The article presents the modern principles of treatment of ankylosing spondylitis

Ankylosing spondylitis (AS) (ankylosing spondylitis, Strumpel disease – Marie – ankylosing spondylitis) is a chronic inflammatory disease of the spine (spondylitis), sacroiliac joints (sacroiliitis), often peripheral joints (arthritis), entheses (enthesitis), in some cases eye (uveitis), cardiovascular system – aortic root (aortitis), other internal organs.




This disease was known in ancient Egypt. The first descriptions of AS in foreign literature were made by A. Strumpel (1884) and P. Marie (1898) and were regarded as a variant of chronic articular rheumatism [1]. In domestic literature, priority is given to V.M. Bekhterev, although the clinical picture of patients with “spinal stiffness” described by Bekhterev differed from the classical AS clinic. However, V.M. Bekhterev drew great attention to the problem of AS, which served as an impetus for the study of AS and other spondylitis

Classification modified New York criteria for the diagnosis of AS (1984):
1. Pain and stiffness in the lower back – more than 3 months., Decreasing after exercise and intensifying at rest.
2. Restriction of movements in the lumbar spine in the sagittal and frontal planes.
3. A decrease in excursion of the chest (in comparison with the norm for sex and age).
4. Bilateral sacroileitis of 2–4 stages or unilateral sacroiliitis of 3-4 stages.
The diagnosis of a specific AS is established in the presence of radiological and at least 1 clinical criterion [3].
The disease can begin in childhood, but the peak falls on the 3rd stage (usually no later than 40 years). Men get sick 2-3 times more often than women. In more than 90% of cases, the genetic marker HLA-B27 is detected. Despite the fact that the clinical picture of AS was described half a century ago, the diagnosis of AS is established on average 7–10 years from the onset of the first manifestations. This is due to several reasons, such as:
– the diversity of the clinical picture in the debut of the disease;
– extravertebral lesions, in connection with which patients turn to various specialists;
– slow development of radiological signs of sacroiliitis, which are crucial;
– spontaneous prolonged remissions in the early years of the disease;
– lack of immunological markers;
– unstable increase in ESR and CRP in the first months and years of the course of the AU;
– lack of sufficient knowledge about the debut of AS in doctors of other specialties.
The clinical presentation of AS is independent of gender and the presence of HLA-B27. In approximately 25% of cases, the disease appears in childhood. Far from always, AS begins with spondylitis or sacroiliitis.

Options for starting the disease

Damage to the spine
Damage to the spine usually begins with the sacroiliac joints with a gradual transition to the overlying departments. Sacroileitis is manifested by intermittent pain in the buttocks, radiating to the gluteal folds, along the back of the thigh, to the inguinal region. Gradually, the pain grows, becomes bilateral. For the early stage of the disease, inflammatory pain in the lower back is also characteristic, for the diagnosis of which the following criteria have been developed:
– age of onset of pain – earlier than 40 years;
– gradually increasing current;
– reduction of pain after exercise;
– lack of improvement at rest;
– night pain.
Pain is considered inflammatory in the presence of 4 out of 5 symptoms. In AS, all parts of the spine are involved in the process. The disease often proceeds under the guise of lumbosacral radiculitis. With damage to the thoracic spine, costovertebral joints, pain in the chest, sometimes of a shingles character, is noted. The pain intensifies with coughing, taking a deep breath, and turning. Damage to the costal vertebral joints reduces the excursion of the chest, which further leads to a decrease in lung capacity. The defeat of the cervical spine occurs at a later date and leads to a decrease in the volume of movement of the head and neck. Spondylitis of the cervical spine can be accompanied by the phenomena of dyscirculatoryencephalopathy. Pain in the spine reflexively causes a muscle spasm, which leads to a limitation of spinal mobility. In the early stages of the disease, the limitation of the range of motion in the spine is caused by inflammation and muscular reflex spasm due to pain; at the stage of developed clinical manifestations of the movement, they are limited due to ossification of the spine. Over time, as a result of inflammatory lesions of the spine, postural changes characteristic of AS occur: the pose of the “supplicant”, the pose of the “proud”.




