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 ≥ grade 2 or one sacroiliac arthritis grade 3 to 4
Note: All ankylosing spondylitis discussed in this article are diagnosed using the “Ankylosing Spondylitis Modified New York Criteria” as the standard.
Non-steroidal anti-inflammatory drugs (NSAIDs)
1. General drug description
These drugs include non-selective antipyretic and anti-inflammatory drugs as well as selective COX-2 inhibitors. Several 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 also in reducing acute phase protein levels.
The efficacy of this class of 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 reappeared after 2 days of discontinuation. 70% to 80% of patients felt that these drugs provided good relief. However, only 15% of patients with spinal pain due to mechanical injury were found to be effective, making this a useful method of identifying whether the back pain was due to inflammation or mechanical injury.
In addition, patients with no improvement in symptoms after the use of 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. Clinical treatment should be observed and the timing of dosing should be adjusted according to the situation in order to achieve optimal efficacy. Long-acting preparations should be administered at night in cases of 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 symptomatic 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 recommend that patients be treated with the smallest effective dose for the shortest duration of therapy, taking into account FDA and European Medicines Agency guidelines.
Recently, especially since the introduction of TNF-α inhibitors into clinical use, some patients have developed NSAIDs resistance. In general, the efficacy of NSAIDs reaches its maximum within 1 to 2 weeks; however, some cases may require longer dosing (roughly 6 weeks) to find the optimal dose. Some patients who are not sensitive to certain NSAIDs drugs may be sensitive to another drug. Therefore, multiple drugs must be tried at the maximum dose.
According to the French guidelines, if a patient has no contraindications to NSAIDs per se and more than 3 drugs applied consecutively are not effective for 3 months at tolerable doses, NSAIDs treatment has failed. And according to the National Institute for Health and Care Excellence (NICE) guidelines, if a patient applies more than 2 drugs that are ineffective for 4 weeks at the maximum dose, the patient has NSAIDs resistance.
The latest edition of the International Ankylosing Spondylitis Academic Societies (ASAS) guidelines follows these criteria, whereas the previous guidelines required patients to be ineffective for 3 months of continuous medication. Patients in the active phase of disease (BASDAI ≥ 4) who are not responding to NSAIDs should be immediately started on a 4-week course of TNF blockers, 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, indicating that cardiovascular side effects are common among NSAIDs.
The strength of cardiovascular system side effects is mainly influenced by the patient’s 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 risk due to the remaining non-selective NSAIDs is similar to that of selective COX-2 inhibitors (with the exception of rofecoxib). Naproxen is the only NSAIDs drug 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 among NSAIDs, followed by ibuprofen.
(2) Gastrointestinal side effects
The gastrointestinal side effects caused by NSAIDs are widely known, and the main reason is that NSAIDs inhibit prostaglandin synthesis in the gastric mucosa. Studies have shown that patients taking NSAIDs for a long period of time are at 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 have a higher risk of gastrointestinal side effects.
The risk of serious gastrointestinal symptoms such as ulcers, 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 that may contribute to 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; recent studies suggest that NSAIDs may contribute to the development of colonic ulcers and their complications. It has been speculated that the use of NSAIDs may lead 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 developing IBD.
3. Medication recommendations
(1) NSAIDs can improve spinal pain, morning stiffness, and spinal function, and can also improve joint and muscle pain at the point of origin and termination. Therefore, NSAIDs should be used as the first line of treatment for ankylosing spondylitis. Treatment needs to be started at the maximum dose and then adjusted according to the patient’s response and tolerance level. Asymptomatic patients do not require the use of NSAIDs.
(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, as this does not further reduce symptoms, but rather exacerbates 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 anti-rheumatic 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 a therapeutic effect 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 a high sedimentation (indicating active disease) and whose lesions involved peripheral joints.
The results of a randomized controlled trial showed that patients with AS treated with SSZ developed acute anterior uveitis to a lesser extent and less frequently. Studies have not found SSZ to be effective in finger (toe) inflammation or stopping point inflammation.
Scholars have studied the effectiveness of methotrexate (MTX) for the treatment of AS. In an open study of 17 patients over a 3-year period, low-dose MTX was found to relieve nocturnal pain, improve systemic status, and reduce blood sedimentation and C-reactive protein levels. In addition, patients’ Schober scores and body precession distance increased, while the dosage of NSAIDs was reduced. On the other hand, imaging revealed that the patients had no worsening of spinal and sacroiliac joint lesions during the study period.
However, in another open study, the researchers administered subcutaneous MTX 12.5 mg per week for one year and did not find any improvement in the patients’ axial symptoms (such as spinal pain, morning stiffness, and spinal mobility). However, anterior uveitis did not occur, and the number of patients who developed peripheral joint inflammation was greatly reduced.
In a recent open study, 20 patients with active AS were given 20 mg of MTX subcutaneously weekly for 16 weeks and their mean BASDAI scores at 16 weeks were found to be unchanged from pre-treatment, while the remaining clinical indicators and CRP levels did not improve, and only a slight but non-significant reduction in joint swelling was noted.
