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ID PMID Title PublicationDate abstract
30188921 Cross-tissue eQTL enrichment of associations in schizophrenia. 2018 The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10-06), epidermal (β = 0.12, p = 3.1 × 10-04), lymphoblastoid (β = 0.19, p = 6.2 × 10-08) and blood (β = 0.19, p = 6.4 × 10-06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.
29408538 Lower Quadriceps Rate of Force Development Is Associated With Worsening Physical Function 2018 Jul OBJECTIVE: To determine the association between quadriceps rate of force development (RFD) and decline in self-reported physical function and objective measures of physical performance. DESIGN: Longitudinal cohort study. SETTING: Community-based sample from 4 urban areas. PARTICIPANTS: Osteoarthritis Initiative participants with or at risk for knee osteoarthritis, who had no history of knee/hip replacement, knee injury, or rheumatoid arthritis (N=2630). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Quadriceps RFD (N/s) was measured during isometric strength testing. Worsening physical function was defined as the minimal clinically important difference for worsening self-reported Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale score, 20-m walk time, and repeated chair stand time over 36 months. RESULTS: Compared with the slowest tertile of RFD, the fastest tertile had a lower risk for worsening of WOMAC physical function subscale score at 36-month follow-up, with an odds ratio (OR) of .68 (95% confidence interval [CI], .51-.92) after adjustment for age, sex, body mass index, depression, history of chronic diseases, and knee pain. In women, in comparison with the slowest tertile of RFD, the fastest tertile had a lower risk for worsening of WOMAC physical function subscale score at 36-month follow-up, with an adjusted OR of .57 (95% CI, .38-.86). This decreased risk did not reach statistical significance in men (OR, 0.81; 95% CI, 0.52-1.27). No statistically significant associations were detected between baseline RFD and walk or chair stand times. CONCLUSIONS: Our results indicate that higher RFD is associated with decreased risk for worsening self-reported physical function but not with decreased risk for worsening of physical performance.
29353127 Physical comorbidities increase the risk of psychiatric comorbidity in immune-mediated inf 2018 Mar OBJECTIVE: We tested the association between physical comorbidity and incident depression, anxiety disorder and bipolar disorder in three immune-mediated inflammatory diseases (IMID): inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) versus age-, sex- and geographically-matched controls. METHODS: Using population-based administrative data we identified 6119 persons with IBD, 3514 persons with MS, 10,206 persons with RA and 97,727 matched controls. We identified incident cases of depression, anxiety disorder and bipolar disorder in these populations. We evaluated the association of physical comorbidities with incident psychiatric comorbidity using Cox regression, adjusting for sociodemographic factors and index year. RESULTS: The risk of incident depression, anxiety disorders and bipolar disorder was higher in each IMID cohort versus their matched cohorts. The risk of incident psychiatric comorbidity increased with an increasing number of physical comorbidities for each psychiatric comorbidity evaluated, across all IMID. Adjustment for physical comorbidity did not attenuate the increased risk of psychiatric comorbidity in the IMID cohorts versus their matched cohorts. CONCLUSION: The increased incidence of psychiatric comorbidity in IMID versus matched general population cohorts is not accounted for by their increased prevalence of physical comorbidities. However, within IMID cohorts, physical comorbidity increases the risk of psychiatric comorbidity.