Damage to peripheral joints 
Peripheral arthritis is observed throughout the disease in more than half of patients and begins mainly with joints of the lower extremities. The most commonly affected are the hip, knee, ankle joints, less commonly the temporomandibular, metatarsophalangeal, and shoulder joints. Peripheral arthritis of any location is a serious problem due to severe pain, as well as due to the destruction of articular surfaces and impaired function. The most unfavorable in relation to the prognosis is coxite, often bilateral. It often develops in patients with childhood illness [8]. Peripheral arthritis in AS is often combined with enthesitis.

Enthesitis
Inflammation of entheses in AS is natural. In AS, enthesitis is manifested by pain during movement, in which the corresponding tendon is involved, soreness, and sometimes swelling of the area of ​​the enthesis. Enthesitis usually appears in the area of ​​the heels, elbows, knees, shoulders, and hips. The underlying bone is involved in the inflammatory process (osteitis), which leads to the development of erosion and further ossification and excessive bone formation. These phenomena underlie the appearance of peculiar radiological changes characteristic of AS: extra-articular bone erosion, subchondral osteosclerosis, bone proliferation (“spurs”) and periostitis. In AS, extra-skeletal lesions are observed: uveitis, changes in the aorta and heart, and kidney damage.

Uveitis
The frequency of uveitis in systemic rheumatic diseases is from 25 to 50%. Uveitis is the most common extra-skeletal manifestation of AS, it can be a manifestation and for a long time the only manifestation of the disease. Uveitis begins acutely and lasts up to 3 months, has a relapsing character, can affect all parts of the uveal tract. Both eyes may be involved in the process in turn. Patients have eye pain, photophobia, lacrimation, conjunctival hyperemia. The development of complications leads to decreased vision and blindness in a young, able-bodied age. Blindness and low vision can make up from 10 to 35% among eye diseases

Damage to the heart and aorta
Damage to the heart and aorta determines the prognosis of the disease and the tactics of therapeutic measures. It is known that there is no relationship between the activity and severity of damage to the musculoskeletal system. Despite the fact that damage to the cardiovascular system often proceeds subclinically, in the section, lesions of the aorta and aortic valves are detected in 24–100% of cases [4, 11].
An early diagnosis of AS helps to avoid unnecessary examinations and protect patients from improper therapy, including surgical procedures, to orient the patient to the systematic administration of non-steroidal anti-inflammatory drugs (NSAIDs), and in case of an unfavorable prognosis of AS, to appoint tumor necrosis factor inhibitors (anti TNF-therapy) in the early stages. Training in physiotherapy and a healthy lifestyle contributes to a more favorable outcome of AS.

AS treatment 
It should be based on the clinical signs of the disease present at the time of the examination (vertebral, articular, enthesic symptoms), their severity, the presence of prognosis indicators: disease activity / inflammation, functionality / ability to work, structural damage, involvement of the hip joints, spinal deformity, general clinical status (age , gender, concomitant diseases and therapy), patient expectations and preferences. The management of a patient with AS requires a mandatory combination of non-pharmacological and pharmacological methods of treatment.

Non-drug treatments
Non-pharmacological methods of treatment include daily execution of a set of physical exercises aimed at maintaining a sufficient amount of movement in the spine and large joints, strengthening skeletal muscles [12]; breathing exercises, back massage, physiotherapeutic procedures with various anti-inflammatory ointments in the form of phonophoresis, balneotherapy: radon and hydrogen sulfide baths. The functional state of the spine in people regularly engaged in exercise therapy and muscle training is better than in patients who, for one reason or another, neglect the exercises. Non-pharmacological methods for AS can include educational programs – schools for patients. They can be carried out both individually and in group mode. Nonpharmacological methods of treatment for AS are of only auxiliary value.