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 in the ASAS/EULAR guidelines, which state that there is no evidence that MTX is effective for AS.
The ASAS/EULAR guidelines also state that there is no evidence that DMARDs (including SSZ and MTX) are effective in reducing medial symptoms, but SSZ can be used to treat peripheral joint inflammation. symptoms, but SSZ can be tried to treat peripheral joint inflammation.
2. Medication recommendations
(1) Although there is a lack of evidence that SSZ can alleviate mid-axis symptoms due to AS, some physicians still use SSZ for patients with mid-axis symptoms only according to their clinical experience.
(2) SSZ (2-3 g daily) can be used in patients with peripheral joint inflammation. However, this drug is not effective in finger (toe) inflammation and onset and termination points.
(3) There is insufficient evidence that MTX or LEF can alleviate mid-shaft or peripheral symptoms due to 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 of controlled trials on the efficacy of small doses for the treatment of AS, some experts believe that systemic application of small or moderate doses of glucocorticoids given 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 that trial, patients who were not sensitive to NSAIDs were grouped separately. They were given 20 mg and 50 mg of prednisone or placebo orally daily for two weeks, and it was found that patients who took 50 mg of prednisone daily had improved symptoms compared to those who took placebo, while those who took 20 mg of prednisone daily were no different from the placebo group.
In addition to this, 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 glucocorticosteroids for AS patients, 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. An 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.Medication recommendations
(1) Systemic glucocorticoids should be avoided in patients with AS, except in special conditions (e.g. pregnancy) where other treatments cannot be used.
(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 can be considered.
(3) Patients with intractable initiation and termination points, peripheral joint inflammation, or hip osteoarthritis may have improvement in symptoms after intra-articular or local glucocorticoid injections.
TNF inhibitors
1.Drug general introduction
Since the discovery of the association of TNF-α with the development of AS, the use of TNF inhibitors for the treatment of AS has achieved significant efficacy and represents 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 pointitis. 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. According to long-term follow-up results, the clinical efficacy of INF lasts up to 8 years and is safe. It has also been reported that 90% of patients who take INF intermittently relapse within 36 weeks, but then resume regular INF use to safely and effectively control their symptoms.
(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 to TNF receptors and lymphotoxin-α efficiently. ETA is also effective in the treatment of arthritis and enthesitis caused by AS and in improving pulmonary function, and its effect in improving peripheral joint inflammation is better than that of SSZ.
In patients with active AS, the clinical efficacy of ETA can be safely sustained 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 can significantly relieve the mid-axis symptoms caused by AS, improve spinal mobility and function, as well as relieve peripheral joint inflammation, enthesitis and acute anterior uveitis, reduce reactive protein levels, and improve patients’ quality of life.
The efficacy of ADA can be safely sustained for 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 continue to provide symptomatic relief in patients with moderate-to-severe acute ulcerative bowel disease when other conventional medications are not effective. In patients with AS combined with IBD, INF significantly reduces the number of IBD episodes and is more effective than placebo, ETA, or ADA. the frequency of IBD episodes in such patients on ETA is the same as on placebo.
Several studies have been conducted to investigate the efficacy of AAU, including a meta-analysis in which INF and ETA were more effective in preventing acute anterior uveitis and another in which ETA was more effective than STZ in preventing acute anterior uveitis. In an open study, ADA reduced the incidence of uveitis in patients with AS in the acute phase. According to another related study, 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 found that spinal inflammation was reduced by about 50% by MRI at 12 weeks, and the treatment effect was maintained until week 104. However, imaging revealed that a 2-year treatment with ETA, INF and ADA did not slow the progression of AS. A database search revealed that TNF, although reducing spinal inflammation in AS, did not prevent organic damage due to 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 (10-point scale) improves by more than two points. If the ASAS criteria are followed, an absolute change in BASDAI of more than 20 (on a 100-point scale) is required.
If a patient discontinues a TNF-α inhibitor midway leading to side effects, another TNF-α inhibitor treatment can be chosen. Some studies have shown that patients who have changed to another TNF inhibitor have better outcomes, therefore, changing TNF drugs can be allowed in the treatment of AS. In addition, no patients who cannot tolerate TNF-α inhibitors have been seen so far.
2.Dosing recommendations
(1) TNF inhibitors are effective in relieving mid-axis symptoms, peripheral joint inflammation, and initiation and termination point inflammation.
(2) Patients in the active phase (BASDAI score ≥4) are more recommended to use TNF inhibitors than conventional drugs.
(3) Patients with mid-axis symptoms who have no contraindications to NSAIDs should be treated with a combination of two NSAIDs for 4 weeks at the maximum tolerated dose.
(4) Patients with AS in the presence of peripheral joint inflammation may be tried with SSZ therapy.
(5) The current study does not recommend the concomitant addition of MTX with INF or other TNF inhibitors.
(6) The efficacy of various TNF inhibitors is basically the same. However, the selection of drugs should be based on the safety of the drugs and the individual conditions of the patients. Monoclonal antibodies are preferred for patients with intestinal diseases.
(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 cannot prevent (at least 2 years later) organic damage.