Rheumatoid arthritis is a chronic systemic autoimmune disease typically affecting middle-aged women, characterised by RF and anti-CCP serology, synovial inflammation, symmetrical joint erosions and joint space narrowing.
Description
Rheumatoid arthritis (RA) is the most common purely erosive inflammatory arthropathy, resulting from immune-mediated synovial proliferation.
Epidemiology
Overall prevalence of 1% and 2-3 times more common in women. Onset generally in adulthood peaking in the 4th and 5th decades. Risk factors:
- Smoking
- Obesity
- Low socioeconomic status
Associated with Felty syndrome (rheumatoid arthritis, splenomegaly and neutropaenia) and Caplan syndrome (rheumatoid arthritis and pneumoconiosis)
Pathogenesis
RA is thought to be triggered by exposure of a genetically susceptible host to an arthritogenic antigen resulting in loss of self-tolerance and a chronic autoimmune response. RF and anti-CCP antibodies are the best-known autoantibodies in RA but there are several other autoantibodies that are fairly specific for RA. The presence of antibodies in rheumatoid arthritis is referred to as seropositive RA. RF is an antibody of any isotype that binds to the Fc portion of IgG.
The autoimmune response in RA is initiated by activated CD4+ helper T cells, which releases inflammatory mediators that stimulate other inflammatory cells leading to tissue injury.
- IFN-γ from Th1 cells activates macrophages and resident synovial cells.
- IL-17 from Th17 cells recruits neutrophils and monocytes.
- RANKL expressed on activated T cells stimulates bone resorption.
- TNF and IL-1 from macrophages stimulates resident synovial cells to secrete proteases that destroy hyaline cartilage.
These changes produce the pannus, a mass of oedematous synovium, inflammatory cells, granulation tissue, and fibroblasts that covers and erodes articular cartilage. Over time, after the cartilage has been eroded, the pannus bridges the apposing bones to form a fibrous ankylosis, which eventually ossifies and results in bony ankylosis.
Swan neck deformity caused by imbalance between the extensor and flexor mechanisms of the fingers, leading to laxity of the volar plate at the PIP joint and contracture of the flexor digitorum profundus tendon at the DIP joint.
Boutonniere deformity caused by damage or rupture of the central slip of the extensor tendon at the PIP joint, causing the lateral bands to slip below the axis of the PIP joint, resulting in unopposed flexion at the PIP and extension at the DIP.
Clinical Features
- Malaise, fatigue, and generalised musculoskeletal pain.
- Joints are swollen, warm, and painful.
- Typically progressive joint enlargement and decreasing range of motion during a chronic waxing and waning course.
- Pattern of joint involvement generally symmetrical, affecting small joints before larger ones.
- Symptoms usually first develop in the hands (MCPJ and PIPJ) and feet, followed by the wrists, ankles, elbows, and knees.
- Radial deviation of wrist, ulnar deviation of fingers, flexion-hypertension of the fingers due to inflammation in tendons, ligaments, and occasionally adjacent skeletal muscle (swan-neck and boutonnière deformities).
Pathological Features
Biochemistry
- About 75% to 85% of patients are positive to RF, ACPA, or both (seropositive RA)
- Anti-citrullinated protein antibodies (anti-CCP) are a hallmark of rheumatoid arthritis
- Positive for rheumatoid factor (45-75%). Not diagnostic of rheumatoid arthritis.
- Anaemia of chronic disease and thrombocytosis
- Neutropenia may be present if Felty syndrome.
Histology
- Synovial cell hyperplasia and proliferation
- Dense inflammatory infiltrates (frequently forming lymphoid follicles) of CD4+ helper T cells, B cells, plasma cells, dendritic cells, and macrophages
- Increased vascularity due to angiogenesis
- Fibrinopurulent exudate on the synovial and joint surfaces
- Osteoclastic activity in subchondral bone, allowing the inflamed synovium to penetrate the bone and cause periarticular erosions and subchondral cysts.
Rheumatoid nodules
- Small firm, nontender, and round to oval masses.
- Infrequent, but typically occur in the subcutaneous tissue of pressure areas such as the forearm, elbows, occiput, and lumbosacral area.
- Microscopically resemble necrotising granulomas with a central zone of fibrinoid necrosis surrounded by a prominent rim of activated macrophages and numerous lymphocytes and plasma cells.
- Severe disease may be associated with leukocytoclastic vasculitis, an acute necrotising vasculitis of small and large arteries that may involve pleura, pericardium, or lung and evolve into a chronic
fibrosing process. Leukocytoclastic vasculitis produces purpura, cutaneous ulcers, and nail bed infarction. Ocular changes such as uveitis and keratoconjunctivitis
Radiological Features
General Features
- Proliferative synovitis (i.e., rheumatoid pannus) is the earliest pathologic abnormality. It appears as thickening and enhancement of the synovial membrane (normally too thin to be visible) and increased synovial fluid.
- Differentiating synovitis and joint fluid may be difficult (both T2 high signal). Using heavily T2-weighted images may show a lower signal intensity of synovitis than a joint effusion.
- Erosions are the imaging and pathologic hallmarks of RA
- Often bilateral, symmetrical and polyarticular pattern of involvement.
