Investigative biological therapies for primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by dryness of the eyes and mouth. The histological feature is mononuclear cell infiltration in exocrine glands, primarily salivary and lachrymal glands. As the disease progresses, some other tissues and organs may be involved and extraglandular manifestations ensue. The major current treatments are palliative and empirical, and in most cases the outcomes are not satisfactory. Emerging data indicate a critical role of lymphocytes in its development and progression. While pioneering work targeting B cells has demonstrated some encouraging results, more trials are warranted to validate the safety and efficacy. In addition, modulation of T cell function with abatacept ameliorates the severity of pSS. Furthermore, clinical trials to inhibit important cytokines involved in its formation have been carried out. In this article, we summarize and compare current biological therapies in order to find new and effective treatments for pSS.

Teriparatide prevented synovial inflammation and cartilage destruction in mice with DMM.

AIM: Emerging data have demonstrated that low-grade inflammation in osteoarthritis, a long-held degenerative disease. The inflamed synovium produces various cytokines that induce cartilage destruction and joint pain. A previous study showed that teriparatide, an FDA approved anti-osteoporotic drug, may enhance cartilage repair. Our study focuses on its role in OA synovitis. MATERIALS AND METHODS: Primary mouse articular chondrocytes were used to determine the most potent cytokines involved in OA inflammation and cartilage destruction. A destabilization of the medial meniscus mouse model was established to investigate the effect of teriparatide in OA, particularly, on synovial inflammation and cartilage degradation. RESULTS: In vitro experiments showed that TNF-α was the most potent inducer of cartilage matrix-degrading enzymes, and that teriparatide antagonized the TNF-α of effect. Consistently, articular cartilage samples from TNF-α transgenic mice contained more MMP-13 positive chondrocytes than those from wild type mice. In addition, more type II collagen was cleaved in human OA cartilage than in normal cartilage samples. CONCLUSIONS: Teriparatide can prevent synovitis and cartilage degradation by suppressing TNF-α mediated MMP-13 overexpression. Together with its chondroregenerative capability, teriparatide may be the first effective disease modifying osteoarthritis drug.

Exploring the Association Between History of Psoriasis (PSO) and Disease Activity in Patients with Psoriatic Arthritis (PsA).

INTRODUCTION: Psoriatic arthritis (PsA) is a common inflammatory disease affecting the peripheral and axial skeleton. History of psoriasis (PSO), either personal or family history, is an important factor in the diagnosis of PsA. We investigated the association between history of PSO and clinical characteristics of PsA. METHODS: PsA patients were consecutive recruited from 2019 to 2020. These patients were subjected to clinical, biochemical, and radiographic examinations, and disease activity was evaluated. Continuous and categorical variables analyses were presented. RESULTS: All registered patients (296 cases) met the classification criteria of PsA. They were divided into three groups based on the history of psoriasis (PSO), as: (1) 145 patients with PSO themselves (pPsA); (2) 96 patients with family history of PSO (fPsA); (3) 55 patients with family history and coexisting PSO themselves (fPsA/PSO). Compared to fPsA/PSO, the levels of CRP, ESR, uric acid, DAPSA, BASDAI, ASDAS, and BASFI were lower in fPsA, but similar to pPsA. The severity of sacroiliitis tended to be more severe in fPsA/PSO than fPsA (OR2 vs. 3 0.508; 95% CI 0.272 to 0.949, p < 0.05). No significant differences were found in HLA-B-27 and common inflammatory articular and extra-articular manifestations among the three groups. Furthermore, there were no differences in LEI, TJC, SJC, and DAS28CRP. Interestingly, a correlation was found between the ages of individuals with PSO and the onset of arthritis, and the earliest arthritis onset occurred in fPsA/PSO patients (p < 0.001). CONCLUSIONS: Our study demonstrates that currently existing cutaneous lesions in patients themselves are correlated with disease activity and severity of axial joint damage, whereas family history does not have an evident impact on the disease activity of PsA.

Dactylitis Is Associated With More Severe Axial Joint Damage and Higher Disease Activity in Axial Psoriatic Arthritis.

