1, Overview: Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the sacroiliac joint, spinal prominence, paraspinal soft tissue and peripheral joints, and can be accompanied by extra-articular manifestations, serious spinal deformity and ankylosis. the prevalence of AS varies from country to country, with 0.05%-0.2% in Japanese natives, and about 0.3% in our preliminary survey. The ratio of men to women is about 2-3:1, and the onset of the disease is slower and milder in women. The age of onset is usually 13-31 years old, with a peak of 20-30 years old, and it is rare after 40 years old and before 8 years old.
The etiology of AS is not known. Genetic and environmental factors have been found to play a role in the development of the disease from epidemiological investigations. The development of AS has been shown to be closely associated with human leukocyte antigen (HLA)-B27, with a significant tendency for family aggregation. One of the pathological signs and early manifestations of AS is sacroiliac arthritis. The typical manifestation of advanced spinal involvement is a “bamboo-like change”. Synovitis of peripheral joints is histologically indistinguishable from rheumatoid arthritis (RA). Tendinopathy is one of the characteristics of the disease.
2. Clinical manifestations: The disease develops insidiously. Patients gradually develop pain and/or morning stiffness in the low back or sacroiliac region, wake up with pain in the middle of the night, have difficulty turning over, and morning stiffness in the low back is obvious when getting up in the morning or after sitting for a long time, but is reduced after activity. Some patients have dull pain in the buttocks or severe pain in the sacroiliac region, which occasionally radiates to the periphery. The pain may be aggravated by coughing, sneezing, or sudden twisting of the lumbar region. In the early stage of the disease, the hip pain is mostly intermittent or alternating on one side, and after a few months, the pain is mostly bilateral and persistent. In most patients, as the disease progresses from the lumbar spine to the thoracic and cervical spine, pain, restricted movement or spinal deformity occurs in the corresponding areas.
Hip and peripheral joint lesions occur in 24-75% of AS patients at the beginning or during the course of the disease, with the knee, ankle and shoulder joints predominating, and occasional involvement of the elbow and small joints of the hand and foot. Arthritis of the large joints of the lower extremities is one of the features of peripheral arthritis in this disease. Arthritis or arthralgia in the hip and knee, as well as in other joints, occurs early in the course of the disease and causes little or no joint destruction or disability. The hip joint is involved in 38%-66% of cases, with localized pain, limited motion, flexion contracture, and joint ankylosis, most of which are bilateral, and 94% of hip symptoms begin within the first 5 years after onset. Uveitis occurs unilaterally or bilaterally in a quarter of patients and can be recurrent or even lead to visual impairment.
The systemic manifestations of the disease are mild, with a few severe cases having fever, fatigue, emaciation, anemia, or other organ involvement. Plantar fasciitis, Achilles tendinitis, and other sites of tendon telangiectasia are common in this disease. Neurologic symptoms arise from compressive spinal neuritis or sciatica, vertebral fractures or incomplete dislocations, and cauda equina syndrome, the latter of which can cause impotence, nocturnal urinary incontinence, bladder and rectal dullness, and loss of ankle reflexes. Very few patients develop fibrosis of the upper lobe of the lung, sometimes accompanied by cavity formation and mistaken for tuberculosis, or the condition may be exacerbated by mycobacterial infection of the offspring. Aortic valve atresia and conduction disorders are seen in 3.5-10% of patients.
3.Diagnostic points.
（The most common and characteristic early complaints of AS are morning stiffness and pain in the lower back. Since low back pain is an extremely common symptom in the general population, but most of it is mechanical non-inflammatory back pain, whereas this disease is inflammatory in nature, the 2009 International AS Assessment Task Force (ASAS) experts on inflammatory back pain recommended the following criteria for the diagnosis of inflammatory back pain: (i) age of onset <40
(2) Physical examination: Sacroiliac joint and paravertebral muscle pressure pain is a positive sign in the early stage of the disease. As the disease progresses, the lumbar lordosis flattens, the movement of the spine is limited in all directions, the extension of the thorax is reduced, and the cervical vertebrae protrude posteriorly. The following methods can be used to examine the progression of sacroiliac joint compression pain or spinal lesions.
