Although the pathogenesis of ankylosing spondylitis is still not fully understood and there is still much confusion in the clinical management, considerable new experience has been gained in recent years with new strategies for its treatment, and in 2009 the 73rd American College of Rheumatology reported the latest diagnostic criteria for ankylosing spondylitis.
Ankylosing spondylitis (AS) is a systemic inflammatory disease characterized by involvement of the spine and sacroiliac joints. The majority of patients present clinically with inflammatory low back pain, stiffness and limitation of motion, and some may have peripheral arthritis, tendon telangiectasia, ophthalmopathy and other extra-articular manifestations. With the in-depth research on the causative factors of AS, although the causative mechanism is still not fully understood and there is still a lot of confusion in clinical diagnosis and treatment, new strategies for its treatment have gained considerable new experience in recent years.
1. Diagnosis
1.1 Diagnostic criteria
The diagnosis of AS is mainly based on clinical diagnosis and X-ray performance. The X-ray of sacroiliitis is divided into 4 grades according to the degree of lesion: grade I, suspicious; grade II, with mild sacroiliac arthritis; grade III, with moderate sacroiliac arthritis; grade IV, with joint ankylosis. At present, the New York standard of 1966 or the revised New York standard of 1984 is still used at home and abroad.
1.1.1 1966 New York standard Definite AS: X-ray confirmed bilateral grade III-IV sacroiliitis with one or more of the following clinical manifestations: ① restriction of movement in three directions of lumbar flexion, extension and lateral bending; ② history or present history of low back pain; ③ thoracic mobility (4th rib space level) less than 2.5cm or unilateral grade III-IV or bilateral grade II sacroiliitis with item ① or item ② + ③. Possible AS: Bilateral grade III-IV sacroiliac arthritis without clinical manifestations.
1.1.2 New York criteria revised in 1984 The diagnostic conditions are
① lower back pain of at least 3 months’ duration, with pain improving with activity but not relieved by rest;
②Lumbar spine movement is limited in the anterior-posterior and lateral flexion directions;
③Thoracic extension range is less than the normal value for the same age and sex;
④Bilateral sacroiliac arthritis grade II-IV, or unilateral sacroiliac arthritis grade III-IV. If the patient has ④ and any 1 of ① to ③ respectively, AS can be diagnosed.
Definite AS: Those who meet radiological criteria and 1 or more clinical criteria. Possible AS: Those who meet 3 clinical criteria or meet radiological criteria without any clinical manifestations. Since the radiological criteria only reflect the morphological changes of the sacroiliac joint, the disease is not early when the sacroiliac joint shows radiological changes. Clinically, some patients with short duration, mild or atypical disease may not fully comply with the above-mentioned diagnostic criteria of AS. For such patients, judgment should be made based on clinical symptoms and signs. Reference can also be made to the European Spondyloarthropathy (SpA) preliminary diagnostic criteria, and those who meet them are included in this category for diagnosis and treatment, and are followed up for observation.
Inflammatory low back pain (IBP) is an important indicator of SpA and AS classification criteria. 2009 73rd Annual American College of Rheumatology reported that a new set of criteria was recently recommended for the definition of IBP, and for those aged <45 years with chronic low back pain >3 months, the following suggest IBP.
(i) Morning stiffness is present;
②Improvement with activity but no relief with rest;
③Waking up in the middle of the night due to low back pain;
④ alternating hip area pain. The study showed that if two of the above four items were present, the specificity of the diagnosis of IBP was 81.2% and the sensitivity was 70.3%, and the specificity of the presence of three items was >95%.
The International Spondyloarthritis Assessment Task Force (ASAS)
The new classification criteria for medial axis SpA of the ASAS are: low back pain for more than 3 months, age of onset <45 years, and either X-ray or MRI confirmed sacroiliac arthritis plus at least 1 SpA manifestation, or HLA?B27 positive plus at least 2 other SpA manifestations, including IBP, arthritis, tendinitis (heel), uveitis, phalangitis, psoriasis rash, Crohn's disease/ulcerative colitis, good response to non-steroidal anti-inflammatory drugs (NSAIDs), family history of SpA, HLA?B27 positivity, and increased C?reactive protein (CRP) levels. The sensitivity of the new criteria was 82.9% and the specificity was 84.4%. The new criteria can reliably classify patients in clinical studies and facilitate the diagnosis of patients with mid-axis SpA who have chronic low back pain.