OBJECTIVE: To investigate the association of dactylitis with disease activity and the severity of damage detected by radiography in patients with axial psoriatic arthritis (axPsA). METHODS: Patients with axPsA who met the Classification Criteria for Psoriatic Arthritis were recruited. Clinical data, radiographic changes, and disease activity in patients with axPsA with or without dactylitis were compared using t tests, Mann-Whitney U tests, or Kruskal-Wallis tests for continuous variables. Chi-square or Fisher exact tests were used for categorical variables, and logistic regression analysis was performed to evaluate the association between dactylitis and damage detected by radiography. RESULTS: A total of 186 patients with axPsA were analyzed and dichotomized according to the presence or absence of dactylitis. Patients with dactylitis, as compared to those without dactylitis, had higher C-reactive protein (P = 0.004), erythrocyte sedimentation rate (P = 0.006), neutrophil-to-lymphocyte ratio (P = 0.04), and platelet-to-lymphocyte ratio (P = 0.02). In addition, patients with dactylitic axPsA, as compared to patients with nondactylitic axPsA, had higher tender joint counts, swollen joint counts, Disease Activity Index for Psoriatic Arthritis (DAPSA) scores, and Health Assessment Questionnaire scores (P < 0.001). Patients with axPsA who had dactylitis, as compared to those who did not, also had higher values for the Disease Activity Score in 28 joints, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Functional Index, and Bath Ankylosing Spondylitis Disease Activity Index (P < 0.05), while fewer of these patients met the criteria for minimal disease activity and low disease activity (P < 0.05). Consistently, they had more severe damage as detected by radiography (P < 0.05), higher sacroiliac scores (odds ratio [OR] 2.08, 95% CI 1.14-3.79; P = 0.02), and a more significant reduction in bone mass density (OR 2.42, 95% CI 1.34-4.37; P = 0.003). No statistical differences were observed regarding HLA-B27 and the Leeds Enthesitis Index between these 2 groups of patients. Notably, only half of the patients with dactylitic axPsA had inflammatory back pain. CONCLUSION: Our study demonstrated that patients with axPsA who had dactylitis had higher disease activity and more severe joint damage compared to those without dactylitis. Careful examination and proper management of axial involvement are recommended.

Risk factors for progression of interstitial lung disease in Sjögren's syndrome: a single-centered, retrospective study.

OBJECTIVE: To identify clinical characteristics and risk factors related to the progression of interstitial lung disease (ILD) in patients with primary Sjögren's syndrome (pSS). METHODS: In this single-centered, retrospective study, a total of 83 identified pSS-ILD patients with relatively complete clinical data were finally enrolled. Clinical symptoms, laboratory data, high-resolution computed tomography (HRCT), and pulmonary function test (PFT) results were collected. A logistic regression analysis was performed to determine the independent risk factors for ILD progression, and a nomogram was plotted to construct a predictive model. RESULTS: The prevalence of pSS-ILD in our study was 18.89%. Among the 83 enrolled patients, 32 (38.6%) underwent ILD progression. The characteristic features associated with the progression of ILD included male sex, non-sicca onset, reticular pattern on HRCT, higher levels of baseline lactic dehydrogenase (LDH), and low baseline forced vital capacity (FVC). The results of multivariate logistic regression indicated that LDH (OR 1.008, p = 0.030) was an independent risk factor for ILD progression, while sicca onset (OR 0.254, p = 0.044) and FVC (OR 0.952, p = 0.003) were protective factors for ILD progression. A simple predictive model for ILD progression in pSS was developed and validated. CONCLUSION: pSS patients with non-sicca onset, high baseline LDH level, and low baseline FVC were at higher risk of ILD progression.

Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis.

Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. For a long time, OA has been considered as a degenerative disease, while recent observations indicate the mechanisms responsible for the pathogenesis of OA are multifaceted. Aging is a key factor in its development. Current treatments are palliative and no disease modifying anti-osteoarthritis drugs (DMOADs) are available. In addition to articular cartilage degradation, cellular senescence, synovial inflammation, and epigenetic alterations may all have a role in its formation. Accumulating data demonstrate a clear relationship between the senescence of articular chondrocytes and OA formation and progression. Inhibition of cell senescence may help identify new agents with the properties of DMOADs. Several anti-cellular senescence strategies have been proposed and these include sirtuin-activating compounds (STACs), senolytics, and senomorphics drugs. These agents may selectively remove senescent cells or ameliorate their harmful effects. The results from preclinical experiments and clinical trials are inspiring. However, more studies are warranted to confirm their efficacy, safety profiles and adverse effects of these agents.

Recent Progresses in the Treatment of Osteoporosis.