① Occipital wall test: In a healthy person in a standing position with both heels pressed against the root of the wall, the posterior occiput should be close to the wall without a gap. In the case of cervical stiffness and/or posterior convexity of the thoracic vertebral segment, the gap increases to more than a few centimeters, resulting in the occipital area not being able to fit against the wall.
②Thoracic expansion: The normal value of the difference between the range of thoracic expansion during deep inspiration and deep expiration is not less than 62.5 px when measured at the level of the 4th rib space, while the thoracic expansion is reduced in those with extensive involvement of the ribs and spine.
(③Schober test: mark the vertical distance of 250px above the midpoint of the posterior superior iliac spine line, then ask the patient to bend over (keeping both knees in upright position) to measure the maximum forward flexion of the spine, and increase the distance above 125px for normal movement, and <100px for spinal involvement
④Pelvic compression: the patient lies on his or her side and compression of the pelvis from the other side can cause sacroiliac joint pain.
⑤Patrick’s test (lower extremity “4” test): The patient lies supine with one knee flexed and the heel placed on the contralateral, straight knee. The examiner presses the flexed knee with one hand (when the hip is in flexion, abduction and external rotation) and presses the contralateral pelvis with the other hand, which is considered positive if it leads to pain in the contralateral sacroiliac joint. The “4” test cannot be completed if there is a knee or hip lesion.
（The earliest changes of AS occur in the sacroiliac joint. x-ray film shows blurring of the subchondral bone margin of the sacroiliac joint, bone erosion, blurring of the joint space, increased bone density and joint fusion. The degree of sacroiliac arthritis on X-ray is usually divided into 5 grades: Grade 0: normal; Grade I: suspicious; Grade II: mild sacroiliac arthritis; Grade III: moderate sacroiliac arthritis; Grade IV: joint fusion and ankylosis. Radiographs of the spine show vertebral osteoporosis and square changes, blurring of the vertebral tuberosities, calcification of the paravertebral ligaments, and bone bridge formation. Extensive and severe ossifying bridges in the late stage are called “bamboo-like spine”. Bone erosion at the pubic symphysis, sciatic tuberosity, and tendon attachment points (e.g., heel bone), with reactive sclerosis and villous changes in adjacent bone, may result in bone formation. For early clinical stage or suspicious cases, CT or magnetic resonance imaging (MRI) examination can be chosen. Due to the greater radiation of CT than ordinary X-ray, it should be used for diagnosis only and should not be repeatedly examined.
(4) Laboratory tests: Patients in the active phase may have increased erythrocyte sedimentation rate (ESR), increased C-reactive protein (CRP), mild anemia and mildly elevated immunoglobulins. Rheumatoid factor (RF) is mostly negative, but a positive RF does not exclude the diagnosis of AS. Although the rate of HLA-B27 positivity in AS patients is about 90%, there is no diagnostic specificity because healthy people are also positive. HLA-B27-negative patients cannot exclude the possibility of AS as long as their clinical manifestations and imaging examinations meet the diagnostic criteria.
4. Diagnostic criteria.
In recent years, the New York criteria for AS revised in 1984 are more often used. For those who temporarily do not meet the above criteria, reference can be made to the diagnostic criteria for spondyloarthropathies (SpA), which mainly include the classification criteria recommended by Amor, the European Spondyloarthropathy Study Group (ESSG), and the 2009 ASAS for medial SpA, the latter two of which are described below.
(1) AS New York criteria revised in 1984: ① lower back pain lasting for at least 3 months, with pain improving with activity but not relieved by rest; ② restricted movement of the lumbar spine in the anterior-posterior and lateral flexion directions; ③ thoracic extension less than the normal value for the same age and sex; ④ bilateral sacroiliac arthritis grade II-IV, or unilateral sacroiliac arthritis grade III-IV. If the patient has ④ and any 1 of ①-③ respectively, the diagnosis of AS can be confirmed.
(2) ESSG diagnostic criteria: inflammatory spinal pain or asymmetric synovitis mainly in the joints of the lower extremities with any 1 of the following additional items, namely: ① positive family history; ② psoriasis; ③ inflammatory bowel disease; ④ urethritis, cervicitis or acute diarrhea within 1 month prior to arthritis; ⑤ alternating bilateral hip pain; ⑥ tendon telangiectasia; and ⑦ sacroiliac arthritis. Those who are eligible can be included in this category for diagnosis and treatment, and be followed up and observed.
