Process In Rheumatoid Arthritis Research Articles

Patients Journey Before Early Rheumatoid Arthritis Diagnosis Contributes to disease's Activity Level: A Real-Life Study.

The help-seeking process in rheumatoid arthritis (RA) patients is challenging, and its study is limited in Latin America. The study describes the real-life journey before patients' incorporation into an early arthritis clinic (EAC) and its impact on baseline and 1-year cumulative disease activity levels. The patient's journey was assessed through a questionnaire that captured the patient's path from the first disease-related symptom to the initial assessment in the EAC. A disease activity (28 joints evaluated)-erythrocyte sedimentation rate (DAS28-ESR) score >5.1 defined a high-disease activity level. The mean of individual consecutive DAS28-ESR scores summarized cumulative DAS28-ESR. Multiple logistic regression analysis identified factors associated with a DAS28-ESR score >5.1 at the first assessment. Linear regression analysis assessed the impact of general practitioner (GP)-first consultant and time on disease-modifying antirheumatic drugs (DMARDs) on baseline and cumulative DAS28-ESR scores. Through January 2023, the EAC had 241 RA patients, among whom 209 (86.7%) completed the patients' journey questionnaire (PJQ) and 176 (84.2%) at least 1 year of follow-up. A GP was the first consultant in 76.6% of the patients, and only 12.4% were prescribed DMARDs. Patients had additional evaluations with either rheumatologists (38.6%) or other specialists (31.6%), and half of them were initiated DMARDs. GP-first consultant (adjusted odds ratio: 2.314, 95% confidence interval: 1.190-4.500, p = 0.013) and time on DMARDs (adjusted odds ratio: 0.738, 95% confidence interval: 0.585-0.929, p = 0.010) were associated with baseline DAS28-ESR score >5.1. The B coefficient magnitudes for GP-first consultant and time on DMARDs to predict cumulative DAS28 progressively decreased during the first year of follow-up. Patients' journey before recent-onset RA diagnosis predicts first-year disease activity levels.

Phosphoproteomic profiling of early rheumatoid arthritis synovium reveals active signalling pathways and differentiates inflammatory pathotypes

BackgroundKinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level.MethodsWe validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics.ResultsDifferential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis.ConclusionsSpecific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.

КЛИНИЧЕСКИЙ СЛУЧАЙ АКРОМЕГАЛИИ У ПАЦИЕНТКИ С РЕВМАТОИДНЫМ АРТРИТОМ

Abstract. Introduction. Acromegaly prevalence is 4.6 cases per 1 million person-years, and its rate is 116.9 new cases per 1 million person-years. At the same time, acromegaly manifestations can be insidious, and despite advances in this area, there are significant delays in the diagnosis of the disease, thereby worsening the prognosis for patients. Aim. To study the clinical course of acromegaly in a female patient with rheumatoid arthritis. Materials and Methods. This article presents a clinical case of a 47-year-old female patient with the proven diagnoses of rheumatoid arthritis and acromegaly. Results and Discussion. Essentially, pathological process in rheumatoid arthritis is systemic autoimmune inflammation that most intensively affects the synovial membrane of joints with maximum intensity. Acromegaly-related arthropathy is a non-inflammatory disease, in which hypertrophy and hyperplasia of cartilage lead to the joint geometry perturbations and metabolic disorders in chondrocytes and, eventually, to degenerative changes. This clinical case is interesting, given the coexistence of two severe diagnoses that have a similar clinical picture of musculoskeletal damages. Conclusions. Related to the findings from this clinical case, attention should be paid to the importance of timely diagnosing acromegaly, considering potential influence of concomitant pathology on the clinical course of the disease

Modeling of rheumatoid arthritis is accompanied by a change in the cortico-papillary ratio of hyaluronidase activity of the kidneys

