Etiology and immunological mechanisms
The exact causes of the disease are not fully understood; however, the main trigger is considered to be an arthritogenic microbial factor persisting in a sensitized organism. The primary significance is attributed to the Epstein–Barr virus.
The mechanism is triggered via molecular mimicry: structural similarity has been discovered 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 also participate in the development of the disease: patients exhibit high antibody titers to their stress proteins, and mycobacterial antigens stimulate the proliferation of negative T lymphocytes in the synovial membrane.
The main effector cells are CD4+ T lymphocytes (Th1). The exact list of autoantigens is still being established, but type II collagen, the RANA nuclear antigen, and the articular cartilage glycoprotein gp39 are implicated.
Humoral factors and markers
Activated T cells release 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 of the IgM class, less often IgG, IgA, IgE) directed against the Fc fragment of own IgG. Plasma cells of the synovial membrane synthesize RF of the IgG class. Autoassociation occurs: antibodies interact with each other (one acts as an antigen for the other), which sustains chronic inflammation. In the seronegative variant, RF is absent, but extra-articular manifestations (e.g., subcutaneous rheumatoid nodules) still form.
- Filaggrin system: Antikeratin antibodies and the antiperinuclear factor play an important role. Normally, the protein precursor (profilaggrin) is located in the keratohyalin 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 formation of anti-citrullinated protein antibodies (ACPAs) serves as a crucial diagnostic test.
Tumor-like transformation theory
In addition to the T-cell theory, there is a hypothesis regarding alterations in the properties of the synovial membrane cells themselves—synoviocytes. Under the influence of triggering cytokines (IL-1 and TNF-α), they acquire features resembling tumor cells.
This is not a true malignant mutation; however, the expression of genes regulating apoptosis (e.g., CD95) and proto-oncogenes (ras, myc) changes in the cells. As a result, synoviocytes enhance the expression of adhesion molecules for interaction with the matrix and actively begin synthesizing enzymes that cause progressive joint destruction.
Stages of joint involvement and classification
The pathogenetic chain of changes in the joint follows a strict sequence:
- Development of productive synovitis.
- Destruction of articular cartilage.
- Joint deformation.
- Formation of ankylosis (complete fusion of joint surfaces).
The disease occurs in various clinical and morphological forms. Seropositive (including Felty's syndrome) and seronegative (adult-onset Still's disease) variants are distinguished. The process often extends beyond the joints, manifesting as rheumatoid vasculitis, lung involvement ("rheumatoid lung"), polyneuropathy, rheumatoid bursitis, or cardiac involvement (carditis, endocarditis, myocarditis, pericarditis).
Briefly: answers to topical questions
What morphological changes are characteristic of the productive synovitis stage?
The stage of productive synovitis (manifest stage) is characterized by pronounced proliferation of synoviocytes with the formation of a pannus. The following morphological changes are distinguished:
- Synovial membrane — hypertrophy of villi, presence of giant cells, and fibrin deposits on the surface, which stimulate fibroblast proliferation.
- Stroma — infiltration by lymphocytes and plasma cells, formation of lymphoid follicles with germinal centers.
- Blood vessels — are in a state of productive inflammation (productive vasculitis).
- Cartilage and bone — beneath the pannus, the cartilage thins, deep cracks, usures (erosions), and areas of calcification appear, while osteoporosis increases in the articular ends of bones and subchondral pseudocysts form.
What is a pannus and what role does it play in rheumatoid arthritis?
A pannus is a layer of aggressive granulation tissue with an inflammatory infiltrate that proliferates from the synovial membrane. It consists of macrophages, T helper cells, plasma cells, and proliferating synovial cells.
The role of the pannus lies in the invasion and destruction of joint structures:
- Cartilage destruction — the tissue creeps onto the articular cartilage and grows into it, causing thinning, formation of deep cracks, usures (erosions), and sequestra.
- Bone involvement — the pannus penetrates through the subchondral plate into the bone, leading to its destruction.
- Outcome — intensive growth of the pannus leads to replacement of cartilage with fibrous tissue, intra-articular adhesions, and the formation of fibro-osseous ankylosis.
What is the microscopic structure of a rheumatoid nodule?
The microscopic structure of a rheumatoid nodule is represented by a central zone of fibrinoid necrosis surrounded by a cellular wall and a connective tissue capsule. The following structural components are distinguished:
- Central zone — consists of masses of fibrinoid necrosis.
- Cellular wall — surrounds the necrotic zone and includes large histiocytes (macrophages), lymphoid and plasma cells, fibroblasts, neutrophils, and sometimes multinucleated giant cells.
- Outer capsule — externally, the nodule is covered by a dense fibrous capsule.
The basis for the formation of such a structure lies in immunopathological reactions involving connective tissue disorganization and productive inflammation.
The pathogenetic chain in the joint is easy to remember by the acronym SDDA: Synovitis → Cartilage (destruction) → Deformation → Ankylosis.
Class and exam questions
What is rheumatoid factor (RF)?
These are autoantibodies (predominantly of the IgM class) produced against the Fc fragment of own immunoglobulins G (IgG). Their interaction with each other sustains chronic inflammation.
What is the role of citrullination in pathogenesis?
Under the action of enzymes, arginine residues in filaggrin molecules are converted into citrulline. Antibodies against these altered regions (ACPAs) are produced, serving as a highly specific marker of the disease.
What is the essence of the tumor-like transformation of synoviocytes?
Under the influence of cytokines, synoviocytes alter the expression of apoptosis genes and proto-oncogenes. They do not become malignant, but they begin aggressively synthesizing enzymes that destroy articular cartilage.
What else to study on this topic
- Morphological structure of rheumatoid nodules
- Felty's syndrome and adult-onset Still's disease
- Extra-articular manifestations: rheumatoid lung and rheumatoid vasculitis
- Differences between seropositive and seronegative variants of the course
- Mechanisms of pannus formation in chronic synovitis
Master the entire topic in the "Pathological Anatomy" course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on "Rheumatoid Arthritis" and 4,414 more pages of the subject
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 153 video lessons on the subject
Other topics in the "Rheumatic Diseases" section
Free video lessons: pathological anatomyShort lessons with study notes — no registration required.
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.