Seronegative spondyloarthropathies

Seronegative spondyloarthropathies (SSA) are a group of related, clinically overlapping chronic inflammatory rheumatic diseases that include idiopathic ankylosing spondylitis (the most common form), reactive arthritis (including Reiter's disease), psoriatic arthritis (PsA), and enteropathic arthritis associated with inflammatory bowel disease.

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Epidemiology

Spondyloarthropathies usually affect people aged 15 to 45. Men predominate among those affected. 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%.

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Symptoms of seronegative spondyloarthropathies

Thus, seronegative spondyloarthropathies have both features that distinguish them from rheumatoid arthritis, as well as similar features common to all diseases;

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

The most characteristic clinical feature of the family of seronegative spondyloarthropathies is inflammatory back pain. Another distinctive feature is enthesitis, inflammation at the sites of attachment of ligaments, tendons, or joint capsule to bone. Enthesitis is considered to be the pathogenetically main, primary lesion in spondyloarthropathies, while synovitis is the main lesion in rheumatoid arthritis.

Often, the trigger for enthesitis is an enthesis injury or tendon overload. Enthesitis manifests itself as pain during movement involving the corresponding muscle. The pain is more pronounced when the affected muscle is strained. Swelling of the surrounding tissues and palpation pain in the area of the involved enthesis are determined. The most common outcome of enthesopathy is ossification of the enthesis with the development of enthesophytes.

The group of seronegative spondyloarthropathies is heterogeneous, it includes a large number of undifferentiated and limited forms. Even the nosological units occupying a leading place in the group are characterized by significant variations in the frequency of development of the same sign. Thus, the marker antigen of seronegative spondyloarthropathies HLA-B27 occurs with a frequency of up to 95% in patients with ankylosing spondylitis (AS) and only in 30% of cases of enteropathic arthritis. The development of sacroiliitis correlates with the carriage of HLA-B27 and is observed in 100% of cases of AS, but only in 20% of patients with Crohn's disease and nonspecific ulcerative colitis. Enthesitis, dactylitis and unilateral sacroiliitis are more pathognomonic for patients with reactive arthritis and PsA.

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

Clinical features	Ankylosing spondylitis	Reactive arthritis	Psoriatic arthritis	Enteropathic arthritis
Age of onset of disease	Young people, teenagers	Young people teenagers	35-45 years old	Any
Gender (male/female)	3:1	5:1	1.1	1:1
HLA-B27	90-95%	80%	40%	30%
Sacroiliitis	100%, double sided	40-60%, one-sided	40%, one-sided	20%, double sided
Syndesmophytes	Small, marginal	Massive, non-marginal	Massive, non-marginal	Small, marginal
Peripheral arthritis	Sometimes asymmetrical, lower limbs	Usually asymmetrical, lower limbs	Usually, asymmetrical, any joints	Usually asymmetrical, lower limbs
Enthesitis	Usually	Very often	Very often	Sometimes
Dactylitis	Not typical	Often	Often	Not typical
Skin lesion	No	Circular balanitis, keratoderma	Psoriasis	Erythema nodosum, pyoderma gangrenosum
Nail damage	No	Onycholysis	Onycholysis	Thickening
Eye damage	Acute anterior uveitis	Acute anterior uveitis, conjunctivitis	Chronic uveitis	Chronic uveitis
Lesions of the oral mucosa	Ulcers	Ulcers	Ulcers	Ulcers
The most common heart lesion	Aortic regurgitation, conduction disturbances	Aortic regurgitation. conduction disturbances	Aortic regurgitation, conduction disturbances	Aortic regurgitation
Lung damage	Upper lobe fibrosis	No	No	No
Gastrointestinal lesions	No	Diarrhea	No	Crohn's disease, ulcerative colitis
Kidney damage	Amyloidosis, IgA nephropathy	Amyloidosis	Amyloidosis	Nephrolithiasis
Urogenital lesions	Prostatitis	Urethritis, cervicitis	No	No

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Cardiac lesions in seronegative spondyloarthropathies

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

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

Cardiac damage	Patients, %	Clinical significance
Myocardial dysfunction (systolic and diastolic)	>10	Rare, not clinically significant
Valve dysfunction	2-10	Often requires treatment
Disturbances in conduction	>10	Often require treatment
Pericarditis	<1	Rare, not clinically significant

Cardiac involvement is most frequently observed in AS and is diagnosed, according to various data, in 2-30% of patients. Several studies have shown that the frequency of cardiac involvement increases with the duration of the disease. The prevalence of cardiac involvement in other seronegative spondyloarthropathies is lower and less studied.