1.2 Differential diagnosis
AS should be differentiated from the following diseases: rheumatoid arthritis, disc herniation, tuberculosis, diffuse idiopathic bone hypertrophy syndrome, iliac dense osteitis, and other spondyloarthropathies.
2. Treatment options and principles
There is no cure for AS. However, if patients with AS are diagnosed and treated in a timely manner, they can control their symptoms and improve their prognosis. Non-pharmacological, pharmacological and surgical treatments should be used to relieve pain and stiffness, control or reduce inflammation, maintain good posture, prevent deformation of the spine or joints, and correct deformed joints if necessary, in order to improve and enhance the quality of life of patients.
2.1 Non-pharmacological treatment
Educate patients and their families about the disease. Advise patients to perform physical functional exercises carefully and without interruption to obtain and maintain the best position of the spinal joints, strengthen the paravertebral muscles and increase lung capacity, which is no less important than drug treatment. When standing, one should try to maintain a posture with the chest up, abdomen tucked in and eyes level in front. Sitting position should also keep the chest upright. You should sleep on a hard bed and take more supine position to avoid promoting flexion deformity position. Pillows should be short and should be discontinued once there is upper thoracic or cervical spine involvement. Reduce or avoid physical activities that cause persistent pain. Regular height measurements and keeping height records is a good measure to prevent early spinal curvature that is not easily detected. Use physical therapy as necessary for joint or other soft tissue pain.
2.2 Drug treatment
2.2.1 Non-steroidal anti-inflammatory drugs (NSAIDs) NSAIDs are one of the main symptomatic drugs traditionally used in the treatment of AS. These drugs prevent the synthesis of prostaglandins by inhibiting the activity of reductase, which in turn produces an anti-inflammatory effect and rapidly relieves patients’ low back pain and pain caused by other attachment points of inflammation, reduces joint pain, swelling and morning stiffness, and improves the quality of life. They play an important role in relieving patients’ clinical symptoms and improving their quality of life. However, adverse reactions in the gastrointestinal tract (nausea, vomiting, abdominal pain, abdominal distension, poor appetite, peptic ulcer, bleeding and perforation in severe cases) and their nephrotoxicity (decreased renal perfusion, water and sodium retention, hyperkalemia, hematuria, proteinuria, interstitial nephritis, and renal necrosis leading to renal insufficiency in severe cases) should also be taken seriously in clinical applications. Currently, there is a preference for the use of selective COX?2 inhibitors to reduce the gastrointestinal toxic side effects of this class of drugs.COX?2 is an inducible enzyme, so selective COX?2 inhibitors (e.g., cibotropic) not only have good anti-inflammatory and analgesic effects, but also have fewer adverse effects [1]. However, COX?2-inhibiting drugs may cause cardiovascular, renal, and allergic adverse effects and need to be taken seriously in their application.
The commonly used NSAIDs (classified by chemical structure) are.
① Propionic acid derivatives: ibuprofen 400-600mg, tid; loxoprofen 60mg, tid;
② benzoic acid derivatives: diclofenac usually at a total dose of 75~150mg・d-1;
③Indolyl acids: indomethacin 25mg, tid, taken immediately after meals. If nocturnal pain or morning stiffness is significant, 50mg or 100mg of indomethacin suppositories should be inserted into the anus at night before going to bed, and significant improvement can be obtained;
④Pyranocarboxylic acid: etodolac 400mg, qd;
⑤Non-acids: nabumetone 1000mg, qd once a night;
(6) Enolic acid: meloxicam 15mg, qd;
(vii) Sulfanilamide: Nimesulide 100-200mg, bid; (viii) Celecoxib: Celecoxib 200mg, bid.
Patients’ liver and kidney function and blood pressure should be tested after 1 month of treatment with NSAIDs and reviewed every 3 to 6 months. It is important to clarify that the concomitant use of 2 or more anti-inflammatory drugs not only does not increase the efficacy, but can increase adverse drug reactions and even have serious consequences. Anti-inflammatory drugs usually need to be used for about 2 months, after the symptoms are completely controlled, the dose can be reduced and consolidated for a period of time with the minimum effective amount, and then consider stopping the drug, too soon to stop the drug is likely to cause recurrence of symptoms. If the efficacy of 1 drug treatment is not obvious in 2-4 weeks, it should be changed to other classes of anti-inflammatory drugs. NSAIDs can reduce clinical symptoms, but cannot change the course of the disease, and should be used in combination with drugs to improve the disease (DMARDs).
