A Randomized Open-labeled Study for Comparing Methods of Using Imrecoxib to Treat AS

Ankylosing spondylitis (AS) is a chronic systemic inflammatory arthritis of unknown etiology, occurring in young men aged 16-25 and presenting the genetic predisposition. AS is a common rheumatic disease, with a prevalence of 0.3 ~ 0.5% in general people of China, which means that about 5 million people in our country suffer from this disease. AS mainly invades the central axis, characterized by the inflammation of sacroiliitis and attachment points. The onset of AS is insidious. The early clinical manifestations are mainly inflammatory low back pain, which gradually affects the lumbar spine, thoracic vertebrae, and cervical vertebrae. The persistent inflammation will gradually stiffen and fuse the joints, causing osteoporosis and destruction of the vertebral body, resulting in the ossification of ligaments, and leading to the disability ultimately. Except for the joint lesions, AS is usually accompanied by multiple extra-articular manifestations, such as uveal inflammation, psoriasis, inflammatory bowel disease, etc. Especially, AS is often complicated with multiple complications symptoms, such as arthritis, arterial disease, fibromyalgia, depression, etc. In summary, AS has seriously affected the normal work and work of patients, which has become the main reason for the labor loss in young and middle-aged people. Therefore, it is of great value for controlling inflammation effectively and alleviate joint pain to improve the life quality of patients and save social labor.

Non-steroid anti-inflammatory drugs (NSAIDs), the anti-inflammatory and analgesic drugs and widely used in rheumatic diseases, can effectively relieve pain and quickly improve the symptoms of inflammatory joint disease. The role of NSAIDs in the treatment of AS is very important, which could not only generate anti-inflammatory effect, but also improve the joint function, delay joint erosion, and prevent the formation of osteophyte. The treatment guidelines of AS in American Rheumatology Association / American Spondyloarthropathy Collaboration in 2015 recommended continuous prescription NSAIDs as the first-line treatment for patients with active AS. In the 2016 ASAS / European Guideline of Axial Spondyloarthropathy, NSAIDs should be treated as the first-line treatment for patients with joint pain and joint stiffness. Those who respond well to NSAIDs are recommended for continuous treatment. The latest 2018 APLAR guidelines also recommend that NSAIDs should be used as first-line treatment for active AS, but the method of continuous treatment or treatment on demand is not discussed because two clinical trials have shown that the efficacy of on-demand is not worse than continuous treatment. In summary, NSAIDs are recommended for the first-line treatment of AS, but the differences in the efficacy, safety, and patient benefit between continuous treatment and on-demand treatment, as well as the treatment course, is controversial yet.

NSAIDs could inhibit the activity of cyclooxygenase (COX), blocking the conversion of arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. In addition, NSAIDs could also inhibit the release of bradykinin, inhibit lymphocyte proliferation, and reduce the migration of granulocyte and macrophages in inflammation. COX includes COX-1 and COX-2. COX-1 induced prostaglandins mainly generate the physiological and protective effect, such as maintaining the integrity of the gastrointestinal mucosa, adjusting the renal blood flow, and guarantee the function of platelets. COX-2 is mainly expressed in macrophages, fibroblasts, cartilage and endothelial cells with a low level in the basic state. Once stimulated by cytokines or endothelin, the expression will tremendously increase several times, induce the production of prostaglandins, and participate in inflammation. NSAIDs could be classified as non-specific COX inhibitors, selective COX-1 inhibitors, and selective COX-2 inhibitors based on the effects of different COX. The main adverse reaction of NSAIDs derives from its inhibitory effect on COX-1, causing adverse gastrointestinal reactions. And the gastrointestinal ulcers and bleeding are also the most common causes of hospitalization and death. The selective COX-2 inhibitor is the new generation of NSAIDs, with better anti-inflammatory and analgesic effects, in that it could specifically inhibit the COX-2 but has no effect on COX-1, greatly reducing the adverse reaction of gastrointestinal tracts and kidneys. Multiple clinical trials and meta-analysis have shown that selective COX-2 inhibitors can significantly reduce the gastrointestinal symptoms and peptic ulcer formation in the endoscopic. Therefore, selective COX-2 owns a much more general application space in rheumatic diseases.

Most of the COX-2 inhibitors in China are not original research drugs previously, and only Celecoxib is available in the United States according to FDA. Unearthing new selective cox-2 inhibitor is necessary. Imrecoxib is a COX-2 inhibitor designed by the Chinese Academy of Medical Sciences and Jiangsu Hengrui Hospital Co., Ltd. in China, which has been approved by the Chinese Food and Drug Administration (CFDA) for marketing. The recommended dose of Imrecoxib is 100mg. bid.po. according to the instructions. Studies in vitro has demonstrated that Imrecoxib could specifically inhibit the COX-2, and inhibit the expression of COX-2 mRNA to restrain the inflammation. Multiple clinical studies have demonstrated that Imrecoxib was effective in treating osteoarthritis, with similar efficiency to Celecoxib but without severe gastrointestinal adverse effect, with a lower percentage of cardiovascular adverse effect, and with relatively good safety. In 2017, the comparison between Imrecoxib and Celecoxib in treating serum-negative spondyloarthropathy (SPA) revealed that the effect of Imrecoxib (10mg.bid.po for 12 weeks) was not worse than that of Celecoxib, which could significantly alleviate disease activity, joint function and inflammatory markers. But there is a lack of study with a large sample size and long course to further demonstrate the effectiveness and safety of Imrecoxib in treating SPA and AS.

The AS disease activity score such as BASDAI and radiological assessment are the main observation indicators for efficacy evaluation in the clinical study of NSAIDs treating AS for the moment. But the evaluation of life quality is also important for patients with AS, which includes 4 respects, the body 's function, disease activity, economic status, and social status. Data from Taiwan shows that a variety of factors can affect the patient 's life quality except for the disease activity, including the course of the disease, drinking, weight, mental, and economic factors, etc. So, adequate life quality assessment and support should be given to the AS patients. However, there is a lack of studies that employed patients self-report and patients' life quality assessment as the main observation indicators. The present study intends to use the results of patients' self-report as the evaluation criteria, to compare the efficacy and safety between continuous treatment and on-demand treatment of Imrecoxib for AS under different treatment modes, which could also provide direct evidence for the optimized applications in rheumatic diseases.

Meanwhile, we also want to find whether on-demand treatment of Imrecoxib could reduce the occurrence of adverse reactions, reduce the economic burden, and bring more benefits under the premise that the on-demand treatment is not worse than continuous use of Imrecoxib in drug efficacy.