29314744 Clinical and economic implications of upper gastrointestinal adverse events in Asian rheum 2018 May AIM: To determine the incidence and direct costs of NSAID-induced upper GI adverse events in Malaysian rheumatology patients. METHODS: A retrospective, multi-centre, cohort study of rheumatology patients on long-term NSAIDs was conducted. Clinical data of patients treated between 2010 and 2013 were collected for a 24-month follow-up period. The costs of managing upper GI adverse events were based on patient level resource use data. RESULTS: Six hundred and thirty-four patients met the inclusion criteria: mean age 53.4 years, 89.9% female, diagnosis of rheumatoid arthritis (RA; 59.3%), osteoarthritis (OA; 10.3%) and both RA and OA (30.3%). Three hundred and seventy-one (58.5%) patients were prescribed non-selective NSAIDs and 263 (41.5%) had cyclo-oxygenase-2 inhibitors. Eighty-four upper GI adverse events occurred, translating into a risk of 13.2% and an incidence rate of 66.2 per 1000 person-years. GI adverse events comprised: dyspepsia n = 78 (12.3%), peptic ulcer disease (PUD) n = 5 (0.79%) and upper GI bleeding (UGIB) n = 1 (0.16%). The total direct healthcare cost of managing adverse events was Malaysian Ringgit (MR) 37 352 (US dollars [USD] 11 419) with a mean cost of MR 446.81 ± 534.56 (USD 136.60 ± 163.42) per patient, consisting mainly of GI pharmacotherapy (33.8%), oesophagoduodenoscopies (23.1%) and outpatient clinic visits (18.2%). Mean cost per patient by GI events were: dyspepsia, MR 408.98 ± 513.29 (USD125.03 ± 156.92); PUD, MR 805.93 ± 578.80 (USD 246.39 ± 176.95); UGIB, MR 1601.94 (USD 489.74, n = 1). CONCLUSION: The economic burden of GI adverse events due to long-term NSAIDs use in Malaysian patients with chronic rheumatic diseases is modest.
30059674 Tofacitinib and TPCA-1 exert chondroprotective effects on extracellular matrix turnover in 2019 Jul OBJECTIVE: Currently, there are no disease-modifying osteoarthritis drugs (DMOADs) approved for osteoarthritis. It is hypothesized that a subtype of OA may be driven by inflammation and may benefit from treatment with anti-inflammatory small molecule inhibitors adopted from treatments of rheumatoid arthritis. This study aimed to investigate how small molecule inhibitors of intracellular signaling modulate cartilage degradation and formation as a pre-clinical model for structural effects. DESIGN: Bovine cartilage explants were cultured with oncostatin M (OSM) and tumour necrosis factor α (TNF-α) either alone or combined with the small molecule inhibitors: SB203580 (p38 inhibitor), R406 (Spleen tyrosine kinase (Syk) inhibitor), TPCA-1 (Inhibitor of κB kinase (Ikk) inhibitor), or Tofacitinib (Tofa) (Janus kinases (Jak) inhibitor). Cartilage turnover was assessed with the biomarkers of degradation (AGNx1 and C2M), and type II collagen formation (PRO-C2) using ELISA. Explant proteoglycan content was assessed by Safranin O/Fast Green staining. RESULTS: R406, TPCA-1 and Tofa reduced the cytokine-induced proteoglycan loss and decreased AGNx1 release 3.7-, 43- and 32-fold, respectively. SB203580 showed no effect. All inhibitors suppressed C2M at a concentration of 3 µM. TPCA-1 and Tofa increased the cytokine reduced PRO-C2 3.5 and 3.7-fold, respectively. CONCLUSION: Using a pre-clinical model we found that the inhibitors TPCA-1 and Tofa inhibited cartilage degradation and rescue formation of type II collagen under inflammatory conditions, while R406 and SB203580 only inhibited cartilage degradation, and SB203580 only partially. These pre-clinical data suggest that TPCA-1 and Tofa preserve and help maintain cartilage ECM under inflammatory conditions and could be investigated further as DMOADs for inflammation-driven osteoarthritis.