Background. Rheumatoid arthritis is a disease that is accompanied by impaired kidney function in most patients, which attracts the attention of researchers to this problem. Both in the joints and in the kidneys, hyaluronic acid plays an important role, the degree of polymerization of which depends on the functioning of these organs. The degradation of hyaluronic acid by hyaluronidases may be a factor involved in the development of the inflammatory process in rheumatoid arthritis as well as in the realization of osmoregulatory functions of the body. In this regard, the purpose of this work was to find out whether the development of this pathology can affect on the hyaluronidase activity in the kidneys. THE AIM: to clarify is in the experiment formation of inflammatory changes in the joints accompanied by a change in the cortico-papillary ratio of hyaluronidase activity in the kidneys.Materials and Methods. A model of rheumatoid arthritis was created in Wistar rats by a single administration of a complete Freund adjuvant. After 7 weeks after injection, the degree of pathological changes in the joints was assessed by radiographic method and the hyaluronidase activity in various kidney zones was determined using zymography.Results. It was revealed that in the cortex and papillary zone of the kidneys, hyaluronidase activity was characteristic of proteins with a molecular weight of 63 and 73 kDa. It has been shown that the development of the inflammatory process is accompanied by a change in the corticopapillary ratio of hyaluronidase activity in the kidneys. In the papillary zone, a decrease in hyaluronidase activity was observed, on average, by 1.6 times, while in the renal cortex, hyaluronidase activity increased by 1.5 times.Conclusion. Such a redistribution of hyaluronidase activity in the cortical and papillary zones of the kidneys in rheumatoid arthritis can lead to a decrease in the effectiveness of the mechanism of osmotic concentration of urine and impaired kidney function.

CX-4945 inhibits fibroblast-like synoviocytes functions through the CK2-p53 axis to reduce rheumatoid arthritis disease severity

Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.

The monocyte cell surface as a novel site of autoantigen generation in Rheumatoid Arthritis

Abstract Citrullination is recognized as a key pathogenic process in rheumatoid arthritis (RA), as evidenced by the formation of anti-citrullinated protein antibodies (APCAs) in the majority of patients; however, the mechanisms that result in citrullinated autoantigen generation are not fully understood. Although the citrullinating enzyme peptidylarginine deiminase IV (PAD4) is predominantly expressed by neutrophils and monocytes, the contribution of monocytes to the citrullinated autoantigen pool has been underexplored. In this study, we utilized multiple complementary methods including flow cytometry, immunofluorescence, and transmission electron microscopy, which revealed a predominantly extranuclear localization of PAD4 in monocytes with a fraction present on the cell surface. Surface PAD4 was enzymatically active and citrullinated both extracellular fibrinogen and endogenous surface proteins in a calcium dose–dependent manner. In addition, human monoclonal ACPAs cloned from patients with RA recognized fibrinogen citrullinated by monocyte-surface PAD4. Mass spectrometry analysis of citrullinated proteins from the cell surface fraction revealed CD11b to be a novel PAD4 substrate. Citrullinated CD11b was recognized by autoantibodies in 60% of ACPA+ RA patients compared to 6% of healthy controls (p=0.0021) and 0% of ACPA− RA patients (p≤0.001). Taken together, our study demonstrates that PAD4 is expressed on the surface of monocytes in an enzymatically active state that renders the monocyte surface a novel site of citrullinated autoantigen generation in RA. Supported by funds received from Bristol-Myers Squibb.

Disruption of endothelial glycocalyx in patients with rheumatoid arthritis

BACKGROUND: Endothelial glycocalyx has an important role in the regulation of endothelial functioning. It is the first to be damaged during the development of autoimmune inflammatory diseases. Thinning of endothelial glycocalyx leads to a violation of the barrier function of blood vessels, the development and maintenance of the inflammatory process. In this context, using endothelial glycocalyx assessment for diagnostic and monitoring of diseases is considered of great interest.
 AIM: To establish the relationship between endothelial glycocalyx thickness with activity, serological profile and risk factors for an unfavorable course of rheumatoid arthritis.
 MATERIALS AND METHODS: The study included 76 patients from 18 to 65 years of both sexes with rheumatoid arthritis. The perfusion boundary region of endothelial glycocalyx determined using a dark-field microscope has been used as the main indicator for assessing the state of endothelial glycocalyx.
 RESULTS: The obtained results have demonstrated a decrease in the initial endothelial glycocalyx thickness in females in the presence of risk factors for an unfavorable course of rheumatoid arthritis. At the same time, no relationship with the serological profile and endothelial glycocalyx thickness has been found. An inverse correlation between endothelial glycocalyx thickness and syndecan-1 level and erythrocyte sedimentation rate has been found. This confirms the fact that endothelial glycocalyxes are involved in the inflammatory process in rheumatoid arthritis. Endothelial glycocalyx assessment using dark-field microscopy made it possible to predict the subsequent appointment of pulse therapy with methylprednisolone in the hospital. On re-examination, endothelial glycocalyx thinning has been observed in the presence of unfavorable risk factors for the course of rheumatoid arthritis, in negative to anti-cyclic citrullinated peptide antibodies patients, or in the absence of response to treatment.
 CONCLUSIONS: The use of dark-field microscopy is unique in its capabilities for intravital and non-invasive assessment of endothelial glycocalyx thickness. It provides important fundamental information deepening knowledge in the pathological physiology of disease. From a clinical point of view, it allows to consider a decrease in endothelial glycocalyx thickness as an additional prognostically unfavorable marker in rheumatoid arthritis.