Pharmacological treatment methods Pharmacological treatment
methods combine drugs of several groups: NSAIDs, muscle relaxants, corticosteroids, anti-TNF-therapy.
NSAIDs
Despite the long-standing use of NSAIDs in the practice of a rheumatologist, in modern EULAR / ASAS recommendations they are still first-line drugs in the treatment of AS, since they are distinguished by a unique combination of analgesic, anti-inflammatory and antipyretic effect [5]. The long-term use and high effectiveness of NSAIDs in relation to inflammatory pain raises the question of their ability to exert not only symptomatic, but also a disease-modifying effect, i.e., slowing down of radiological progression. Recent observation by A. Wanders et al. confirmed that NSAIDs can slow the radiological progression (ossification) in the spine. According to this study, it turned out that the average values ​​of x-ray changes were significantly less in patients who took NSAIDs continuously, not on demand. However, it has not been established that it affects the retardation of ossification of the spine: suppression of active inflammation or the direct effect of NSAIDs on bone tissue – suppression of osteoblast activity. According to morphological studies, inflammation in the area of ​​entheses and bone (osteitis) in AS continues throughout the disease and is not inclined to completely fade, even when ankylosis of the spine or joint occurs, which is the basis for long-term administration of drugs of this group. After the diagnosis of AS (regardless of the stage of the disease), NSAIDs should be prescribed to the patient immediately. AS is the only rheumatological disease in which prolonged use of NSAIDs is pathogenetically substantiated, highly effective and has no alternative except for TNF-a inhibitors. The first goal of NSAIDs is to relieve pain. This is usually achieved after 2 weeks. If the main symptoms of the disease are night pain in the spine and morning stiffness, then the appointment of prolonged forms of drugs is desirable. Sometimes, to eliminate pain and morning stiffness, a consistent change of 2-3 drugs is necessary.
The most effective drugs for treating AS are the classic (standard) drugs: diclofenac, indomethacin, ketoprofen, naproxen. However, the frequency of adverse reactions in this group of drugs, especially with prolonged use, which is required in the treatment of AS, makes it preferable to select selective COX-2 inhibitors. In turn, moderately selective (meloxicam, nimesulide, nabumetone, etodolac) and highly selective (celecoxib, valdecoxib, etoricoxib, lumiracoxib) stand out among the latter. The choice of the drug should be based on an analysis of the advantages and disadvantages of various NSAID groups, taking into account the presence of analgesic, anti-inflammatory effects in combination with good tolerance (safety in relation to the gastrointestinal tract (GIT) and the cardiovascular system). In Russia, many drug experts, possessing the indicated properties, consider nimesulide (Nise). The advantages of this drug are noted by many world experts. In an article on the 25th anniversary of the use of nimesulide in Italy, C. Mattia et al. pointed to the apparent predominance of the positive qualities of this medicine [6]. These findings are confirmed by clinical studies of scientists from NIIR them. V.A. Nasonova – A.E. Karateev et al. A retrospective analysis of the frequency of complications from the gastrointestinal tract, cardiovascular system and liver in patients admitted to the NIIR from 2007 to 2008 and who took nimesulide at a dose of 200 mg for at least 12 months. before admission, showed that in addition to effective analgesic, anti-inflammatory properties, Nise has good tolerance. Nimesulide has established itself as an effective tool for pain relief. It has high bioavailability – already 30 minutes after oral administration, a significant concentration of the drug in the blood is reached, which is at least 25% of the maximum. The full analgesic and anti-inflammatory effect of nimesulide occurs 1-3 hours after administration.



