Seronegative spondyloarthropathies

Seronegative spondyloarthropathies (SSA) form a group of interrelated, clinically intersecting chronic inflammatory rheumatic diseases, which includes idiopathic ankylosing spondylitis (the most common form), reactive arthritis (including Reiter's disease), psoriatic arthritis (PsA), and enteropathic arthritis associated with inflammatory diseases intestines.

[1], [2], [3]

Epidemiology

Spondyloarthropathies usually suffer from 15 to 45 years of age. Among the sick, men prevail. As it turned out, the prevalence of seronegative spondyloarthropathies in the population is close to that of rheumatoid arthritis and is 0.5-1.5%. 

[4], [5], [6], [7], [8], [9]

Symptoms of seronegative spondyloarthropathies

Thus, seronegative spondyloarthropathies have both signs that distinguish them from rheumatoid arthritis, and similar, common for all diseases;

• absence of rheumatoid factor;
• absence of subcutaneous nodules;
• asymmetric arthritis;
• X-ray signs of sacroiliitis and / or ankylosing spondylitis;
• the presence of clinical crossover;
• the tendency to accumulate these diseases in families;
• association with the histocompatibility antigen HLA-B27.

The most characteristic clinical feature of the family of seronegative spondyloarthropathies is back pain of an inflammatory nature. Another distinctive feature is enthesitis, inflammation in the places of attachment of ligaments, tendons or capsules of the joint to the bone. It is believed that entesite is pathogenetically important, a primary lesion in spondyloarthropathies, while synovitis is the main lesion in rheumatoid arthritis.

Quite often the trigger of entesites is a trauma of enthesies or reloading of tendons. Enthesites are manifested by pain during movement, in which the corresponding muscle participates. More clearly, pain occurs when the muscle concerned is stressed. Puffiness of surrounding tissues and palpation tenderness are determined in the area of involved entesis. The most frequent outcome of enthesopathy is ossification of entesis with the development of enthesophytes.

The group of seronegative spondyloarthropathies is heterogeneous, it includes a large number of undifferentiated and limited forms. Even the leading nosological units in the group have significant variations in the frequency of development of the same trait. Thus, the marker antigen of seronegative spondyloarthropathies HLA-B27 occurs at a frequency of up to 95% in patients with ankylosing spondylitis (AC) and only 30% of cases of enteropathic arthritis. The development of sakroileitis correlates with the carrier of HLA-B27 and is observed in 100% of cases of AS, but only in 20% of patients with Crohn's disease and ulcerative colitis. Entheses, dactylite and a one-sided process are more pathognomonic for patients with reactive arthritis and PsA.

Comparative characteristics of clinical features of major spondyloarthropathies (Kataria R, Brent L., 2004)

Clinical Features	Ankylosing spondylitis	Reactive arthritis	Psoriatic arthritis	Enteropathic arthritis
Age at onset of illness	Young people, teenagers	Young people teenagers	35-45 years old	Any
Sex (male / female)	3: 1	5: 1	1.1	1: 1
HLA-B27	90-95%	80%	40%	Thirty%
Sacroiliitis	100%, two-sided	40-60%, unilateral	40%, one-sided	20%, two-sided
Syndetic Maths	Small, marginal	Massive, non-border	Massive, non-border	Small, marginal
Peripheral arthritis	Sometimes asymmetrical, lower limbs	Usually, asymmetrical, lower limbs	Usually, asymmetric, any joints	Usually. asymmetrical, lower limbs
Enteite	Usually	Often	Often	Sometimes
Dactylite	Not typical	Often	Often	Not typical
Skin lesion	No	Circular balanitis, keratoderma	Psoriasis	Nodular erythema, gangrenous pyoderma
The defeat of nails	No	Onycholysis	Onycholysis	Thickening
Eye disease	Acute anterior uveitis	Acute anterior uveitis, conjunctivitis	Chronic uveitis	Chronic uveitis
Lesion of the oral mucosa	Ulcers	Ulcers	Ulcers	Ulcers
The most common lesion of the heart	Aortic regurgitation, conduction disorders	Aortic regurgitation. violation of	Aortic regurgitation, conduction disorders	Aortic regurgitation
Defeat lung	Upper- lobe fibrosis	No	No	No
Gastrointestinal lesions	No	Diarrhea	No	Crohn's disease, ulcerative colitis
Defeat of kidneys	Amyloidosis, IgA-nephropathy	Amyloidosis	Amyloidosis	Nephrolithiasis
Genitourinary lesions	Prostatitis	Urethritis, cervicitis	No	No