2.2.2 disease-modifying drugs For the treatment of AS patients, NSAIDs are mainly used to relieve symptoms, and DMARDs, the second-line drugs, can relieve and improve the disease and should be used early. This class of drugs is slower to work than NSAIDs, and it takes 1-6 months for clinical symptoms to improve.
Sulfasalazine (SSZ): SSZ is the most studied drug in the DMARDs class for AS. SSZ inhibits leukocyte mobility, reduces proteolytic enzyme activity, and inhibits various cytokines such as interleukin (IL)?6, IL?1α, IL?1β, and tumor necrosis factor (TNF). The drug can improve AS joint pain, swelling and stiffness, has a good anti-inflammatory effect, slows down the process of joint destruction, is effective in peripheral joint lesions, reduces serum IgA levels [2], and prevents recurrence and reduces lesions in anterior uveitis complicated by AS, but there is a lack of evidence for its therapeutic effect on the mesial joint lesions of AS and its effect on improving disease prognosis. The usual recommended dosage is 2.0g per day, divided into 2 to 3 oral doses.
Increasing the dosage to 3.0g daily may improve the efficacy, but there is also a significant increase in adverse effects. The drug has a slow onset of action, usually 4 to 8 weeks after administration. The dose and duration of treatment are adjusted according to the patient’s condition or response to treatment and are usually maintained for 1 to 3 years. To compensate for the slow onset of SSZ and the lack of anti-inflammatory effect, a fast-acting anti-inflammatory drug is usually used in combination with it. Adverse effects of this class of drugs include nausea, vomiting, anorexia, dyspepsia, abdominal pain, diarrhea, rash, asymptomatic transaminase elevation and reversible spermopenia, and occasionally leukocytopenia and thrombocytopenia. It is contraindicated in persons with allergy to sulfonamide. While treating with SSZ, care should be taken to individualize the dose, and its adverse effects are increased with its dose. Blood tests and liver function should be checked regularly while taking the drug.
Methotrexate (MTX): MTX is a folic acid antagonist that blocks dihydrofolate reductase activity so that folic acid cannot be converted to physiologically active tetrahydrofolate and exerts a coenzyme effect, thereby blocking DNA synthesis, inhibiting the expression of cytokines such as tumor necrosis factor and interleukins, and exerting an anti-inflammatory effect [3].
MTX can be used when treatment with SSZ and NSAIDs is ineffective in patients with active AS, but comparative observations have shown that this drug has only improved peripheral arthritis, low back pain, stiffness and iritis, as well as erythrocyte sedimentation rate (ESR) and CRP levels, while there is no evidence of improvement in radiological lesions of the medial joints. 15 mg per week for six months to three years. The efficacy of oral and intravenous injection is similar.
It is generally believed that small doses of MTX are effective, well tolerated in the long term, and have few adverse effects. The drug can produce adverse effects such as bone marrow suppression and oral ulcers due to folic acid deficiency, and treatment can be accompanied by folic acid supplementation. Other common adverse reactions include gastrointestinal discomfort, liver damage, interstitial inflammation and fibrosis, hematocrit, hair loss, rash, etc. It can also cause miscarriage, abnormal fetus and affect fertility. Therefore, blood test, liver function and other related items should be reviewed regularly before and after the drug is administered. All adverse reactions can disappear after discontinuation of the drug. Not recommended for elderly, obese, diabetic, liver disease, kidney disease, active peptic ulcer patients. It is contraindicated in pregnant women.
