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ID PMID Title PublicationDate abstract
31372961 Usability of Prefilled Syringe and Autoinjector for SB4 (An Etanercept Biosimilar) in Pati 2019 Sep INTRODUCTION: This study aimed to compare the usability of subcutaneous administration of SB4 (an etanercept biosimilar) via prefilled syringe (PFS) and autoinjector (AI) based on injection site pain, patient preference, and safety in patients with rheumatoid arthritis (RA). METHODS: This was an open-label, single-arm, multicenter study to evaluate the usability and safety of the AI and PFS of SB4. Adult patients with RA received two injections of SB4 via the PFS, followed by six injections by the AI every week, up to 8 weeks. The primary endpoint was the change in injection site pain score immediately post-injection from week 1 (PFS) to week 3 (AI). Injection site pain after 15-30 min post-injection, overall impression, and preference for PFS and AI were also assessed. Safety was assessed up to 11 weeks after the first injection. RESULTS: A total of 54 patients were enrolled and 52 patients (96.3%) completed the 8-week treatment period. The mean difference in pain scores between PFS and AI was - 0.057 and the 95% CI of the difference was [- 0.63, 0.51], which was within the equivalence margin of ± 5. Overall impression of the device slightly favored the AI. Overall preference for the AI was more favorable when compared to the PFS in all categories. Adverse events were mild to moderate and found to be generally consistent with those expected for reference etanercept. There were no deaths or serious adverse events reported. CONCLUSIONS: This study demonstrated comparable usability and safety between the PFS and AI when self-administrated by patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03193957. FUNDING: Samsung Bioepis.
30156758 Pharmacokinetics, Safety, and Tolerability of the Dual Inhibitor of Tumor Necrosis Factor- 2019 May The dual-variable domain immunoglobulin ABBV-257 binds tumor necrosis factor-α and interleukin 17A. Following single ascending doses ( 0.3, 1.0, and 3.0 mg/kg intravenously; 0.3 and 3.0 mg/kg subcutaneously) in a randomized, double-blind, placebo-controlled study in healthy subjects (n = 40; n = 29 evaluated for pharmacokinetics), maximum observed serum concentration (C(max) ) increased dose-proportionally, whereas area under the serum concentration-versus-time curve trended to more than dose-proportional increase. Absolute subcutaneous bioavailability was ∼80%, and the time to C(max) (t(max) ) occurred 6 to 8 days after subcutaneous administration. The terminal-phase harmonic mean elimination half-life (t(½) ) ranged from 5.5 to 11 days following intravenous and subcutaneous administration. In another randomized, placebo-controlled study, rheumatoid arthritis (RA) patients (n = 8) received ABBV-257 30 mg/kg subcutaneously every other week for 8 weeks. Following the fourth dose, C(max) was 7.69 μg/mL, and t(max) occurred ∼4 days after dosing; t(½) was ∼16 days. Most individuals (single-dose study, 97%; multiple-dose study, 83%) developed antidrug antibodies (ADAs). Generally, subjects with higher ADA titers had shorter ABBV-257 t(½) and lower exposure. One serious adverse event (cerebral ischemia, considered unrelated to treatment, resolved with interventions) occurred in an RA patient who received ABBV-257. Because of the high incidence of ADA-mediated drug clearance, ABBV-257 is no longer being developed.
