Unknown trigger or triggers stimulate or activate a disturbed immunologic response in a genetically susceptible individual. Immune response genes congregated on the short arm of chromosome 6 in the segment called the major histo-compatibility complex. HLA antigens are the result of expression of genes in this segment.
Class I
- Consists of 3 related types of molecules : HLA-A, B, C
- Antigens are identified on all cells (except RBC and early embryonic tissue)
- Their function is identification of self, development of tolerance and strong graft rejection responses
Class II
- Code for molecules termed HLA-DR, DQ and DP
- These are involved in antigen presentation to T helper cells and are present on B cells, macrophages and activated T or killer cells
- Aberrant induction of Class II antigen expression on cells other than those normally evident causes inflammation in some auto immune diseases
Class III
- Antigens are coded from a locus between Class I and II regions
- Consist of soluble proteins primarily involved in the complement cascade
Class I antigens are associated with arthropathies of the axial skeleton, e.g. Ankylosing Spondylitis (B27), Reiters (B27), Psoriatic arthropathy (B27 and B38)
Class II antigens have association with Rheumatoid arthritis (DR1 and DR4), Sjogrens’ Syndrome (DR2 and DR3), JRA and SLE (DR2)
- The reason that more than one group of alleles can increase susceptibility to a disease is due to shared epitopes between molecules of each group
- For instance DR4 subgroup has 5 subtypes, of these only two, Dw4 and Dw14, promote susceptibility to RA
- They share a common epitope in their beta chain
- Rheumatoid arthritis is associated with HLA Dw4 locus and the HLA DR4 allotype in 60-80% of cases compared to only about 20-25% in the general population
- Sero-negative patients account for 24% of those with the HLA DR4 allotype and sero-positive patients 55%, indicating that they may be separate disease processes
- The immune response triggers production of auto antibodies which form immune complexes and trigger synovial proliferation and inflammation resulting in the typical pathological features of Rheumatoid Arthritis
Incidence
- Affects 3% of the population
- Approximately 300,000 RA sufferers in Australia
- Usually presents in the 4th decade of life
- M:F incidence 1:3
- May affect any synovial joint and less commonly also cartilaginous joints and enthesies
- Increased incidence in first degree relatives of RA patients
Pathogenesis
- Unknown stimulus activates immune system, with antibody / complement initiation of synovial inflammation and extra-articular manifestations in genetically susceptible individuals
- Viral (EB virus implicated), bacterial (component of bacterial cell wall may be stimulus), environmental, endogenous collagen or perhaps an emotional stimulus
- Stimulus causes formation of anti-IgG Ab (Rh factor)
- Activation of immune system, releases proteolytic enzymes and digests tissues
- Immune reaction leads to complement fixation and release of interleukin 1, phosphorylase A2, prostaglandin E2 and plasminogen and induces synthesis of collagenase
- The end result is degradation of matrix proteoglycan, chondrocyte death, cartilage breakdown, augmenting the process of irreversible joint destruction
- It is postulated that cartilage is a necessary factor for the chronic process to begin and be maintained, due to the fact that little recurrence is seen in artificial joint replacements
- Process blocked by early administration of cortisone, because proteoglycan synthesis is inhibited and existing proteoglycans are degraded
Pathology
- Begins as non specific inflammatory synovitis
- Non specific increase in capillaries
- Proliferation of synoviocytes, then hypertrophy of synovium, then villi formation
- Lymphocytic and plasma cell infiltrate mainly perivascular and formation of lymphocytic nodules
- Focal fibrinoid deposition
- Cellular necrosis
- Highly vascular reduplicated synovium covers articular surface, leading to pannus formation
- At the cartilage-pannus junction macrophages and fibroblasts are the predominant cell types
- Presence of macrophages and collagenase markers within cells and the subsequent collagenolysis of the eroded bone matrix suggest that these cells may be responsible for a major portion of the bone erosion
- These cells also secrete lysosomal enzymes such as proteases, cathepsin and elastase which are capable of degrading proteoglycan
- RA articular cartilage specimens in a significant portion contain anti-collagen (Type II) antibodies
- Pannus erodes the articular cartilage, cartilage may fragment and make intra-articular loose bodies
- Subchondral bone is exposed and secondary osteoarthritis may result
- There is associated local myositis
Rheumatoid Nodule
- Central fibrinoid necrosis (fibrin, degraded collagen and cellular fragments), surrounded by a radially disposed palisades of local histiocytes and beyond that by inflammatory granulation tissue, which is vascular and later becomes fibrotic.
- Perivascular plasma cells and lymphocytes
- Generally in Rh positive patients and usually implies more severe disease and vasculitis.
- Seen on extensor surfaces, olecranon, lateral aspects of fingers, gluteal, Achilles, trochanters, ischial tuberosities, scapular spine, sacrum and occiput (if bedridden)
- May become apparent before the actual onset of the arthritis
- May persist indefinitely or regress at any time
Neuropathies
- Vasculitic causes motor and sensory peripheral neuropathy
- May be due to entrapment or compression
- Affects
- Median at wrist (carpal tunnel)
- Ulna at elbow
- Radial (posterior interosseous nerve)
Tendon Rupture
- Proteolytic enzymes from the hypertrophic synovitis
- Direct synovial invasion of the tendon
- Intratendinous nodules may prevent free gliding of a tendon
- Attrition, where the tendon is abraded running over sharp bony prominences
- Extensor tendon rupture is more common than flexor and ulnar tendons before radial tendons