The pathogenesis of cardiac lesions in seronegative spondyloarthropathies has not been elucidated. However, data have been accumulated on their association with the presence of the HLA-B27 antigen, a marker of this group of diseases, consistently associated with the development of severe isolated aortic regurgitation and AV block (67 and 88%, respectively). In several studies of patients with SSA, cardiac lesions were detected only in carriers of the HLA-B27 antigen. The HLA-B27 antigen is present in 15-20% of men with a permanent pacemaker installed due to AV block, which is higher than its prevalence in the population as a whole. Cases of AV block development in patients carrying HLA-B27 who do not have joint and ophthalmological symptoms of SSA have been 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 a separate disease.

Histopathological changes occurring in the structures of the heart in AS were described by Buiktey V.N. et al. (1973). Subsequently, similar observations were obtained in other seronegative spondyloarthropathies.

Histopathological and pathological features of cardiac lesions in seronegative spondyloarthropathies

Region		Changes
Aorta		Intimal proliferation, focal destruction of elastic tissue with inflammatory cells and fibrosis, fibrous thickening of the adventitia, dilation
Vasa vasorum of the aorta, artery of the sinus node, artery of the AV node		Fibromuscular proliferation of the intima, perivascular infiltration of inflammatory cells, obliterating endarteritis
Aortic valve		Dilation of the ring, fibrosis of the base and progressive shortening of the cusps, rounding of the free edge of the cusps
Mitral valve		Fibrosis of the base of the anterior leaflet (hump), dilation of the annulus secondary to left ventricular dilatation
Conductive system		Obliterating endarteritis of the supplying arteries, fibrosis
Myocardium		Diffuse increase in interstitial connective tissue

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

Most patients require conservative or no treatment. In rare cases, surgical treatment is indicated.

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

Several cases have been described. Mitral regurgitation in AS may also develop secondary to aortic regurgitation as a result of left ventricular dilatation. Diagnosed using echocardiography.

Atrioventricular block is the most common cardiac lesion in SSA, described in AS, Reiter's disease and PsA. It develops more often in men. In patients with AS, intraventricular and AV block are found in 17-30% of cases. In 1-9% of them, the trifascicular block is broken. In Reiter's disease, AV block occurs in 6% of patients, and complete block develops rarely (less than 20 cases have been described). AV block is considered an early manifestation of Reiter's disease. A feature of AV blocks in seronegative spondyloarthropathies is their transient nature. The unstable nature of the block is explained by the fact that it is based primarily not on fibrotic changes, but on a reversible inflammatory reaction. This is also confirmed by the data of electrophysiological examination of the heart, during which, significantly more often, even in the presence of concomitant fascicular blockades, a block is detected at the level of the AV node, and not the underlying sections, where fibrous changes are more likely to be expected.

In case of a complete block, the installation of a permanent pacemaker is indicated, in case of an incomplete block - conservative management. An episode of a complete block may not have relapses for more than 25 years, but the installation of a pacemaker is still necessary, since it is well tolerated by patients and does not lead to a decrease in life expectancy,

The prevalence of sinus bradycardia in seronegative spondyloarthropathies is unknown, but it has been detected during active electrophysiological studies. The cause of sinus node dysfunction is probably a decrease in the lumen of the node artery as a result of proliferation of its intima. Similar processes have been described in thickening of the aortic root and the artery of the AV node.

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

Pericarditis is the rarest of the cardiac lesions found in SSA. It is found as a histopathological finding in less than 1% of patients.

Myocardial dysfunction (systolic and diastolic) has been described in a small group of patients with AS and Reiter's disease. The patients had no other cardiac manifestations of SSA and no diseases that could lead to myocardial damage. Histological examination of the myocardium was performed in some patients, which revealed a moderate increase in the amount of connective tissue without inflammatory changes and amyloid deposition.

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

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Classification issues of seronegative spondyloarthropathies

The clinical spectrum of the disease turned out to be much broader than was initially realized, so some less clearly defined forms were classified as undifferentiated spondyloarthropathies. Differentiation among these forms, especially in the early stages, is not always possible due to the unclear expression of clinical features, but this, as a rule, 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.
• G. Enteropathic arthritis associated with Crohn's disease and ulcerative colitis.
• D. Undifferentiated spondyloarthritis.

Initially, the group of seronegative spondyloarthropathies also included Whipple's disease, Behcet's syndrome, and juvenile chronic arthritis. Currently, these diseases are excluded from the group for various reasons. Thus, Behcet's disease does not involve the axial skeleton and is not associated with HLA-B27. Whipple's disease is rarely accompanied by sacroiliitis and spondylitis, data on the carriage of HLA-B27 in it are contradictory (from 10 to 28%), and the proven infectious nature distinguishes the disease from other spondyloarthropathies. According to the general opinion, juvenile chronic arthritis is a group of heterogeneous diseases, many of which subsequently evolve into rheumatoid arthritis, and only individual variants can be considered as precursors to the development of seronegative spondyloarthropathies in adults. The question of whether the relatively recently described BARNO syndrome, which manifests itself as synovitis, pustulosis of the palms and soles, hyperostosis, frequent damage to the sternoclavicular joints, the development of aseptic osteomyelitis, sacroiliitis, axial damage to the spine with the presence of HLA-B27 in 30-40% of patients, belongs to the SSA remains unresolved.