[10], [11], [12],

Cardiac lesions in seronegative spondyloarthropathies

Cardiac lesions, as a rule, do not serve as the main pathological manifestation of seronegative spondyloarthropathies, are described in all diseases of this group. Cardiac lesions in the form of isolated aortic regurgitation and atrioventricular (AV) blockade are most specific for seronegative spondyloarthropathies. Mitral regurgitation, myocardial (systolic and diastolic) dysfunction, other rhythm disturbances (sinus bradycardia, atrial fibrillation), pericarditis are also described.

Variants of cardiac involvement in patients with seronegative spondyloarthropathies and their clinical significance

Cardiac lesion	Patients, %	Clinical significance
Myocardial dysfunction (systolic and diastolic)	> 10	Rarely, not clinically relevant
Valve dysfunction	2-10	Often, requires treatment
Violations of the conduct	> 10	Often, require treatment
Pericarditis	<1	Rarely, not clinically relevant

Heart failure is most often observed in AS and diagnosed, according to different data, in 2-30% of patients. Several studies have shown that the incidence of cardiac lesions increases as the "length of service" of the disease increases. The prevalence of cardiac lesions in other seronegative spondyloarthropathies is less and less studied.

The pathogenesis of the development of cardiac lesions of seronegative spondyloarthropathies is not disclosed. At the same time, data on their association with the presence of HLA-B27 antigen, a marker of this group of diseases, stably associated with the development of severe isolated aortic regurgitation and AV blockade (67% and 88%, respectively) have been accumulated. In several studies of patients with PAS, heart damage was detected only in carriers of the HLA-B27 antigen. HLA-B27 antigen is present in 15-20% of men with a permanent pacemaker due to AV blockade, which is higher than its prevalence in the population as a whole. The cases of development of AV blockade in patients with HLA-B27 carriers without joint and ophthalmologic symptoms of SSA are described. These observations even allowed some authors to propose the concept of "HLA-B27-associated heart disease" and to consider cardiac lesions in patients with seronegative spondyloarthropathies as symptoms of an individual disease.

Hypopathological changes that appeared in the heart structures in AS were described by Buiktey V.N. Et al. (1973). Later similar observations were obtained with other seronegative spondyloarthropathies.

Histopathological and pathologoanatomical signs of cardiac involvement in seronegative spondyloarthropathies

Region		Changes
Aorta		Proliferation of the intima, focal destruction of the elastic tissue with inflammatory cells and fibrosis, fibrous thickening of adventitia, dilatation
Vasa vasorum of the aorta, artery of the sinus node, artery of the AV node		Fibrous-muscle proliferation of the intima, perivascular infiltration of inflammatory cells, obliterating endarteritis
Aortic valve		Extension of the ring, base fibrosis and progressive shortening of the valves, curvature of the free margin of the valves
The mitral valve		Fibrosis of the base of the anterior valve ("hump"), widening of the ring secondary to the dilatation of the left ventricle
Conducting system		Obliterating endarteritis of the arteries supplying, fibrosis
Myocardium		Diffuse enlargement of interstitial connective tissue

Isolated aortic regurgitation is described for all seronegative spondyloarthropathies. Unlike rheumatic aortic regurgitation, it is never accompanied by stenosis. The prevalence of the occurrence of aortic regurgitation in AS is from 2 to 12% of cases, with Reiter's disease - about 3%. Clinical symptoms are absent in most cases. The subsequent surgical correction is necessary for the attitude of only 5-7% of patients. The diagnosis of "aortic regurgitation" may be suspected if there is a diastolic murmur of a soft blowing timbre and is confirmed in Doppler echocardiography (DEHOKG).