As is known, the pharmacological effect of all NSAIDs is associated with the blockade of COX-2, and the complications associated with their intake from the gastrointestinal tract are mainly determined by the suppression of the activity of COX-1 in the gastrointestinal mucosa. But COX-1 also takes part in the development of inflammation, and therefore a local decrease in its activity in the area of ​​damage should be considered as a positive factor. Nimesulide has this effect – it only slightly affects the “structural” COX-1 of the gastric mucosa, but significantly reduces the effects of this enzyme in the area of ​​inflammation. Recently, the question of the central effects of NSAIDs related to their ability to penetrate the tissue of the central nervous system and affect the development of a number of links in the pathogenesis of chronic pain has been actively discussed. associated with the activation of the central pain system (the phenomenon of “central sensitization”). Nimesulide, obviously, has such an effect, which is confirmed by the data of experimental and clinical studies. There is good reason to believe that nimesulide has a number of pharmacological effects, independent of the class-specific effect on COX-2. In particular, it suppresses the overproduction of major pro-inflammatory cytokines (interleukin-6, TNF-a), reduces the activity of metalloproteinases.
The effectiveness of nimesulide for the relief of acute and chronic pain in rheumatic diseases (RH) is confirmed by a series of clinical trials. So, there is evidence of its use in postoperative pain management. In acute rheumatic inflammation of the periarticular soft tissues – enthesitis, bursitis and tendonitis, it exhibits a good therapeutic effect, comparable or more pronounced than the effect of high doses of the “traditional” NSAIDs – diclofenac and naproxen. In particular, W. Wober et al. conducted a study in which 122 patients with subacromial bursitis and tendonitis took nimesulide 200 mg / day or diclofenac 150 mg / day for 14 days. At the same time, a “good” or “excellent” response to treatment was somewhat more often observed in individuals taking nimesulide – 82.3%, compared with 78.0% in the diclofenac group.
Nimesulide is effective in acute lower back pain (NES). According to a clinical trial conducted by Finnish scientists, nimesulide at a dose of 100 mg 2 p. / Day was superior to ibuprofen at a dose of 600 mg 3 p. / Day both in severity of analgesic effect and in restoration of spinal function. By the 10th day of therapy, the use of nimesulide provided an improvement in functional activity by more than 2 times. This makes nimesulide (Nise) very attractive for the treatment of pain in ankylosing spondylitis.
One of the most valuable advantages of nimesulide for clinical practice is its good gastrointestinal tolerance. Indeed, it is the development of the pathology of the digestive system, which is one of the class-specific complications of NSAIDs, that is one of the main parameters that determine the ratio of risk and benefit for this class of painkillers.
The risk of liver complications when using nimesulide (Nise) is not higher than that of “traditional” NSAIDs. An analysis of the available literature data and clinical studies shows that the negative dynamics of laboratory biochemical parameters, indicating the development of liver pathology, is noted with the use of nimesulide with the same frequency as with other NSAIDs. When analyzing reports of hepatotoxic reactions, it turned out that the total number of messages when using diclofenac was 990, ibuprofen – 590, and nimesulide – only 152. Most importantly, the life-threatening pathology – liver failure was recorded by WHO in 21 patients receiving diclofenac, and 32 patients receiving ibuprofen. While taking nimesulide, this complication was noted only in 4 cases. It becomes clear
In 2013, the lack of specific hepatotoxicity of nimesulide was confirmed by another population study. S. Gulmez et al. studied the causes of acute liver failure in 9479 people who were on the list of people who needed emergency liver transplantation (European Union, 2005-2007). NSAIDs have become the etiological factor of this potentially fatal complication in 40 cases, paracetamol – in 192. The relative risk (RR) of acute liver failure for different drugs is different. According to the results of the study, nimesulide was less dangerous than paracetamol and ibuprofen, and in fact is equal to drugs such as diclofenac and ketoprofen. In Russia, not a single case of severe hepatotoxic reactions has been described .
