Splenectomy at early stage of autoimmune arthritis delayed inflammatory response and reduced joint deterioration in mice.

The spleen plays a role in innate and adaptive immunity, and autoimmune diseases like rheumatoid arthritis (RA). We investigated the effect of splenectomy in early and moderate stages of autoimmune arthritis in a mouse model. To induce recombinant human G1-induced arthritis (GIA), BALB/c mice were immunized intraperitoneally three times in 4-week intervals with the rhG1 antigen. Mice were splenectomized on day 7 (SPE1) or day 35 (SPE2) after the initiation of immunization; tested for clinical severity, joint radiological and histological changes, serum levels of inflammatory cytokines and autoantibodies, and rhG1-specific immune responses; and compared to those in control mice with spleen left intact. Circulating Tregs and T-helper subset ratios in the spleen and inguinal lymph nodes (LNs) were also examined using flow cytometry. The onset of severe inflammatory response was significantly delayed in SPE1 and SPE2 groups compared to control mice at early stages of GIA, which was associated with increased circulating Tregs. After the third immunization, as disease progressed, the severity scores were robustly increased in all mice. Nevertheless, in splenectomized mice, we observed reduced joint deterioration and cartilage damage, more Th2 cells in LNs, and reduced levels of pro-inflammatory cytokines and autoantibodies in their sera. Mesenteric LN cells of splenectomized mice exhibited weaker response in vitro against the rhG1 antigen compared to control mice spleen. In conclusion, splenectomy in the early stages of GIA delayed the inflammatory response, suggesting a protective effect against the development and progression of severe destructive arthritis.

Inhibition of the TIM-1 and -3 signaling pathway ameliorates disease in a murine model of rheumatoid arthritis.

Members of the T-cell immunoglobulin and mucin (TIM) family, which is crucial for T-cell function, are implicated in autoimmunity. TIM-1 and -3 play distinct roles in autoimmunity, with TIM-1 acting as a costimulatory molecule and TIM-3 regulating Th1 responses. We investigated the therapeutic potential of anti-TIM-1 (RMT1-10) and anti-TIM-3 (RMT3-23) antibodies in an autoimmune arthritis model. Zymosan A was used to induce arthritis in female SKG mice. The arthritis scores, histology, mRNA expression, cytokine levels, micro-computed tomography, and flow cytometry results were obtained. The application of RMT1-10 reduced the arthritis scores, histological damage, and CD4+ T-cell infiltrations, and it suppressed interleukin (IL)-6 and -17A and reduced TIM-3 mRNA expressions. RMT3-23 also lowered arthritis severity, improved histology, and reduced serum levels of tumor necrosis factor (TNF)-α and IL-17A. RMT3-23 inhibited intracellular TNF-α and IL-6 and early apoptosis. An amelioration of autoimmune arthritis was achieved by blocking the TIM-1 and -3 signaling pathways via RMT1-10 and RMT3-23 administration, leading to a widespread decrease in inflammatory cytokines. Both antibodies exhibited therapeutic effects, suggesting TIM-1 and -3 as potential targets for rheumatoid arthritis.

Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade.

Sustained inflammatory invasion leads to joint damage and progressive disability in several autoimmune rheumatic diseases. In recent decades, targeting M1 macrophage polarization has been suggested as a promising therapeutic strategy for autoimmune arthritis. P300/CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) that exhibits a strong positive relationship with the proinflammatory microenvironment. However, whether PCAF mediates M1 macrophage polarization remains poorly studied, and whether targeting PCAF can protect against autoimmune arthritis in vivo remains unclear. Commonly used drugs can cause serious side effects in patients because of their extensive and nonspecific distribution in the human body. One strategy for overcoming this challenge is to develop drug nanocarriers that target the drug to desirable regions and reduce the fraction of drug that reaches undesirable targets. In this study, we demonstrated that PCAF inhibition could effectively inhibit M1 polarization and alleviate arthritis in mice with collagen-induced arthritis (CIA) via synergistic NF-κB and H3K9Ac blockade. We further designed dextran sulfate (DS)-based nanoparticles (DSNPs) carrying garcinol (a PCAF inhibitor) to specifically target M1 macrophages in inflamed joints of the CIA mouse model via SR-A-SR-A ligand interactions. Compared to free garcinol, garcinol-loaded DSNPs selectively targeted M1 macrophages in inflamed joints and significantly improved therapeutic efficacy in vivo. In summary, our study indicates that targeted PCAF inhibition with nanoparticles might be a promising strategy for treating autoimmune arthritis via M1 macrophage polarization inhibition.