The Immunomodulatory and Anti-Inflammatory Effect of Curcumin on Immune Cell Populations, Cytokines, and In Vivo Models of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a widespread chronic autoimmune disorder affecting the joints, causing irreversible cartilage, synovium, and bone degradation. During the course of the disease, many immune and joint cells are activated, causing inflammation. Immune cells including macrophages, lymphocytes, neutrophils, mast cells, natural killer cells, innate lymphoid cells, as well as synovial tissue cells, like fibroblast-like synoviocytes, chondrocytes, and osteoclasts secrete different proinflammatory factors, including many cytokines, angiogenesis-stimulating molecules and others. Recent studies reveal that curcumin, a natural dietary anti-inflammatory compound, can modulate the response of the cells engaging in RA course. This review comprises detailed data about the pathogenesis and inflammation process in rheumatoid arthritis and demonstrates scientific investigations about the molecular interactions between curcumin and immune cells responsible for rheumatoid arthritis development to discuss this herbal drug’s immunoregulatory role in RA treatment.

Prediction of disease flare by biomarkers after discontinuing biologics in patients with rheumatoid arthritis achieving stringent remission

To elucidate the disease-flare process in rheumatoid arthritis (RA) after discontinuing biological disease-modifying antirheumatic drugs (bDMARDs), we first focused on RA-flare prediction after achieving stringent remission criteria. Patients with RA who maintained a simplified disease activity index ≤ 3.3 for ≥ 3 months during November 2014–January 2018 in our medical centre in Tokyo, Japan, were eligible. The primary endpoint was flare (disease activity score 28—erythrocyte sedimentation rate ≥ 3.2 with increase from baseline > 0.6) within 2 years after bDMARD discontinuation. Comprehensive clinical assessments, ultrasonographic evaluation of 40 joints, and blood sampling for 12 biomarkers were performed every 2–3 months for 2 years unless patients experienced flare. Flare-positive and flare-negative patients were compared using univariate and Kaplan–Meier analyses. Thirty-six patients (80.6% female, median disease duration, 5.2 years; median treatment period with discontinued bDMARD, 2 years; median remission duration, 18 months) were enrolled. Twenty patients (55.6%) experienced RA flare 43–651 (median, 115) days after the first skipped date of bDMARDs. Two patients who withdrew without disease flare were excluded from the comparison. Clinical and ultrasonographic evaluations did not show significant between-group differences; Kaplan–Meier analysis showed that higher baseline soluble tumour necrosis factor receptor 1 (sTNFR1) concentration impacted subsequent disease flare (p = 0.0041); higher baseline interleukin (IL)-2 concentration was exclusively beneficial to patients with lower sTNFR1 (p = 0.0058), resulting in remission maintenance in 83.3% of patients with lower sTNFR1 and higher IL-2. We demonstrated the usefulness of combined biomarker evaluation for predicting sustained remission after bDMARD discontinuation in RA.

Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing.

Rheumatoid arthritis is a chronic, systemic joint disease in which an autoimmune response translates into an inflammatory attack resulting in joint damage, disability and decreased quality of life. Despite recent introduction of therapeutic agents such as anti-TNFα, even the best current therapies fail to achieve disease remission in most arthritis patients. Therefore, research into the mechanisms governing the destructive inflammatory process in rheumatoid arthritis is of great importance and may reveal novel strategies for the therapeutic interventions. To gain deeper insight into its pathogensis, we have developed for the first time a three-dimensional synovium-on-a-chip system in order to monitor the onset and progression of inflammatory synovial tissue responses. In our study, patient-derived primary synovial organoids are cultivated on a single chip platform containing embedded organic-photodetector arrays for over a week in the absence and presence of tumor-necrosis-factor. Using a label-free and non-invasive optical light-scatter biosensing strategy inflammation-induced 3D tissue-level architectural changes were already detected after two days. We demonstrate that the integration of complex human synovial organ cultures in a lab-on-a-chip provides reproducible and reliable information on how systemic stress factors affect synovial tissue architectures.

