Ankylosing spondylitis (AS) is a chronic rheumatic inflammatory disease that primarily affects the spine and sacroiliac joints. The quality of life of patients with AS is greatly reduced and the risk of disability and death is increased, while the high cost of treatment and the reduced ability of patients to work cause a great economic loss to society. Therefore, it is particularly important to treat AS in a rational and effective manner.
At present, the treatment of AS is mainly divided into non-pharmaceutical and pharmaceutical methods. The former mainly includes rehabilitation exercises, physical therapy and surgery. Non-surgical treatment can improve the symptoms and increase the mobility of the spine but cannot slow down the progression of the disease. Patients are generally advised to start rehabilitation exercises as soon as they are diagnosed, and are advised to do more exercises that enhance spinal mobility (e.g., swimming, running, etc.). Physical therapy is also recommended for better results.
Drug treatment for AS has always been very limited. However, with the development of biopharmaceutical technology, there has been a huge leap in the efficacy of drugs for AS. In conclusion, the goal of treatment is to control symptoms, reduce inflammatory response, maintain and restore spine and joint function as much as possible, prevent further organic damage caused by the disease, prevent disability due to the disease, and enable the patient to live as high a quality of life as possible.
In a recent article in Turk J Med Sci, the Turkish scholar Sari reviewed the pharmacological treatment of AS. This article includes almost all the current pharmacological treatments for AS and is intended to be a reference for both the patient and the physician in order to develop a more rational treatment plan.
The diagnosis of ankylosing spondylitis should meet both imaging criteria and one of the following clinical criteria
1. Clinical criteria
(1) Low back pain and stiffness for more than 3 months, aggravated by activity and not relieved by rest.
(2) Restriction of lumbar spine movement in both the sagittal and coronal positions.
(3) Restricted thoracic movement compared to normal people of the same age and sex.
2.Imaging criteria
Bilateral sacroiliac arthritis ≥ level 2 or one sacroiliac arthritis level 3 to 4
Note: All ankylosing spondylitis discussed in this article are diagnosed using the “Modified New York Criteria for Ankylosing Spondylitis” as the criteria.
Non-steroidal anti-inflammatory drugs (NSAIDs)
1. General drug description
NSAIDs are the first-line drugs currently used in the treatment of AS. A number of randomized controlled trials have shown that NSAIDs are effective in AS, mainly in reducing spinal pain, relieving morning stiffness and improving spinal function, especially in peripheral joint pain, and in reducing acute phase protein levels.
The efficacy of these drugs is dose dependent. Most patients experienced significant relief of low back pain and stiffness within 48 days of taking the full dose, but symptoms returned after 2 days of discontinuation. 70% to 80% of patients felt that these drugs provided good relief. However, it was effective in only 15% of patients with spinal pain due to mechanical injury, which is a useful way to identify whether low back pain is due to inflammation or mechanical injury.
In addition, patients with no improvement in symptoms after NSAIDs tend to have a poor prognosis. Several studies have shown that selective or non-selective NSAIDs are equally effective in the treatment of AS, with no significant difference between the two. The question of how to decide the dose of NSAIDs is often encountered in clinical practice, and several studies have shown that the dose of NSAIDs should be adjusted according to the degree of the patient’s symptoms. The dose of NSAIDs should be adjusted according to the degree of the patient’s symptoms. Clinical treatment should be observed and the timing of dosing should be adjusted according to the situation to achieve the best efficacy. Long-acting formulations should be administered at night for patients with severe nocturnal pain and morning stiffness.
The maximum recommended dose of each type of NSAIDs is as follows.
Drug name Maximum recommended dose (mg) Diclofenac sodium
150
Naproxen
1000
Aceclofenac
200
Celecoxib
400
Etodolac
600
Etoricoxib
90
Clopirofen
200
Protaxon
400
Ibuprofen 2400 indomethacin 150 ketoprofen 200 meloxicam 15 nimesulide 200 piroxicam 20 tenoxicam 20
Another question is whether NSAIDs should be taken when symptoms are present or whether they should be taken regularly over time. Patients who take NSAIDs regularly for more than a year continue to experience pain relief and improved function. In addition, there is evidence that long-term continuous use of NSAIDs can slow down lesions found on imaging. However, given the cardiovascular and gastrointestinal side effects associated with NSAIDs, the authors of this article, taking into account FDA and European Medicines Agency guidelines, recommend that patients be treated with the smallest effective dose for the shortest possible duration of therapy.