(3) The 2009 ASAS recommended classification criteria for mid-axis SpA: patients with age of onset <45
SpA features include: ① inflammatory back pain; ② arthritis; ③ starting and ending points (Achilles tendon); ④ ocular uveitis; ⑤ finger (toe) inflammation; ⑥ psoriasis; ⑦ Crohn’s disease/ulcerative colitis; ⑧ good response to non-steroidal anti-inflammatory drugs (NSAIDs); ⑨ family history of SpA; ⑩ HLA-B27 positive; 11 elevated CRP.
5. Differential diagnosis.
(1) Intervertebral disc herniation: It is one of the common causes of low back pain. The disease is in the spine, without fatigue, wasting, fever and other systemic manifestations, mostly of acute onset, mostly limited to lumbar pain, aggravated by activity and relieved by rest; often lateral curvature when standing; 1-2 tender plate machine points on palpation in the spinal bony prominence. All laboratory tests are normal. The main difference between it and AS can be confirmed by CT, MRI or spinal canalography. Narrow or anteriorly narrowed and posteriorly wide or equal width anteriorly and posteriorly on lumbar X-ray; labral hyperplasia or small free bony masses at the posterior superior or inferior corners of the vertebral body margin; CT can confirm.
(2) Diffuse idiopathic bone hypertrophy (DISH) syndrome: the onset is mostly in men over 50 years of age, who also have spinal pain, stiffness, and progressively increasing spinal motion limitation. The clinical presentation and x-ray findings are often similar to those of AS. However, calcification of the ligaments, often involving the cervical and low thoracic vertebrae, is often seen on X-ray, with flowing calcification and ossification connecting at least 4 anterolateral vertebral bodies.
(3) Iliac dense osteoarthritis: Most commonly seen in middle-aged and young women, especially those with a history of multiple pregnancies, childbirth, or in long-term standing occupations. The main manifestation is chronic lumbosacral pain, which is aggravated by exertion and is self-limiting. Clinical examination is not abnormal except for muscle tension in the lumbar region. The diagnosis mainly relies on anteroposterior radiographs, and the typical presentation is an obvious osteosclerotic area in the iliac bone along the middle and lower 2/3 of the sacroiliac joint, triangular in shape with the tip upward, uniform in density, not invading the sacroiliac joint surface, without joint stenosis or erosion, with clear boundaries, and normal bone quality and joint space on the sacral side.
(4) Others: AS is the prototype of SpA and must be differentiated from other SpA associated with sacroiliac arthritis such as psoriatic arthritis, enteropathic arthritis or Wright’s syndrome in the diagnosis. In addition, osteoarthritis of the spine, RA and tuberculosis involving the sacroiliac joint or spine need to be further differentiated based on other clinical features of interest.
6. Treatment goals, protocols and principles.
(1) Treatment goals for AS patients
(1) Relief of symptoms and signs: Eliminate or minimize symptoms such as back pain, morning stiffness and fatigue as much as possible.
(2) Restoration of function: To restore the patient’s physical function, such as spinal mobility, social mobility and work ability, to the greatest extent possible.
③Prevent joint damage: To prevent new bone formation, bone destruction, bony ankylosis and spinal deformation in patients with involvement of the hip, shoulder, mid-shaft and peripheral joints.
④Improve the quality of life of patients: including socioeconomic factors, work, medical retirement, and retirement.
⑤ Prevent complications of spinal diseases: prevent spinal fractures and flexion contractures, especially in the cervical spine.
(2) Treatment options and principles
There is no cure for AS. However, patients can achieve symptom control and improve prognosis if they are diagnosed and treated reasonably in a timely manner. 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.
Non-pharmacological treatment
①Education of patients and family members about the disease is an integral part of the overall treatment plan, which helps patients to actively participate in treatment and cooperate with physicians. The long-term plan should also include the patient’s psychosocial and rehabilitation needs.
② Advise the patient to be reasonably and consistently physically active to obtain and maintain the best position of the spinal joints, strengthen the paravertebral muscles and increase lung capacity; swimming is one of the good and effective adjuncts to treatment.
