Ankylosing Spondylitis (AS) is a chronic progressive disease that affects the sacroiliac joints, spondylolisthesis, paraspinal soft tissues, and peripheral joints, and may be associated with extra-articular manifestations. AS is the prototype of spondylolisthesis or primary AS, while other spondylolisthesis complicated by sacroiliac arthritis is secondary AS, usually referred to as the former and referred to in this guideline.
The prevalence of AS is reported differently in different countries, with 0.05% to 0.2% in Japanese natives and 0.26% in our preliminary survey. It was previously thought that the disease was more common in men, with a male to female ratio of 10.6:1; now the male to female ratio is reported to be 5:1, except that the onset of the disease is slower and less severe in women. The age of onset is usually between 13 and 31 years, and it is rare after 30 years of age and before 8 years of age.
The cause of AS is not known. Epidemiological investigations have revealed that genetic and environmental factors play a role in the development of the disease. It has been shown that the onset of AS is closely related to HLA-B27 (hereafter referred to as B27), and there is a clear tendency for familial onset. The rate of B27 positivity in the normal population varies greatly by race and region, for example, 4% to 13% in Caucasians in Europe and 2% to 7% in China, but the rate of B27 positivity in AS patients is 91% in China. Other data show that the prevalence of AS is 0.1% in the general population, 4% in the family line of AS patients, and up to 11%-25% in the first-degree relatives of B27-positive AS patients, suggesting an increased risk of AS in B27-positive patients or those with a family history of AS. However, approximately 80% of B27-positive individuals do not develop AS, and approximately 10% of AS patients are B27-negative, suggesting that other factors are involved in the pathogenesis, such as intestinal bacteria and intestinal inflammation.
One of the pathological hallmarks and early manifestations of AS is sacroiliac arthritis. The typical manifestation of spinal involvement in advanced stages is a bamboo-like spine. Synovitis of peripheral joints is histologically indistinguishable from rheumatoid arthritis. Terminal tendinopathy is one of the features of the disease. Focal mesangial necrosis of the aortic root can cause annular dilatation of the aorta as well as shortening and thickening of the aortic valve cusps, leading to incomplete aortic valve closure.
Clinical manifestations
The onset of the disease is insidious. Patients gradually develop pain and/or stiffness in the low back or sacroiliac region, wake up in the middle of the night with pain, have difficulty turning over, and have significant stiffness in the low back upon rising in the morning or after sitting for a long time, but it is relieved after activity. Some patients feel dull pain in the buttocks or severe pain in the sacroiliac region, which occasionally radiates to the periphery. The pain can be aggravated by coughing, sneezing, or sudden twisting of the back. In the early stage of the disease, the pain is mostly intermittent on one side, and after a few months, the pain is mostly persistent bilaterally. As the disease progresses from the lumbar spine to the thoracic and cervical spine, pain, restricted movement or spinal deformity occurs in the corresponding area. It has been reported that about 45% of our patients start with peripheral arthritis.
Peripheral arthropathy is present in 24% to 75% of AS patients at the beginning or during the course of the disease, with the knee, hip, ankle, and shoulder joints predominating, and occasional involvement of the elbow and small joints of the hand and foot. Asymmetric, few-joint or single-joint arthritis and arthritis of the large joints of the lower extremities are the characteristics of peripheral arthritis in this disease. In our patients, arthritis or arthralgia of the knee and other joints, except the hip, is mostly transient and rarely or hardly causes joint destruction and disability. The hip joint is involved in 38% to 66% of cases, showing localized pain, limitation of movement, flexion twist and joint ankylosis, most of which are bilateral, and 94% of the hip symptoms start within the first 5 years after the onset of the disease. The disease is more likely to occur at a younger age and in those with peripheral joint disease.
The systemic manifestations of the disease are mild, with a few severe cases having fever, fatigue, wasting, anemia, or other organ involvement. Metatarsal fasciitis, Achilles tendinitis, and other areas of tendon terminal disease are common in this disease. 1/4 of patients develop uveitis during the course of the disease, alternating unilaterally or bilaterally, which usually resolves spontaneously and can lead to visual impairment with repeated attacks. Neurological 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 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 considered tuberculosis, which can also be exacerbated by concurrent mycobacterial infections. Aortic valve atresia and conduction disturbances are seen in 3.5-10% of patients, and AS can be complicated by IgA nephropathy and amyloidosis.