30005674 Emotional processes and stress in children affected by hereditary angioedema with C1-inhib 2018 Jul 13 BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent edema of unpredictable frequency and severity. Stress, anxiety, and low mood are among the triggering factors most frequently reported. Impaired regulation and processing of emotions, also known as alexithymia, may influence outcomes. The aim of this study was to confirm the presence of alexithymia and stress in children with C1-INH-HAE, to determine whether they are also present in children affected by other chronic diseases, and to investigate their relationship with C1-INH-HAE severity. Data from children with C1-INH-HAE (n = 28) from four reference centers in Italy were compared with data from children with type 1 diabetes (T1D; n = 23) and rheumatoid arthritis (RA; n = 25). Alexithymia was assessed using the Alexithymia Questionnaire for Children scale; perceived stress was assessed using the Coddington Life Event Scale for Children (CLES-C). RESULTS: Mean age (standard deviation [SD]) in the C1-INH-HAE, T1D, and RA groups was 11.8 (3.3), 11.7 (2.9), and 11.1 (2.6) years, respectively. Mean C1-INH-HAE severity score was 5.9 (2.1), indicating moderate disease. Alexithymia scores were similar among disease groups and suggestive of difficulties in identifying and describing emotions; CLES-C scores tended to be worse in C1-INH-HAE children. C1-INH-HAE severity was found to correlate significantly and positively with alexithymia (p = 0.046), but not with perceived stress. Alexithymia correlated positively with perceived stress. CONCLUSIONS: Alexithymia is common in children with chronic diseases. In C1-INH-HAE, it may result in increased perceived stress and act as a trigger of edema attacks. Comprehensive management of C1-INH-HAE children should consider psychological factors.
29674445 Druggable negative allosteric site of P2X3 receptors. 2018 May 8 Allosteric modulation provides exciting opportunities for drug discovery of enzymes, ion channels, and G protein-coupled receptors. As cation channels gated by extracellular ATP, P2X receptors have attracted wide attention as new drug targets. Although small molecules targeting P2X receptors have entered into clinical trials for rheumatoid arthritis, cough, and pain, negative allosteric modulation of these receptors remains largely unexplored. Here, combining X-ray crystallography, computational modeling, and functional studies of channel mutants, we identified a negative allosteric site on P2X3 receptors, fostered by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains. Using two structurally analogous subtype-specific allosteric inhibitors of P2X3, AF-353 and AF-219, the latter being a drug candidate under phase II clinical trials for refractory chronic cough and idiopathic pulmonary fibrosis, we defined the molecular interactions between the drugs and receptors and the mechanism by which allosteric changes in the LF, DF, and LB domains modulate ATP activation of P2X3. Our detailed characterization of this druggable allosteric site should inspire new strategies to develop P2X3-specific allosteric modulators for clinical use.
30571257 Dysregulated IL-1β-GM-CSF Axis in Acute Rheumatic Fever That Is Limited by Hydroxychloroq 2018 Dec 4 BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease are autoimmune consequences of group A streptococcus infection and remain major causes of cardiovascular morbidity and mortality around the world. Improved treatment has been stymied by gaps in understanding key steps in the immunopathogenesis of ARF and rheumatic heart disease. This study aimed to identify (1) effector T cell cytokine(s) that might be dysregulated in the autoimmune response of patients with ARF by group A streptococcus, and (2) an immunomodulatory agent that suppresses this response and could be clinically translatable to high-risk patients with ARF. METHODS: The immune response to group A streptococcus was analyzed in peripheral blood mononuclear cells from an Australian Aboriginal ARF cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing. The immunomodulatory drug hydroxychloroquine was tested for effects on this response. RESULTS: We found a dysregulated interleukin-1β-granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine axis in ARF peripheral blood mononuclear cells exposed to group A streptococcus in vitro, whereby persistent interleukin-1β production is coupled to overproduction of GM-CSF and selective expansion of CXCR3(+)CCR4(-)CCR6(-) CD4 T cells. CXCR3(+)CCR4(-)CCR6(-) CD4 T cells are the major source of GM-CSF in human CD4 T cells and CXCL10, a CXCR3 ligand and potent T helper 1 chemoattractant, was elevated in sera from patients with ARF. GM-CSF has recently emerged as a key T cell-derived effector cytokine in numerous autoimmune diseases, including myocarditis, and the production of CXCL10 may explain selective trafficking of these cells to the heart. We provide evidence that interleukin-1β amplifies the expansion of GM-CSF-expressing CD4 T cells, which is effectively suppressed by hydroxychloroquine. RNA sequencing showed shifts in gene expression profiles and differentially expressed genes in peripheral blood mononuclear cells derived from patients at different clinical stages of ARF. CONCLUSIONS: Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis, where GM-CSF plays a pivotal role, we propose that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease after ARF.