Splenectomy modulates the immune response but does not prevent joint inflammation in a mouse model of RA.

The spleen is the largest secondary lymphoid organ which is involved in the development of B cells and also in systemic (auto)immune responses. Using the recombinant human G1 domain-induced arthritis (GIA) model in splenectomized and control BALB/c mice, we investigated the role of the spleen in the induction and pathogenesis of autoimmune arthritis. Splenectomized mice developed GIA with a similar clinical picture to the control group. However, we observed significant alterations in the humoral and cellular immune responses in splenectomized mice. In the sera of the splenectomized mice, we found lower pro-inflammatory cytokine and anti-rhG1 IgM levels, but higher IL-4, anti-rhG1 IgG1 and anti-CCP and RF antibodies. The arthritis induction in the splenectomized group was associated with a significant expansion of activated helper T cells and an increase in the proportion of the circulating B1 and marginal zone B cell subsets. Importantly, immunization of the splenectomized mice with rhG1 induced the formation of germinal centers in the inguinal- and mesenteric lymph nodes (i/mLNs) which showed an active immune response to rhG1. Finally, both B and T cells from the mLNs of the splenectomized mice showed decreased intracellular Ca2+ signaling than those of the control group. Collectively, these findings indicate that the presence of the spleen is not critical for the induction of GIA, and in its absence the autoimmune arthritis is most likely promoted through the compensatory activity of the i/mLNs. However, our data implies the immunological role of the spleen in arthritis which could be further assessed in human RA.

RORγt+Foxp3+ regulatory T cells in the regulation of autoimmune arthritis.

RORγt+Foxp3+regulatory T (Treg) cells, known as T regulatory 17 cells (Tr17 cells), are a novel subset of Treg cells, which have the potential to regulate the development of experimental autoimmune encephalomyelitis (EAE) thorough a specific repression of T helper 17 (Th17) cell-mediated inflammation. However, the function of Tr17 cells the development of other autoimmune diseases such as autoimmune arthritis remains unclear. Collagen-induced arthritis (CIA) was found to be prolonged in Foxp3creRORγtfl/fl mice, in which Tr17 cells were deleted, compared with Foxp3wtRORγtfl/fl mice. Tr17 cells were significantly increased in ankle joints (AJ) compared with draining lymph nodes after the onset of arthritis. CC chemokine receptor 6 (CCR6) was up-regulated on Tr17 cells compared to RORγt negative Treg cells. CD25, cytotoxic T-lymphocyte antigen 4 (CTLA-4), glucocorticoid-induced TNF-receptor (GITR), and inducible T-cell co-stimulator (ICOS) expression was also up-regulated on Tr17 cells compared to RORγt negative Treg cells. IL-10-producing cells and Blimp-1+ and T-bet+ cells were increased in Tr17 cells compared to RORγt-negative Treg cells. Tr17-enriched Treg cells significantly suppressed proliferation of conventional T cells through IL-10 compared with CCR6-Treg cells. Tr17 cells increased during the clinical course of CIA and accumulated in inflamed joints. Taken together, it appears that Tr17 cells play a crucial role in the regulation of autoimmune arthritis.

Osteoimmunology as an intrinsic part of immunology.

