularly FN, to "record" inflammatory insults via post-translational modification by inflammation-associated enzymes that are subsequently "read" by resident tissue fibroblasts, establishing a direct link between inflammation and tissue homeostasis and pathogenesis through the matrix.
31791950 Tuberculosis in biologic users for rheumatic diseases: results from the South African Biol 2020 Feb OBJECTIVES: To evaluate the rate of tuberculosis (TB) in biologic users for rheumatic diseases in South Africa, the effectiveness of our latent TB infection (LTBI) programme, risk factors and outcome. METHODS: TB cases were collected from the South African Biologics Registry (SABIO), rheumatologists and pharmaceutical companies. Demographics, LTBI screening and treatment, biological and disease modifying antirheumatic drug (DMARD) therapies, TB diagnosis and outcomes were recorded. RESULTS: 96 TB cases were collected from 1999 to June 2017: rheumatoid arthritis 55, ankylosing spondylitis 27, psoriatic arthritis 4, and juvenile inflammatory arthritis 10. The TB rate was 1240/100 000 person years for biologic users (n=96) versus the biologic naive cohort of 0/100 000 years with an incidence rate difference of 0.0124 (p<0.0001). 60/96 had pulmonary and 36/96 had extra-pulmonary TB. Reactivation TB occurred in 45/96 cases. TB occurred in all biologics licenced in South Africa, the majority in monoclonal inhibitors (1683/100 000 person years) compared with etanercept (861/100 000 person years) and non-tumour necrosis factor (TNF) inhibitors (681/100 000 person years). The incidence rate ratio for monoclonal inhibitors compared with etanercept was 1.96 (p=0.005) and 2.47 (p=0.002) compared with non-TNF inhibitors with no significant difference between non-TNF inhibitors and etanercept (p=0.336). From those (12.9%) who screened LTBI positive, 14 developed TB, while the majority (77) screened LTBI negative. Black race, male sex, younger age and residence in the Western Cape were statistical risk factors. Two drug resistant TB cases and six deaths occurred. CONCLUSION: Reactivation and new onset TB is a significant risk for all biologics users in SA. Screening for LTBI is an imperative preventative strategy.
35097341 Assessment of Various Measurement Methods to Assess First Metatarsal Elevation in Hallux R 2019 Jul BACKGROUND: While metatarsus primus elevatus (MPE) has been implicated in the development of hallux rigidus, previous studies have presented conflicting findings regarding the relationship between MPE and arthritis. This may be due to the variety of definitions for MPE and the radiographic measurement techniques that are used to assess it. Additionally, previous studies have only assessed elevation of the first metatarsal with respect to the floor or the second metatarsal, and not with respect to the proximal phalanx. The aim of this study was to examine the reliability of new radiographic measurements that consider the elevation of the first metatarsal in relation to the proximal phalanx, rather than in relation to the second metatarsal as previously described, to assess for MPE. In addition, we aimed to determine whether the elevation of the first metatarsal was significantly different in patients with hallux rigidus than in a control population. METHODS: A retrospective chart review was conducted from prospectively collected registry data at the investigators' institution to identify patients with hallux rigidus (n = 65). A size-matched control cohort of patients without evidence for first metatarsophalangeal (MTP) joint arthritis was identified (n = 65). Patients with a previous history of foot surgery, rheumatoid arthritis, or hallux valgus were excluded. Five blinded raters of varying levels of training, including 2 research assistants, 1 senior orthopedic resident, 1 foot and ankle fellowship-trained orthopedic surgeon, and 1 attending musculoskeletal fellowship-trained radiologist, evaluated 7 radiographic measurements for their reliability in assessing for MPE in hallux rigidus and control groups. Four of the 7 were newly designed measurements that include the relationship of the first MTP joint. Inter- and intrarater reliability were calculated using intraclass correlation coefficients (ICCs) and categorized by Landis and Koch reliability thresholds. The measurements between the hallux rigidus and control populations were compared using an independent t test. RESULTS: Six of the 7 radiographic