30134146 Bromodomain and extraterminal domain-containing protein inhibition attenuates acute inflam 2018 Nov Inflammation is a major contributor to the secondary damage that occurs after spinal cord injury (SCI). The inflammatory response is coordinated by many different signaling modalities including the epigenetic modification of promoters and enhancers. Bromodomain and extraterminal domain-containing proteins (BETs; Brd2, Brd3, Brd4, BrdT) are epigenetic readers that bind acetylated histones to promote transcription of pro-inflammatory genes. BET inhibition is anti-inflammatory in animal models of cancer, rheumatoid arthritis, and coronary artery disease. However, the role of BETs in neuroinflammation remains largely unexplored. In this study, we investigated the role of BETs in promoting inflammation in neural cells and the ability of the BET inhibitor JQ1 to decrease inflammation acutely after SCI. Expression of BET mRNA was assessed via qPCR in purified primary mouse macrophages, astrocytes, neurons, oligodendrocytes, and microglia, as well as in naïve, sham-injured, and contusion-injured mouse spinal cord. Brd2, Brd3, and Brd4 mRNA were expressed in all purified primary neural cells and in the uninjured and injured mouse spinal cord. BET inhibition significantly attenuated proinflammatory signaling in all activated cell populations in vitro. To investigate the effects of BET modulation after SCI, the BET inhibitor JQ1 was injected intraperitoneally (30 mg/kg, bidaily) 3 h after spinal cord contusion in adult female C57BL/6 mice. By 3 days post-injury, BET inhibition significantly decreased pro-inflammatory cytokine expression and leukocyte recruitment to the injury site. However, this decrease did not lead to locomotor improvements or smaller lesion size. Taken together, our data implicate BETs as regulators of multiple key pro-inflammatory cytokines, and suggest that BETs can be pharmacologically inhibited to reduce inflammation acutely after SCI.
29929117 Psychiatric comorbidity increases mortality in immune-mediated inflammatory diseases. 2018 Jul OBJECTIVE: We determined the association between any common mental disorder (CMD: depression, anxiety disorder, bipolar disorder) and mortality and suicide in three immune-mediated inflammatory diseases (IMID), inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA), versus age-, sex- and geographically-matched controls. METHODS: Using administrative data, we identified 28,384 IMID cases (IBD: 8695; MS: 5496; RA: 14,503) and 141,672 matched controls. We determined annual rates of mortality, suicide and suicide attempts. We evaluated the association of any CMD with all-cause mortality and suicide using multivariable Cox regression models. RESULTS: In the IMID cohort, any CMD was associated with increased mortality. We observed a greater than additive interaction between depression and IMID status (attributable proportion 5.2%), but a less than additive interaction with anxiety (attributable proportion -13%). Findings were similar for MS and RA. In IBD, a less than additive interaction existed with depression and anxiety on mortality risk. The IMID cohort with any CMD had an increased suicide risk versus the matched cohort without CMD. CONCLUSION: CMD are associated with increased mortality and suicide risk in IMID. In MS and RA, the effects of depression on mortality risk are greater than associations of these IMID and depression alone.
29501539 Contribution of MTHFR gene variants in lupus related subclinical atherosclerosis. 2018 Aug OBJECTIVE: Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR) to atherosclerotic disease characterizing SLE patients. METHODS: Peripheral DNA samples from 150 SLE patients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (c. 677C > T and c. 1298A > C). All SLE patients and 30 age sex matched RA patients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0). RESULTS: Hyperhomocysteinemia was detected in 26.0% of SLE patients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RA patients could potentially account for the observed differences between the groups. In SLE patients, both hyperhomocysteinemia and MTHFR 677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0-35.8) and 5.2 (1.1-24.0), respectively]. MTHFR 677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2-20.6)]. CONCLUSIONS: Hyperhomocysteinemia and MTHFR 677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLE patients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE.
30472651 Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases 2019 Feb OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506.