③Standing should try to maintain a posture with chest up, abdomen in and eyes flat in front. Sitting position should also keep the chest upright. One should sleep on a hard bed and take more supine positions to avoid positions that promote flexion deformity. Pillows should be short and should be discontinued once there is upper thoracic or cervical spine involvement.
④Give necessary physical therapy for painful or inflamed joints or soft tissues.
⑤ Smokers are advised to quit smoking; patient smoking is one of the risk factors for poor functional prognosis.
Drug treatment
①NSAIDs: They can rapidly improve patients’ low back pain and morning stiffness, reduce joint swelling and pain and increase range of motion, and are preferred for symptomatic treatment of patients with early or advanced AS. They are widely available and have roughly equivalent efficacy for AS.
The more common adverse effects of NSAIDs are gastrointestinal discomfort and a few can cause ulcers; other less common ones are cardiovascular diseases such as hypertension. They may be accompanied by headache, dizziness, liver and kidney damage, hematocrit, edema and allergic reactions. The physician should choose one NSAIDs drug for each patient’s specific case. Concomitant use of ≥2 NSAIDs not only does not increase the efficacy, but also increases the adverse drug reactions and even brings serious consequences. Regardless of the NSAIDs used, not only to achieve symptomatic improvement, but also to delay or control progression of the disease, it is usually recommended to continue using them at the appropriate drug dose for a longer period of time. To assess whether a particular NSAIDs is effective, the same dose should be used consistently and regularly for at least 2 weeks. If 1 drug is not effective for 2-4 weeks, it should be switched to other NSAIDs of a different class, and adverse drug reactions should be monitored and adjusted promptly.
Biologics: Anti-tumor necrosis factor (TNF)-alpha antagonists include etanercept, infliximab, and adalimumab. They have been evaluated in several randomized, double-blind, placebo-controlled trials for the treatment of AS, with overall efficacy rates of 50%-75%. The method of application is based on the “Guidelines for the diagnosis and treatment of RA”, but the dose of infliximab is usually higher than that for RA.
Patients who are not satisfied with the efficacy of one TNF-α antagonist or who cannot tolerate it may have better efficacy with another agent. However, its long-term efficacy and effect on axial joint x-ray lesions in AS are yet to be studied further. Studies suggest that patients who initially respond well appear to sustain efficacy for at least 2 years. The use of TNF-α antagonists may also reduce the rate of recurrence of uveitis. Although it is recommended that TNF-α antagonists be used only in patients with “definitive” AS according to classification criteria, studies suggest that they may be used in patients who lack typical clinical radiological changes and meet the “probable” or SpA criteria for AS classification. The NSAIDs have been administered but moderately severe active spinal lesions are present; moderately severe active peripheral arthritis is present despite the use of NSAIDs and one other disease-controlling agent.
The most significant adverse reactions to TNF-α antagonists were infusion reactions or point-of-injection reactions, ranging from nausea, headache, pruritus, and vertigo to hypotension, dyspnea, and chest pain. Other adverse reactions were an increased chance of infection, including common respiratory tract infections and opportunistic infections (tuberculosis), but the difference was not statistically significant compared with placebo. Pretreatment screening for tuberculosis significantly reduces the incidence of tuberculosis associated with TNF-α antagonist therapy and is now routine. Exacerbations of demyelinating disease, lupus-like syndrome, and congestive heart failure have also been reported, but the incidence is low. Routine blood and urine tests, liver and kidney functions should be reviewed regularly during drug administration.
(iii) Salazosulfapyridine: It can improve joint pain, swelling and stiffness in AS, and reduce serum IgA levels and other laboratory activity indicators, and is particularly suitable for improving peripheral arthritis in patients with AS. To date, there is a lack of evidence on the therapeutic effect of this product on the mesial joint lesions of AS and on improving the prognosis of the disease. The usual recommended dosage is 2.0g/day in 2-3 oral doses. Increasing the dose to 3.0g/d increases the efficacy but also increases the adverse effects. The onset of action of this product is slow, usually 4-6 weeks after dosing. To increase patient tolerability. It is usually started at 0.25g 3 times daily and then increased by 0.25g weekly up to 1.0g twice daily, or the dose and duration of treatment may be adjusted according to the condition or the patient’s response to treatment and maintained for 1-3 years. To compensate for the slow onset of action of salazosulfapyridine and the lack of anti-inflammatory effects, one of the fast-acting NSAIDs is usually used in combination with it. Adverse reactions include gastrointestinal symptoms, rash, hematocrit, headache, dizziness, and reduced spermatozoa and abnormal morphology in men (recoverable with discontinuation). It is contraindicated in patients with sulfa allergy.