31379807 Human Memory Th17 Cell Populations Change Into Anti-inflammatory Cells With Regulatory Cap 2019 Autoimmune diseases are characterized by an aberrantly activated immune system, resulting in tissue damage and functional disability in patients. An important therapeutic goal is to restore the deregulated immunological balance between pro- and anti-inflammatory T cells. This imbalance is illustrated by elevated levels and activity of memory Th17 cell populations, such as Th17, Th1/Th17, and Th17.1 cells, in various autoimmune diseases. These cells are characterized by the chemokine receptor CCR6, RORC expression and production of IL-17A, IFNγ, and TNFα. Using rheumatoid arthritis (RA) as a model of autoimmune disease, we here demonstrate that pro-inflammatory memory CCR6+ Th cells can switch into anti-inflammatory cells with regulatory capacity using the active vitamin D metabolite 1,25(OH)(2)D(3). Memory CCR6+ Th cells, excluding Tregs, were sorted from healthy controls or treatment-naïve patients with early rheumatoid arthritis (RA) and cultured with or without 1,25(OH)(2)D(3). Treatment with 1,25(OH)(2)D(3) inhibited pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFNγ in memory CCR6+ Th cells from both healthy controls and RA patients. This was accompanied by induction of anti-inflammatory factors, including IL-10 and CTLA4. Interestingly, these formerly pathogenic cells suppressed proliferation of autologous CD3+ T cells similar to classical Tregs. Importantly, the modulated memory cells still migrated toward inflammatory milieus in vitro, modeled by RA synovial fluid, and retained their suppressive capacity in this environment. These data show the potential to reset the pathogenic profile of human memory Th cells into non-pathogenic cells with regulatory capacity.
30789801 Oral administration of alpha-lipoic acid did not affect lipid peroxidation and antioxidant 2019 Jul Rheumatoid arthritis (RA) is a chronic inflammatory disease in which oxidative stress could play a substantial pathological role. Alpha-lipoic acid (ALA) has been known as a "universal" and "ideal" antioxidant. The purpose of this study was to investigate the effects of oral administration of Alpha-lipoic acid (ALA) on lipid peroxidation and antioxidant biomarkers in Rheumatoid arthritis (RA) patients. The study was a randomized, double-blinded, placebo-controlled clinical trial. 70 RA patients were randomized 1:1 to two groups using blocked randomization method and received 1200 mg/day ALA or placebo for 8 weeks. Fasting blood samples were obtained before and after the intervention to analyze total antioxidant capacity (TAC), antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and arylesterase (ARE) activities] and malondialdehyde (MDA). We observed significant increase in serum TAC (0.11 mmol/L; p=0.033) and ARE (13.76 U/mL; p=0.046) and significant decline in MDA (-0.36 nmol/L; p=0.002), in ALA group. However, these changes in ALA-treated group were not statistically significant when compared with placebo-treated group (p > 0.05). Also, within- and between-group differences of whole blood SOD and GSH-Px were not statistically significant (p > 0.05). In conclusion, unexpectedly, ALA therapy did not affect the oxidative status of RA patients in the present clinical trial. It seems that more comprehensive clinical trials in RA patients are still warranted to clarify the effectiveness of ALA which has been known as a potent antioxidant.
31287398 Choice of the most appropriate biological disease-modifying anti-rheumatic drug for inject 2020 May OBJECTIVES: To determine which biological disease-modifying anti-rheumatic drug (bDMARD) is most appropriate for spacing in patients with rheumatoid arthritis (RA) who have persistent stable symptoms. METHODS: In patients with sustained low disease activity (LDA) or better for ≥3 months who were treated with bDMARDs, the interval between bDMARD injections was extended 1.5 times, and treatment continuation rates at 104 weeks were calculated for each drug. Patients who discontinued therapy owing to adverse reactions and those who withdrew for reasons unrelated to the drugs were excluded. Whether patients could remain in LDA or better after injection spacing was investigated. The targeted drugs were an anti-tumour necrosis factor (TNF) inhibitor (golimumab [GOL]) and 2 non-TNF inhibitors (tocilizumab [TCZ] and abatacept [ABT]). RESULTS: The spacing evaluation included 57, 93, and 40 patients who received GOL subcutaneous injection (SC), TCZ (SC in 21 and drip intravenous injection [DIV] in 72), and ABT (SC in 12 and DIV in 22), respectively. At 104 weeks, the number of patients who discontinued therapy owing to adverse reactions did not significantly differ among the drugs. At 104 weeks, the treatment continuation rate was 0.71 for TCZ SC, 0.70 for GOL, 0.69 for TCZ DIV, 0.55 for ABT SC, and 0.50 for ABT DIV. The continuation rate for ABT was significantly lower than those for GOL and TCZ. No significant difference in continuation rates was observed between SC and DIV. CONCLUSIONS: When the injection interval was extended, GOL and TCZ were superior to ABT in terms of continuation rate.
