Ankylosing spondylitis (AS) is a systemic inflammatory disease characterized by the involvement of the spine and sacroiliac joints, which mostly manifests clinically as inflammatory low back pain, stiffness, and limitation of motion. With the in-depth research on the causative factors of AS, although the causative mechanism is still not fully understood and there are still many confusions in clinical diagnosis and treatment, in addition to the traditional therapeutic measures, new strategies for the treatment of AS have also gained promising new experiences in recent years. The main hot spots and advances in AS treatment in recent years are summarized below.
1. Non-steroidal anti-inflammatory drugs (NSAID).
NSAID is one of the main symptomatic drugs traditionally used in the treatment of AS, which can inhibit the inflammatory process and reduce joint pain, swelling and morning stiffness. Commonly used drugs include indomethacin and diclofenacs. In 2005, WandersA et al. conducted a randomized controlled trial to test the effect of long-term continuous NSAID treatment and NSAID treatment only when necessary on the imaging performance of AS patients. 215 patients with AS. Patients were randomized to either long-term continuous NSAID therapy or NSAID therapy when necessary and were observed for 2 years in a randomized, double-blind clinical trial using Celecoxib, Ketoprofen, and placebo as controls. The results of the trial showed that the treatment regimen of continuous NSAID slowed the progression of the disease in symptomatic AS patients with imaging findings without increasing the toxic effects, suggesting that the therapeutic effects and mechanisms of NSAID in AS deserve further investigation. In a 12-week study, Barkhuizen A et al. also showed that treatment of AS patients with celecoxib 200 mg and 400 mg once daily was effective in improving signs and symptoms and was well tolerated.
NSAID drugs have been clinically validated over a long period of time, affirming their role in alleviating patients’ clinical symptoms and other manifestations, and play an important role in treating and improving patients’ quality of life. However, the side effects of this class of drugs in terms of gastrointestinal tract and its nephrotoxicity should also be paid attention to in clinical application.COX-2 is the inducing enzyme, so selective COX-2 inhibitors not only have good anti-inflammatory and analgesic effects, but also have fewer side effects. Dougados et al. conducted a 6-week randomized, double-blind, placebo-controlled trial to evaluate the short-term therapeutic effects of celecoxib in patients with AS. Ketoprofen 100 mg twice daily, and Celecoxib 100 mg twice daily. The results confirmed the anti-inflammatory effect of the daily dose of Celecoxib 200 mg and showed a significant improvement in pain relief and activity function in AS patients. However, with the widespread and in-depth clinical application, there are increasing concerns about the adverse effects of COX-2 inhibitor drugs causing cardiovascular, renal and allergic reactions.
2. disease-modifying anti-rheumatic drugs (DMARD).
At present, the treatment of AS patients, or NSAID drugs to relieve symptoms, but for NSAID difficult to control patients, the second-line class of drugs DMARD to treat, relieve and improve the condition.
(1), Sulfasalazine SSZ.
SSZ is the most studied drug in the DMARD class for the treatment of AS. SSZ inhibits leukocyte motility, decreases proteolytic enzyme activity, and inhibits a variety of cytokines such as interleukin-6, interleukin-1α, interleukin-1β, and tumor necrosis factor, etc. Chen J concluded from a comparative analysis of trials in MEDLINE and other resources that patients and physicians believe that SSZ can There is no clear evidence of improvement in function, pain, or flexibility of spinal motion, and patients with high levels of ESR and peripheral arthritis in early AS may benefit from treatment with SSZ. Savastano M et al. reported a case of a male patient with AS who lost his hearing due to bilateral auditory nerve effects caused by treatment with SSZ. Therefore, while treating with SSZ, attention should be paid to the individualization of the dose, and the side effects increase with the dose.
(2) Methotrexate MTX, also known as methotrexate or methotrexate, is a folic acid antagonist with a high affinity for dihydrofolate reductase, which binds to it in a competitive manner and blocks the activity of the enzyme so that folic acid cannot be converted into physiologically active tetrahydrofolate, which plays a coenzyme role, and deoxyuridine cannot be converted into deoxynucleotide, which blocks DNA synthesis. The methotrexate also blocks DNA synthesis. Gonzalez-Lopez L et al. evaluated the effects and safety of MTX in patients with active AS in a controlled trial with placebo. They conducted a double-blind, randomized, 24-week, placebo-controlled trial in patients with active AS, thereby comparing the response of MTX 7.5 mg/week to placebo in patients with active AS. In the 24-week purposeful treatment analysis, MTX was effective in 53% of 17 MTX-treated patients compared with 17% of 18 placebo-treated patients (p=0.03) The authors concluded that MTX is effective and safe in patients with AS, but the durability of its effects and the safety of its long-term use need to be evaluated in long-term studies.ChenJ, Liu C. concluded that the efficacy of MTX in patients with AS has not been statistically significant and that higher quality, larger samples and longer-term randomized controlled trials are needed to verify the efficacy and toxic effects of MTX in patients with AS. Because MTX is a cytotoxic drug, common adverse effects include: nausea, dyspepsia, alopecia, bone marrow suppression, and serious adverse effects should be liver damage and lung lesions. Therefore, attention should be paid to weighing the pros and cons, paying attention to its toxic side effects and monitoring liver function in its application. If the above-mentioned drugs are ineffective, other DMARD drugs such as Airova and cyclosporine can be used as appropriate.
