Personal non-commercial use only. The Journal of Rheumatology Copyright© 2002. All rights reserved. www. jrheum. org Downloaded on August 1, 2023 from signs and symptoms in patients with chronic AS13, psoriatic arthritis14, and the SpA of Crohn’s15 is comparable if not superior to RA, suggesting a central role for proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) in the pathogenesis of these diseases. Our own experience with etanercept suggests that this drug is very efficacious in suppressing axial and peripheral joint disease even in established cases that have proven resistant to conventional therapies. We have shown using MRI that the primary lesion in the spine, enthesitis and osteitis, neither of which were apparent on radiography, either completely regressed or improved after treatment, and this was accompanied by major improvements in clinical and laboratory measures of disease activity, including a fall in the acute phase response as measured by the C-reactive protein16. These data confirm that different anatomical regions of inflammation and not just synovitis respond to anti-TNF therapy. Similarly, other investigators have recently used MRI to monitor the efficacy of other biologics such as infliximab17 and other novel agents and have reported similar findings18. Although MRI identifies a clear pathology occurring at the bone marrow and related enthesis as well as the synovial joints, there are still a number of unresolved issues. First, the relationship between inflammation and bone damage in AS is not fully defined and the question remains: is there a linear relationship between inflammation in AS and other SpA and subsequent joint ankylosis? The original histological studies by Bywaters19 suggested that bone ankylosis may be independent of the associated inflammation, although these observations were based on a limited number of histological sections. Also, experimental models of AS and in particular the ANKENT mouse have prominent joint fusion without much discernible inflammation20. It is noteworthy, too, that diffuse idiopathic skeletal hyperostosis (DISH), a disease that can sometimes resemble AS, is not regarded as having an inflammatory component. Even though enthesitis is regarded as the primary pathological abnormality in SpA21-23, definitive proof of the relationship between enthesitis and osteitis and bone ankylosis is still lacking. However, recent MRI and radiographic studies in early disease24 indicate that MRI bone changes predate radiographic abnormalities, suggesting that in AS, enthesitis and osteitis is primary and bone changes such as sclerosis or syndesmophytes are secondary. Therefore, to demonstrate unequivocally that these new drugs constitute true DMARD in SpA, it will be necessary to show that sustained reversal of the inflammation at the enthesis and adjacent bone prevents subsequent radiological fusion of the joint and associated loss of function. Evidence so far is reassuring, as studies conducted to date with biologic agents have shown dramatic response, even when used to treat patients where a degree of irreversible joint fusion had already occurred, suggesting that there is room for disease modification even at later stages. However, confirmation of this can only be achieved by the systematic and controlled longitudinal observation of large cohorts of patients. From a theoretical perspective, inflammation generally hinders new bone formation and tends to favor the development of osteoporosis. It will therefore be important to carefully document that suppression of inflammation at the spinal entheses is not associated with increased new bone formation with joint fusion …