An important factor contributing to the popularity of nimesulide among other drugs of this medicinal group is the low cost, making it available to the vast majority of the inhabitants of our country. After all, the main consumers of NSAIDs are patients suffering from chronic diseases of the joints and spine, elderly people with low income.
In addition to the standard forms for oral administration, preparation for local use is also presented – Nise gel containing 1% of the active substance. Local forms of NSAIDs are a useful and safe tool that can be used for adjuvant therapy both when applied to the skin, and in the form of phonophoresis with ointment on the painful area [13].
 Glucocorticosteroids (GCS)
For the treatment of AS, systemic use of GCS is not recommended. But these drugs are effective as a local therapy for peripheral arthritis in relapsing synovitis. The effectiveness of HA in the treatment of AS is not in doubt, but they are less effective in the treatment of enthesitis (apparently, due to the lower concentration of the active substance in the avascular zone of entheses). In these cases, local injections of corticosteroids into the area of ​​entheses are highly effective.
Muscle relaxants
It is known that pain in the spine is accompanied by muscle spasm, the presence of which in turn exacerbates pain and spasm. It was found that the simultaneous use of NSAIDs and muscle relaxants reduces back pain, and also helps to maintain spinal mobility.
Basic anti-inflammatory drugs
Synthetic Basic anti-inflammatory drugs: sulfasalazine, methotrexate, leflunomide are not recommended in the treatment of axial forms of AS due to inefficiency. But with peripheral arthritis, this group of drugs is used with a positive effect, which is recommended to be evaluated no earlier than 3 months later. Sulfasalazine is taken in a daily dose of 2-3 g. The use of methotrexate, depending on the effectiveness, toxicity can be in a dose of 10 to 15-20 mg per week and must be accompanied by folic acid, excluding the day of taking methotrexate. With intolerance to methotrexate, the patient may be prescribed the drug Arava. The latter is taken at 20 mg / day after a 3-day intake of an induction dose of 100 mg/day for 3 days.
Genetically engineered biologicals (GEB)
Recently, significant progress has been made in the treatment of diseases of the joints and spine due to the use of HIFP. The high efficiency of this group of drugs is confirmed by numerous studies and long-term use in medical practice. In AS, these drugs provide a distinct reduction in pain and inflammation in the spine, joints and joints. Approved for use in the treatment of AS include infliximab, adalimumab, etanercept, golimumab, Certolizumab pegol. A fundamental difference in the effectiveness of these drugs in relation to the effect on the main symptoms (pain, stiffness, enthesitis, peripheral arthritis) has not been established. Treatment of GEB should be started if there is no effect in the treatment of both NSAIDs and NSAIDs in combination with NSAIDs (sulfasalazine at a maximum dose of 3 g / day) for 3 months. The effect of TNF-a inhibitors on uveitis (as opposed to effects on the spine and peripheral arthritis) is poorly understood. A group of employees of NIIR them. V.A. Nasonova (A.A. Godzenko, A.G. Bochkova, Sh.F. Erdes, and others) studied the effect of TNF-a inhibitors: infliximab, adalimumab, and etanercept on the frequency of uveitis attacks in patients with AS. The study found that TNF-a inhibitors effectively affect uveitis in patients with AS. Three studied drugs (infliximab, adalimumab, etanercept) significantly reduced the frequency of exacerbation of uveitis in comparison with standard anti-inflammatory therapy. The criteria for assessing the response to treatment are a global assessment of the patient’s well-being on a 100 mm visual analogue scale (VAS), pain in the spine according to VAS, a functional assessment of the patient (BASFI),




Surgical treatment
In cases of involvement in the process of the hip joints with the development of coxitis and subsequent functional impairment in patients, endoprosthetics of the hip joint can be performed. Spinal surgery (corrective osteotomy) can be performed if necessary.
Despite significant progress in the treatment of AS in recent years, many unresolved problems remain: monitoring of patients, the immunogenicity of GBS, and their effectiveness on the effectiveness and safety of therapy, etc. This leaves the management and treatment tactics of AS patients in the focus of attention of scientists and doctors.




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