In most patients, treatment is conservative or not required. In rare cases, surgical treatment is indicated.

Mitral regurgitation is the result of subaortic fibrosis of the anterior valve of the mitral valve with the limitation of its mobility ("subaortal hump" or "subaortal crest"). It is much less common than aortic lesion. In literature

Several cases are described. Mitral regurgitation in AS can also develop secondary to aortic as a result of dilatation of the left ventricle. Diagnose with DEHO KG.

Atrioventricular blockade is the most common cardiac lesion in CCA, described in AS, Reiter's disease and PsA. It often develops in men. In patients with AS intraventricular and AV blockade is detected in 17-30% of cases. In 1-9% of them, a three-beam blockade is broken. In Reiter's disease, AV blockade occurs in 6% of patients, and a complete blockade develops rarely (less than 20 cases are described). AV-blockade refers to the early manifestations of Reiter's disease. The peculiarity of AV blockade in seronegative spondyloarthropathies is their transient nature. The unstable nature of the block is due to the fact that it is based not on fibrotic changes, but on reversible inflammatory responses, on its basis. This is confirmed by the data of the electrophysiological study of the heart, during which much more often, even in the presence of concomitant bundle blockades, a block is found at the level of the AV node, rather than subject parts, where it is more likely to expect fibrotic changes.

When the episode of complete blockade shows the installation of a permanent pacemaker, with incomplete - conservative management. The episode of a complete blockade may not have relapses for more than 25 years, but the pacemaker installation should still be performed, as it is favorably tolerated by patients and does not lead to a decrease in life expectancy,

The prevalence of sinus bradycardia in seronegative spondyloarthropathies is unknown, it was detected with an active electrophysiological study. The cause of dysfunction of the sinus node, apparently, is a decrease in the lumen of the artery of the node as a result of the proliferation of its intima. The same processes are described in the thickening of the root of the aorta and the artery of the AV node.

Several cases of atrial fibrillation have been described in patients with PAS who did not have other cardiac and extracardiac diseases. Atrial fibrillation can not be unequivocally interpreted as one of the manifestations of seronegative spondyloarthropathies.

Pericarditis is the rarest of the variants of cardiac lesions detected with PAS. As a histopathological finding, less than 1% of patients were found.

Myocardial dysfunction (systolic and diastolic) is described in a small group of patients with AS and Reiter's disease. Patients lacked other cardiac manifestations of PAS and any diseases that could cause myocardial damage. A part of the patients underwent a histological examination of the myocardium, during which a moderate increase in the amount of connective tissue without inflammatory changes and amyloid deposition was observed.

In recent years, the problem of the accelerated development of atherosclerosis in SSA has been studied. Data were obtained on the increased risk of atherosclerotic lesion of the coronary arteries and the development of myocardial ischemia in patients with PsA and AS.

[13], [14], [15], [16], [17]

The classification of seronegative spondyloarthropathies

The clinical spectrum of diseases was much wider than initially realized, therefore, some less definite forms were classified as undifferentiated spondyloarthropathies. Differentiation among these forms, especially in the early stages, is not always possible due to the unclear severity of the clinical features, but this usually does not affect the tactics of their treatment.

Classification of seronegative spondyloarthropathies (Berlin, 2002)

• A. Ankylosing spondylitis.
• B. Reactive arthritis, including Reiter's disease.
• B. Psoriatic arthritis.
• D. Enteropathic arthritis associated with Crohn's disease and ulcerative colitis.
• D. Undifferentiated spondylitis.

