The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease during which fibroblast-like synoviocytes (FLS) contribute to both joint inflammation and destruction. FLS represent the core component of the synovial membrane. Following inflammation of this membrane, an effusion of cell-rich synovial fluid (SF) fills the joint cavity. Unlikely, SF has been shown to contain fibroblasts with some shared phenotypic traits with the synovial membrane FLS. These cells are called SF-FLS and their origin is still unclear. They are either brought into the synovium via migration through blood vessels, or they could originate within the synovium and exist in projections of the synovial membrane. SF-FLS function and phenotype are poorly documented compared to recently well-characterized synovial membrane FLS subsets. Furthermore, no study has yet reported a SF-FLS single-cell profiling analysis. This review will discuss the origin and cellular characteristics of SF-FLS in patients with RA. In addition, recent advances on the involvement of SF-FLS in the pathogenesis of RA will be summarized. Current knowledge on possible relationships between SF-FLS and other types of fibroblasts, including synovial membrane FLS, circulating fibrocytes, and pre- inflammatory mesenchymal (PRIME) cells will also be addressed. Finally, recent therapeutic strategies employed to specifically target SF-FLS in RA will be discussed.

Case Report: Extensive digital gangrene as a primary manifestation of late-onset systemic lupus erythematosus.

Background: Digital gangrene is a rare but serious complication of systemic lupus erythematosus (SLE). It occurs usually in middle-aged patients with longer disease duration. Case: Herein we report the case of a 56-year-old man (with no history suggestive of Raynaud's phenomenon, diabetes mellitus, smoking, trauma, infection, or chemical exposure), who presented with SLE and digital gangrene was among the first signs. He presented with a one-month history of joint pain, hair loss, photosensitivity, mouth ulcers, malar rash, dyspnea, and digital pain. Physical examination revealed painful and diffuse erythematous skin lesions in the extremities and back, as well as cyanosis in the fingers. We noted lymphocytopenia (600 cells/mm 3), and an elevated C-reactive protein (15.1 mg/l) on laboratory tests. Immunological tests were positive for antinuclear antibodies (ANA) with Title 1:400. Pulmonary computed tomography revealed pulmonary fibrosis, and pulmonary function tests revealed the restrictive pulmonary disease. Diagnosis of SLE with lung involvement was retained. The immunological assessment in search of elements in favor of a vascular origin of the patient's skin lesions was negative. Treatment was initiated with 200 mg/day hydroxychloroquine. For dermal and pulmonary involvement, intravenous (IV) pulse therapy was used with methylprednisolone (1,000 mg/d for three consecutive days monthly) and cyclophosphamide (1 g/month). Calcium blocking agents were also prescribed. However, the lesions did not improve. The patient was given two infusions of rituximab (1 g) at a 14-day interval with a marked improvement ofthe majority of vasculitis lesions, and a partial improvement of dyspnea. Conclusions: Digital gangrene is a rare complication of late-onset SLE, especially as a primary manifestation.

SFRP5 Enhances Wnt5a Induced-Inflammation in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Background: Tissue derived fibroblast-like synoviocytes (td-FLS) are key actors in pannus formation and contribute to joint destruction and inflammation during rheumatoid arthritis (RA). Several members of the Wnt family, including Wnt5a, may contribute to RA td-FLS activation and can potentially serve as therapeutic targets. Objective: The present work aimed to investigate the expression of Wnt5a signaling elements in RA td-FLS and their potential precursors (fluid derived (fd) FLS and fibrocytes). We also studied the role of Wnt5a in RA td-FLS pro-inflammatory activity and whether the inhibitor SFRP5 could restore Wnt5a-induced synovial dysfunction in vitro. Materials and Methods: The levels of Wnt5a, SFRP5, Wnt5a receptors/coreceptors and Wnt5a pro-inflammatory targets were determined in cultured RA td-FLS, fd-FLS and fibrocytes using qPCR under basal conditions. The expression of pro-inflammatory molecules was assessed after RA td-FLS stimulation with Wnt5a and SFRP5 at different time points. Results: Our data showed that td-FLS, fd-FLS and fibrocytes from patients with RA expressed similar levels of Wnt5a and a set of Wnt5a receptors/coreceptors. We also demonstrated that Wnt5a stimulated the expression of the pro-inflammatory targets, especially IL1ß, IL8 and IL6 in RA td-FLS. Wnt5a-induced inflammation was enhanced in the presence of SFRP5. Furthermore, Wnt5a alone and in conjunction with SFRP5 inhibited the gene expression of TCF4 and the protein levels of the canonical coreceptor LRP5. Conclusion: Wnt5a pro-inflammatory effect is not inhibited but enhanced by SFRP5 in RA td-FLS. This research highlights the importance of carefully evaluating changes in Wnt5a response in the presence of SFRP5.

A Rare Case of Hypophosphataemic Osteomalacia in von Recklinghausen Neurofibromatosis.

BACKGROUND: Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a one of the more common hereditary autosomal disorders. However, osteomalacia in neurofibromatosis type 1 is very rare tumour-induced osteomalacia; fibroblast growth factor-23 is usually implicated. PATIENTS AND METHODS: We report the case of a patient with a history of von Recklinghausen neurofibromatosis who presented with hypophosphataemic osteomalacia. RESULTS: The patient was treated with high-dose calcitriol and oral phosphate with clinical improvement. CONCLUSION: Even though it is a rare entity, we must consider the diagnosis of hypophosphataemic osteomalacia in patients with neurofibromatosis in order to deliver appropriate treatment. LEARNING POINTS: Osteomalacia during von Recklinghausen disease is a rare presentation of an uncommon condition and has a poorly understood mechanism.The treatment of oncogenic osteomalacia includes tumour removal which, however, is not always possible.Administration of calcitriol alone is not sufficient and phosphorus intake is mandatory to improve symptoms.

Multifocal tuberculosis on certolizumab pegol in a patient followed for rheumatoid arthritis.

Tuberculosis must be considered in front of deterioration in general condition in patient with rheumatic disease under biological therapy. Rheumatologists may pay attention and screen infections before and after prescribing biological therapy.