Smoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not ...known, since deleterious, protective and neutral observations have been made.
To determine the effect of smoking on joint damage progression.
Smoking status was assessed in 3158 RA patients included in six cohorts (Leiden Early Arthritis Clinic (Leiden-EAC), BARFOT, Lund, Iceland, NDB and Wichita). In total 9412 radiographs were assessed. Multivariate normal regression and linear regression analyses were performed. Data were summarised in a random effects inverse variance meta-analysis.
When comparing radiological progression for RA patients that were never, past and current smokers, smoking was significantly associated with more severe joint damage in Leiden-EAC (p=0.042) and BARFOT (p=0.015) RA patients. No significant associations were found in the other cohorts, though a meta-analysis on the six cohorts showed significantly more severe joint damage progression in smokers (p=0.01). Since smoking predisposes to ACPA, analyses were repeated with ACPA as additional adjustment factor. Then the association was lost (meta-analysis p=0.29).
This multi-cohort study indicated that the effect of smoking on joint damage is mediated via ACPA and that smoking is not an independent risk factor for radiological progression in RA.
Spinal high mobility group box 1 protein (HMGB1) plays crucial roles in arthritis-induced pain; however, the involvement of peripheral HMGB1 has not been examined previously. In this study, we ...addressed the role of peripheral HMGB1 and explored if sex contributes differentially to nociception in arthritis. We found Hmgb1 expression to be elevated in the ankle joints of male and female mice subjected to collagen antibody-induced arthritis. Blocking the action of peripheral HMGB1, however, only reversed collagen antibody-induced arthritis-mediated hypersensitivity in males. Intra-articular injection of the toll-like receptor (TLR)4-activating, partially reduced disulfide, but not the fully reduced all-thiol, HMGB1 evoked mechanical hypersensitivity in both sexes. A sex-dependent temporal profile in expression of inflammatory factors in the ankle joint was observed in response to intra-articular injection of disulfide HMGB1, with male mice showing a delayed, yet longer-lasting increase in mRNA levels for several of the investigated factors. Intra-articular HMGB1 did not induce cellular infiltration in the ankle joint suggesting its action on tissue resident cells. To further explore possible sex differences in cellular involvement, we used the macrophage inhibitor, minocycline, and mice with specific TLR4 depletion in myeloid cells or nociceptors. We found that inhibition of resident macrophages attenuated HMGB1-induced pain-like behavior only in male mice. Interestingly, although the contribution of TLR4 on myeloid cells to nociception was minimal in females compared to males, TLR4 on nociceptors are important for HMGB1-induced pain in both sexes. Collectively, our work highlights sex- and cellular location-dependent roles of HMGB1 and TLR4 in peripheral pain mechanisms.
Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate ...with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations.
2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses.
During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88).
The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.
Essentials
Activated FVII (FVIIa) and FX (FXa) are inhibited by tissue factor pathway inhibitor (TFPI).
A monoclonal antibody, mAb2F22, was raised against the N‐terminal fragment of TFPI (1‐79).
...mAb2F22 bound exclusively to the K1 domain of TFPI (KD ∼1 nm) and not to the K2 domain.
mAb2F22 interfered with inhibition of both FVIIa and FXa activities and restored clot formation.
Summary
Background
Initiation of coagulation is induced by binding of activated factor VII (FVIIa) to tissue factor (TF) and activation of factor X (FX) in a process regulated by tissue factor pathway inhibitor (TFPI). TFPI contains three Kunitz‐type protease inhibitor domains (K1–K3), of which K1 and K2 block the active sites of FVIIa and FXa, respectively.
Objective
To produce a monoclonal antibody (mAb) directed towards K1, to characterize the binding epitope, and to study its effect on TFPI inhibition.
Methods
A monoclonal antibody, mAb2F22, was raised against the N‐terminal TFPI(1‐79) fragment. Binding data were obtained by surface plasmon resonance analysis. The Fab‐fragment of mAb2F22, Fab2F22, was expressed and the structure of its complex with TFPI(1‐79) determined by X‐ray crystallography. Effects of mAb2F22 on TFPI inhibition were measured in buffer‐ and plasma‐based systems.
Results
mAb2F22 bound exclusively to K1 of TFPI (KD ~1 nm) and not to K2. The crystal structure of Fab2F22/TFPI (1‐79) mapped an epitope on K1 including seven residues upstream of the domain. TFPI inhibition of TF/FVIIa amidolytic activity was neutralized by mAb2F22, although the binding epitope on K1 did not include the P1 residue. Binding of mAb2F22 to K1 blocked TFPI inhibition of the FXa amidolytic activity and normalized hemostasis in hemophilia human A‐like plasma and whole blood.