30178083 Measuring the bioactivity of anti-IL-6/anti-IL-6R therapeutic antibodies: presentation of 2018 Nov IL-6 has an important role in the pathogenesis of autoimmunity and chronic inflammation. Several mAbs that target IL-6 or the IL-6 receptor (IL-6R) have been established and approved for the treatment of various diseases such as multicentric Castleman's disease and rheumatoid arthritis. Quality control of therapeutic antibodies requires accurate determination of bioactivity. However, current cell-based anti-proliferation assays are tedious, time consuming, and result in high variation. We therefore developed a reporter gene assay (RGA) based on an IL-6-dependent DS-1 cell line that stably expressed the reporter luciferase controlled by the serum-induced element (SIE) response element, which was a key element located downstream of the IL-6 signaling pathway. The RGA method demonstrated good performance characteristics after careful optimization, including high specificity, stability, accuracy, precision, and robustness. It also had superior precision and sensitivity. The assay is simple compared with the traditional anti-proliferation assay. This novel RGA based on the IL-6-IL-6R-STAT3 pathway can be useful, in conjunction with the anti-proliferation bioassay, to determine the bioactivity of anti-IL-6/anti-IL-6R therapeutic mAbs. Graphical abstract The mechanism sketch of the reporter gene assay for the bioactivity determination of anti-IL-6/anti-IL-6Rα mAbs.
29883892 Microdialysis combined with RRLC-MS/MS for the pharmacokinetics of two major alkaloids of 2018 Aug 15 Bi qi capsule (BQC) is a traditional Chinese medicine prescription that is clinically used for the treatment of rheumatoid arthritis. Strychnine and brucine, as two typical kinds of alkaloids, are the primary active and neurotoxic constituents of BQC. In this study, a sensitive and reliable rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) quantitative method was used to determine the concentrations of brucine and strychnine in rat brain and blood dialysates. The blood-brain barrier (BBB) penetration of free brucine and strychnine and their pharmacokinetic characteristics were investigated by the validated RRLC-MS/MS method coupled with in vivo microdialysis for the first time. The dialysate brain-blood AUC ratios of brucine were 0.098, 0.44 and 0.40 respectively at 0.4, 0.8 and 1.6 g kg(-1) doses of BQC, and the dialysate brain-blood AUC ratios of strychnine were 0.20, 1.25 and 2.06 respectively at 0.4, 0.8 and 1.6 g kg(-1) doses of BQC. The high brain-blood AUC ratios of brucine and strychnine were observed in medium and high dose groups of BQC. In addition, the effects of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on brucine and strychnine across BBB were also studied using the above method as well as molecular docking. The results prompted that brucine was the substrate of P-gp, and strychnine might be the inhibitor of P-gp. Brucine and strychnine showed high brain penetration, so it is very important to well control the clinic dosage of BQC and manufactory quality for avoiding the side effects and obtaining good therapeutic efficacy. Our study could be further used in investigating BBB penetration for other drugs caused neurotoxicity.
29500936 CTLA-4Ig (abatacept) balances bone anabolic effects of T cells and Wnt-10b with antianabol 2018 Mar Activated lymphocytes promote inflammation and bone destruction in rheumatoid arthritis (RA), making T cells and B cells therapeutic targets. Indeed, pharmacological blockade of CD28 costimulation using CTLA-4Ig (abatacept), approved for amelioration of RA, renders T cells dormant (anergic). CTLA-4Ig also promotes bone accretion in healthy mice; surprisingly, however, this effect is driven exclusively through upregulation of bone formation, rather than anti-inflammatory effects on resorption. In the study presented here, we utilized T cell receptor β gene and Wnt-10b gene knockout mice to investigate the roles of T cells and Wnt-10b in CTLA-4Ig-induced bone anabolism. Ablation of either T cells or Wnt-10b not only abolished CTLA-4Ig-induced bone anabolism but also, paradoxically, suppressed bone formation leading to bone loss. Stalled bone formation was accompanied by bone marrow stromal cell expression of the Wnt pathway inhibitor sclerostin. Our data suggest that an immunoskeletal pivot may promote or suppress bone formation, depending on the net outcome of CTLA-4Ig action directed independently on T cells and osteoblast-linage cells that counter Wnt-10b-induced bone anabolism, by secretion of sclerostin. While CTLA-4Ig action is tipped in favor of bone formation under physiological conditions, pathological immunodeficiency may lead to suppressed bone formation and skeletal damage.