Osteoporosis (OP) is a chronic bone disease characterized by aberrant microstructure and macrostructure of bone, leading to reduced bone mass and increased risk of fragile fractures. Anti-resorptive drugs, especially, bisphosphonates, are currently the treatment of choice in most developing countries. However, they do have limitations and adverse effects, which, to some extent, helped the development of anabolic drugs such as teriparatide and romosozumab. In patients with high or very high risk for fracture, sequential or combined therapies may be considered with the initial drugs being anabolic agents. Great endeavors have been made to find next generation drugs with maximal efficacy and minimal toxicity, and improved understanding of the role of different signaling pathways and their crosstalk in the pathogenesis of OP may help achieve this goal. Our review focused on recent progress with regards to the drug development by modification of Wnt pathway, while other pathways/molecules were also discussed briefly. In addition, new observations made in recent years in bone biology were summarized and discussed for the treatment of OP.

ATF4-modified serum exosomes derived from osteoarthritic mice inhibit osteoarthritis by inducing autophagy.

Activating transcription factor 4 (ATF4) is critical for chondrocyte proliferation and bone formation. Exosomes are considered as promising gene-delivery vehicles for the treatment of osteoarthritis (OA). This study utilized the serum-derived exosomes from OA mice as the gene-delivery vehicles for ATF4 gene therapy and explored their therapeutic effects on OA. Meniscus injury-induced OA model was established by the excision of anterior part of medial meniscus in the right knee of C57BL/6J mice. Exosomes were isolated from serum samples of sham and OA mice, and were referred to as sham-Exo and OA-Exo, respectively. ATF4-overexpressing OA-Exo (ATF4-OA-Exo) was developed by introducing ATF4 mRNA into OA-Exo via electroporation. Four weeks after surgery, OA mice received intra-articular injections of sham-Exo, OA-Exo, and ATF4-OA-Exo, respectively. The results showed that intra-articular injection of ATF4-OA-Exo alleviated articular cartilage degeneration or damage and inflammatory response of OA mice. Autophagy was weakened in knee joint cartilage of OA mice, which was partially restored by intra-articular injection of ATF4-OA-Exo. Further in vitro assays revealed that ATF4-OA-Exo promoted chondrocyte autophagy and inhibited chondrocyte apoptosis in the TNF-α- or tunicamycin-treated chondrocytes. Together, ATF4-modified serum exosomes derived from OA mice protect cartilage and alleviate OA progression by inducing autophagy.

Erythropoietin enhances meniscal regeneration and prevents osteoarthritis formation in mice.

Osteoarthritis (OA) is a leading cause of pain and disability, and knee is the most commonly afflicted joint. Meniscal tear due to injury or degeneration is an established factor for OA pathogenesis. Previous studies have demonstrated that meniscectomy does not reduce the OA incidence. We hypothesized that enhancing meniscal regeneration may prevent OA formation and progression. We first investigated the developmental pattern of mouse meniscus. Knee joint samples were collected at embryonic stages as well as after birth for histological and immunohistochemical studies. The results showed that meniscal cells underwent active proliferation and apoptosis at embryonic day 19.5 and Day 1 after birth. Collagen I (Col-1) is a major type of matrix protein in matured meniscus. Meniscal cells isolated from 3-month-old mice were used to examine the effect of selected factors on the molecules related to cell proliferation, angiogenesis, inflammation, extracellular matrix proteins and matrix degradation enzymes. Overall assessment indicated that EPO had optimal effect on meniscal regeneration. An organ culture system of mouse meniscus was established to test the effect of EPO on in vitro cultured menisci. EPO upregulated the expression of Col-1, Col-2 and VEGF-A, and downregulated the expression of MMP-13. Finally, we established a mouse model of meniscus injury induced OA (MIO), and mice were subjected to PBS or EPO treatments. The results demonstrated that EPO enhanced meniscal repair and prevented OA formation. EPO may become an effective Disease Modifying Osteoarthritis Drug and may be used for early treatment for meniscal injury to prevent OA progression.

The pathogenesis and treatment in antineutrophil cytoplasmic antibody associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a systemic autoimmune disease characterized by leukocytoclastic inflammation of small blood vessels. Commonly detected autoantibodies include anti-protease 3 (PR3) and anti-myeloperoxidase (MPO). Although cell necrosis plays an important role in the production of autoantibodies and the pathogenesis of AAV, the correlation between their titers and disease activity remains elusive. As improved detection techniques facilitate early diagnosis, a satisfactory efficacy can be achieved in patients with mild to medium severe AAV treated with glucocorticoids and immunosuppressants. However, resistant and relapsing AAV, sometimes life-threatening, do exist in clinical practice. In-depth understanding of pathogenesis of AAV may lend novel insight into the mechanism responsible for its formation and help find effective targeted therapies for refractory patients.