Initially, the Whipple disease, Behcet's syndrome and juvenile chronic arthritis were also included in the group of seronegative spondyloarthropathies. Currently, these diseases are excluded from the group for various reasons. So, with Behcet's disease there is no axial skeletal lesion and association with HLA-B27. Whipple's disease is rarely accompanied by sakroileitis and spondylitis; data on the carriage of NLA-B27 are inconsistent with it (10 to 28%), and the proven infectious nature distinguishes the disease from other spondyloarthropathies. Admittedly, juvenile chronic arthritis is a group of heterogeneous diseases, many of which later evolve into rheumatoid arthritis, and only a few can be considered as a precursor to the development of seronegative adult spondyloarthropathies. The question of whether the BARNO syndrome, which manifests itself synovitis, pustules of the palms and soles, hyperostosis, frequent lesion of the sternoclavicular joints, the development of aseptic osteomyelitis, sacroiliitis, axial spine injury with the presence of NLA-B27 in 30-40% patients,

Diagnosis of seronegative spondyloarthropathies

In typical cases, when there is well-defined clinical symptomatology, attributing the disease to the SSA group is not a difficult problem. In 1991, the European Group for the Study of Spondyloarthritis developed the first clinical guidelines for the diagnosis of seronegative spondyloarthropathies.

The criteria of the European Group for the Study of Spondyloarthritis (ESSG, 1941)

Back pain of an inflammatory nature or predominantly asymmetric synovitis of the joints of the lower limbs in combination with at least one of the following:

• positive family history (according to AS, psoriasis, acute anterior uveitis, chronic inflammatory bowel disease);
• psoriasis;
• chronic inflammatory bowel disease;
• urethritis, cervicitis, acute diarrhea 1 month before arthritis;
• intermittent pain in the buttocks;
• enthesopathy;
• sacroiliac bilateral II-IV stage or one-sided III-IV stage.

These criteria were created as classification and can not be widely applied in clinical practice, since their sensitivity in patients with an anamnesis of the disease of less than 1 year is up to 70%.

Developed further B. Amor et al. Diagnostic criteria showed a high sensitivity in various studies (79-87%), to some extent due to a decrease in their specificity (87-90%). These criteria allow us to estimate the degree of reliability of the diagnosis in scores and give better results in the diagnosis of undifferentiated spondylitis and early cases of the disease.

[18], [19], [20],

Criteria for the diagnosis of seronegative spondyloarthropathies (Amor V., 1995)

Clinical or anamnestic signs:

• Night pain in the lumbar region and / or morning stiffness in the lower back - 1 point.
• Oligoarthritis is asymmetric - 2 points.
• Periodic pain in the buttocks - 1-2 points.
• Sausage-like fingers on hands and feet - 2 points.
• Talalgia or other enterosopathies - 2 points.
• Irit - 2 points.
• Non-gonococcal urethritis or cervicitis less than 1 month before the debut of arthritis - 1 point.
• Diarrhea less than 1 month before the debut of arthritis - 1 point.
• Presence or preceding psoriasis, balanitis, chronic enterocolitis - 2 points.

X-ray signs:

• Sacroiliitis (bilateral stage II or unilateral stage III-IV) - 3 points.

Genetic features:

• The presence of HLA-B27 and / or the presence of a family member in the history of spondylitis, reactive arthritis, psoriasis, uveitis, chronic enterocolitis - 2 points.

Sensitivity to treatment:

• Reduction in 48 hours of pain on the background of taking non-steroidal anti-inflammatory drugs (NSAIDs) and / or stabilization for early relapse - 1 point.
• The disease is considered reliable spondyloarthritis, if the sum of scores by 12 criteria is greater than or equal to 6.

[21], [22], [23], [24], [25]

Treatment of seronegative spondyloarthropathies

Treatment of ankylosing spondylitis

Currently, there are no medicines that have a significant effect on the processes of ossification in the spinal column. Positive effect on the course and prognosis of AS basic drugs used in the treatment of other rheumatic diseases (including sulfasalazine and methotrexate) has not been proven, therefore, in the first place, patients are treated by exercise therapy. Its effectiveness in the AU, at least in the analysis of the immediate results (up to 1 year), is a proven fact. Long-term research results on this issue are not yet available. As a result of a randomized controlled trial, a greater effectiveness of group programs was shown than individualized ones. The program, consisting of hydrotherapeutic exercises for 3 hours twice a week, resulted in a 3-week application to improve overall health and mobility of the lumbar-thoracic spine, which, according to objective and subjective assessments, was noted for 9 months. During the same period, the need for NSAIDs decreased in patients.

