Causes and pathogenesis of juvenile ankylosing spondylitis

The cause of juvenile spondyloarthritis is unknown, the reason for the development of this pathology is obviously polyetiological.

The current level of knowledge is limited by the understanding of predisposing factors and individual links in pathogenesis. The origin of this disease is determined by a combination of genetic predisposition and environmental factors. Among the latter, the most important role is played by infections, primarily some strains of Klebsiella, other enterobacteria, and their associations interacting with the antigenic structures of the macroorganism, for example, the HLA-B27 antigen. The high frequency of carriage of this antigen (70-90%) in patients with juvenile spondyloarthritis compared to 4-10% in the population confirms the role of HLA-B27 in the pathogenesis of the disease.

Several theories have been proposed to explain the involvement of HLA-B27 in the pathogenesis of juvenile spondyloarthritis.

• The "two gene theory" suggests the presence of a hypothetical "ankylosing spondylitis gene" located near HLA-B27 on chromosome 6.
• The "one gene theory" based on the structural similarity of HLA-B27 with a number of infectious pathogens, is presented in several versions:
  • receptor theory;
  • hypothesis of cross-tolerance or simple molecular mimicry;
  • plasmid hypothesis;
  • altered immune response theory.

At the same time, a more or less logical explanation for the development of ankylosing spondylitis and JAS in B27-negative individuals has not yet been found, and attempts to search for other antigens that cross-react with HLA-B27, the so-called B7-CREG (“cross reactive group”) antigens, have also not clarified this issue.

Confirmation of the hereditary nature of ankylosing spondylitis and juvenile spondylitis is the tendency, noted by V.M. Bekhterev, to the accumulation of diseases from the spondyloarthritis group in families of patients with juvenile spondylitis. Thus, according to observations of the children's clinic of the Institute of Rheumatology of the Russian Academy of Medical Sciences, 20% of patients had repeated cases of the disease in the family, and in 1/3 of such families two or more members were ill. It is important to emphasize that among patients with a heredity burdened by ankylosing spondylitis, approximately the same number of HLA-B27-negative patients (about 15%) were observed as with JAS in general. Evidence of the genetic relationship of the entire group of spondyloarthritis is the high percentage of repeated cases of these diseases in various combinations in families of patients with juvenile spondyloarthritis, and this is more typical for juvenile onset than for adult patients.

Other endogenous factors that play a significant role in the pathogenesis of juvenile spondyloarthritis include neuroendocrine factors, especially an imbalance of sex hormones, which may explain the predominant incidence of juvenile spondyloarthritis in males and the most frequent development of the disease in adolescence.

The premorbid background is of great importance in the development of juvenile spondyloarthritis. It is noteworthy that there is a fairly high frequency of multiple signs of connective tissue dysplasia, including anomalies in the structure of bones, hernias of various localizations, cryptorchidism, etc. In 2/3 of patients, the onset of the disease is preceded by the impact of some provoking factor, usually trauma and/or hypothermia.

In the absence of indications of a chronological connection between the disease and direct trauma to the joint, chronic trauma to the articular and ligamentous apparatus can have a significant impact, especially when engaging in strength sports and martial arts, which have become popular in recent years among children and adolescents.

The interaction of genetic and environmental factors triggers a complex cascade of immunological reactions, the peculiarity of which is the predominance of CD4 ⁺ lymphocyte activity and the imbalance of CD8 ⁺ cells responsible for the elimination of bacterial antigens. This leads to the production of many proinflammatory cytokines, the spectrum of which in juvenile spondyloarthritis is somewhat different from rheumatoid arthritis and, in addition to tumor necrosis factor TNF-alpha, TNF-beta includes interferon y, IL-4, IL-6, IL-2. Increased production of IL-4, which, according to some data, serves as a stimulator of fibroplastic processes, apparently serves as one of the causes of fibrosis formation, causing the development of ankylosis.

The main morphological substrate of pathological changes in juvenile ankylosing spondylitis (as well as in spondyloarthritis in general) is the development of inflammation in the area of entheses (places of attachment of joint capsules, ligaments and tendons, fibrous parts of intervertebral discs to bones), while synovitis, unlike rheumatoid arthritis, is considered a secondary process. Scientific studies in recent years using MRI have provided evidence of this long-noted phenomenon. Characteristic of juvenile ankylosing spondylitis is the lesion of low-mobility joints (sacroiliac, intervertebral, symphysis, etc.), as well as hip joints, which differ from other peripheral joints in their vascularization features, with the development of inflammatory changes in them leading to chondroid metaplasia of the joint capsules and synovial membranes, their subsequent ossification and ankylosis.

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