Conclusion
mAb2F22 blocked TFPI inhibition of both FVIIa and FXa activities and mapped a FXa exosite for binding to K1. It reversed TFPI feedback inhibition of TF/FVIIa‐induced coagulation and restored clot formation in FVIII‐neutralized human plasma and blood.
Objective
The appearance of anti–citrullinated protein antibodies (ACPAs) in the circulation represents a major risk factor for developing rheumatoid arthritis (RA). Patient‐derived ACPAs have been ...shown to induce pain and bone erosion in mice, suggesting an active role in the pathogenicity of RA. We undertook this study to investigate whether ACPAs can induce tenosynovitis, an early sign of RA, in addition to pain and bone loss and whether these symptoms are dependent on peptidyl arginine deiminase 4 (PAD4).
Methods
Monoclonal ACPAs generated from plasma cells of RA patients were transferred to wild‐type and PAD4‐deficient mice. Pain‐like behavior and macroscopic inflammation were monitored for a period of 4 weeks, followed by the analyses of tenosynovitis in the ankle joints using magnetic resonance imaging (MRI) and bone microarchitecture in the tibia using an X‐ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections.
Results
The combination of 2 monoclonal ACPAs (1325:04C03 and 1325:01B09) induced long‐lasting pain‐like behavior and trabecular bone loss in mice. Although no synovitis was observed macroscopically, we detected tenosynovitis in the ACPA‐injected mice by MRI. Microscopic analyses of the joints revealed a cellular hyperplasia and a consequent enlargement of the tendon sheath in the ACPA‐treated group. In PAD4−/− mice, the effects of ACPAs on pain‐like behavior, tenosynovitis, and bone loss were significantly reduced.
Conclusion
Monoclonal ACPAs can induce tenosynovitis in addition to pain and bone loss via mechanisms dependent on PAD4‐mediated citrullination.
To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes.
Data were obtained for 520,392 children and adults with type 1 diabetes ...from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA
(IQR) and proportions of individuals with HbA
< 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA
< 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA
category compared to previous estimates were calculated.
Median HbA
varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA
< 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA
< 58 mmol/l (<7.5%) increased and proportions of people with HbA
≥ 75 mmol/mol (≥9.0%) decreased.
Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.
Baleen from mysticete whales is a well-preserved proteinaceous material that can be used to identify migrations and feeding habits for species whose migration pathways are unknown. Analysis of δ
C ...and δ
N values from bulk baleen have been used to infer migration patterns for individuals. However, this approach has fallen short of identifying migrations between regions as it is difficult to determine variations in isotopic shifts without temporal sampling of prey items. Here, we apply analysis of δ
N values of amino acids to five baleen plates belonging to three species, revealing novel insights on trophic position, metabolic state and migration between regions. Humpback and minke whales had higher reconstructed trophic levels than fin whales (3.7-3.8 versus 3-3.2, respectively) as expected due to different feeding specialization. Isotopic niche areas between baleen minima and maxima were well separated, indicating regional resource use for individuals during migration that aligned with isotopic gradients in Atlantic Ocean particulate organic matter. Phenylanine δ
N values confirmed regional separation between the niche areas for two fin whales as migrations occurred and elevated glycine and threonine δ
N values suggested physiological changes due to fasting. Simultaneous resolution of trophic level and physiological changes allow for identification of regional migrations in mysticetes.
Damage-associated molecular pattern molecules (DAMPs) are endogenous molecules that are constitutively expressed and released upon tissue damage, resulting in activation of the immune system. In the ...absence of injury or infection, DAMPs play important intracellular roles. However, once released subsequent to cell damage or cell stress, DAMPs promote activation of innate immune cells and recruitment and activation of antigen-presenting cells engaged in host defense and tissue repair. This process involves pattern recognition receptors, such as the Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE). Several of the TLRs and RAGE have been implicated to play key roles not only in the detection of injury but also in pain signaling. Pain-like behavior is reduced in TLR2- and TLR4-deficient mice, and after injection of TLR2-, TLR4-, and RAGE antagonists in experimental models of nerve injury, arthritis, and bone cancer pain. This suggests that the pathological processes in these models are associated with release of endogenous TLR and RAGE ligands, and further that DAMPs play an important role in persistent pain. There is now a rapidly growing list of DAMPs in the literature and here we give an overview of DAMPs that have been associated with nociceptive signaling.
PDF