3.Biological agents.
With the in-depth research on AS, new biological agents for the treatment of AS have been carried out in recent years to alleviate and improve the disease, and the research on them has become the current hot spot of research. In recent years, anti-TNF-α therapy has been tried at home and abroad for the treatment of AS, and has achieved better efficacy. At present, the biological agents used clinically for the treatment of AS mainly include soluble TNF-a receptor (Etanercept) and anti-TNF-α monoclonal antibody (Infliximab).
(1), Etanercept.
Etanercept is a fully humanized dimeric fusion protein formed by fusing the extracellular segment of the TNF-α receptor p75 with the human IgG1 Fc segment, which binds with high affinity to TNF-α, causing the loss of biological activity of TNF-α. Etanercept has been approved for the treatment of rheumatoid arthritis, AS, polyarticular juvenile rheumatoid arthritis and psoriatic Etanercept has also been extensively studied for the treatment of AS. In the study conducted by Gorman, 40 patients were treated with either 25 mg of Etanercept (25 mg 2 times/week) or placebo in two groups.
(i) patients entering the study continued with DMARD (40%) and hormones (25%); and (ii) different efficacy evaluation parameters were used. After 6 months of treatment, the main efficacy evaluation parameters such as morning stiffness and nocturnal spinal pain improved significantly in the treatment group and did not change in the placebo group. The combined disease activity score did not improve at 6 weeks, but improved significantly at 6 months. a study by InmanRD et al. of 20 patients with AS showed significant improvement in signs and symptoms in adult patients with early AS after at least 24 weeks with Etanercept. treatment of AS with Etanercept improved clinical symptoms and acute analogs of the spine and sacroiliac joints including MRI MaksymowychWP et al. studied two groups of AS patients, one group treated with placebo versus Etanercept for 16 weeks in a randomized controlled trial, and the other group treated with Infliximab after conventional treatment was ineffective. After analyzing these data, Maksymowych WP concluded that Etanercept may correct cartilage destruction to some extent and may improve the clinical symptoms of AS, but larger and more in-depth studies are needed to verify this. The main adverse effects of Etanercept include infusion reactions, delayed metaplasia, increased chance of infection, exacerbation of heart failure, and a possible increase in the incidence of lupus-like syndrome and malignancies of the lymphatic system and bone marrow.
(2), Infliximab.
Infliximab is a chimeric anti-TNF-α monoclonal antibody on the human/mouse IgG1K isotype chain, consisting of a human constant region and a murine variable region that binds specifically to human TNF-α and does not inhibit the activity of TNF-β.
Infliximab has been approved for the treatment of active rheumatoid arthritis, Crohn’s disease, psoriatic arthritis and AS. It is also effective in reactive arthritis, spondyloarthropathies of undetermined classification, adult Still’s disease, and nodular disease. Infliximab was administered at a dose of 5 mg/kg by intravenous infusion three times at 0, 2, and 6 weeks in a 12-week open study conducted in Berlin in June 2000 in patients with severe AS with a mean disease duration of 5 years. As a result, 9 of the 10 patients showed an improvement in the BathAS Disease Activity Index (BASDAI) of >50%, with a mean improvement in BASDAI of >70% after 4 weeks of treatment initiation and, more importantly, a significant improvement in SF-36 quality of life, particularly in the somatic health component, after 4 weeks of treatment. Since then, open studies of Infliximab for AS or SpA have been conducted in Belgium, Canada, France, and Spain, with similar treatment responses of 80% in all patients.
SchattemanL observed by intra-articular injection of 100 mg Infliximab into the joint cavity in three patients who met the diagnostic criteria for AS New York, in patients with recurrent knee osteoarthritis despite NSAID, SSZ, and intra-articular hormone injections, with significant clinical and biological changes and MRI findings of improvement. The authors concluded that intra-articular injection of Infliximab is a safe and effective alternative to the non-intestinal route in patients with AS with refractory monoarthritis, as evidenced by the efficacy of intra-articular injection of Infliximab in patients with difficult to control manifestations of arthritis.
