Etiology and Immunologic Mechanisms
The exact causes remain fully unclarified, but an arthritogenic microbial factor persisting in a sensitized organism is considered the primary trigger. The Epstein-Barr virus is assigned the major role.
The mechanism is triggered via antigenic mimicry: structural homology is found between the virus, type II collagen, and HLA-DR chain epitopes. Consequently, the induced immune response (originally directed against latent infections or commensal microbes) switches to self-tissues, resulting in autoaggression. Mycobacteria are also implicated: patients show high titers of antibodies to mycobacterial stress proteins, and mycobacterial antigens stimulate the proliferation of autoreactive T lymphocytes in the synovial membrane.
The primary effector cells are CD4+ T lymphocytes (Th1). The exact list of autoantigens is still being defined, but current targets include type II collagen, nuclear antigen RANA, and articular cartilage glycoprotein gp39.
Humoral Factors and Markers
Activated T cells secrete cytokines and directly interact with macrophages and synoviocytes. This leads to the proliferation of B lymphocytes and capillary endothelium, as well as the production of specific autoantibodies.
- Rheumatoid Factor (RF): These are autoantibodies (most commonly IgM class, less frequently IgG, IgA, IgE) directed against the Fc fragment of autologous IgG. Synovial plasma cells synthesize IgG-class RF. Auto-association occurs: antibodies interact with one another (acting as both antibody and antigen), which sustains chronic inflammation. In seronegative variants, RF is absent, but extra-articular manifestations (such as subcutaneous rheumatoid nodules) still develop.
- Filaggrin System: Antikeratin antibodies and the antiperinuclear factor play an important role. Normally, the protein precursor (profilaggrin) is located in keratohyaline granules of the buccal epithelium. Following proteolysis and phosphorylation, filaggrin is formed. Under the action of the enzyme peptidylarginine deiminase, arginine residues are converted into citrulline. The generation of anti-citrullinated protein antibodies (ACPA/anti-CCP) serves as a critical diagnostic test.
Tumor-Like Transformation Theory
In addition to the T-cell theory, there is a hypothesis regarding alterations in the properties of synovial cells themselves—synoviocytes. Under the influence of trigger cytokines (IL-1 and TNF-α), they acquire traits resembling tumor cells.
This is not a true malignant mutation; however, cells alter the expression of apoptosis-regulating molecules (such as CD95) and proto-oncogenes (ras, myc). Consequently, synoviocytes increase the expression of adhesion molecules for matrix interaction and actively synthesize enzymes that drive progressive joint destruction.
Stages of Joint Involvement and Classification
The pathogenetic chain of joint changes follows a strict sequence:
- Development of productive synovitis.
- Destruction of articular cartilage.
- Joint deformation.
- Formation of ankylosis (complete fusion of articular surfaces).
Manifestations occur in various clinical and morphological forms, including seropositive (including Felty syndrome) and seronegative (adult-onset Still's disease) variants. The process frequently extends beyond the joints, presenting as rheumatoid vasculitis, pulmonary involvement ("rheumatoid lung"), polyneuropathy, rheumatoid bursitis, or cardiac involvement (carditis, endocarditis, myocarditis, pericarditis).