Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory and analgesic effects mainly by inhibiting cyclooxygenase (COX) and blocking prostaglandin production. They are used intermittently and “as needed” for symptomatic treatment. However, studies have shown that continued use of NSAIDs for 2 years can effectively delay or inhibit the progression of spinal imaging in AS and improve the condition. Thus, the question of whether NSAIDs should be used “as needed” for the treatment of AS or continued for a long period of time has become a major concern. A. The dilemma of preventing structural damage to the spine in AS Unlike rheumatoid arthritis, the term “structural damage to the spine” in AS refers to complete or incomplete spinal ankylosis due to new bone formation Although erosive structural changes can occur in the early stages of AS, they have less impact on spinal function and activity in the long term and are therefore not included in the list of “structural damage to the spine”. The term “structural damage to the spine” is not used. Studies have found that palliative antirheumatic drugs (DMARDs) including salazosulfapyridine, methotrexate, and leflunomide have shown improvement in peripheral arthropathy in AS, but there is no reliable evidence that they are effective in AS with mesial joint involvement. In recent years, anti-TNFα biologics have been widely used clinically, and its rapid and effective improvement of the systemic inflammatory response in AS, especially the control of pre-existing vertebral inflammation, has been confirmed, but it is not effective in inhibiting new bone formation in the spine. It was found that Dickkopf-1 (DKK-1) plays an important role in the process of bone and joint remodeling and that DKK-1 is dysfunctional in AS patients. Although anti-TNFα agents inhibit the regulatory effect of TNFα on DKK1, they cannot inhibit the upregulation of the Wnt pathway that has already started, which stimulates osteoblasts and increases bone alkaline phosphatase and osteocalcin, while decreasing osteoclastic precursor cells and increasing bone mineral, leading to new bone formation; therefore, anti-TNFα biological agents cannot block the occurrence of new bone formation in AS with pre-existing spinal inflammatory lesions process. In 1975, Boersma et al. reported a retrospective study of 40 cases of AS treatment and found that the proportion of patients without spinal ossification was significantly higher on radiographs with continuous use of protamine compared with those with intermittent use of protamine or without protamine, and that if ossification was already progressing before the application of protamine, the development of ossification was halted or greatly delayed with continuous use. In 2005, Wander et al. conducted a 2-year randomized controlled trial of 215 patients with AS, one group with long-term continuous NSAIDs (96 patients completed the trial, including 68 with celecoxib and 28 with other NSAIDs) and one group with on-demand NSAIDs (86 patients completed the trial, including 86 with celecoxib). (67 with celecoxib and 19 with other NSAIDs). The results showed no significant difference in efficacy and adverse effects in the long-term continuous NSAID group compared with the on-demand NSAIDs group, but the modified Stoke ankylosing spondylitis spine x-ray score (mSASSS) progression was significantly lower [(1.5 ± 2.5) ∝ (0.4 ± 1.7), P = 0.002], suggesting that continuous NASID use may slow down the progression of spine imaging in patients with symptomatic AS. spine imaging progression. Several other studies further confirm and support that NSAIDs do inhibit ossification and act mainly through inhibition of COX-2. For example, indomethacin inhibited bone scab formation induced by continuous electrical stimulation for 2 weeks; a meta-analysis of 16 randomized and 2 quasi-randomized studies of NSAID inhibition of heterotopic ossification after hip surgery (4763 patients in total) found that moderate to high doses of NSAIDs reduced the risk of heterotopic ossification after hip surgery by 59%, whereas low-dose aspirin did not reduce this risk. tibia in COX1 knockout rats The addition of the exogenous COX-2 inhibitory substrate prostaglandin E2 restored ossification. The study of COX isoform expression in inflammatory synovial tissues found that COX2 expression was highest in the inflammatory synovial vessel wall of AS compared with rheumatoid arthritis, psoriatic arthritis and osteoarthritis, while there was no significant difference in COX1, thus there is a theoretical basis for using selective or non-selective NSAIDs that can inhibit COX-2 for the treatment of AS. The mechanism of inhibition of new bone formation by NSAIDs may be that, after COX-2 inhibition, prostaglandin E2 decreases, which leads to upregulation of DKK1 and inhibition of the pathway, thus reducing osteoprotegerin, on the other hand, inhibiting osteogenic proteins and suppressing the osteogenic process. The decision of whether to use NSAIDs continuously or intermittently depends on: (1) the type of disease: for AS patients with predominantly mid-axis joint involvement, long-term continuous use of NSAIDs is recommended; for those with predominantly peripheral joint involvement, there are no reports of continuous use of NSAIDs to inhibit structural damage, so the use of NSAIDs on an as-needed basis is still preferred. The use of NSAIDs is mainly as needed. (2) Disease stage: Patients with advanced AS with predominantly mid-axis joint involvement do not need long-term NSAIDs if the spine and sacroiliac joints are completely fused, and inflammatory symptoms are not obvious and inflammatory indicators are normal.(3) Adverse drug reactions: Although the study by Wander et al. did not find statistically significant differences in adverse reactions related to NSAIDs between the continuous and on-demand groups, the former appeared to have increased adverse reactions. Adverse reactions in the former appeared to be increasing (41% ∝ 38% for dyspepsia; 11% ∝ 6% for abdominal pain; 9% ∝ 3% for hypertension), and the long-term use of rofecoxib, a selective COX-2 inhibitor, leading to increased cardiovascular adverse events and eventual withdrawal from the market is still fresh in the memory. Therefore, the gastrointestinal and cardiovascular adverse effects of NSAIDs should be kept in mind during treatment. In younger AS patients with predominantly spinal involvement, who do not have risk factors for gastrointestinal and cardiovascular disease and who wish not only to achieve symptomatic improvement but also to delay or control progression, treatment with NSAIDs may be continued for a longer period of time, subject to close follow-up observation.