30702804 The "green nail" phenomenon in ICG-enhanced fluorescence optical imaging - a potential too 2019 Feb BACKGROUND AND OBJECTIVES: Early diagnosis of psoriatic arthritis poses a particular challenge. A novel fluorescence optical imaging technique, the Xiralite® system is very useful in this regard as it allows for visualization of microvasculature and perfusion. The present study is the first to systematically examine fluorescence optical signals in a large psoriatic arthritis cohort. PATIENTS AND METHODS: In the primary study, we reviewed and analyzed extra-articular fluorescence optical signal patterns in 241 imaging sequences obtained from 187 psoriatic arthritis patients; 36 fluorescence optical sequences from 31 patients with rheumatoid arthritis served as controls. In a follow-up study, 203 consecutive fluorescence optical sequences from 54 psoriatic arthritis patients and 149 control subjects with various inflammatory rheumatic disorders were retrospectively evaluated in order to validate the primary study results in terms of the patterns previously identified. RESULTS: Psoriatic arthritis patients exhibited three different fluorescence optical signal patterns in projection of the nails that have not been previously described. One of these patterns was the "green nail" sign, which was highly specific (97 %) for psoriatic arthritis. In the follow-up study, the specificity of this phenomenon in psoriatic arthritis was 87 % in comparison to the control cohort. CONCLUSIONS: In the present study, fluorescence optical signals in the nail region proved to be highly specific for psoriatic arthritis. The "green nail" phenomenon seems to be of particular diagnostic interest as a potential sign of impaired microcirculation of the nail bed.
31427438 Patients with rheumatoid arthritis facing sick leave or work disability meet varying regul 2019 Nov OBJECTIVES: To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system's performance, across European countries. METHODS: We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates. RESULTS: Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (β=-0.5 (95% CI -0.9 to -0.2) and β=-0.5 (95% CI -1.0 to -0.1), respectively). The Scandinavian and Bismarckian system scored best on patients' and rheumatologists' perceptions of regulations and system performance. CONCLUSIONS: There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country's wealth.
31865244 Naltrexone (NTX) relieves inflammation in the collagen-induced- arthritis (CIA) rat models 2020 Feb OBJECTIVE: Our aim was to study the efficacy and mechanism by which NTX alleviate arthritis in CIA rat models in vivo. METHODS: Female Wistar rats were randomly divided into 6 groups, their weights were observed and the severity of arthritis and pathological changes were evaluated by HE staining. T lymphocyte subsets were detected by flow cytometry. The expression of cytokines was detected in peripheral serum by ELISA. Real time PCR, immunohistochemical staining and western blot analysis were utilized to detect the mRNA and protein expression of opioid receptors, TLR4, RANKL and /NF-κB in synovial tissue and the spleen. RESULTS: The weight of the rats in the 10 mg/kg NTX group decreased the least, and had the least severe arthritis. CD4(+) T cells, Th1 cells and Treg cells increased, and CD8(+)T cells, Th1 cells and Th17 cells decreased in the splenic lymphocytes. The expression of proinflammatory cytokines decreased, and the expression of anti-inflammatory cytokines increased. MOR and DOR were strongly expressed in the spleen, whereas KOR and DOR were strongly expressed in synovial tissue. The expression of TLR4, NF-κB and RANKL was reduced in the spleen and synovium in the NTX group. CONCLUSIONS: NTX relieved the severity of arthritis in the CIA rat models at a concentration of 10 mg/kg by regulating T lymphocyte subsets and the expression of cytokines. NTX affected opioid receptors to inhibit the TLR4/NF-κB signaling pathway, regulating the systemic immune response and decreasing osteoclast differentiation, thereby alleviating inflammation and the erosion of articular cartilage along with bone tissue.
