*Review* **Modeling Rheumatoid Arthritis In Vitro: From Experimental Feasibility to Physiological Proximity**

**Alexandra Damerau 1,2 and Timo Gaber 1,2,\***


Received: 9 October 2020; Accepted: 23 October 2020; Published: 25 October 2020

**Abstract:** Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease that a ffects the connective tissue and primarily the joints. If not treated, RA ultimately leads to progressive cartilage and bone degeneration. The etiology of the pathogenesis of RA is unknown, demonstrating heterogeneity in its clinical presentation, and is associated with autoantibodies directed against modified self-epitopes. Although many models already exist for RA for preclinical research, many current model systems of arthritis have limited predictive value because they are either based on animals of phylogenetically distant origin or su ffer from overly simplified in vitro culture conditions. These limitations pose considerable challenges for preclinical research and therefore clinical translation. Thus, a sophisticated experimental human-based in vitro approach mimicking RA is essential to (i) investigate key mechanisms in the pathogenesis of human RA, (ii) identify targets for new therapeutic approaches, (iii) test these approaches, (iv) facilitate the clinical transferability of results, and (v) reduce the use of laboratory animals. Here, we summarize the most commonly used in vitro models of RA and discuss their experimental feasibility and physiological proximity to the pathophysiology of human RA to highlight new human-based avenues in RA research to increase our knowledge on human pathophysiology and develop e ffective targeted therapies.

**Keywords:** in vitro models; rheumatoid arthritis; cytokines; mesenchymal stromal cells; co-culture; tissue engineering; 3D cell culture; explants; joint-on-a-chip