Thalidomide: Thalidomide has immunomodulatory effects [4] and can inhibit tumor necrosis factor?alpha (TNF?alpha) gene expression, as well as angiogenesis and adhesion factor activity, resulting in significant improvement in clinical symptoms and ESR and C-reactive protein [5]. The initial dose is 50 mg d-1, with increments of 50 mg every 10 days up to 200 mg d-1 for maintenance treatment. Inadequate doses are ineffective, and symptoms are likely to recur rapidly after discontinuation of the drug. The main adverse effects of this drug include drowsiness, thirst, liver and kidney damage, reduction of blood cells, microscopic hematuria and peripheral neuritis. Therefore, those who choose this drug should be closely monitored, and blood and urine routine should be checked weekly at the beginning of the drug, and liver and kidney function should be checked every 2 to 4 weeks. Regular neurological examination should be performed for long-term users to detect possible peripheral neuritis in time. Thalidomide affects fetal development and should only be used in pregnancy and in women at risk of conception.
Leflunomide (LEF): By inhibiting the activity of dihydroorotic acid dehydrogenase, thus affecting pyrimidine synthesis in activated lymphocytes [6-7], it can effectively improve the clinical symptoms and control the disease activity of AS. LEF has a different action link with MTX and has a superimposed effect on the inhibition of pyrimidine and purine synthesis, and can be used in combination to exert better efficacy in recalcitrant AS. The dose of LEF is 10-20mg-d-1. The main adverse effects include diarrhea, pruritus, hypertension, elevated liver enzymes, skin rash, alopecia and transient leukocyte decline. Liver function and white blood cells should be checked regularly at the beginning of the drug. It is contraindicated in pregnant women due to its teratogenic effect.
Hydroxychloroquine (HCQ): it acts as an anti-inflammatory agent by inhibiting DNA polymorphic enzymes and preventing DNA replication and RNA and protein synthesis, affecting the expression of inflammatory genes; inhibiting lymphocyte chemotaxis and phagocytosis; stabilizing lysosomal membranes and reducing tissue damage [8]. The drug has a slow onset of action, with peak efficacy 3 to 4 months after administration, with usage of 200-400 mg・d-1, and clinical indicators such as ESR and CRP can be significantly reduced after treatment. The drug has accumulative effect and is easily deposited in the pigment epithelial cells of the retina, causing retinal degeneration and resulting in blindness. In addition, in order to prevent myocardial damage, electrocardiogram should be checked before and after the use of the drug. Patients with heart disease such as sinus node insufficiency, slow heart rhythm and conduction block should be prohibited. Other adverse reactions include dizziness, headache, skin rash, itching and tinnitus.
Glucocorticoids (corticosteroids, CS): Its mechanism of action is to activate the hypothalamic-pituitary-adrenal axis and suppress cellular and humoral immunity, which has powerful anti-inflammatory and immunosuppressive effects and can rapidly reduce joint pain and swelling. This drug is indicated for patients with significant joint inflammation or extra-articular symptoms that cannot be controlled by NSAIDs or in whom slow-acting drugs have not yet taken effect [9], and can be used to relieve symptoms with a low-dose glucocorticoid (prednisone 10 mg d-1), which acts as a “bridge” until DMARDs take effect. For lower back pain that cannot be controlled by other treatments, corticosteroid sacroiliac joint injections under CT guidance can improve the symptoms in some patients and the effect can last for about 3 months. For long term monoarticular (e.g. knee) effusion associated with this disease, long-acting corticosteroid joint cavity injections are feasible and repeated at intervals of 3-4 weeks, usually no more than 2-3 times. Adverse effects of hormones include: infection, hypertension, hyperglycemia, hyperlipidemia, hypokalemia, osteoporosis, aseptic osteonecrosis, cataract, weight gain, and water and sodium retention. Oral treatment with glucocorticoids not only cannot stop the development of the disease, but also brings adverse effects due to long-term treatment, and is generally not used as routine treatment. During treatment, attention should be paid to calcium and vitamin supplementation to prevent osteoporosis.
In a few cases with important organ involvement that cannot be controlled by small doses of hormones, high-dose methylprednisolone (MP, 15 mg kg-1 d-1) shock therapy can be considered [10], qd, with 5% glucose 250 mL, slowly administered intravenously for 1 to 2 h for 3 d. MP shock therapy can only address the symptoms in the acute phase, but the efficacy cannot be sustained and must be used in conjunction with DMARDs. The efficacy of MP shock therapy can only resolve the symptoms in the acute phase, and cannot be sustained. It should be emphasized that common adverse effects of high-dose MP shock therapy include: flushing, insomnia, headache, fatigue, elevated blood pressure, transient elevation of blood glucose, and serious adverse effects include: infection, upper gastrointestinal hemorrhage, water and sodium retention, precipitation of hypertensive crisis, psychiatric symptoms, and cardiac arrhythmia. The occurrence of infection should be closely observed before, during and after high-dose shock therapy, and anti-infective drugs should be added if necessary.
