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.

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.

Bone Marrow Mesenchymal Stem Cells Overexpressing HIF-1α Prevented the Progression of Glucocorticoid-Induced Avascular Osteonecrosis of Femoral Heads in Mice.

Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)-PGE-2 (prostaglandin E2)-HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2-/-) mice were subjected to micro-computed tomography and histological examinations. Compared with their WT littermates, COX-2-/- mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.

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.