Diagnostic points
The most common and characteristic early complaint of AS is 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 following 5 items help to differentiate inflammatory back pain caused by spondylitis from non-inflammatory back pain caused by other causes: (1) back discomfort occurred before the age of 40; (2) slow onset; (3) symptoms lasted for at least 3 months; (4) back pain was accompanied by morning stiffness; and (5) back discomfort decreased or disappeared after activity. If four of the above five items are met, inflammatory back pain is supported.
2.Physical examination Sacroiliac joint and paravertebral muscle pressure is a positive sign in the early stage of the disease. With the progress of the disease, it can be seen that the lumbar lordosis flattens, the movement of the spine is restricted in all directions, the extension of the thorax is reduced, and the cervical vertebrae protrude back. The following methods can be used to check the progress of sacroiliac joint pain or spinal lesions: ① Occipital wall test: In normal people, when the heels are pressed against the wall in an upright position, the posterior occiput should be close to the wall without gaps. 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 2.5 cm when measured at the level of the 4th rib space, while the thoracic expansion is reduced in those with extensive rib and vertebral involvement. ③Schober test: mark the midpoint of the posterior superior iliac spine at a vertical distance of 10 cm above and 5 cm below the midpoint of the posterior superior iliac spine, and then ask the patient to bend over (keeping both knees in an upright position) to measure the maximum forward flexion of the spine, and the normal movement increases the distance by more than 5 cm, while the spinal involvement increases the distance by less than 4 cm. ④Pelvic compression: the patient lies on his side, and pressing the pelvis from the other side can cause pain in the sacroiliac joint. ⑤Patrick’s test (lower extremity) ⑤Patrick’s test (lower extremity 4-way test): The patient lies on his back with one knee flexed and the heel placed on the opposite knee that is straight. 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, and the pain in the contralateral sacroiliac joint is considered positive. Those with knee or hip lesions cannot complete the 4-character test either.
The earliest change of AS occurs in the sacroiliac joint. X-rays of this area show blurred subchondral bone margins, bone erosion, blurred joint spaces, increased bone density and joint fusion. The degree of lesion of sacroiliac arthritis on X-ray is usually classified into 5 grades: grade 0 is normal, grade I is suspicious, grade II has mild sacroiliac arthritis, grade III has moderate sacroiliac arthritis, and grade IV has joint fusion ankylosis. For clinically suspicious cases where the X-ray has not yet shown clear or grade II or higher bilateral sacroiliac arthritic changes, computed tomography (CT) should be used, and the advantage of this technique is that there are fewer false positives. However, because the upper part of the sacroiliac joint anatomy is ligamentous, the irregularity and widening of the joint space on imaging caused by its attachment makes the judgment difficult. In addition, subchondral aging of the iliac portion of the sacroiliac joint similar to joint space narrowing and erosion is a natural phenomenon and should not be considered abnormal. Magnetic resonance imaging (MRI) is better than CT for understanding cartilage lesions, but it is prone to false positive results in determining sacroiliac arthritis, and because it is expensive, it should not be done as a routine examination at present.
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 advanced stages are called “bamboo-like spine”. Bone erosion of the pubic symphysis, sciatic tuberosity and tendon attachment points (such as the heel bone), with reactive sclerosis and villous changes in adjacent bone, may appear new bone formation.
4.Laboratory examination In active patients, increased blood sedimentation, increased C-reactive protein and mild anemia can be seen. Rheumatoid factor is negative and immunoglobulins are mildly elevated. Although the rate of HLA-B27 positivity in AS patients is about 90%, there is no diagnostic specificity because normal people also have HLA-B27 positivity, and HLA-B27 negative patients cannot be excluded from AS as long as their clinical manifestations and imaging examinations meet the diagnostic criteria.
