Overview
Ankylosing Spondylitis (AS) is a chronic progressive disease that affects the sacroiliac joints, spondylolisthesis, paraspinal soft tissues and peripheral joints, and may be accompanied by extra-articular manifestations. AS is the prototype or primary form of spondyloarthropathy, while other spondyloarthropathies complicated by sacroiliac arthritis are secondary AS, usually referred to as the former and in this guideline.
The prevalence of AS has been reported differently in different countries, such as 0.13%-0.22% in the United States, 0.05%-0.2% in Japanese natives, and 0.26% in China. Previously, the disease was thought to be more common in men, with a male to female ratio of 10.6:1; now the male to female ratio is reported to be 2:1 to 3:1, 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, with rare onset after 30 years of age and before 8 years of age.
The cause of AS is unknown. HLA-B27 (hereafter referred to as B27) is strongly associated with the development of AS and has a clear familial tendency to develop. The rate of B27 positivity in the normal population varies greatly by race and region, for example, 4%-13% in Caucasians in Europe, 2%-4% in Blacks in the United States, and 2%-7% in China. The positive rate of B27 in A S patients in China is 91%. The prevalence of AS in the general population is about 0.1%, and in the family line of AS patients is 4%, and in B27-positive AS patients, the prevalence of AS in their first-degree relatives is as high as 11%-25%. This strongly suggests that B27-positive individuals or those with a family history of AS are at increased risk of developing AS.
Other factors such as intestinal bacteria and intestinal inflammation are involved in the development of AS. one of the pathological signs and early manifestations of AS is sacroiliitis. 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 aortic valve closure insufficiency.
Clinical manifestations]
The onset of the disease is insidious. The most common symptom is low back pain, which can start with peripheral arthritis in atypical cases. Patients gradually develop pain and/or stiffness in the low back or sacroiliac region, waking up in the middle of the night with pain, difficulty in turning over, and stiffness in the low back when rising in the morning or after sitting for a long time, but relieved after activity. Some patients feel dull pain in the buttocks or severe pain in the sacroiliac region, occasionally radiating 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 bilateral and persistent. As the lesion progresses from the lumbar spine to the thoracic and cervical spine, pain, limitation of motion or spinal deformity occurs in the corresponding area.
Peripheral arthropathy develops in 24-75% of AS patients at the beginning or during the course of the disease, mostly in the knee, hip, ankle and shoulder joints, with 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%-66% of cases, showing localized pain, restricted movement, flexion-twisting and joint ankylosis, most of which are bilateral, and 94% of 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 inflammation 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. It is sometimes accompanied by cavity formation and is considered tuberculosis, and can also be exacerbated by concurrent mycobacterial infections. Aortic 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 are mechanical back pain non-inflammatory pain, whereas this disease is inflammatory. 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 occurs before the age of 40;
(2) Slow onset;
(3) Symptoms persist for at least 3 months;
(4) Back pain with morning stiffness;
(5) Back discomfort decreases or disappears after activity. If 4 of the above 5 items are met, inflammatory back pain is supported.
2. Sacroiliac joint and paravertebral muscle 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 in all directions is restricted, the extension of the thorax is reduced, and the cervical vertebrae protrude. The following methods can be used to examine the progression of sacroiliac joint compression pain or spinal lesions.
(1) Occipital wall test: In a normal person in an upright position, the posterior occiput should be close to the wall without gaps. In the case of cervical stiffness and/or thoracic segmental deformity of the posterior convexity, the gap increases to more than a few centimeters, resulting in the occipital region not being able to fit against the wall.
(2) Thoracic 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 those with extensive rib and vertebral involvement will have reduced thoracic expansion.
(3) Schober test: measure the vertical distance of 10cm up and 5cm down from the midpoint of the posterior superior iliac spine line, 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 increase the distance by more than 5cm for normal movement, and by more or less 4cm for spinal involvement.(4) Pelvic compression: the patient lies on his side, and compression of the pelvis from the other side can cause sacroiliac joint pain.
(5) Patrick’s test (lower extremity 4-way test): The patient lies supine 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 of the contralateral sacroiliac joint can be induced, which is considered positive.
The earliest change of AS occurs in the sacroiliac joint. The X-ray of this area shows blurred subchondral bone margin, bone erosion, blurred joint space, 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. Computed tomography (CT) should be used for clinical or suspected cases where the X-ray has not yet shown clear or grade II or higher bilateral sacroiliac arthritic changes. This technique also has the advantage of having 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 test 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 at the pubic symphysis, sciatic tuberosity and tendon attachment points (such as the heel bone), with reactive sclerosis and villi-like changes in adjacent bone, and new bone formation may occur.
4. In active patients, increased blood sedimentation, increased C-reactive protein and mild anemia are seen. Rheumatoid factor negative immunoglobulins are mildly elevated. Although the rate of HLA-B27 positivity in AS patients is about 90%, it has no diagnostic specificity, while negative can help to exclude AS and positive cannot be used as a basis for diagnosis of AS in the country.
5. The diagnosis of AS now still follows the New York criteria of 1966, or the New York criteria revised in 1984, with the following conditions.
(1) New York criteria (1966): bilateral or unilateral sacroiliac arthritis confirmed by X-ray (graded according to the aforementioned grade 0-IV), with one or two of the following clinical manifestations attached, respectively, namely
①Lumbar spine motion is limited in all 3 directions of anterior flexion, lateral flexion and posterior extension;
②History or existing symptoms of low back pain;
Based on the above, the diagnosis of definite AS requires: X-ray confirmed grade III-IV bilateral sacroiliac arthritis with at least 1 of the above clinical manifestations; 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, respectively.
(2) Revised New York criteria (1984).