30345821 Comparison of Radiographic and Clinical Results After Extended Distal Chevron Osteotomy Wi 2019 Mar BACKGROUND: We compared the radiographic and clinical outcomes of moderate and severe hallux valgus treated by extended distal chevron osteotomy (EDCO) and distal soft tissue release (DSTR). METHODS: We performed a retrospective analysis comparing the utility of EDCO for the treatment of moderate (36 patients, 46 feet) and severe (36 patients, 42 feet) hallux valgus. The radiologic outcomes were evaluated based on the preoperative and 3-year follow-up x-rays. The clinical results were investigated based on the 3-year follow-up Manchester-Oxford Foot Questionnaire (MOXFQ), patient satisfaction, and postoperative complications. RESULTS: The mean postoperative intermetatarsal angle, hallux valgus angle, tibial sesamoid position, and relative metatarsal bone length were significantly different compared with the preoperative values for both the moderate and severe groups ( P < .001). At 3-year follow-up, intergroup differences were observed in the mean postoperative intermetatarsal angle ( P = .001), hallux valgus angle ( P = .003), and tibial sesamoid position ( P = .013); however, mean radiographic results were within the normal range for both groups. There were no intergroup differences for either the first metatarsal bone length ( P = .172) or shortening ( P = .621). No significant difference in MOXFQ ( P = .525) was evident between the groups at 3-year follow-up. In satisfaction analysis, 82.6% of the moderate group reported good to excellent results, as did 81.0% of the severe group ( P = .815). A total of 7 complications were reported in each group ( P = 1.000). CONCLUSION: The present study showed that midterm mean radiographic results of both moderate and severe hallux valgus treated by EDCO with DSTR were favorable, and those values were within the normal range. Clinical outcomes were comparable between the 2 groups, including overall efficacy. Based on these results, we recommend EDCO with DSTR as an efficient and reliable operative option for both moderate and severe hallux valgus. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
30289001 Extended Sinus Tarsi Approach for Treatment of Displaced Intraarticular Calcaneal Fracture 2019 Feb BACKGROUND: We compared the radiographic results and clinical outcomes of patients operated on via the extended sinus tarsi approach (ESTA) and the extended lateral approach (ELA) for treatment of displaced intraarticular calcaneal fractures. METHODS: We retrospectively studied the utility of the ELA (46 patients, 52 feet) and the ESTA (56 patients, 64 feet) in patients operated on between January 2009 and March 2015. We evaluated pre- and postoperative x-rays and computed tomography (CT) data. Pain, patient-reported functional outcomes, satisfaction, and postoperative complications were investigated at the 3-year follow-up. RESULTS: Neither the postoperative nor 3-year follow-up Böhler angles, nor the calcaneal width, differed significantly between the 2 groups (both P > .05). However, the maximum step-off of the posterior facet on the 3-month CT follow-up of the ESTA group was significantly less than that of the ELA group ( P < .05). We found no significant between-group differences in terms of postoperative translation ( P = .232) or angulation ( P = .132) of the sustentacular fragment on the 3-month CT follow-up. At the 3-year follow-up, we found no significant between-group difference in the mean visual analog scale pain score at rest ( P = .641) or during weightbearing ( P = .525). We found no significant between-group difference in the Foot Function Index (FFI) ( P = .712) or self-reported satisfaction ( P = .823). The ELA group experienced significantly more wound complications ( P = .041) and nonunions ( P = .041) than the ESTA group. Four instances of superficial peroneal nerve injury were reported in the ESTA group ( P = .127). CONCLUSION: Compared with the ELA, the ESTA afforded comparable, favorable radiological results and clinical outcomes, associated with fewer wound complications and nonunions. We suggest that the ESTA is an effective operative option when treating displaced, intraarticular calcaneal fractures. LEVEL OF EVIDENCE: Level III, comparative study.