Diagnosis of seronegative spondyloarthropathies

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

Criteria of the European Spondyloarthritis Study Group (ESSG, 1941)

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

• positive family history (for 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;
• enthesopathies;
• bilateral sacroiliitis stage II-IV or unilateral stage III-IV.

These criteria were created as classification criteria and cannot be widely used in clinical practice, since their sensitivity in patients with a disease history of less than 1 year is up to 70%.

The diagnostic criteria developed later by V. Amor et al. showed greater sensitivity (79-87%) in various studies, to some extent due to a decrease in their specificity (87-90%). These criteria allow one to evaluate the degree of reliability of the diagnosis in points and give better results in the diagnosis of undifferentiated spondyloarthritis and early cases of the disease.

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

Clinical or anamnestic signs:

• Night pain in the lumbar region and/or morning stiffness in the lumbar region - 1 point.
• Asymmetrical oligoarthritis - 2 points.
• Periodic pain in the buttocks - 1-2 points.
• Sausage-shaped fingers and toes - 2 points.
• Thalalgia or other enthesopathies - 2 points.
• Irit - 2 points.
• Non-gonococcal urethritis or cervicitis less than 1 month before the onset of arthritis - 1 point.
• Diarrhea less than 1 month before the onset of arthritis - 1 point.
• Presence or previous psoriasis, balanitis, chronic enterocolitis - 2 points.

Radiological signs:

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

Genetic features:

• The presence of HLA-B27 and/or a history of spondyloarthritis, reactive arthritis, psoriasis, uveitis, chronic enterocolitis in relatives - 2 points.

Treatment sensitivity:

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

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Treatment of seronegative spondyloarthropathies

Treatment of ankylosing spondylitis

Currently, there are no drugs that have a significant effect on the ossification processes in the spinal column. The positive effect on the course and prognosis of AS of basic drugs used in the treatment of other rheumatic diseases (including sulfasalazine and methotrexate) has not been proven, so therapeutic exercise comes first in the treatment of patients. Its effectiveness in AS, at least when analyzing the immediate results (up to 1 year), is a proven fact. Remote results of studies on this issue are not yet available. As a result of a randomized controlled study, group programs were shown to be more effective than individualized ones. The program, consisting of hydrotherapeutic sessions for 3 hours twice a week, led to an improvement in general health indicators and an increase in the mobility of the lumbar-thoracic spine after 3 weeks of use, which was noted for 9 months according to objective and subjective assessments. During the same period, patients had a reduced need for NSAIDs.

Of the drugs used to treat AS, NSAIDs have long been proven to be effective. There is no advantage to treatment with any particular drug. COX-2 inhibitors show efficacy similar to that of non-selective drugs. It is unknown whether continuous NSAID use has long-term advantages over intermittent treatment in preventing structural damage.

Glucocorticoids can be used for local intra-articular administration (including sacroiliac joints). The effectiveness of systemic glucocorticoid treatment 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, was also effective only in peripheral arthritis, reducing synovitis and not affecting axial lesions. Leflunomide demonstrated insignificant effectiveness in relation to AS in an open study. The effectiveness of methotrexate is questionable and has not been proven; there are only a few pilot studies on this matter.

The effectiveness of intravenous use of bisphosphonates in AS was determined. In patients with AS, a decrease in pain in the spine and some increase in its mobility were noted against the background of treatment with pamidronic acid; 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 currently placed on the use of biologically active agents, in particular monoclonal anti-TNF-a antibodies. During clinical trials, disease-modifying properties of at least two drugs were revealed - infliximab and etanercept. At the same time, the widespread use of these drugs in AS is hindered not only by their high cost, but also by the lack of long-term data on their safety, the possibility of disease control and prevention of structural changes. In this regard, it is recommended to approach the prescription of these drugs strictly individually, using them with 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, when there is a focus of this infection. Macrolide antibiotics and fluoroquinolones are used. It is necessary to treat the patient's sexual partner. Long-term use of antibiotics does not improve the course of reactive arthritis or its manifestations. Antibiotics are ineffective in the case of postenterocolitic arthritis.

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

Glucocorticoids are used as a local treatment by intra-articular injection and injection into the area of affected entheses. Local application of glucocorticoids is effective in conjunctivitis, iritis, stomatitis, keratoderma, balanitis. In case of prognostically unfavorable systemic manifestations (carditis, nephritis), systemic administration of drugs in a short course can be recommended. Large controlled studies of the effectiveness of local and systemic application of glucocorticoids have not been conducted.