Of the drugs used to treat AS, the long-proven efficacy of NSAIDs, there are no advantages in treatment with any specific drug. The COX-2 inhibitors show efficacy similar to that of nonselective drugs. It is not known whether in the case of continuous NSAID application, there are long-standing advantages over non-permanent treatment to prevent structural damage.

Glucocorticoids can be used for local intra-articular injection (including sacroiliac joints). The effectiveness of systemic treatment of glucocorticoids and in AS is significantly lower than in rheumatoid arthritis. A positive response to such treatment is more often observed in patients with peripheral arthritis. Sulfasalazine, according to several clinical trials, also proved effective only in peripheral arthritis, reducing synovitis and without affecting axial lesions. Insignificant effectiveness with respect to the AS in an open study was demonstrated by leflunomide. The effectiveness of methotrexate is doubtful and has not been proved, there are only single pilot studies on this issue.

The effectiveness of intravenous application of bisphosphonates in AC has been determined. In patients with AS with a background of treatment with pamidronic acid, pain in the spine and a slight increase in its mobility were noted, an increase in the effect was achieved with an increase in the dose of the drug.

The main hopes for the treatment of AS are now placed on the use of biologically active agents, in particular monoclonal anti-TNF-a antibodies. During the clinical trials, disease-modifying properties of at least two drugs - infliximab and etanercept - were revealed. However, the wide use of these drugs in AS is impeded not only by the high cost, but also by the absence of remote data on their safety, the possibilities of controlling the disease and preventing structural changes. In this regard, it is recommended to approach the prescription of these drugs strictly individually, using them for high uncontrolled activity of the inflammatory process.

Treatment of reactive arthritis

Treatment of reactive arthritis includes antimicrobials, NSAIDs, glucocorticoids and disease-modifying agents. Antibiotics are effective only for the treatment of acute reactive arthritis associated with chlamydial infection, in the event that there is a focus of this infection. Macrolide antibiotics and fluoroquinolones are used. It is necessary to treat the patient's sexual partner. Prolonged use of antibiotics does not improve the course of reactive arthritis or its manifestations. In the case of post-enterocolitis arthritis, antibiotics are ineffective.

NSAIDs reduce inflammatory changes in the joints, but do not affect the course of extraarticular lesions. Large clinical trials of the efficacy of NSAIDs in patients with reactive arthritis have not been conducted.

Glucocorticoids are used as a local treatment with the help of intraarticular administration and introduction into the area of affected enteroses. Topical application of glucocorticoids is effective for conjunctivitis, iritis, stomatitis, keratoderma, balanitis. For prognostically unfavorable systemic manifestations (carditis, nephritis), it is possible to recommend a systemic prescription of drugs with a short course. There were no large controlled studies of the effectiveness of local and systemic use of glucocorticoids.

Disease-modifying agents are used for prolonged and chronic course of the disease. Slight efficacy in placebo-controlled studies showed sulfasalazine at a dose of 2 g / day. The use of sulfasalazine a contributed to a reduction in inflammatory changes in the joints, and there was no effect on the progression of joint lesions. Clinical trials of other disease-modifying drugs for the treatment of reactive arthritis are not available.

Treatment of psoriatic arthritis

For the choice of the volume of treatment determine the clinical-anatomical version of the joint syndrome, the presence of systemic manifestations, the degree of activity, the nature of skin manifestations of psoriasis.

Drug treatment of psoriatic arthritis includes two areas:

1. the use of simite-modifying drugs;
2. application of disease-modifying drugs.