Macrophage migration inhibitory factor promoter polymorphisms are associated with disease activity in rheumatoid arthritis patients from Southern Mexico.

BackgroundMacrophage migration inhibitory factor (MIF) is a cytokine capable of stimulating inflammatory cytokine and matrix metalloproteinase production from macrophages and synovial fibroblasts, which leads to persistent inflammation and bone degradation, two of the major pathological processes in rheumatoid arthritis (RA). The aim of this study was to evaluate the association of MIF promoter polymorphisms (−794CATT5‐8 rs5844572 and −173G > C, rs755622), circulating MIF levels, and mRNA expression with RA susceptibility and disease activity.MethodsA case–control study was conducted in 200 RA patients and 200 control subjects (CS) from Southern Mexico. Genotyping was performed by conventional PCR and PCR‐RFLP methods. MIF mRNA expression was quantified by real‐time PCR and MIF serum levels were determined by an ELISA kit.ResultsThe 7,7 (−794CATT5‐8) and −173CC (−173G > C) genotypes were associated with higher disease activity in RA patients. MIF serum levels were increased, and MIF mRNA expression was reduced in RA patients as compared to CS. In addition, RA patients with moderate disease activity had higher MIF levels than those with low disease activity. The −794CATT5‐8 and −173G > C MIF polymorphisms were not associated with RA susceptibility.ConclusionThese results suggest an important role of MIF polymorphisms and MIF serum levels with disease activity in RA.

Эффективность самоконтроля активности процесса при ревматоидном артрите в амбулаторной практике

Эффективность самоконтроля активности процесса при ревматоидном артрите в амбулаторной практике

Chemical composition of Erycibe schmidtii and antiproliferative activity of scopoletin on immature dendritic cells

Immature dendritic cells (iDCs) play very important roles in the pathological process of rheumatoid arthritis (RA). Therefore, it is urgent to search for natural products with antiproliferative activity on iDCs for anti-RA drug discovery. Erycibe schmidtii, a traditional Chinese medicine, has been used to treat RA in China. Its bioactive ingredients on RA are still unclear. In this study, twenty compounds including a new caffeoylquinic acid derivative, 3-O-caffeoyl-4-O-syringoylquinic acid methyl ester (16), were isolated from E. schmidtii. Their structures were elucidated by NMR and mass spectroscopic analysis, and comparison with literature data. Seventeen compounds were obtained from this plant for the first time, and ten were first found from the genus Erycibe. Scopoletin (1, 5.0 μM) functionally reduced proliferation level of bone marrow immature dendritic cells (BM-iDCs) more than 50%, relative to vehicle. However, scopoletin (1) exhibited no effect on the phagocytosis or survival of BM-iDCs in vitro.

Anti-arthritic properties of crude extract from Chenopodium ambrosioides L. leaves.

To evaluate the effect of hydroalcoholic crude extract (HCE) from Chenopodium ambrosioides leaves on the development of type II collagen-induced arthritis (CIA) and on pro-inflammatory cytokine balance. Collagen-induced arthritis was induced in DBA1/J mice. On the 21st day, the mice were treated orally with HCE or methotrexate, daily. Six weeks after beginning the treatment, the following measures were determined: lymphoid organs cell numbers, percentage of blood cells, IL-6, IFN-γ, TNF-α and IL-17 serum concentrations, activity of hepatic and kidney glutathione S-transferase, hepatic 7-ethoxyresorufin-O-deethylase activity, bone density and histopathology. Treatment of CIA mice with HCE 5mg/kg (HCE5) reduced the percentage of neutrophils and macrophages and the number of bone marrow cells and increased the lymphocyte numbers and the inguinal lymph node cellularity. This treatment inhibited the serum concentration of IL-6 and TNF-α, which may be related to the preservation of bone density and to the slight thickening of periarticular tissues, with minimal fibrosis and fibroblast proliferation in the joints. The CIA group presented advanced articular erosion and synovial hyperplasia. Phytochemical analysis showed mainly flavonols. HCE5 presented anti-arthritic potential and reduced IL-6 and TNF-α, which participate directly in the development and maintenance of the inflammatory process in rheumatoid arthritis.