Recently, especially since the introduction of TNF-α inhibitors in clinical practice, some patients have developed resistance to NSAIDs. In general, the efficacy of NSAIDs is maximized within 1 to 2 weeks; however, in some cases it may take a longer period of dosing (approximately 6 weeks) to find the optimal dose. Some patients who are not sensitive to certain NSAIDs may be sensitive to another drug. Therefore, it is important to try multiple drugs at the maximum dose.
According to the French guidelines, if a patient has no contraindications to NSAIDs and more than 3 consecutive drugs are not effective for 3 months at a tolerable dose, then NSAIDs treatment has failed. According to the UK National Institute for Health and Care Excellence (NICE) guidelines, a patient is NSAIDs resistant if more than 2 drugs have been administered for 4 weeks at the maximum dose.
The latest edition of the International Ankylosing Spondylitis Society (ASAS) guidelines follows these criteria, whereas the previous guidelines required patients to take 3 months of continuous medication failure. Patients in the active phase of disease (BASDAI ≥ 4) who have not responded to NSAIDs should immediately begin 4 weeks of TNF blocker therapy, followed by expert opinion on the need for further biologic therapy.
2. Side effects of NSAIDs
Previously, studies of NSAIDs for the treatment of AS were short-lived and the study population was small. After the introduction of selective COX-2 inhibitors, a large number of long-term studies were conducted to compare their efficacy with that of traditional non-selective drugs. It was found that the side effects of NSAIDs for AS were similar to those of other rheumatic diseases, with no major differences in safety between long-acting and short-acting agents.
(1) Cardiovascular side effects
Rofecoxib was the first NSAID to be reported to have cardiovascular side effects. Subsequent studies have found similar side effects with other COX-2 inhibitors and traditional non-selective NSAIDs, suggesting that cardiovascular side effects are common among NSAIDs.
The strength of cardiovascular side effects is influenced by patient age, cardiovascular history, and the dose of NSAIDs. Younger patients rarely experience serious cardiovascular system side effects when treated with NSAIDs because they rarely have underlying cardiovascular system disease.
In addition, there was no significant difference in the incidence of cardiovascular side effects whether NSAIDs were taken continuously or only when they were symptomatic. Although NSAIDs have antithrombotic effects, they can cause or exacerbate hypertension, which may exacerbate cardiovascular systemic risk.
With the exception of naproxen, the cardiovascular system risks associated with the remaining nonselective NSAIDs are similar to those associated with selective COX-2 inhibitors (with the exception of rofecoxib). Naproxen is the only NSAIDs reported to be free of cardiovascular side effects. The reason for this is that higher doses (550 mg twice daily) of naproxen inhibit platelet thrombosis and reduce platelet aggregation. diclofenac has the highest cardiovascular systemic risk of the NSAIDs, followed by ibuprofen.
(2) Gastrointestinal side effects
The gastrointestinal side effects caused by NSAIDs are widely known, mainly due to the inhibition of prostaglandin synthesis in the gastric mucosa by NSAIDs. Studies have shown that patients taking NSAIDs for a long time have an increasing risk of gastrointestinal side effects. However, short-term use of NSAIDs does not prevent the risk of gastrointestinal side effects. In comparison, patients taking NSAIDs on a long-term basis are at a higher risk of gastrointestinal side effects.
The risk of serious gastrointestinal symptoms such as ulceration, bleeding and perforation was 5.4 times higher in patients taking NSAIDs, and the risk of complications was dose dependent. Although the risk of serious gastrointestinal complications is lower with selective COX-2 inhibitors than with non-selective NSAIDs, the two classes of drugs are equally likely to cause dyspepsia and mild gastrointestinal reactions, which are the main cause of discomfort in most patients.