Biological agents: The concentration of serum TNF?α is obviously increased in AS patients, and TNF?α is also present in sacroiliac joint tissues, therefore, biological treatment targeting TNF?α has been started recently and has achieved more positive efficacy. Anti-TNF?α biological agents: there are three types of TNF?α-targeted inhibitors, namely infliximab (trade name remicade or class gram), etanercept (etanercept, trade name Enbrel, has been localized, called Yicep) and adalimumab (trade name Humira).
Other drugs: Yunque (99Tc methylene diphosphonate) This drug can continuously scavenge free radicals in the body by gaining and losing electrons through low-valent technetium, protect the activity of superoxide dismutase, and inhibit the activity of inflammatory factors such as interleukin?1β and TNF?α and the formation of immune complexes, thus controlling the development of AS. Huang Jianmin et al [11] observed 83 patients with AS treated with Yunque and found that after 3-5 d of treatment, most patients had varying degrees of relief of low back pain, peripheral joint pain, hip mobility, and morning stiffness, with an overall efficiency of 89% and no significant adverse effects.
It has strong anti-inflammatory, analgesic and immunosuppressive effects on lymphocytes, monocytes and macrophages, and can also improve microcirculation and enhance adrenocortical function. This drug is mainly used for rheumatoid arthritis, but in recent years, it has also been used for the treatment of AS in China. It has certain effect on controlling joint pain and reducing morning stiffness. Dosage: 20mg for the first time, tid, 10mg after disease control, 2-3 times daily maintenance. Adverse reactions include gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea), menstrual disorders, amenorrhea in women (individual functional uterine bleeding), inhibition of spermatogenesis, liver and kidney damage, leukopenia, rash or hyperpigmentation. Due to the effect of this drug on germ cells, it should be used with caution or contraindicated for those who intend to have children, such as taking it for a short time and in small doses.
Pamidronate (pamidronate): a diphosphonate drug, which has an inhibitory effect on bone resorption. It can inhibit the production of TNF?α, IL?1β, IL?6 and other inflammatory cytokines by macrophage cell lines cultured in vitro, and has obvious efficacy in the treatment of AS patients with poor results of NSAID therapy, but the maintenance of its efficacy is not long after discontinuation. Its adverse effects are mainly mild arthralgia and myalgia and fever after intravenous injection.
Paflin is a capsule of Paeoniflorin, which can treat rheumatoid arthritis, systemic lupus erythematosus and other autoimmune diseases through anti-inflammation and regulation of immune function, and can also be used for AS. 600mg is the usual dose, 2-3 times daily. The main adverse effects include increased stool frequency, mild diarrhea and poor appetite.
2.3 Surgical treatment
Surgical treatment of AS is indicated for patients with refractory pain, loss of function and imaging evidence of destruction of joint structures. The narrowing of the hip joint space, joint ankylosis and deformity in some patients are the main causes of disability in this disease. To improve joint function and quality of life, total hip arthroplasty is indicated, and the decision to operate should not be based on age.
Surgery of the spine has many indications in AS [12], including kyphosis, absence of compensatory and loss of horizontal vision and segmental instability, as well as some rare neurological complications such as spinal stenosis, myelopathy, and the rare cauda equina syndrome. Closed wedge lumbar osteotomy is used to repair disability due to kyphosis and can result in excellent functional recovery in terms of balance and horizontal visualization. Fusion may be considered in those patients with stage instability of the spine due to spinal pseudarthrosis. Surgical correction of the cervical spine is indicated in patients with AS who have special indications.
2.4 Summary
Early diagnosis and early pharmacological treatment of AS is the key to relieving symptoms and controlling the disease process, as well as greatly reducing the incidence of disability, reducing patient suffering, and improving the quality of life of patients. In the clinical use of drug therapy, multiple drug regimens can be used alternately according to the individual patient’s condition, and attention should be paid to drug interactions and adverse effects of long-term drug use to give full play to the drug interactions. With the research on its pathogenesis, its treatment regimen is being improved, and new therapeutic drugs will be discovered continuously.