Osteoimmunology has emerged as a field linking immunology and bone biology, but it has yet to be recognized as belonging to mainstream immunology. However, the extent of the research fields immunology actually covers has been enormously widened, and it is now ready to include such an interdisciplinary subject. One of the most obvious examples of an interaction between the immune and bone systems is the pathogenesis of rheumatoid arthritis, where bone resorption is increased by the autoimmune response. Moreover, the regulation of the immune system by bone cells has been clearly demonstrated by the finding that osteoprogenitor cells contribute to hematopoietic stem cell maintenance as well as the suppression of hematopoietic malignancy. Thus, the bidirectional dialogue has been established and inevitably will lead to the union of bone and immunity. Here, I summarize the history and concept of osteoimmunology, providing a perspective on the future of immunology.

Membrane-bound IL-6R is upregulated on Th17 cells and inhibits Treg cell migration by regulating post-translational modification of VASP in autoimmune arthritis.

Autoimmune arthritis is characterized by impaired regulatory T (Treg) cell migration into inflamed joint tissue and by dysregulation of the balance between Treg cells and Th17 cells. Interleukin-6 (IL-6) is known to contribute to this dysregulation, but the molecular mechanisms behind impaired Treg cell migration remain largely unknown. In this study, we assessed dynamic changes in membrane-bound IL-6 receptor (IL6R) expression levels on Th17 cells by flow cytometry during the development of collagen-induced arthritis (CIA). In a next step, bioinformatics analysis based on proteomics was performed to evaluate potential pathways affected by altered IL-6R signaling in autoimmune arthritis. Our analysis shows that membrane-bound IL-6R is upregulated on Th17 cells and is inversely correlated with IL-6 serum levels in experimental autoimmune arthritis. Moreover, IL-6R expression is significantly increased on Th17 cells from untreated patients with rheumatoid arthritis (RA). Interestingly, CD4+ T cells from CIA mice and RA patients show reduced phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Bioinformatics analysis based on proteomics of CD4+ T cells with low or high phosphorylation levels of VASP revealed that integrin signaling and related pathways are significantly enriched in cells with low phosphorylation of VASP. Specific inhibition of p-VASP reduces the migratory function of Treg cells but has no influence on effector CD4+ T cells. Importantly, IL-6R blockade restores the phosphorylation level of VASP, thereby improving the migratory function of Treg cells from RA patients. Thus, our results establish a link between IL6R signaling and phosphorylation of VASP, which controls Treg cell migration in autoimmune arthritis.

Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca2+ Influx in Nkx2-3 Knock-out Mice.

B cells play a crucial role in the pathogenesis of rheumatoid arthritis. In Nkx2-3-deficient mice (Nkx2-3-/-) the spleen's histological structure is fundamentally changed; therefore, B cell homeostasis is seriously disturbed. Based on this, we were curious, whether autoimmune arthritis could be induced in Nkx2-3-/- mice and how B cell activation and function were affected. We induced arthritis with immunization of recombinant human proteoglycan aggrecan G1 domain in Nkx2-3-/- and control BALB/c mice. We followed the clinical picture, characterized the radiological changes, the immune response, and intracellular Ca2+ signaling of B cells. Incidence of the autoimmune arthritis was lower, and the disease severity was milder in Nkx2-3-/- mice than in control BALB/c mice. The radiological changes were in line with the clinical picture. In Nkx2-3-/- mice, we measured decreased antigen-induced proliferation and cytokine production in spleen cell cultures; in the sera, we found less anti-CCP-IgG2a, IL-17 and IFNγ, but more IL-1ß, IL-4 and IL-6. B cells isolated from the lymph nodes of Nkx2-3-/- mice showed decreased intracellular Ca2+ signaling compared to those isolated from BALB/c mice. Our findings show that the transcription factor Nkx2-3 might regulate the development of autoimmune arthritis most likely through modifying B cell activation.

Cytology of synovial fluid.