30882703 A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy 2019 Mar BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by swelling, pain, and synovial damage. Effective methods lack in the treatment of RA. A traditional prescription in use for thousands of years in China, Huangqi Guizhi Wuwutang granule (HGWG) is still chosen to relieve pain and prevent joint malformation in RA patients. However, no evidence-based medical research has been organized to assess the effectiveness and safety of HGWG for RA. METHODS/DESIGN: We will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial to determine whether HGWG can relieve pain and protect joints. We will randomly divide 120 patients with active RA into 2 groups, treated for 12 weeks. Main measurement is the rate of ACR50 score (American College of Rheumatology) from the baseline to 12 weeks. Secondary measurements include rate of ACR20/70, change of Disease Activity Score (DAS) 28, Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient Assessment of Arthritis Pain, Patient Global Assessment of Arthritis, and AIS score. The time points are set as baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, and 48 weeks. In addition, the rate of ACR50 from the baseline to 2 weeks, 4 weeks, 8 weeks, 24 weeks, and 48 weeks' follow-up are also the secondary outcome measures. DISCUSSION: The findings of this research will elucidate the efficacy and safety of HGWG and provide an alternative treatment for RA. In addition, our data will benefit the clinical decision-making on active RA and possibly be incorporated into future guidelines. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03593837.
29654949 Relevance and feasibility of a systematic screening of multimorbidities in patients with c 2019 Jan OBJECTIVES: EULAR recently proposed to screen multimorbidities in chronic inflammatory rheumatic diseases. The aims of the study were to define the most common multimorbidities in chronic inflammatory rheumatic diseases, compare the screening approach performed in the clinic with the recent EULAR recommendations, validate the points to consider for the systematic standardized multimorbidity screening proposed by EULAR and assess feasibility of such a screening in a daily clinic. METHODS: Data were collected prospectively during a 1-day multimorbidity clinic. Diabetes, hypertension, CVD damage, chronic respiratory diseases, osteoporosis and preventive measures were assessed. The comparison with EULAR points to consider was performed retrospectively. RESULTS: We included 200 consecutive patients (157 with rheumatoid arthritis, 37 spondyloarthritis, and 6 connective tissue diseases or vasculitis). The most common multimorbidities already diagnosed in our patients were hypertension (26%) and diabetes (7.5%). Screening showed that 61.5% (CI95%: 54.6%-67.9%) patients presented at least one undiagnosed or uncontrolled diseases: diabetes (6%), hypertension (20.6%), dyslipidemia (16.1%) valvulopathies (16.8%), peripheral artery disease (4.5%); carotid stenosis (6.5%) and aortic aneurysm (5.5%). Overall, 39.9% patients had incomplete cancer screening and 52.8% incomplete vaccine schedule. Undiagnosed pulmonary obstruction and risk of sleep apnea were suspected in 15.5% and 40.1% patients, respectively. CONCLUSION: This study underlines the relevance of a systematic screening of multimorbidities in chronic inflammatory rheumatic diseases and its feasibility in a 1-day clinic. Spirometry and sleep apnea screening should be added to EULAR points to consider. The long-term impact of such screening needs to be evaluated.
30894578 Inflammatory disease and C-reactive protein in relation to therapeutic ionising radiation 2019 Mar 20 Chronic inflammation underlies many autoimmune diseases, including hypothyroidism, hyperthyroidism, and rheumatoid arthritis, also type-2 diabetes and osteoarthritis. Associations have been suggested of high-dose ionising radiation exposure with type-2 diabetes and elevated levels of C-reactive protein, a marker of chronic inflammation. In this analysis we used a proportional hazards model to assess effects of radiotherapy on risks of subsequent inflammatory disease morbidity in 110,368 US radiologic technologists followed from a baseline survey (1983-1989/1994-1998) through 2008. We used a linear model to assess log-transformed C-reactive protein concentration following radiotherapy in 1326 technologists. Relative risk of diabetes increased following radiotherapy (p < 0.001), and there was a borderline significant increasing trend per treatment (p = 0.092). For osteoarthritis there was increased relative risk associated with prior radiotherapy on all questionnaires (p = 0.005), and a significant increasing trend per previous treatment (p = 0.024). No consistent increases were observed for other types of inflammatory disease (hypothyroidism, hyperthyroidism, rheumatoid arthritis) associated with radiotherapy. There was a borderline significant (p = 0.059) increasing trend with dose for C-reactive protein with numbers of prior radiotherapy treatments. Our results suggest that radiotherapy is associated with subsequent increased risk of certain inflammatory conditions, which is reinforced by our finding of elevated levels of C-reactive protein.