5. Diagnostic criteria Different criteria have been used in recent years, but the 1966 New York criteria, or the 1984 revised New York criteria, are still being used. However, for those who temporarily do not meet the above criteria, reference can be made to the European preliminary diagnostic criteria for spondyloarthropathies, and those who meet them can also be included in this category for diagnosis and treatment, and follow-up observation.
(1) New York criteria (1966): Bilateral or unilateral sacroiliac arthritis confirmed by X-ray (according to the aforementioned 0-IV classification) with one or two of the following clinical manifestations, respectively, namely: ① limitation of lumbar spine motion in all three directions of anterior flexion, lateral flexion and posterior extension; ② history or existing symptoms of low back pain; ③ thoracic extension less than 2.5 cm. based on the above points, the requirements for a definite diagnosis of AS are X-ray confirmed grade III-IV bilateral sacroiliac arthritis with at least 1 of the above clinical manifestations attached; or X-ray confirmed grade III-IV unilateral sacroiliac arthritis or grade II bilateral sacroiliac arthritis with 1 or 2 of the above clinical manifestations attached, respectively.
(2) Revised New York criteria (1984): ① the duration of lower back pain lasting 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 sacroiliitis grade II-IV, or unilateral sacroiliitis grade III-IV. The diagnosis of AS can be confirmed if the patient has ④ and any 1 of ① to ③ respectively.
(3) European Spondyloarthropathy Study Group criteria: inflammatory spondylodynia or asymmetric, lower extremity joint-based synovitis with any 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 bilateral alternating hip pain; ⑥ tendon terminal disease; ⑦ sacroiliac arthritis.
6. Differential diagnosis AS should be differentiated from the following diseases.
(1) Rheumatoid arthritis (RA): the main differences between AS and RA are.
(1) AS is more prevalent in men while RA is more prevalent in women.
(2) AS invariably has sacroiliac joint involvement, while RA rarely has sacroiliac joint lesions.
(3) AS involves the whole spine from the bottom up, while RA only affects the cervical spine.
(4) Peripheral arthritis in AS is few-joint, asymmetric, and predominantly in the joints of the lower extremities; in RA, it is multi-joint, symmetric, and can develop in all joints of the extremities.
5) AS has no rheumatoid nodules visible in RA.
(6) The RF of AS is negative, while the positive rate of RA is 60%-95%.
7) AS is mostly HLA-B27 positive, while RA is associated with HLA-DR4. The chance of AS and RA occurring in the same patient is 1/100,000 to 1/200,000.
(2) Disc herniation: Disc herniation is one of the common causes of inflammatory low back pain. The disease is limited to the spine without systemic manifestations such as fatigue, wasting, fever, etc. All laboratory tests, including blood sedimentation, are normal. The main difference between it and AS can be confirmed by CT, MRI or spinal canal imaging.
(3) Tuberculosis: For unilateral sacroiliac joint lesions, it should be distinguished from tuberculosis or other infectious arthritis.
(4) Diffuse idiopathic hypertrophy of bone (DISH) syndrome: this disease develops in men over 50 years of age, and patients 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 no erosion of the sacroiliac and spondylolisthesis joints, no increased stiffness in the morning, normal blood sedimentation and negative HLA-B27. Based on the above characteristics, the disease can be distinguished from AS.
(5) Iliac dense osteoarthritis: This disease is mostly seen in young women, and its main manifestation is chronic lumbosacral pain and stiffness. There is no abnormality in clinical examination other than muscle tension in the lumbar region. The diagnosis mainly relies on X-ray posteroanterior plain radiographs, which typically show 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, so it is different from AS.
(6) Others: AS is the prototype of seronegative spondyloarthropathy and must be differentiated from other spondyloarthropathies associated with sacroiliac arthritis such as psoriatic arthritis, enteropathic arthritis or Wright’s syndrome in the diagnosis.
Treatment options and principles
There is no cure for AS. However, with timely diagnosis and appropriate treatment, patients can achieve symptom control 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.
1.Non-pharmacological treatment
(1) Education of patients and their families about the disease is an indispensable 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) Advising patients to engage in careful and uninterrupted physical activity to obtain and maintain the best position of the spinal joints, strengthen paravertebral muscles and increase lung capacity is no less important than pharmacologic therapy.