Examination of synovial fluid from swollen and painful joints can contribute substantially to the diagnosis of joint diseases. After a skillful arthrocentesis the sample processing must follow swiftly, because the synovial fluid can not be effectively fixed due to its viscosity. The viscosity test and cellularity assessment with particular reference to the neutrophilic granulocyte fraction, as well as the examination of the native preparation in polarized light, are some specific steps in the processing of these samples. Diagnostic images include traumaticinfectiousand autoimmune arthritides, arthropaties associated with crystals and, least often, with tumors. Conclusion: The cytological examination of synovial fluid has its own pre-analytical and analytical characteristics. Respecting and supplementing them with nonmorphological examinations can significantly contribute to the successful treatment of pathological joint conditions.

Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T-lymphocyte antigen-4.

CD4+  Foxp3+ regulatory T (Treg) cells can control both cellular and humoral immune responses; however, when and how Treg cells play a predominant role in regulating autoimmune disease remains elusive. To deplete Treg cells in vivo at given time-points, we used a mouse strain, susceptible to glucose-6-phosphate isomerase peptide-induced arthritis (GIA), in which the deletion of Treg cells can be controlled by diphtheria toxin treatment. By depleting Treg cells in the GIA mouse model, we found that a temporary lack of Treg cells at both priming and onset exaggerated disease development. Ablation of Treg cells led to the expansion of antigen-specific CD4+ T cells including granulocyte-macrophage colony-stimulating factor, interferon-γ and interleukin-17-producing T cells, and promoted both T-cell and B-cell epitope spreading, which perpetuated arthritis. Interestingly, specific depletion of cytotoxic T-lymphocyte antigen-4 (CTLA-4) on Treg cells only, was sufficient to protect mice from GIA, due to the expansion of CTLA-4- Treg cells expressing alternative suppressive molecules. Collectively, our findings suggest that Treg cells, independently of CTLA-4, act as the key driving force in controlling autoimmune arthritis development.

Acacetin regulated the reciprocal differentiation of Th17 cells and Treg cells and mitigated the symptoms of collagen-induced arthritis in mice.

BACKGROUND AND AIM: The immune-regulative effect of acacetin on the development of autoimmune arthritis remains unexplored. This study aims to investigate the potential effect of acacetin on the treatment of collagen-induced arthritis (CIA) in mice and clarify its underlying mechanism. METHODS AND RESULTS: In a type II collagen (CII)-induced autoimmune arthritis model, acacetin significantly repressed the incidence of CIA, prevented the pathological alteration, and reduced CII-specific IgG and IgG1 levels. Flow cytometry assay suggested that the recipients of acacetin showed the expansion of Treg cells and the decreasing Th17 cells in spleen and inguinal lymph nodes after the initiation of CIA. In vitro experiment suggested that in addition to altering the pro-inflammatory production in dendritic cells, engagement of acacetin relieved the generation of Th17 cells and maintained the ratio of Treg cells under Th17-polarized condition. The addition of acacetin inhibited the T cell proliferation, as well as the expression of the transcriptional coactivator TAZ, which regulated the balance of Treg/Th17 immunity, in a dose-dependent manner. CONCLUSION: Our data demonstrated that acacetin mitigated the development of CIA and might be a potential agent for the treatment of autoimmune arthritis.

Could knee inflammatory synovitis be induced by pembrolizumab?

Pembrolizumab, a selective anti-PD-1 humanized monoclonal antibody, reactivates T cells to fight cancer. Immune-related adverse events such as autoimmune colitis, pneumonitis, hepatitis, nephritis, hypophysitis, and thyroiditis may occur during, or weeks to months after therapy. Pemprolizumab-induced synovitis is rarely reported. With the wide use of immunotherapy to treat cancers, physicians need to be aware of this rare immune-related adverse event and provide immediate treatment to avoid permanent joint damage.

Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo.