30936065 Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive r 2019 Jun OBJECTIVE: The strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC. METHODS: We first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case-control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants. RESULTS: HLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10(-36), OR=2.29). DRβ1:37N had an independent protective effect (p=5.81×10(-16), OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRβ1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility. CONCLUSIONS: We provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.
31831064 Will savings from biosimilars offset increased costs related to dose escalation? A compari 2019 Dec 12 INTRODUCTION: Biosimilar infliximab has the potential for appreciable cost savings compared to its reference biologic, but dose escalation is common and increases costs. We compared frequency of dose escalation and associated Medicare-approved amount so as to determine the break-even point at which infliximab dose escalation would offset the cost savings of using a biosimilar, referent to alternatively using golimumab. METHODS: We studied Medicare enrollees with rheumatoid arthritis (RA) initiating infliximab or golimumab. Frequency of dose escalation was summarized descriptively over 18 months, as were Medicare-approved amounts for reimbursement. Analyses were repeated conditioning on high adherence (i.e., non-discontinuation, > 10-week gap). Multivariable-adjusted logistic regression and mixed models evaluated factors associated with infliximab dose escalation. RESULTS: A total of 5174 infliximab and 2843 golimumab initiators were observed. Dose escalation was rare for golimumab (5%) but common for infliximab (49%), and was even more common (72%) for infliximab among patients who persisted on treatment. Regardless of dose escalation, the adjusted least square mean dollar amounts were appreciably higher for golimumab ($28,146) than for infliximab ($21,216) and greater among persistent patients (cost difference $9269, favoring infliximab). Only when patients escalated infliximab to ≥ 8 mg/kg every 6 weeks was golimumab IV at break-even or less expensive. After controlling for multiple factors, physician ownership of the infusion center was associated with greater likelihood of infliximab dose escalation (odds ratio = 1.25, 95% CI 1.09-1.44). CONCLUSION: Despite frequent dose escalation with infliximab that often increase its dose by threefold or more, the savings from the current price of its biosimilar substantially offsets the costs of an alternative infused TNFi biologic for which no biosimilar is available.
30590833 Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients 2019 May 1 OBJECTIVE: Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study. METHODS: In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks' double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v. RESULTS: In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study. CONCLUSION: No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab. TRIAL REGISTRATION NUMBERS: ASCERTAIN (NCT01768572); Study 1309 (NCT02097524).
31572358 N-Glycosylation Site Analysis of Citrullinated Antigen-Specific B-Cell Receptors Indicates 2019 Many autoimmune diseases are hallmarked by autoreactive B and plasma cell responses that are directly or indirectly involved in disease pathogenesis. These B-cell responses show large variability between diseases, both in terms of the secreted autoantibody repertoire and the dynamics and characteristics of the underlying B-cell responses. Hence, different mechanisms have been proposed to explain the emergence of autoreactive B cells in an otherwise self-tolerant immune system. Notably, most mechanistic insights have been obtained from murine studies using models harboring genetic modifications of B and T cells. Given recent technological advances that have rendered autoreactive human B cells accessible for analysis, we here discuss the phenomenon of extensive N-glycosylation of the B-cell receptor (BCR) variable domain of a prototypic human autoreactive B-cell response and its potential role in the generation of autoimmunity. Anti-citrullinated protein antibodies (ACPA) hallmark the most disease-specific autoimmune response in Rheumatoid Arthritis (RA). Remarkably, ACPA-IgG are heavily N-glycosylated in the variable domain due to somatic mutations that generate abundant N-glycosylation consensus sequences. These sites, obtained from full-length BCR sequences of ACPA-expressing B cells from 12 ACPA-positive RA patients, were here analyzed in detail. Sites that required a single nucleotide mutation to be generated were defined as single somatic hypermutation (s-SHM) sites, whereas sites requiring multiple mutations were defined as m-SHM sites. IgG sequences of 12 healthy donors were used as control. Computational modeling of the germinal center reaction (CLONE algorithm) was used with the germline counterparts of ACPA-IgG heavy chain (HC) sequences to simulate the germinal center response. Our analyses revealed an abundance of N-glycosylation sites in ACPA-IgG HC that frequently required multiple mutations and predominated in specific positions. Based on these data, and taking into account recent insights into the dynamics of the ACPA-response during disease development, we here discuss the hypothesis that N-glycosylation sites in ACPA-IgG variable domains could lead to alternative, possibly antibody affinity-independent selection forces. Presumably, this occurs during germinal center responses allowing these B cells to escape from putative tolerance checkpoints, thereby driving autoreactive B cell development in the pathogenesis of RA.