When combined with conventional non-selective NSAIDs and proton pump inhibitors, misoprostol or double doses of H2 receptor inhibitors, the effects on the gastrointestinal tract are similar to those of selective COX-2 inhibitors. Previous studies have identified several risk factors for serious gastrointestinal side effects when taking NSAIDs, including age 60 years or older, history of ulcers and their complications, concomitant steroid hormones or anticoagulants, high dose aspirin dosing (325 mg/g), alcohol consumption, smoking, high dose or concomitant use of 2 NSAIDs, and underlying H. pylori infection, etc.
Traditionally, NSAIDs were thought to cause ulcers in the posterior duodenum; more recent studies suggest that NSAIDs may contribute to colonic ulcers and their complications. It has been speculated that the use of NSAIDs may contribute to the development of inflammatory bowel disease (IBD). However, studies have found that the use of selective COX-2 inhibitors does not increase the risk of developing IBD. The results of prospective controlled trials suggest that there is no evidence that taking non-selective NSAIDs increases the risk of IBD.
3. Dosing recommendations
(1) NSAIDs can improve spinal pain, morning stiffness, and spinal function, as well as joint and muscle pain at the point of origin and destination. Therefore, NSAIDs should be used as the first-line treatment for ankylosing spondylitis. Treatment should start at the maximum dose and be adjusted according to patient response and tolerance. NSAIDs are not required in asymptomatic patients.
(2) There is no difference in efficacy between selective and non-selective NSAIDs. The main considerations when selecting a drug are the risk of side effects, price, dosing interval (the smaller the number of doses, the greater the chance of complications), individual response to the drug, and drug interactions.
(3) Patients with nocturnal pain and morning stiffness may take long-acting preparations at night.
(4) Concomitant administration of multiple NSAIDs should be avoided because it does not further alleviate the symptoms, but rather aggravates the gastrointestinal side effects of the drug.
(5) Naproxen is recommended for patients with high risk factors in the cardiovascular system.
(6) Patients with AS combined with IBD can take NSAIDs during the inactive phase of IBD.
Disease modifying antirheumatic drugs (DMARDs)
1. General description of drugs
Disease modifying antirheumatic drugs (DMARDs) are drugs used to suppress synovial inflammation and prevent organic damage in the treatment of rheumatic diseases. However, none of the DMARDs have been found to have a “disease-modifying” effect on ankylosing spondylitis.
There are many studies on the effects of salazosulfapyridine (SSZ) in the treatment of AS, and two meta-analyses have demonstrated the therapeutic effects of SSZ in AS. The first meta-analysis found that SSZ reduced pain, shortened the duration of morning stiffness, and decreased blood sedimentation compared to the placebo group. Another meta-analysis showed that SSZ was more effective in patients with early disease who had high sedimentation (indicating active disease) and peripheral joint involvement.
Results from a randomized controlled trial showed that patients with AS treated with SSZ had less acute anterior uveitis and occurred less frequently. Studies have not found SSZ to be effective for finger (toe) inflammation or stopping point inflammation.
The effectiveness of methotrexate (MTX) in treating AS has been investigated. In an open study of 17 patients over a 3-year period, low-dose MTX was found to relieve nocturnal pain, improve general condition, and reduce sedimentation and C-reactive protein levels. In addition, patients’ Schober scores and pronation distances increased, and the dosage of NSAIDs was reduced. On the other hand, imaging revealed no worsening of the spine or sacroiliac joint lesions during the study.
However, in another open study, researchers administered MTX 12.5 mg subcutaneously weekly for one year and did not find any improvement in axial symptoms (such as spinal pain, morning stiffness, and spinal motion). However, anterior uveitis did not occur, and the number of patients with peripheral joint inflammation was greatly reduced.
In a recent open study of 20 patients with active AS who were given 20 mg MTX subcutaneously weekly for 16 weeks, their mean BASDAI scores at 16 weeks were unchanged from pre-treatment, and there was no improvement in the remaining clinical parameters or CRP levels, with only a slight but non-significant reduction in joint swelling.
Similarly, in a randomized controlled trial comparing MTX with naproxen and other drugs, researchers found no difference in outcomes between patients using MTX and those using placebo in several areas, including peripheral arthropathy, and the ASAS/EULAR guidelines state that there is no evidence that MTX is effective in AS.