④Glucocorticoids: Oral or intravenous systemic corticosteroids are generally not advocated for the treatment of AS because of their large adverse effects and inability to stop the course of AS. Persistent tendon telangiectasia and persistent synovitis may respond well to topical corticosteroid therapy. Anterior uveitis can be better controlled by pupil dilation and hormonal spotting. Systemic hormone or immunosuppressive therapy may be required for refractory iritis. Intra-articular glucocorticoid injections for intractable peripheral arthritis (e.g., knee) effusions that do not respond well to systemic medications are feasible, and repeated injections should be given 3-4 weeks apart, usually no more than 2-3 times/year. Similarly, CT-guided intra-sacroiliac joint glucocorticoid injections are an option for patients with intractable sacroiliac joint pain. Similar to heel pain-like tendon telangiectasia can also be treated with local injections of glucocorticoids.
⑤ Other drugs: Some male patients with refractory AS showed significant improvement in clinical symptoms, ESR and CRP after the application of thalidomide (thalidomide). The initial dose of thalidomide is 50 mg/night, and the dose is increased by 50 mg every 10-14 d to 150-200 mg/night for maintenance, and 300 mg/d for maintenance in foreign countries. Insufficient dose is not effective, and the symptoms are likely to recur rapidly after discontinuation of the drug. The adverse effects of this product include drowsiness, thirst, decreased blood cells, increased liver enzymes, microscopic hematuria and tingling sensation at the fingertips. Therefore, routine blood, urine and liver and kidney functions should be checked regularly during the initial period of use. Regular neurological examination should be done for long-term drug users to detect possible peripheral neuritis in time. For patients who lack the efficacy of the above treatments, methotrexate and anti-rheumatic phytochemicals (see RA diagnosis and treatment guidelines) can be used for AS peripheral joint involvement, etc. However, their efficacy on mid-axis arthropathy is uncertain and further studies are needed.
(3) Surgical treatment
Joint space narrowing, ankylosis and deformity caused by hip joint involvement are the main causes of disability in this disease. Artificial total hip arthroplasty is the best choice. After the replacement, the joint pain of most patients is controlled, the function of some patients is normalized or close to normal, and the life expectancy of the replaced joint is 90% over 10 years.
7. Disease course and prognosis: It should be emphasized that the disease varies greatly in clinical severity, with some patients experiencing repeated and continuous progression and others in a relatively stable state for a long time. Patients with mild AS with only localized involvement can maintain almost full function and employability. However, some patients develop severe limitations in skeletal activity or life-threatening extramusculoskeletal complications. There is usually individual variation in disease activity. Symptoms usually persist for decades. Rarely, a “burn-out” phase of disease activity may occur, followed by long-term remission. The risk of developing lymphoma in AS does not appear to be significantly increased.
Several indicators have been shown to be informative in determining the prognosis of AS, including: hip arthritis of the hip; salami-like fingers or toes; poor efficacy of NSAIDs; elevated ESR (>30 mm/1h); limited lumbar spine mobility; oligoarthritis and age of onset <16 years. Several other factors may also be associated with poor prognosis in patients with AS, such as smoking, progressively worsening radiological changes, active lesions (as assessed by the Disease Activity Index), functional impairment (as assessed by self-report), low educational attainment, presence of other SpA-related conditions (e.g., psoriasis, inflammatory bowel disease), male gender, history of uveitis, and a variety of conditions involving kinesthetic flexibility (ability to bend rapidly, repeatedly and twisting and stretching) or occupational activities that involve body vibration (e.g., driving a truck or operating heavy equipment). In addition, the prognosis is poor for delayed diagnosis, untimely and unreasonable treatment, and non-adherence to long-term functional exercise. Long-term follow-up under the supervision of a specialist should be emphasized.