CD31, a trans-homophilic inhibitory receptor expressed on both T- and B-lymphocytes, drives the mutual detachment of interacting leukocytes. Intriguingly, T cell CD31 molecules relocate to the immunological synapse (IS), where the T and B cells establish a stable interaction. Here, we show that intact CD31 molecules, which are able to drive an inhibitory signal, are concentrated at the periphery of the IS but are excluded from the center of the IS. At this site, were the cells establish the closest contact, the CD31 molecules are cleaved, and most of the extracellular portion of the protein, including the trans-homophilic binding sites, is shed from the cell surface. T cells lacking CD31 trans-homophilic binding sites easily establish stable interactions with B cells; at the opposite, CD31 signaling agonists inhibit T/B IS formation as well as the ensuing helper T cell activation and function. Confocal microscopy and flow cytometry analysis of experimental T/B IS shows that the T cell inhibitory effects of CD31 agonists depend on SHP-2 signaling, which reduces the phosphorylation of ZAP70. The analysis of synovial tissue biopsies from patients affected by rheumatoid arthritis showed that T cell CD31 molecules are excluded from the center of the T/B cell synapses in vivo. Interestingly, the administration of CD31 agonists in vivo significantly attenuated the development of the clinical signs of collagen-induced arthritis in DBA1/J mice. Altogether, our data indicate that the T cell co-inhibitory receptor CD31 prevents the formation of functional T/B immunological synapses and that therapeutic strategies aimed at sustaining CD31 signaling will attenuate the development of autoimmune responses in vivo.

Causal Relationship Between Autoimmune Arthritis and Temporomandibular Disorders.

OBJECTIVE: Accumulating evidence has indicated a close interrelation between autoimmune arthritis (AA) and temporomandibular disorders (TMD), but the causality is still unclear. The study aimed to explore the causal inference between AA and TMD using a bidirectional Mendelian randomization analysis. METHODS: Online genome-wide association study data on rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, and TMD were obtained from the FinnGen and IEU databases. Causality was using the inverse variance-weighted method as the primary analysis and supplemented by other methods. Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, and leave-one-out methods, were conducted to investigate the stability and reliability of the results. RESULTS: The inverse variance-weighted test indicated that several AA types could causally increase the TMD risk, including overall RA (odds ratio [OR] = 1.348, 95% confidence interval [CI] = 1.1232-1.618, P = .001), subtype nRA (OR = 1.118, 95% CI = 1.044-1.197, P = .001), and AS (OR = 1.060, 95% CI = 1.024-1.097, P = .001). Moreover, the causal association of the above combinations has been proven to be stable and reliable using sensitivity and other tests. CONCLUSION: These findings suggest that RA and AS might be causally associated with an increased risk of TMD. However, more studies are needed to check the causal effects of AA on TMD and analyse the potential mechanisms further.

Causal association between sleep traits and autoimmune arthritis: Evidence from a bidirectional Mendelian randomization study.

OBJECTIVE: To explore whether there is a genetic causal relationship between sleep traits and the risk of autoimmune arthritis (AA). METHODS: Univariable and multivariable Mendelian randomization was employed using genome-wide association studies data to assess sleep traits' associations with AAs, including rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. The inverse-variance weighted method served as the primary analysis, supplemented by the CAUSE method to improve power and mitigate false positives. Mediation Mendelian randomization was used to quantify direct and indirect effects. RESULTS: Significant associations were shown between insomnia symptoms and increased risk of overall RA (odds ratio = 2.75, 95% confidence interval 1.45-5.22) and seronegative RA (odds ratio = 6.95, 95% confidence interval 2.47-19.56). CAUSE results revealed an association of insomnia symptoms with overall RA and seronegative RA, as well as the sleep duration with overall RA. After the adjustment for body mass index, alcohol status, smoking status, and physical activity levels, multivariable analyses revealed that genetic predisposition to insomnia symptoms and prolonged sleep duration showed independent negative associations with the risk of overall RA and seropositive RA. In the reversed multivariable analyses, a borderline negative association was shown in the overall RA-sleep duration and a positive association of seropositive RA with the risk of insomnia symptoms. CONCLUSION: This study demonstrated a potential bidirectional causal relationship that genetic predisposition to insomnia symptoms and shorter sleep duration was associated with the risk of AA, especially RA. Genetic predisposition to RA was also associated with decreased sleep duration, as well as increased insomnia symptom risk.

