Mr Outside and Mr Inside: classic and alternative views on the pathogenesis of rheumatoid arthritis

Different strategies can be applied to overcome an obstacle: one may either overcome it from the 'outside' or break it from the 'inside'. Similar strategies have been successfully used by two American football players in the 1940s, known as 'Mr Outside' and 'Mr Inside'. In this article, the authors propose similar concepts for initiating joint inflammation. Arthritis may start 'outside' as a primary inflammation of the synovial membrane (synovitis), which later spreads over to adjacent structures resulting in penetration into the bone marrow (outside-in concept). Alternatively, arthritis may start 'inside', in the bone marrow space, and later encroaches upon the synovium (inside-out concept). The authors discuss these two fundamentally different viewpoints on the pathogenesis of arthritis, each one of which bears attractive explanations for the mystery of the pathogenesis of arthritis.