measurements were found to have substantial to almost perfect interrater reliability (ICC, 0.800-0.953) between all levels of training, except for the proximal phalanx-first metatarsal angle, which showed moderate reliability (ICC, 0.527). Substantial to almost perfect intrarater reliability (ICC, 0.710-0.982) was demonstrated by the measurements performed by research assistants. All 7 of the measurements taken by the musculoskeletal fellowship-trained radiologist demonstrated significant differences in first metatarsal elevation between the hallux rigidus and control populations, with the hallux rigidus group showing increased elevation (P < .001-.019). CONCLUSION: This study confirmed the reliability of 7 radiographic measurements used to assess for MPE, including 3 previously established and 4 newly described measurements. Observers across all levels of training were able to demonstrate reliable measurements. In addition, the measurements were used to show that patients with hallux rigidus were more likely to have MPE compared with patients without radiographic evidence for first MTP arthritis. These measurements could be used in future work to examine how the presence of MPE relates to the etiology and progression of hallux rigidus, and how it affects the results of operative treatment. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
31662859 Gut microbiome in chronic rheumatic and inflammatory bowel diseases: Similarities and diff 2019 Oct INTRODUCTION: Inflammatory bowel diseases (IBDs) and chronic rheumatic diseases (CRDs) are systemic chronic disorders sharing common genetic, immune and environmental factors. About half of patients with IBD develop rheumatic ailments and microscopic intestinal inflammation is present in up to half of CRD patients. IBD and CRD patients also share a common therapeutic armamentarium. Disequilibrium in the complex realm of microbes (known as dysbiosis) that closely interact with the gut mucosal immune system has been associated with both IBD and CRD (spondyloarthritis and rheumatoid arthritis). Whether dysbiosis represents an epiphenomenon or a prodromal feature remains to be determined. METHODS: In an attempt to further investigate whether specific gut dysbiosis may be the missing link between IBD and CRD in patients developing both diseases, we performed here a systematic literature review focusing on studies looking at bacterial microbiota in CRD and/or IBD patients. RESULTS: We included 80 studies, with a total of 3799 IBD patients without arthritis, 1084 CRD patients without IBD, 132 IBD patients with arthropathy manifestations and 12 spondyloarthritis patients with IBD history. Overall, this systematic review indicates that an increase in Bifidobacterium, Staphylococcus, Enterococcus, Lactobacillus, Pseudomonas, Klebsiella and Proteus genera, as well as a decrease in Faecalibacterium, Roseburia genera and species belonging to Verrucomicrobia and Fusobacteria phyla are common features in IBD and CRD patients, whereas dozens of bacterial species are specific features of CRD and IBD. CONCLUSION: Further work is needed to understand the functions of bacteria and of their metabolites but also to characterize fungi and viruses that are commonly found in these patients.
31281705 Mixed Cryoglobulinemia in a Patient with Juvenile Idiopathic Arthritis. 2019 Cryoglobulinemia is a rare illness of cryoglobulin accumulation in the blood which can typically present with arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. It is classified as mixed cryoglobulinemia when cryoglobulins contain more than one immune component such as IgM rheumatoid factor and polyclonal IgG. Typically, it presents in the setting of clonal hematologic disease, viral infection, or certain connective tissue diseases. Herein, we report the case of a 24-year-old man diagnosed and treated as mixed cryoglobulinemia in the setting of juvenile idiopathic arthritis (JIA). Investigations for viral etiologies, including HBV, HCV, and HIV, and all serologic tests were negative. Additionally serum protein and urine protein electrophoresis did not reveal monoclonal gammopathy; however, testing for plasma cryoglobulins was positive, and qualitative analysis revealed a faint polyclonal pattern. Thus, he was diagnosed with cryoglobulinemia in the setting of JIA, which has not been reported in the literature before. He dramatically improved upon initiation of rituximab and methotrexate.