Symptom-modifying drugs include NSAIDs and glucocorticoids. Treatment with PsA has a number of features, but compared with other rheumatic diseases. According to the Institute of Rheumatology RAMS, the use of glucocorticoids in psoriatic arthritis is less effective than with other rheumatic diseases, in particular rheumatoid arthritis. The introduction of glucocorticoids intraarticularly or into affected enterises has a more distinct positive effect than their systemic application. In the opinion of V.V. Badokin, this can be due to many circumstances, in particular with a small involvement of humoral immune disorders in the development and progression of the disease, difficulties in adequately assessing the degree of activity of the inflammatory process and, accordingly, determining indications for the appointment of glucocorticoids, and insignificant inflammation of the synovial membrane. The features of the body's response to glucocorticoids in psoriatic arthritis may be determined by the low density of glucocorticoid receptors in the tissues, as well as the violation of the interaction of glucocorticoids with their receptors. Difficulties in the treatment of precisely such a disease as PsA are due to the fact that the systemic administration of glucocorticoids often leads to the destabilization of psoriasis with the formation of more severe, torpid to the treatment and associated with a higher risk of severe psoriatic arthritis (pustular psoriasis). Immunopathologic disorders in the basis of the pathogenesis of PsA are the main target of the treatment of this disease with disease-modifying drugs, the principles of their application are developed and are successfully used in the main inflammatory diseases of the joints and spine.

Sulfasalazine is one of the standard drugs in the treatment of psoriatic arthritis. It does not cause exacerbation of dermatosis, while in some patients it facilitates the resolution of psoriatic skin changes.

The disease-modifying properties of methotrexate in psoriatic arthritis is a universally recognized fact. It is distinguished by the most favorable ratio of efficacy and tolerability in comparison with other cytotoxic drugs. The choice of methotrexate is also dictated by its high therapeutic efficacy against skin manifestations of psoriasis. In the treatment of psoriatic arthritis disease-modifying drugs are used and gold preparations. The target for them are macrophages and endothelial cells, taking part in different stages of development of the pathological process, including the earliest. Gold preparations inhibit the release of cytokines, in particular IL-1 and IL-8, enhance the functional activity of neutrophils and monocytes that inhibit the presentation of the antigen to T cells, reduce the infiltration of the T- and B-lymphocytes of the synovium and psoriatic skin, inhibit the differentiation of macrophages. One of the factors that make it difficult to widely introduce gold preparations into the complex treatment of psoriatic arthritis is their ability to cause exacerbation of psoriasis.

For the treatment of psoriatic arthritis, a relatively new leflupomide preparation, a pyrimidin synthesis inhibitor, has been used which has been shown to be effective in the treatment of skin and joint damage with PcA (TOPAS study).

Taking into account the leading role of TNF-a in the development of inflammation in psoriatic arthritis, in modern rheumatology much attention is paid to the development of highly effective biological agents: chimeric monoclonal antibodies to TNF-a-infliximab (remakeide), rFNO-75 Fc IgG (etanertsent), palL -1 (anakinra).

Long-term treatment with disease-modifying drugs allows you to monitor the activity of psoriatic arthritis and the course of its main syndromes, slows down the rate of disease progression, promotes patient survival and improves the quality of life. Treatment of psoriatic arthritis also has its own distinctive features.

Treatment of enteropathic arthritis

Efficacy, including long-term observations, of sulfasalazine has been proven. Azathioprine, glucocorticoids and methotrexate are also widely used. High efficiency was shown by infliximab. With respect to NSAIDs, studies have been conducted that have convincingly shown that their use contributes to an increase in the permeability of the intestine and, thus, can enhance the inflammatory process in it. Paradoxically, NSAIDs are widely used in patients with epteropathic arthritis, which are often well tolerated.

Treatment of systemic manifestations of seronegative spondyloarthropathies, including heart damage, obeys the general principles of treatment of the leading clinical syndrome (heart failure or rhythm disturbances and conduction of the heart, etc.).

Background

A group of seronegative spondyloarthropathies was formed in the 1970s. After a detailed study of cases of seronegative rheumatoid arthritis. It turned out that in many patients the clinical picture of the disease differs from that of a seropositive variant; often the development of spondyloarthritis, the defeat of sacroiliac joints, arthritis of peripheral joints is asymmetric, not synovitis prevails, and enthesitis, there are no subcutaneous nodules, there is a family predisposition to the onset of the disease. Prognostically, these "forms" were evaluated as more favorable than the rest of the cases of seronegative and sferospozitive rheumatoid arthritis. Later, a close associative relationship between spondyloarthritis and the carrier of the histocompatibility antigen HLA-B27, which was absent in rheumatoid arthritis, was found.

[26], [27], [28], [29],