Incidence Rate of Cardiovascular Events in Rheumatoid Arthritis: An Observational Cohort Study in Saudi Arabia.

Purpose: Rheumatoid arthritis (RA) doubles the morbidity of cardiovascular disease (CVD) and leads to a 50% increase in mortality compared to the general population. This study aims to estimate the CVD incidence among RA patients in Saudi Arabia (SA), vital for assessing CVD burdens within this group. Patients and Methods: This retrospective study took place at two centers in the Eastern Province of SA, including all adult RA patients who visited the rheumatology clinic from 2016 to 2021 and were prescribed disease-modifying antirheumatic drugs (DMARDs). CVD incidence was determined by the diagnosis of ischemic heart disease (IHD), stroke/transient ischemic attack (TIA), venous thromboembolism (VTE), heart failure (HF), and arrhythmia post-RA diagnosis. Additional data collected included demographics, CVD risk factors, comorbidities, RA-related factors, and medication usage. Results: The study comprised 651 patients, 80.5% of whom were females with an average age of 51. The overall CVD incidence was 11.2 per 1000 person-years, with males experiencing five times more incidents than females. The prevalence of CVD risk factors included 18.7% with hypertension, 7.8% with hyperlipidemia, 18.9% with diabetes, and 42.9% with obesity. Significant predictors of CVD were male gender and RA duration, with adjusted odds ratios (aOR) of 3.17 (95% CI 1.10 to 9.14, P=0.033) and 64.81 (95% CI 3.68 to 1140.6, P=0.004), respectively. Conclusion: This unique study from SA examined the CVD incidence in RA patients, identifying long disease duration and male gender as significant predictors. Effective reduction of CVD risk in RA patients requires aggressive management of modifiable risk factors and regular risk assessments.

Recombinant Human Proteoglycan Aggrecan-G1 Domain-induced Arthritis (GIA) Mouse Model.

The recombinant human proteoglycan aggrecan-G1 domain (rhG1)-induced arthritis (GIA) mouse model is a complex model of rheumatoid arthritis (RA). In GIA, autoimmune arthritis is induced by repeated intraperitoneal immunization of genetically susceptible BALB/c mice with the rhG1 antigen emulsified in the adjuvant dimethyldioctadecylammonium (DDA). This article describes the steps for producing and purifying the rhG1 antigen, the immunization protocol, methods for following the clinical picture of arthritis, and the evaluation of relevant laboratory parameters. In this model, the autoimmune arthritis develops stepwise, similar to RA: First is the preclinical stage (after the first immunization, days 0-20) with no sign of inflammation but detectable T and B cell activation; next, the stage of early arthritis (after the second immunization, days 21-41), where the first definitive signs of arthritis appear together with autoantibody production; and then the severe late-stage arthritis (after the third immunization, after day 42), which presents with massive inflammation of the limbs, leading to cartilage and bone destruction and finally ankylosis. The protocols described here provide sufficient information for investigators to use the GIA model to study different aspects of autoimmune arthritis. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Induction of recombinant human proteoglycan aggrecan-G1 domain (rhG1)-induced arthritis (GIA) Support Protocol 1: Production of rhG1-Xa-mFc2a fusion protein with CHOK1 mammalian expression system Support Protocol 2: Purification of the rhG1-Xa-mFc2a fusion protein by affinity chromatography Support Protocol 3: Preparation of DDA adjuvant Support Protocol 4: Clinical assessment of arthritis Support Protocol 5: Measurement of serum antibody levels and cytokines Support Protocol 6: Measurement of rhG1-induced proliferation and cytokine production in spleen cell culture Support Protocol 7: Histological assessment of arthritic limbs Support Protocol 8: Evaluation of arthritis with micro-computed tomography.

Potential therapeutic targets beyond cytokines and Janus kinases for autoimmune arthritis.

