Tripterygium Glycosides

Rheumatoid arthritis is an autoimmune disease primarily characterized by chronic symmetric arthritis. While rheumatoid arthritis with elevated eosinophils exhibits distinct clinical features, the potential coexistence of immunoglobulin (Ig)G4-related disease warrants clinical vigilance. This article reports a case of a patient presenting with polyarticular swelling and pain accompanied by morning stiffness. Positive tests for anti-keratin antibody, anti-cyclic citrullinated peptide antibody, anti-perinuclear factor, and rheumatoid factor were observed with a significantly elevated erythrocyte sedimentation rate, leading to a definitive diagnosis of rheumatoid arthritis. The patient also exhibited elevated peripheral blood eosinophils and showed poor response to treatments, such as leflunomide and tripterygium glycosides. After switching to methotrexate and tocilizumab, the patient's joint symptoms improved significantly, but peripheral blood eosinophilia showed no notable improvement. During the course of the disease, the patient developed lymphadenopathy and parotid gland enlargement. Lymph node ultrasound revealed a hypoechoic nodule in the left supraclavicular area, abnormal lymph nodes in both axillae and the right inguinal region, and visible lymph nodes in the bilateral cervical and left inguinal areas. Parotid ultrasound indicated hypoechoic nodules within both parotid glands and widening of the parotid ducts. Further bone marrow aspiration biopsy showed no significant abnormalities, while lymph node pathological biopsy suggested infiltration of IgG4-positive cells. Subsequent serum IgG4 testing revealed elevated level of IgG4. The patient was ultimately considered likely to have rheumatoid arthritis complicated with IgG4-related disease. Treatment was adjusted to regular infusions of rituximab (500 mg every six months), resulting in significant improvement of joint swelling and pain, as well as marked reductions in C-reactive protein and eosinophil levels, achieving disease remission. Through case analysis and literature review, this article discusses the diagnosis and treatment of rheumatoid arthritis patients with elevated eosinophils. For patients with rheumatoid arthritis with elevated eosinophils, it is necessary to be vigilant of the possibility of concurrent IgG4-related diseases. The use of rituximab provides novel perspectives for clinical treatment strategies.

Tripterygium glycoside tablet (TGT), a first-line anti-inflammatory drug for rheumatoid arthritis (RA), is severely limited in clinical use by male reproductive toxicity with unclear mechanisms. This study aimed to confirm TGT's anti-RA efficacy, characterize its reproductive toxicity in collagen-induced arthritis (CIA) rats, and elucidate whether the NELL2-Lumicrine system mediates such damage.

TGT's anti-inflammatory efficacy in CIA rats was evaluated via arthritis scoring, histopathology, and cytokine quantification. Male reproductive toxicity was assessed using sperm analysis, fertilization evaluation, histopathology, and hormone measurement. NELL2-Lumicrine system targets were identified by immunofluorescence and Western blot. Integrated metabolomic and transcriptomic analyses explored TGT's effects on testicular metabolism and gene expression. Molecular docking, dynamics simulation, and cell co-culture experiments verified inhibitory effects of TGT's bioactive components on the NELL2-Lumicrine system.

TGT alleviated joint swelling, reduced arthritis scores, and decreased serum TNF-α/IL-1β in CIA rats. However, TGT impaired sperm quality and fertilization capacity, increased sperm/embryo abnormalities, and induced testicular-epididymal damage, with hypothalamic-pituitary-gonadal axis hormone dysregulation. Mechanistically, TGT downregulated NELL2 and downstream targets (ROS1, OVCH2, ADAM28, ADAM3), disrupting sperm maturation. Multi-omics revealed TGT disrupted testicular steroid biosynthesis and Fgf signaling linked to the NELL2-Lumicrine system. Computational modeling and in vitro experiments confirmed triptolide and triptonide bind NELL2 strongly, suppressing its signaling pathway.

Our data provide the first evidence that TGT induces male reproductive toxicity by inhibiting the NELL2-Lumicrine system, downregulating NELL2 and its downstream targets (ROS1, OVCH2, ADAM28, and ADAM3), which are essential for sperm maturation.