31087542 Reducing or Maintaining the Dose of Subcutaneous Tocilizumab in Patients With Rheumatoid A 2019 Oct OBJECTIVE: To evaluate the efficacy and safety of increasing the dose interval of subcutaneous tocilizumab (TCZ-SC) in patients with rheumatoid arthritis (RA) who are in clinical remission. METHODS: RA patients with active disease and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or to a biologic agent were entered into a single-arm treatment phase with 162 mg of TCZ-SC administered once weekly (TCZ-SC 162 mg qw) as monotherapy or in combination with a csDMARD for 24 weeks. Patients who achieved clinical remission at weeks 20 and 24 were randomized to continue with the same regimen or to switch to 162 mg TCZ-SC administered every 2 weeks (TCZ-SC 162 mg q2w) for 24 weeks (open-label). Patients with a Disease Activity Score in 28 joints (DAS28) of <2.6 were considered to be in clinical remission. RESULTS: In total, 179 (45%) of 401 patients in the single-arm phase achieved clinical remission and were randomized to continue to receive TCZ-SC 162 mg qw (n = 89) or to switch to TCZ-SC 162 mg q2w (n = 90) for 24 weeks. At week 48, significantly more patients treated with TCZ-SC 162 mg qw remained in clinical remission compared to patients who received TCZ-SC 162 mg q2w (90% versus 73%; P = 0.004). The results of other efficacy measures revealed greater efficacy with TCZ-SC 162 mg qw, but none of the efficacy outcomes in this group were significantly different from those in patients treated with TCZ-SC 162 mg q2w, except for the mean change from baseline in the DAS28 score at week 48 (mean change -4.07 points [SD 1.29] versus -3.65 points [SD 1.35]; P = 0.034). Tolerability and safety parameters were similar between the treatment groups. CONCLUSION: Increasing the dose interval of TCZ-SC in patients with RA was associated with a lower likelihood of maintaining remission after 24 weeks and was not associated with better tolerability. However, most patients were able to sustain remission with a half-dose of TCZ-SC, and therefore this strategy deserves further investigation.
30712330 Rapid spread of mannan to the immune system, skin and joints within 6 hours after local ex 2019 Jun Psoriasis (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are common diseases dependent on environmental factors that activate the immune system in unknown ways. Mannan is a group of polysaccharides common in the environment; they are potentially pathogenic, because at least some of them induce Ps-, PsA- and RA-like inflammation in mice. Here, we used positron emission tomography/computed tomography to examine in-vivo transport and spread of mannan labelled with fluorine-18 [(18) F]. The results showed that mannan was transported to joints (knee) and bone marrow (tibia) of mice within 6 h after intraperitoneal injection. The time it took to transport mannan, and its presence in blood, indicated cellular transport of mannan within the circulatory system. In addition, mannan was filtered mainly through the spleen and liver. [(18) F]fluoromannan was excreted via kidneys, small intestine and, to some extent, the mouth. In conclusion, mannan reaches joints rapidly after injection, which may explain why mannan-induced inflammatory disease is targeted to these tissues.