The ASAS/EULAR guidelines also state that there is no evidence that DMARDs (including SSZ and MTX) are effective in reducing medial joint symptoms, but that SSZ can be used to treat peripheral joint inflammation. The ASAS/EULAR guidelines also state that there is no evidence that DMARDs (including SSZ and MTX) reduce medial symptoms, but SSZ can be tried for peripheral joint inflammation.
2. Medication recommendations
(1) Although there is a lack of evidence that SSZ relieves mid-axis symptoms caused by AS, some physicians still use SSZ for patients with only mid-axis symptoms according to their clinical experience.
(2) SSZ (2-3 g daily) may be used in patients with peripheral joint inflammation. However, this drug is not effective in finger (toe) inflammation or onset and endpoint inflammation.
(3) There is insufficient evidence that MTX or LEF can alleviate mid-shaft or peripheral symptoms caused by AS.
(4) Treatment with SSZ should be considered for patients with acute anterior uveitis.
Corticosteroids
1. General drug discussion
There are few data on the use of glucocorticoids for the treatment of AS, and although there is a lack of results from controlled trials on the efficacy of small doses for AS, some experts believe that systemic application of small or moderate doses of glucocorticoids does not improve the symptoms of AS.
However, in a recent small randomized controlled trial, positive results were seen after oral administration of high-dose prednisone over two weeks in patients with active disease. In this trial, patients who were not sensitive to NSAIDs were grouped separately. They were given 20 mg, 50 mg of prednisone or placebo orally daily for two weeks and found that patients taking 50 mg of prednisone daily had improved symptoms compared to those taking placebo, while those taking 20 mg of prednisone daily were no different from the placebo group.
In addition, some scholars have also administered intravenous glucocorticoids to subjects and found that patients’ symptoms improved after treatment. However, the French guidelines do not recommend systemic glucocorticoids for patients with AS, except in certain special cases (e.g., pregnancy).
The ASAS/EULAR guidelines also discourage the systemic administration of glucocorticoids to patients with AS who have mid-axis symptoms. Despite the lack of data from controlled trials, topical glucocorticoids can be recommended for patients with peripheral joint inflammation and enthesitis. One open study evaluated the efficacy of glucocorticoid injections in the sacroiliac joint and found significant improvement in sacroiliac joint pain, and that imaging-guided injections were more effective than blind injections.
2. Recommendations for medication administration
(1) Systemic glucocorticoids should be avoided in patients with AS, except for special conditions (e.g. pregnancy) where other treatments are not available.
(2) For patients with severe sacroiliac joint pain that is not treated with maximum doses of NSAIDs, glucocorticoid injections in the sacroiliac joint under imaging guidance may be considered.
(3) Patients with intractable enthesitis, peripheral joint inflammation, or hip osteoarthritis may have improved symptoms with intra-articular or local glucocorticoid injections.
TNF inhibitors
1. General information of drugs
Since the discovery of TNF-α in relation to the development of AS, TNF inhibitors have been used to treat AS with remarkable efficacy and represent a revolutionary advance in the pharmacological treatment of AS. The TNF inhibitors currently approved for the treatment of AS are infliximab (INF), etanercept (ETA), adalimumab (ADA), and griseofulvin (GOL).
(1) Infliximab (INF)
INF is a human-mouse somatic monoclonal antibody to TNF-α and is the first biologic agent tested in a randomized controlled trial for the treatment of AS. The results of the trial showed that INF was effective in reducing patients’ mid-shaft and peripheral joint symptoms, including initiation and termination point inflammation. In addition, it was effective in improving quality of life, improving spinal mobility and reducing C-reactive protein levels.
INF has a rapid onset of action, with the most pronounced effect after 2 weeks of treatment. The clinical efficacy of INF has been shown to last up to 8 years at long-term follow-up and is safe. It has also been reported that 90% of patients who take INF intermittently relapse within 36 weeks, but then return to INF on a regular basis for safe and effective symptom control.
(2) Etanercept (ETA)
ETA is a dimeric human fusion protein that links two human p75 TNF receptors through the Fc segment of IgG1, and binds TNF receptors and bound lymphotoxin-α efficiently. It is also effective in the treatment of arthritis and enthesitis caused by AS and in improving pulmonary function, and is more effective than SSZ in improving peripheral joint inflammation.