In a pilot study by BraunJ et al, patients treated with Infliximab for 2 years had slower progression in imaging compared to conventional therapy in a randomized control setting, and serious side effects were rare with anti-TNF therapy, but serious infections, including tuberculosis, have been reported. With proper attention and management, these can be largely avoided. In a study evaluating long-term treatment of AS patients with infliximab in Canada, Kobelt G et al. showed a high cost-effectiveness of treating active AS patients with infliximab. Although the efficacy of infliximab in the treatment of AS has been confirmed, the durability of its efficacy and relapse after discontinuation remain to be further investigated and addressed. baraliakosX et al. analyzed the response to infliximab and relapse after discontinuation in patients with AS treated with infliximab for a sustained period of time. METHODS: Forty-two patients with AS treated with Infliximab for 3 years were followed up regularly for 1 year after discontinuation of Infliximab treatment to observe relapse. RESULTS: At 52-week follow-up after discontinuation of Infliximab treatment, all but one of the AS patients had an active relapse. In patients with moderate to severe congestive heart failure, Infliximab may exacerbate heart failure. Some patients may experience infusion reactions to Infliximab during and 1-2 h after the infusion, including headache, nausea, increased blood pressure or shortness of breath, or palpitations, chest pain, dizziness, pruritus, fever, rash, and flushing. These reactions are usually mild and infusion reactions that lead to treatment interruption are uncommon. Usually these reactions occur with the first infusion and are easily controlled by the medication. Late onset metabolic reactions may also occur. Preliminary results of anti-TNF therapy in AS suggest that it may improve signs and symptoms, maintain joint function, and improve quality of life in most patients with refractory AS. The long-term efficacy and adverse effects need to be further confirmed by increasing the number of cases and conducting multicenter, double-blind, placebo-controlled studies. Since biologics are expensive, the indications should be strictly controlled, the disease should be closely observed, and the drug should be selected according to the patient’s financial situation.
However, it is still controversial whether anti-TNF therapy can improve the progress of ossification in patients, and further studies are needed.
4.Other treatments.
(1), response to stop (Thalidomide).
(Thalidomide) can inhibit the production of TNF-α and IL-l2 by monocytes, and can also synergistically stimulate human T lymphocytes and helper T cell response, as well as inhibit angiogenesis and adhesion molecule activity. The clinical observation shows that the response stop can reduce the serum TNF-α level of leprosy patients by 5O%~80%.
Huang Feng et al. conducted a 1-year open trial to verify whether response arrest has potential therapeutic effects on ankylosing spondylitis (AS) and to investigate its mechanism of action at the genetic level. Seven clinical indicators (BASDAI, BASFI, Likert scale for generalized pain and spinal pain, time to morning stiffness, and overall patient and physician evaluations) were used as the primary efficacy indicators, and six other clinical indicators (chest expansion and spinal pain) were used. Six other clinical indicators (chest expansion, finger distance, occipital wall distance, Schober test, blood sedimentation and c-reactive protein level) were used as secondary efficacy indicators. Inflammatory gene expression profiles in peripheral blood mononuclear cells (PBMC) of some patients were also studied by gene microarray and then validated by reverse transcription-polymerase chain reaction (RT-PCR). A total of 26 patients completed the trial with few and mild toxicities, and 80% of the patients had improvements of more than 20% in four of the seven major efficacy measures. Between the 3rd and 6th months of treatment, certain indices decreased significantly, and pain symptoms disappeared in 9 patients; at the same time, tumor necrosis factor (TNF)-α transcripts in PBMC were significantly reduced in patients. Conclusions Reactivation is a promising drug for refractory AS, and its biological mechanism of action is related to the suppression of inflammatory factor TNF-a gene expression. However, because of its effects on fetal development, it is contraindicated in women who are pregnant or at risk of conception. Peripheral neuropathy may occur in some cases. Other side effects include morning sleepiness, dry mouth and constipation.
(2) Pamidronate.
Pamidronate is a diphosphonate drug that has an inhibitory effect on bone resorption. Recent studies have found that it can inhibit the antigen-presenting effect of monocytes by inhibiting IL-1β production, macrophage growth, migration, differentiation and viability. Pamidronate inhibits the production of TNF-α, IL-1β, IL-6 and other inflammatory cytokines by macrophage cell lines cultured in vitro.
Akerkar et al. treated 16 patients with active AS who were not well treated with NSAID with pamidronate. 16 patients with AS with a mean disease duration of 12.3 years were randomized to 2 groups, one group was treated with pamidronate 6 times/month for 6 months, 30 mg/dose for the first 3 months and 60 mg/dose for the last 3 months; the other group was treated with pamidronate only for 3 months, 60 mg/dose for the last 3 months. The results of the clinical trial were summarized and showed that pamidronate had significant efficacy in the treatment of AS patients who had poor results with NSAID therapy, but its efficacy was not maintained for long after discontinuation.
Akerkar also analyzed several studies on the treatment of AS with pamidronate and concluded that pamidronate is a promising treatment option for AS, especially in early AS patients with short duration of disease. Its side effects are mainly mild arthralgia and myalgia, fever, etc. after intravenous injection.
5. Outlook.
From the beginning of the recognition of AS as a disease, with the research on its pathogenesis, its treatment plan has been continuously improved and new therapeutic drugs have been discovered. Although the pathogenesis is still unclear and no curative treatment plan or drug has been researched, better results have been achieved in improving patients’ clinical symptoms and quality of life and alleviating their conditions, especially the research on biological agents in recent years has shown that The treatment of AS has a very good prospect.