Sex-based differences in association between circulating T cell subsets and disease activity in untreated early rheumatoid arthritis patients

BackgroundIt is not known if sex-based disparities in immunological factors contribute to the disease process in rheumatoid arthritis (RA). Hence, we examined whether circulating T cell subset proportions and their association with disease activity differed in male and female patients with untreated early rheumatoid arthritis (ueRA).MethodsProportions of T cell subsets were analyzed in peripheral blood from 72 ueRA DMARD- and corticosteroid-naïve patients (50 females and 22 males) and in 31 healthy age- and sex-matched controls. Broad analysis of helper and regulatory CD4+ T cell subsets was done using flow cytometry. Disease activity in patients was assessed using DAS28, CDAI, swollen joint counts, tender joint counts, CRP, and ESR.ResultsMultivariate factor analyses showed that male and female ueRA patients display distinct profiles of association between disease activity and circulating T cell subset proportions. In male, but not female, ueRA patients Th2 cells showed a positive association with disease activity and correlated significantly with DAS28-ESR, CDAI, and swollen and tender joint counts. Likewise, proportions of non-regulatory CTLA-4+ T cells associated positively with disease activity in male patients only, and correlated with DAS28-ESR. In contrast, there was a negative relation between Th1Th17 subset proportions and disease activity in males only. The proportions of Th17 cells correlated positively with DAS28-ESR in males only, while proportions of Th1 cells showed no relation to disease activity in either sex. There were no significant differences in proportions of T cell subsets between the sexes in patients with ueRA.ConclusionsOur findings show sex-based differences in the association between T cell subsets and disease activity in ueRA patients, and that Th2 helper T cells may have a role in regulating disease activity in male patients.

Vagus Nerve Stimulation

Treatments for psoriasis and psoriatic arthritis have progressed at a rapid rate over the past 20 years, but treating patients with recalcitrant disease still remains a difficult task. Current therapies for these diseases involve topical agents, phototherapy, and systemic immunosuppression. However, the role of the nervous system in psoriasis and psoriatic arthritis remains largely unexplored. Recent animal studies and clinical trials have demonstrated that vagus nerve stimulation can decrease inflammatory processes in rheumatoid arthritis and inflammatory bowel disease. In this article, we outline the existing knowledge of the nervous system’s role in chronic inflammatory disease and discuss how these findings could be utilized in the future for treatment of psoriasis and psoriatic arthritis.

THE ROLE OF VITAMINS IN THE TREATMENT OF RHEUMATOID ARTHRITIS

It is well known that the inflammatory process in rheumatoid arthritis (RA) is mediated by free radicals. Antioxidant vitamins can neutralize oxidative cell damage, so they suggested alleviate symptoms and prevent progression of RA. This article provides an overview of a current literature about clinical role of the antioxidant vitamins in patients with RA. In general, only a few clinical trials focused on this issue, and just a high dose vitamin E supplementation demonstrated moderate clinical efficacy in RA. On the other hand, convincing evidence exist that Mediterranean diet, rich in antioxidants, may reduce inflammatory activity, increase physical functioning and improve general well-being. In conclusion, patients with RA should follow antioxidant-rich diet (grains, fruits, vegetables) rather than take vitamin supplementation.

Elevated IgA Plasmablast Levels in Subjects at Risk of Developing Rheumatoid Arthritis.