In patients with active AS, the clinical efficacy of ETA has been shown to be safe for 7 years. In previous trials, ETA was administered at a dose of 25 mg twice weekly, but the current dose commonly used in clinical practice is 50 mg weekly. randomized controlled trials have shown that high doses (100 mg weekly) are still safe but do not significantly increase their efficacy. Patients tend to relapse after discontinuation of the drug, but the efficacy does not diminish after reintroduction of the drug.
(3) Adalimumab (ADA)
ADA is a complete human TNF-α antibody. The recommended dose is 40 mg subcutaneously every other week. randomized controlled trials have shown that ADA significantly relieves mid-axis symptoms caused by AS, improves spinal mobility and function, and relieves peripheral joint inflammation, enthesitis and acute anterior uveitis, reduces reactive protein levels, and improves quality of life.
The efficacy of ADA can be safely sustained for up to 5 years. ADA remains effective in patients with underlying disease.
Several studies have demonstrated that both INF and ADA can treat moderate to severe Crohn’s disease. In addition, INF and ADA have been shown to provide symptomatic relief in patients with moderate-to-severe acute ulcerative bowel disease when other conventional medications have failed. In patients with AS combined with IBD, INF significantly reduces the number of IBD episodes more frequently than placebo, ETA, or ADA, and the frequency of IBD episodes in these patients on ETA is the same as on placebo.
AAU has been used clinically to treat AS alone, and several studies have been conducted to investigate the efficacy of AAU. In an open study, ADA reduced the incidence of uveitis in patients with AS in the acute phase. Another study showed that monoclonal TNF inhibitors were the most effective in preventing uveitis.
(4) Other applications
In addition to improving the clinical symptoms of AS, TNF inhibitors can also reduce spinal inflammation.
In a double-blind controlled trial, researchers tested four INF inhibitors: INF, ETA, ADA and GOL. The results showed a reduction in spinal inflammation of about 50 percent by MRI at 12 weeks, and the treatment effect was maintained until week 104. However, imaging revealed that 2 years of treatment with ETA, INF and ADA did not slow the progression of AS. A database search revealed that TNF, while reducing spinal inflammation in AS, did not prevent the organic damage caused by AS.
Because of the high price of TNF-α inhibitors, the effect of TNF-α inhibitors should be evaluated at 6 to 12 weeks and should not be continued when they are found to be ineffective. According to the French Society of Rheumatology criteria, TNF inhibitor therapy is considered ineffective when the patient’s BASDAI (on a 10-point scale) improves by more than two points. According to the ASAS criteria, an absolute change in BASDAI of more than 20 (on a scale of 100) is required.
If a patient discontinues a TNF-α inhibitor in the middle of a treatment period that causes side effects, another TNF-α inhibitor may be used. Studies have shown that patients who have switched to another TNF inhibitor have better outcomes, so switching TNF drugs may be allowed in the treatment of AS. In addition, no patient has been found to be intolerant to TNF-α inhibitors.
2.Dosing recommendations
(1) TNF inhibitors are effective in relieving mid-shaft symptoms, peripheral joint inflammation, and panniculitis.
(2) TNF inhibitors are recommended for patients in the active phase (BASDAI score ≥ 4) compared to conventional drugs.
(3) Patients with mid-axis symptoms who do not have contraindications to NSAIDs should be treated with a combination of two NSAIDs for 4 weeks at the maximum tolerated dose.
(4) Patients with AS who have peripheral joint inflammation may be treated with SSZ on a trial basis.
(5) Current studies do not recommend the concomitant use of MTX with INF or other TNF inhibitors.
(6) The efficacy of various TNF inhibitors is basically the same. However, the choice of drug should be based on the safety of the drug and the patient’s individual situation, with monoclonal antibodies preferred in patients with intestinal disease.
(7) After 12 weeks of continuous use of a TNF inhibitor is ineffective, another TNF inhibitor can be tried.
(8) According to MRI results, TNF inhibitors can reduce spinal inflammation but do not prevent organic damage (at least 2 years later).