Disease-modifying agents are used in protracted and chronic disease. Sulfasalazine at a dose of 2 g/day showed minor effectiveness in placebo-controlled studies. The use of sulfasalazine helped to reduce inflammatory changes in the joints, and there was no effect on the progression of joint lesions. There are no clinical trials of other disease-modifying drugs for the treatment of reactive arthritis.

Treatment of psoriatic arthritis

To select the volume of treatment, the clinical and anatomical variant of the joint syndrome, the presence of systemic manifestations, the degree of activity, and the nature of the skin manifestations of psoriasis are determined.

Drug treatment of psoriatic arthritis includes two directions:

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

Symptom-modifying drugs include NSAIDs and glucocorticoids. Their treatment for PsA has a number of features compared to other rheumatic diseases. According to the Institute of Rheumatology of the Russian Academy of Medical Sciences, the use of glucocorticoids in psoriatic arthritis is less effective than in other rheumatic diseases, in particular rheumatoid arthritis. The introduction of glucocorticoids intra-articularly or into the affected entheses has a more pronounced positive effect than their systemic use. According to V.V. Badokina, this may be due to many circumstances, in particular, the small participation of humoral immune disorders in the development and progression of the disease, the difficulties in adequately assessing the degree of activity of the inflammatory process and, accordingly, determining the indications for the administration of glucocorticoids, and the insignificant severity of inflammation of the synovial membrane. The specifics of the body's response to glucocorticoids in psoriatic arthritis are probably determined by the low density of glucocorticoid receptors in tissues, as well as by the disruption of the interaction of glucocorticoids with their receptors. Difficulties in treating a disease such as PsA are due to the fact that systemic administration of glucocorticoids often leads to 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). Immunopathological disorders underlying the pathogenesis of PsA are the main target of treating this disease with disease-modifying drugs, the principles of which have been developed and 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, and in some patients it helps resolve psoriatic skin changes.

The disease-modifying properties of methotrexate in psoriatic arthritis are a generally recognized fact. It is distinguished by the most favorable ratio of effectiveness and tolerability in comparison with other cytotoxic drugs. The choice of methotrexate is also dictated by its high therapeutic effectiveness in relation to skin manifestations of psoriasis. In the treatment of psoriatic arthritis, disease-modifying drugs are also used gold preparations. The target for them are macrophages and endothelial cells participating in different stages of the pathological process, including the earliest ones. Gold preparations inhibit the release of cytokines, in particular IL-1 and IL-8, enhance the functional activity of neutrophils and monocytes that inhibit antigen presentation to T cells, reduce the infiltration of T and B lymphocytes of the synovial membrane and skin affected by psoriasis, inhibit the differentiation of macrophages. One of the circumstances that complicates the widespread introduction of gold preparations into the complex treatment of psoriatic arthritis is their ability to cause an exacerbation of psoriasis.

For the treatment of psoriatic arthritis, a relatively new drug, leflupomide, is used, an inhibitor of pyrimidine synthesis, the effectiveness of which has also been proven in relation to skin lesions and joint syndrome in PsA (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 drugs: chimeric monoclonal antibodies to TNF-a - infliximab (remicade), rTNF-75 Fc IgG (etanercent), palL-1 (anakinra).

Long-term treatment with disease-modifying drugs allows controlling the activity of psoriatic arthritis and the course of its main syndromes, slows down the rate of disease progression, helps maintain the ability of patients to work and improves their quality of life. Treatment of psoriatic arthritis has its own distinctive features.

Treatment of enteropathic arthritis

Sulfasalazine has been proven to be effective, including in long-term observations. Azathioprine, glucocorticoids, and methotrexate are also widely used. Infliximab has shown high effectiveness. Studies have been conducted on NSAIDs that have convincingly shown that their use increases intestinal permeability and, thus, can intensify the inflammatory process in it. Paradoxically, NSAIDs are widely used in patients with epteropathic arthritis, who usually tolerate them well.

Treatment of systemic manifestations of seronegative spondyloarthropathies, including cardiac lesions, is subject to the general principles of treatment of the leading clinical syndrome (heart failure or cardiac rhythm and conduction disorders, etc.).

History of the issue

The 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 in the seropositive variant; the development of spondyloarthritis is often observed, the sacroiliac joints are affected, arthritis of the peripheral joints is asymmetrical, enthesitis rather than synovitis predominates, subcutaneous nodules are absent, and there is a familial predisposition to the development of the disease. Prognostically, these "forms" were assessed as more favorable than other cases of seronegative and seropositive rheumatoid arthritis. Later, a close associative relationship was discovered between spondyloarthritis and the carriage of the histocompatibility antigen HLA-B27, which is absent in rheumatoid arthritis.

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