The disease process in rheumatoid arthritis (RA) starts years before the clinical diagnosis is made, and elevated levels of disease-specific autoantibodies can be detected during this period. Early responses to known or novel autoantigens likely drive the eventual production of pathogenic autoimmunity. Importantly, the presence of disease-specific autoantibodies can identify individuals who are at high risk of developing RA but who do not currently have arthritis. The goal of the current study was to characterize plasmablasts from individuals at risk of developing RA. We investigated antibody-secreting plasmablasts derived from a well-characterized cohort of individuals who were at risk of developing RA, based on RA-related serum autoantibody positivity, as compared to patients with early (<1 year) seropositive RA as well as healthy control subjects. The plasmablast antibody repertoires of at-risk subjects were analyzed using DNA barcode-based methods with paired heavy- and light-chain gene sequencing. Cells were single-cell sorted, the cell- and plate-specific DNA barcodes were sequentially added, and next-generation sequencing was performed. Total plasmablast levels were similar in the antibody-positive (1%) and control (0.4-1.6%) groups. However, increased frequencies of IgA+ versus IgG+ plasmablasts were observed in the antibody-positive group (39% IgA+ and 37% IgG+) as compared to other groups (1-9% IgA+ and 71-87% IgG+). Paired antibody sequences from antibody-positive subjects revealed cross-isotype clonal families and similar sequence characteristics in the IgA and IgG plasmablast repertoires. Antibody-positive individuals also demonstrated elevated serum levels of IgA isotype anti-cyclic citrullinated peptide 3 antibodies. The IgA plasmablast dominance in these antibody-positive individuals suggests that a subset of RA-related autoantibodies may arise from mucosal immune responses and may be involved in early disease pathogenesis in individuals who are at risk of developing RA.

NLRP3 and CARD8 Polymorphisms Influence Higher Disease Activity in Rheumatoid Arthritis.

SummaryBackgroundThe activation of NLRP3-inflammasome may contribute to inflammatory processes in rheumatoid arthritis (RA). Functional polymorphisms in the genes coding for its components NLRP3 and CARD8 were associated with a proinflammatory phenotype. Our aim was to investigate the influence of these polymorphisms on RA susceptibility and disease activity at the time of diagnosis and after six months of treatment.MethodsA group of 128 RA patients treated with methotrexate and 122 healthy controls were genotyped for NLRP3 rs35829419 (p. Q705K) and CARD8 rs2043211 (p. C10X) polymorphisms.ResultsRA susceptibility was not influenced by the investigated polymorphisms or their interaction. The investigated polymorphisms explained 8% of variability in DAS28 at the time of diagnosis. Carriers of NLRP3 rs35829419 or CARD8 rs2043211 polymorphisms had significantly higher DAS28 at the time of diagnosis (p=0.003; p=0.022; respectively). Polymorphic CARD8 rs2043211 TT genotype was also associated with higher DAS28 after six months of treatment (p=0.033).ConclusionsGenetic variability of inflammasome components may contribute to higher disease activity at the time of diagnosis and after 6 months of methotrexate treatment in RA patients. Better understanding of the immunological mechanisms behind a more active course of RA may suggest novel treatment approaches in a subset of patients with a proinflammatory phenotype.

Cartilage destruction in rheumatoid arthritis, its association with functional impairments

The paper discusses the mechanisms of destructive processes in rheumatoid arthritis (RA). At the present stage, in addition to suppress inflammation, the goals of treatment are to prevent cartilage and bone destruction in the affected joints. Prediction of destructive processes in RA plays an important role as the irreversibility of functional changes in RA directly correlates with the degree of joint injury. The paper discusses the mechanisms of articular cartilage and bone destruction and the significance of different biochemical markers for estimating the degree of injury and for predicting further destruction of small hand and foot joints. In RA, the investigators identify not only clinical (activity indicators), but also biological (bone, cartilage, and synovium damage markers) predictors for joint injury: CТXII is a marker for cartilage degradation (collagen type II) and CTXI is a marker for bone degradation (collagen type I) and their trends over 4–12 or more weeks. Although the occurrence of erosions is considered to be a major manifestation of joint destruction progression in RA, the functional activity in its early stages is shown to depend on the estimate of joint space narrowing (cartilage degradation) to a greater extent than on that of erosions when evaluating the destruction by the modified Sharp method. Several randomized placebocontrolled studies (RPCSs) have assessed the association of patients' functional capacity with joint space narrowing or with the number of erosions. In RA, cartilage degradation has been demonstrated to play a larger role in irreversible function loss than bone destruction. The possibility of suppressing cartilage degradation, which is indicated in RPCSs of the efficacy of adalimumab, correlates with a better functional outcome in patients with RA. Serum markers for cartilage metabolism may be not only predictors for further radiographic progression, but also be used to evaluate therapeutic effectiveness.