29858267 HLA-DQA1, -DQB1, and -DRB1 Alleles Associated with Acute Tubulointerstitial Nephritis in a 2018 Jul 15 Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury with various origins. HLA-DQA1, -DQB1, and -DRB1 have been associated with development of tubulointerstitial nephritis and uveitis (TINU) syndrome in case reports and small case series, but information about HLA genetic susceptibility to drug hypersensitivity-related ATIN (D-ATIN) or other types of ATIN is limited. In this article, we genotyped 154 patients with ATIN of different causes and 200 healthy controls at HLA-DQA1, -DQB1, and -DRB1 loci. We found that there was no difference between patients with D-ATIN and TINU in the carrier's frequency of HLA-DQA1, -DQB1, or -DRB1 Patients with Sjogren's syndrome-ATIN and IgG4-related ATIN presented a different pattern of tested HLA alleles. HLA-DQA1*0104 (p value corrected by false discovery rate method [Pc] = 4.72 × 10(-22), odds ratio [OR] = 13.81), -DQB1*0503 (Pc = 1.95 × 10(-14), OR = 9.51), and -DRB1*1405 (Pc = 8.06 × 10(-19), OR = 12.80) were significant risk alleles for the occurrence of D-ATIN and TINU. There were no significant associations between tested HLA alleles and ATIN induced by other causes. Patients with D-ATIN/TINU carrying HLA-DQA1*0104/DQB1*0503/DRB1*1405 had higher peak serum creatinine and more severe renal tubulointerstitial inflammatory impairment. They also had significantly higher levels of tubular HLA-DR and HLA-DQ expression, which were correlated with the numbers of interstitial CD4(+) T lymphocytes (r = 0.975, p < 0.001 and r = 0.832, p = 0.005, respectively) and monocytes/macrophages (r = 0.721, p = 0.004 and r = 0.615, p = 0.02, respectively). In conclusion, patients with D-ATIN or TINU have genetic susceptibility in HLA-DQA1, -DQB1, and -DRB1 alleles. HLA-DQA1*0104/DQB1*0503/DRB1*1405 serves as a significant risk haplotype for development of D-ATIN and TINU, which might facilitate renal tubulointerstitial inflammation by enhancing Ag-presenting capacity of renal tubular cells.
29604049 Aberrant cell signalling in PBMCs upon IFN-α stimulation in primary Sjögren's syndrome p 2018 Jul Primary Sjögren's syndrome (pSS) is a complex systemic autoimmune disease with heterogeneous disease manifestations. Genetic predisposition, hormonal and environmental factors are all thought to contribute to disease etiology and pathogenesis. A better understanding of the disease pathogenesis is required in order to establish new targeted therapies. We analysed MAPK/ERK and JAK/STAT signalling networks in peripheral blood mononuclear cells (PBMCs) upon stimulation with interferon alpha 2b (IFN-α2b) by flow cytometry to define potentially dysfunctional intracellular signalling pathways involved in disease pathogenesis. Cells derived from pSS patients displayed small but significant increases in basal phosphorylation levels of numerous signalling proteins compared to cells from healthy donors. The phosphorylation profiles following stimulation with IFNα2b differed significantly between pSS patients and healthy donors, especially regarding STAT1 Y701. PCA further grouped patients according to clinical characteristics. Type I IFN induced gene expression was found to negatively correlate with the IFN-α2b induced phosphorylation of STAT3 S727 in T cells and positively with pSTAT1 Y701 in B cells. Increases in pSTAT1 Y701 were associated with the presence of autoantibodies. Our results indicate involvement of both STAT3 S727 and STAT1 Y701 pathways in pSS patients. Therapies targeting these pathways might therefore be beneficial for certain subgroups of patients.
30101437 Clinical relevance of serum antibodies to GD1b in immune-mediated neuropathies. 2018 Dec Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.