(3) When standing, one should try to maintain a posture with chest up, abdomen tucked in and eyes level 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 upper thoracic or cervical spine involvement occurs.
(4) Reduce or avoid physical activities that cause persistent pain. Measure height regularly. Keeping height records is a good measure to prevent early spinal curvature that is not easily detected.
(5) Select the necessary physical therapy for painful or inflamed joints or other soft tissues.
2.Medication
(1) non-steroidal anti-inflammatory drugs (referred to as anti-inflammatory drugs): this class of drugs can quickly improve the patient’s low back pain and stiffness, reduce joint swelling and pain and increase the range of motion, whether early or late AS patients are preferred for symptomatic treatment. There is a wide variety of anti-inflammatory drugs, but their efficacy against AS is roughly equivalent. Indomethacin is particularly effective for AS, but has more adverse effects. Indomethacin can be the drug of choice if the patient is young and has no gastrointestinal, liver, kidney or other organ disease or other contraindications. The method is: Indomethacin 25mg, 3 times daily, immediately after meals. For nocturnal pain or significant morning stiffness, an indomethacin suppository of 50mg or 100mg, inserted into the anus before going to bed at night, can obtain significant improvement. Other optional drugs such as acimexin 90mg once daily; diclofenac usually at a total daily dose of 75-150mg; nabumetone 1000mg once a night; meloxicam 15mg once a day; and etodolac 400mg once a day; rofecoxib 25mg once a day; celecoxib 200mg twice a day are also used in the treatment of this disease.
The more frequent adverse reactions of anti-inflammatory drugs are gastrointestinal discomfort and a few can cause ulcers; other less common ones are headache, dizziness, liver and kidney damage, hematocrit, edema, hypertension and allergic reactions. The physician should choose one anti-inflammatory drug for each patient. The use of 2 or more anti-inflammatory drugs at the same time will not increase the efficacy, but will increase the 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 is reduced and consolidated for a period of time with the minimum effective amount, then consider stopping the drug, too soon to stop the drug is likely to cause recurrence of symptoms. If a drug is not effective for 2 to 4 weeks of treatment, it should be changed to other anti-inflammatory drugs of different categories. In the process of drug use should always pay attention to monitoring adverse drug reactions and timely adjustment.
(2) Salazosulfapyridine: This product can improve joint pain, swelling and stiffness in AS, and reduce serum IgA levels and other laboratory activity indicators. It is especially suitable for improving peripheral arthritis in patients with AS, and has the effect of preventing recurrence and reducing lesions in anterior uveitis complicated by this disease. To date, there is a lack of evidence on the therapeutic effect of this product on the mesial arthropathy of AS and on improving the prognosis of the disease. The usual recommended dosage is 2.0g per day, divided into 2 to 3 oral doses. Increasing the dose to 3.0g/d increases the efficacy but also increases the number of adverse effects. The product has a slow onset of action, usually 4 to 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 until 1.0g twice daily, or the dose and duration of treatment are adjusted according to the condition, or the patient’s response to treatment, and maintained for 1 to 3 years. To compensate for the slow onset of action of salazosulfapyridine and its weak anti-inflammatory effect, a fast-acting anti-inflammatory drug is usually used in combination with it. Adverse reactions include gastrointestinal symptoms, rash, hematocrit, headache, dizziness, and reduced spermatozoa and abnormal morphology in males (recovered with discontinuation of drug). It is contraindicated in patients with sulfonamide hypersensitivity.
(3) Methotrexate: Methotrexate may be used in patients with active AS when treatment with salbutamol and NSAIDs is ineffective. However, comparative observations showed that this product only improved the manifestations of peripheral arthritis, low back pain and stiffness and iritis, as well as blood sedimentation and C-reactive protein levels, while there was no evidence of improvement in imaging changes of the medial joints. Usually methotrexate 7.5 to 15 mg, the dose can be increased as appropriate in individual severe cases, orally or by injection once a week for a period of six months to three years. At the same time, 1 anti-inflammatory drug can be used. Although low-dose methotrexate has the advantage of having fewer adverse effects, its adverse effects are still a problem that must be noted in treatment. These include gastrointestinal discomfort, liver injury, interstitial lung inflammation and fibrosis, hematocrit, alopecia, headache and dizziness, etc. Therefore, routine blood tests, liver function and other related items should be reviewed regularly before and after the drug is administered.