Synovial inflammation and destruction of articular cartilage and bone are hallmarks of autoimmune arthritis. Although current efforts to inhibit proinflammatory cytokines (biologics) or block Janus kinases (JAK) appear to be promising in many patients with autoimmune arthritis, adequate disease control is still lacking in a significant proportion of autoimmune arthritis patients. The possible adverse events from taking biologics and JAK inhibitors, such as infection, remain a major concern. Recent advances showing the effects of a loss of balance between regulatory T cells and T helper-17 cells as well as how the imbalance between osteoblastic and osteoclastic activities of bone cells exaggerates joint inflammation, bony destruction and systemic osteoporosis highlight an interesting area to explore in the search for better therapeutics. The recognition of the heterogenicity of synovial fibroblasts in osteoclastogenesis and their crosstalk with immune and bone cells provides an opportunity for identifying novel therapeutic targets for autoimmune arthritis. In this commentary, we comprehensively review the current knowledge regarding the interactions among heterogenic synovial fibroblasts, bone cells and immune cells and how they contribute to the immunopathogenesis of autoimmune arthritis, as well as the search for novel therapeutic targets not targeted by current biologics and JAK inhibitors.

Effect of JAK inhibitors on the three forms of bone damage in autoimmune arthritis: joint erosion, periarticular osteopenia, and systemic bone loss.

BACKGROUND: The types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three types of bone loss have not been reportedly explored in depth. We aimed to clarify how JAK inhibitors influence the various types of bone loss in arthritis by modulating osteoclastic bone resorption and/or osteoblastic bone formation. METHODS: Collagen-induced arthritis (CIA) mice were treated with a JAK inhibitor after the onset of arthritis. Micro-computed tomography (µCT) and histological analyses (bone morphometric analyses) on the erosive calcaneocuboid joint, periarticular bone (distal femur or proximal tibia), and vertebrae were performed. The effect of four different JAK inhibitors on osteoclastogenesis under various conditions was examined in vitro. RESULTS: The JAK inhibitor ameliorated joint erosion, periarticular osteopenia and systemic bone loss. It reduced the osteoclast number in all the three types of bone damage. The JAK inhibitor enhanced osteoblastic bone formation in the calcaneus distal to inflammatory synovium in the calcaneocuboid joints, periarticular region of the tibia and vertebrae, but not the inflamed calcaneocuboid joint. All the JAK inhibitors suppressed osteoclastogenesis in vitro to a similar extent in the presence of osteoblastic cells. Most of the JAK inhibitors abrogated the suppressive effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells, while a JAK inhibitor did not affect this effect due to less ability to inhibit IFN-γ signaling. CONCLUSIONS: The JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting osteoclastogenesis and promoting osteoblastogenesis. These results indicate that the effect of JAK inhibitors on osteoclastogenesis and osteoblastogenesis depends on the bone damage type and the affected bone area. In vitro studies suggest that while JAK inhibitors inhibit osteoclastic bone resorption, their effects on osteoclastogenesis in inflammatory environments vary depending on the cytokine milieu, JAK selectivity and cytokine signaling specificity. The findings reported here should contribute to the strategic use of antirheumatic drugs against structural damages in RA.

Futuristic Novel Therapeutic Approaches in the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and joint destruction, leading to significant morbidity and reduced quality of life. Although significant progress has been made in the management of RA over the past few decades, many patients still fail to respond adequately to currently available therapies. This article aims to review the current landscape of RA treatment and explore potential novel therapeutic approaches that hold promise for the future. Advances in our understanding of the underlying pathogenesis of the disease have led to the identification of new targets and the development of innovative treatment strategies. This review focuses on emerging therapies including small molecule inhibitors, targeted biologics, cell-based therapies, and gene editing technologies that have shown potential in preclinical and early clinical trials. Additionally, we discuss the challenges and opportunities associated with the use of these new approaches in the treatment of RA. By elucidating the future of novel therapeutic approaches, this article provides insights that can guide clinicians and researchers in their efforts to improve outcomes for patients with RA.