31329997 OCCUPATIONAL EXPOSURE ASSESSMENT AT A THERAPEUTIC RADON SPA FACILITY IN HUNGARY. 2019 Oct 1 In order to estimate occupational exposure of workers in a therapeutic radon spa facility, radon concentration in the workplace air was investigated at Markhot Ferenc Hospital, Eger, Hungary. The investigated balneotherapeutic facility and its natural hot spa water are used for treatments and rehabilitations of rheumatic patients. Radon concentration, radon decay products at a bathhouse, treatment rooms and a consultation room were continuously measured in August and September 2018. In the present study, different levels of radon concentration among the observation sites and its clear temporal variations were found, though radon concentrations in the investigated sites were below 300 Bq m-3. Regarding such radon fluctuation and low equilibrium factor level (0.1), the annual effective doses of workers are estimated to be around 0.5 mSv year-1.
31209146 The association between RANK, RANKL and OPG gene polymorphisms and the risk of rheumatoid 2019 Jun 28 The receptor activator of nuclear factor-κB (RANK) and the osteoprotegerin (OPG) cascade system have been reported to be essential in osteoclastogenesis. In recent years, several studies have investigated the association between polymorphisms of RANK, its ligand RANKL and OPG genes and the risk of rheumatoid arthritis (RA) in different populations. However, the results arising from these studies were conflicting. To determine the association between RANK, RANKL and OPG gene polymorphisms and the risk of RA. We conducted a hospital-based case-controlled study in Changzhou with 574 RA cases and 804 controls. The genotyping of RANK gene rs1805034 polymorphism was conducted by single base extension combined with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). We also undertook a meta-analysis of the literature referring to polymorphisms of RANK, RANKL and OPG genes and RA risk. This case-controlled study found that the polymorphism in the RANK gene rs1805034 was not related to RA risk. Stratification analyses by sex and age suggested that RANK gene rs1805034 polymorphism was not associated with the risk of RA among groups of male, female, age ≤ 55 and age > 55. Our meta-analysis found that the rs2277438 polymorphism in RANKL gene increased the risk of RA, whereas RANK gene rs1805034, OPG gene rs3102735, OPG gene rs2073618, OPG gene rs3134069 polymorphisms were not related to RA susceptibility. In conclusion, this case-controlled study and meta-analysis indicated that the RANKL gene rs2277438 polymorphism increased the RA risk, and that RANK gene rs1805034, OPG gene rs3102735, OPG gene rs2073618, OPG gene rs3134069 polymorphisms were not related to RA risk.
30770509 Validity and Responsiveness of Combined Inflammation and Combined Joint Damage Scores Base 2019 Sep OBJECTIVE: The RAMRIS [Outcome Measures in Rheumatology rheumatoid arthritis (RA) magnetic resonance imaging (MRI) Scoring system] is used in clinical RA trials. We have investigated methods to combine the RAMRIS features into valid and responsive scores for inflammation and joint damage. METHODS: We used data from 3 large randomized early RA trials to assess 5 methods to develop a combined score for inflammation based on RAMRIS bone marrow edema, synovitis, and tenosynovitis scores, and a combined joint damage score based on erosions and joint space narrowing. Methods included unweighted summation, normalized summation, and 3 different variants of weighted summation of the RAMRIS features. We used a derivation cohort to calculate summation weights to maximize the responsiveness of the combined score. Construct validity of the combined scores was examined by assessing correlations to imaging, clinical, and biochemical measures. Responsiveness was tested by calculating the standardized response mean (SRM) and the relative efficiency of each score in a validation cohort. RESULTS: Patient characteristics, as well as baseline and followup RAMRIS scores, were comparable between cohorts. All combined scores were significantly correlated to other imaging, clinical, and biochemical measures. Inflammation scores combined by normalized and weighted summation had significantly higher responsiveness in comparison to unweighted summation, with SRM (95% CI) for unweighted summation 0.62 (0.51-0.73), normalized summation 0.73 (0.63-0.83), and weighted summation 0.74 (0.64-0.84). For the damage score, there was a trend toward higher responsiveness for weighted summation. CONCLUSION: Combined MRI scores calculated by normalized or weighted summation of individual MRI pathologies were valid and responsive.