(4) Glucocorticoids: In a few cases, when symptoms cannot be controlled even with high-dose anti-inflammatory drugs, methylprednisolone 15mg/(kg?d) shock treatment for 3 days can temporarily relieve pain. For lower back pain that cannot be controlled by other treatments, corticosteroid sacroiliac joint injection under the guidance of CT can improve the symptoms in some patients, and the efficacy can last for about 3 months. Long-acting corticosteroid joint cavity injections are feasible for long-term monoarticular (e.g., knee) effusions associated with this disease. Repeated injections should be given at intervals of 3 to 4 weeks, usually no more than 2 to 3 times. Oral glucocorticosteroid treatment can neither stop the development of the disease nor bring adverse effects due to long-term treatment.
(5) Other drugs: Some male patients with refractory AS showed significant improvement in clinical symptoms and blood sedimentation and C-reactive protein after the application of thalidomide (reaction stop). The initial dose is 50mg/d, and the dose is increased by 50mg every 10 days to 200mg/d for maintenance, and 300mg/d for maintenance in foreign countries. Insufficient dose is ineffective, 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, those who choose this treatment 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 2-4 weeks. Regular neurological examination should be done for long-term users to detect possible peripheral neuritis in time.
3.Biological agents :
The main drugs that are currently active and effective in controlling inflammation can significantly reduce joint destruction and disability, reduce the amount of hormones and osteoporosis.
Anti-tumor necrosis factor-α (TNF-α) has been used abroad for the treatment of AS that is active or ineffective to anti-inflammatory drug therapy. infliximab and etanercept are the two agents available so far. infliximab is a monoclonal antibody against tumor necrosis factor, and its usage is: 3-5 mg/kg, IV, repeated once at 4-week intervals, usually used 3-6 times. Patients with peripheral arthritis, tendon terminal inflammation and spinal symptoms, as well as C-reactive protein, can be significantly improved after treatment. However, the long-term efficacy and the effect on radiographic lesions of the midshaft joints have yet to be studied. Adverse reactions include infections, severe allergic reactions and lupus-like lesions.
Etanercept is a recombinant human soluble tumor necrosis factor receptor fusion protein that binds reversibly to TNF-α and competitively inhibits the binding of TNF-α to the TNF receptor site. It has been used abroad for the treatment of active AS. 25 mg of this product is administered subcutaneously twice a week for 4 months, and the patient can continue the original dose of anti-rheumatic drugs during treatment. 80% of the patients’ conditions can be improved, such as the relief of morning stiffness, spinal back pain and tendonitis, increased chest expansion, slowed blood sedimentation and/or decreased C-reactive protein. The efficacy of this product is rapid and does not decrease with the duration of administration. The main adverse effect of this product is infection.
At present, there is no experience and report on the use of the above two biological agents for the treatment of AS in China.
4.Surgical treatment The hip joint involvement causes joint space narrowing, ankylosis and deformity, which is the main cause of disability of the disease. In order to improve the joint function and quality of life of patients, total hip replacement is the best choice. The majority of patients have their joint pain controlled, some have normal or near-normal function, and 90% of the life expectancy of the replaced joint is more than 10 years.
It should be emphasized that the severity of the disease varies greatly in clinical manifestations, with some patients experiencing recurrent and continuous progression, while others remain relatively quiescent for long periods of time and can work and live normally. However, the prognosis is poor in patients with younger age of onset, earlier involvement of the hip joint, recurrent episodes of iridocyclitis and secondary amyloidosis, delayed diagnosis, untimely and unreasonable treatment, and non-adherence to long-term functional exercise. In conclusion, this is a chronic progressive disease and should be followed up for a long time under the guidance of a specialist.