①The duration of lower back pain lasts for at least 3 months, and the pain improves with activity but does not decrease with rest;
(2) Restricted movement of the lumbar spine in the anterior-posterior and lateral flexion directions;
③Thoracic extension 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. The diagnosis of AS can be confirmed if the patient has ④ and any 1 of ①-③ respectively.
From the above 2 criteria, it can be seen that they both lack sensitivity for diagnosis in early stage patients. For this reason, patients who temporarily do not meet the diagnostic criteria for AS, but whose presentation meets the initial diagnostic criteria for spondyloarthropathies developed by the European Spondyloarthropathy Research Group, may be included in this category for diagnosis and treatment to avoid delays. The diagnostic criteria are: inflammatory spinal pain or asymmetric synovitis predominantly of the lower extremity joints with any of the following additional items, namely.
①positive family history ;
② psoriasis;
③ inflammatory bowel disease;
④Urethritis, cervicitis or acute diarrhea within 1 month prior to arthritis ;
⑤ alternating bilateral hip pain ;
⑥Tendon terminal disease;
⑦ sacroiliac arthritis.
[Differential diagnosis
Ankylosing spondylitis should be differentiated from the following diseases.
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, whereas RA rarely has sacroiliac joint lesions.
(3) AS involves the entire 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 the surrounding joints.
(5) AS does not have rheumatoid nodules visible in RA.
Treatment options and principles]
There is no cure for AS. However, if patients can be diagnosed and treated in time, they can achieve symptom control and improve prognosis. Non-pharmacological, pharmacological, and surgical treatment 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 exercise to obtain and maintain the best position of the spinal joints, strengthen paravertebral muscles and increase lung capacity is no less important than pharmacotherapy.
(3) When standing, one should try to maintain a posture with the chest up, abdomen tucked in and eyes level in front. The 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 necessary physical therapy for painful or inflamed joints or other soft tissues
2. Drug treatment
(1) Non-steroidal anti-inflammatory drugs (referred to as anti-inflammatory drugs): this class of drugs can rapidly 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. 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 Acemetacin 90mg once daily. Diclofenac can be used with reference to the instructions depending on the brand, dosage form and dose, usually with a total daily dose of 75~150mg; nabumetone 1000mg once a night; meloxicam 15mg once a day; and etodolac 400mg once a day. Newer drugs rofecoxib 25mg once daily and celecoxib 200mg twice daily are also used for the treatment of this disease.
Other less common adverse reactions include 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 take about 2 months to use, and after the symptoms are fully controlled, the dose is reduced and consolidated for a period of time with the minimum effective amount, and then discontinuation is considered; stopping the drug too soon is likely to cause recurrence of symptoms. If a drug is not effective for 2-4 weeks of treatment, it should be switched to other anti-inflammatory drugs of a different class. In the process of drug administration, attention should always be paid to monitoring adverse drug reactions and timely adjustment.
(2) Salicyclovir: 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 AS patients, and has the effect of preventing recurrence and reducing lesions in the 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/day, divided into 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 until 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 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 (reversible with discontinuation of the drug). It is contraindicated in patients with sulfonamide hypersensitivity.
(3) Methotrexate: Methotrexate may be used in patients with active AS when treatment with salazosulfapyridine and non-steroidal anti-inflammatory drugs is ineffective. However, comparative observations showed that it 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 radiographic lesions of the medial joints. Usually methotrexate 7.5mg-15mg, with an increase in dose as appropriate for individual severe cases, is given orally or by injection once a week for a period ranging from 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 effect can last for about 3 months. Long-acting corticosteroid joint cavity injections are feasible for long-term monoarticular (e.g., knee) effusion associated with this disease. Repeated injections should be given 3-4 weeks apart, usually no more than 2-3 times. Oral glucocorticoid therapy 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 (Thalidomide, Response Stop). The initial dose of 100 mg/d was increased by 100 mg every 10 days to 300 mg/d for maintenance. Insufficient dose is ineffective, and the symptoms are likely to recur rapidly after discontinuation of the drug. Adverse effects of this product include drowsiness, thirst, decreased blood cells, increased liver enzymes, microscopic hematuria and tingling sensation at the fingertips. Therefore, people 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
Anti-tumor necrosis factor-alpha monoclonal antibody-infliximab (trade name: Classic) has been used for the treatment of AS that is active or ineffective to anti-inflammatory drug therapy. the method is: 3mg-5mg/kg of this product, IV, repeated once at an interval of 4 weeks, usually used 3-6 times. Patients with peripheral arthritis, tendon terminalitis and spinal symptoms, as well as C-reactive protein, can be significantly improved after treatment. However, its long-term efficacy and its effect on the radiographic lesions of the medial joints are yet to be studied further. Adverse reactions include infections, severe allergic reactions, and lupus-like lesions.
Etanercept (trade name: Yicep, Enzyme), a recombinant human soluble tumor necrosis factor receptor fusion protein, binds reversibly to TNFα and competitively inhibits the binding of TNFα 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. In 80% of patients, the disease improves in terms of morning stiffness, back pain, tendonitis, chest expansion, blood sedimentation and C-reactive protein. The efficacy of the drug is rapid and does not decrease with the duration of administration. The main adverse effect of this product is infection.
In recent years, the efficacy of using the above two biological agents for the treatment of AS is very good in China.
4. Surgical treatment
Joint space narrowing, ankylosis and deformity caused by hip joint involvement are the main causes of disability in this 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 this disease can be characterized by mild or moderate episodes of acute spondylitis alternating with periods of near or complete quiescence and is a chronic progressive disease. Long-term follow-up is required. If treated appropriately, it can be non-disabling or very mildly disabling, and the patient can participate in normal work with no impact on quality of life. In a small number of patients, the disease is difficult to control and may become progressive and disabling. The prognosis for patients with refractory iritis and secondary amyloidosis is poor.