- Sharply defined, non-proliferative, marginal erosions, without sclerotic borders
- Sites of predilection:
- Hands: Most commonly affects MCP joints II–V, PIP joints, and intercarpal joints. DIP joints are typically spared until late disease. Bony erosions are more frequent at the capitate, triquetrum, and lunate, as well as the radial aspects of the 2nd and 3rd metacarpals. Symmetry is typical for synovitis and tenosynovitis, but bone involvement can be less consistently bilateral.
- Wrist: Frequently affects the distal radioulnar joint (DRUJ), ulnar styloid, and radiocarpal joint.
- Feet: Commonly involved but often after manifestation in the hands. The lateral aspect of the 5th metatarsal head is often the earliest site. Other sites include MTP joints II–IV and the interphalangeal joints. Retrocalcaneal bursitis with erosions and Achilles tendonitis also common.
- Bone marrow oedema may precede the development of bone erosions, usually at the subchondral bone.
- Joint effusions are usually seen in early RA.
- Tenosynovitis – Although any tendon may be affected, the flexor digitorum, extensor digitorum, and extensor carpi ulnaris are frequently involved
- Fibrotic pannus (usually indicating end-stage RA) appears hypovascular after the intravenous administration.
- Swan-Neck – Hyperextension of the PIPJ and flexion of the DIPJ
- Boutonniere Deformity – Flexion of the PIPJ and hyperextension of the DIPJ
XR
- Marginal erosions
- Initially occuring in the intracapsular articular margins of bone which is not covered by cartilage termed the bare area
- Early bone pattern is loss of cortical distinctness, followed by dot-dash cortical loss with uncovering of the underlying trabaculae.
- Subchondral erosions follow
- Pencil-in-cup appearance in phalanges indicates late aggressive disease
- Joint swelling and effusion
- Periarticular osteopaenia related to soft tissue hyperaemia
MRI
- T1:
- Synovial joint fluid and bone marrow oedema has low signal intensity.
- Bone erosions appear as sharply marginated areas of trabecular bone loss with a cortical defect and loss of normal high T1 marrow signal.
- T2:
- Increased synovial volume (high signal intensity fluid) associated with synovitis.
- Fibrotic pannus is intermediate to low signal intensity
- STIR T2-weighted or fat-suppressed T2-weighted: Suppresses fat and highlights oedema.
- Ill-defined high signal intensity at the insertion of the synovial membrane representing bone marrow oedema (non-specific)
- T1 FS Gd+:
- The use of fat suppression increases the contrast between the inflamed synovium and adjacent structures
- Thickened, rapidly-enhancing synovium representing proliferative synovitis.
- May be seen in the erosions
- Normal synovium may show some enhancement
- Thickened, enhancing synovial sheath representing tenosynovitis.
- Enhancement between of beneath the metatarsal heads representing intermetatarsal and submetatarsal bursitis
- Fibrotic pannus usually does not enhance
US
- B-mode:
- Anechoic fluid which can be expelled from region by transducer pressure.
- Synovitis appears as hypoechoic intra-articular material that is non-displaceable/non-compressible, representing thickening of the synovial sheath.
- Non-compressibility is useful to distinguishing synovium from joint fluid
- Bone erosions are seen as intra-articular discontinuities of the bone surface that are visible in two perpendicular planes (best seen at ulnar styloid process, the radial aspect of the second MCP joint, the ulnar aspect of the fifth MCP joint, and the lateral aspect of the fifth MTP joint)
- Rheumatoid nodules appear as hypoechoic mass lesions with well-defined hypo- to anechoic centres, representing necrosis.
- Colour:
- Hyperaermia of synovial sheath.
- High signal on Doppler imaging suggests the presence of proliferative, hypervascularized pannus tissue in the erosion
Diagnosis & Classification
- Patients requires at least one swollen joint after exclusion of other causes of synovitis
- Scores ≥ 6 are classified as RA
Typical bone erosions can be classified as RA regardless of score
| 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis | |
| Joint Involvement | |
| 1 large joint | 0 |
| 2 – 10 large joints | 1 |
| 1 – 3 small joints | 2 |
| 4 – 10 joints | 3 |
| > 10 joints | 5 |
| Serology | |
| Negative RF and negative ACPA | 0 |
| Low-positive RF or low-positive ACPA | 2 |
| High-positive RF or high-positive ACPA | 3 |
| Acute Phase Reactants | |
| Normal CRP and normal ESR | 0 |
| Abnormal CRP or abnormal ESR | 1 |
| Duration of Symptoms | |
| < 6 weeks | 0 |
| ≥ 6 weeks | 1 |
Differential Diagnosis
- Gout: Tophi appear poorly defined on US and are usually hyperechoic with a hypoechoic rim. Rat-bite juxta-articular erosions (vs. marginal erosions).
- Osteoarthritis: Asymmetric joint space narrowing (vs. symmetric/uniform) with osteophyte formation, involving the DIP and PIP joints (vs. PIP and MCP, wrist and MTP joints). STT and 1st CMC joint involvement is also typical. In the hip, characteristic feature of OA is osseous hypertrophy along the inferomedial femoral neck (buttressing). Joint malalignment results from cartilage loss (vs. tendon and ligamentous dysfunction/laxity).
Management
Therapies include corticosteroids, other immunosuppressants such as methotrexate, and, most notably, TNF antagonists, which are effective in many patients.