Rheumatoid Arthritis

Rheumatoid arthritis(RA) is a progressive systemic autoimmune disease of the synovial joints. It is characterized by symmetric erosive synovitis that often results in severe joint destruction despite medical therapy. RA often presents with associated fatigue and lassitude before the symmetric polyarthralgias erupt. Later on there is limitation of motion due to pain or joint destruction. Despite the fact that RA may involve any synovial joint, it has a predilection for the small joints of the hands (metacarpophalangeal joints and proximal interphalangeal joints, but not distal interphalangeal joints). The carpal articulations and the large joints (knees, hips) are commonly affected as well. One can actually reach the critical 4 diagnostic criteria with pathology observed in the hands alone if there is symmetric involvement (see criteria below). As the disease progresses, erosion of ligaments leads to ulnar deviation, swan-neck and boutonniere deformities as well as hitchhiker's thumb deformities. Shoulder involvement with rotator cuff tears and mechanical instability are common. In the feet, clawing of the toes and dorsal subluxations of the metaphalangeal joints evolve. The subtalar joint is also frequently involved resulting in an everted foot. Cervical spine, erosions of the transverse ligament of C-1 can result in subluxation of C-1 on C-2, and eventually superior migration of C2 towards the foramen magnum and brainstem.

Rheumatoid arthritis affects 1-3% of the adult population and is associated with more than 9 million physician visits and more than 250,000 hospitalizations per year. (15) There is a female predominance of about 3 to 1 with a peak age of onset from 35 to 45 years. Genetic factors clearly play a role, but there is also low disease penetrance and environmental risk factors may play a significant role as well. Several poor prognostic factors associated with a more severe form of RA have been reported. These include: presence of rheumatoid nodules, poor response to medications, rapid rate of radiographic joint destruction, and a high latex fixation titer.

Despite the fact that the primary cause of rheumatoid arthritis is unknown current research has focused on interrelationships of infectious agents, genetics, and autoimmunity. Rheumatoid factors are immunoglobulins (IgM) that react with the Fc portion of other IgG molecules. Rheumatoid factors are thought to contribute to RA’s pathology however they are actually found in about 3% of the normal non-rheumatoid population. Nevertheless significantly higher titers are seen in patients with rheumatoid arthritis. Rheumatoid arthritis also is found with higher incidence in those patients who have specific HLAs (A genetic determinant of the major histocompatability proteins {MHC} present on all nucleated cells in the body) including HLA-DR4, DR1, Dw14, or Dw15 hypervariable regions. Rheumatoid synovium is characterized by a massive tumor-like expansion of stromal connective tissue cells known as pannus. This invasive tissue is filled with lymphoid cells as well as fibroblast-like cells and new blood vessels. These cells are not malignant despite their rapid proliferation. This inflammatory tissue is stimulated by factors such as platelet derived growth factor (PDGF), fibroblast growth factor (FGF), Interleukin-I (IL-1), and tumor necrosis factor (TNF). Rheumatoid factor containing immune complexes are known to precipitate out of the superficial layers of cartilage and further stimulate pannus. This cascade ultimately results in continuous pain, progressive deformity and disability.

There is no one diagnostic laboratory or histologic test, nor any radiographic finding that is pathopneumonic for rheumatoid arthritis which is why the diagnostic criteria were established. Rheumatoid factor is only present in 85% of patients with rheumatoid arthritis, and but can frequently be a predictor of the severe and unremitting form of the disease. Inflammatory markers like erythrocyte sedimentation rate and C-reactive protein will flare with disease presentation. Inflammatory synovitis can be defined by synovial fluid analysis with a WBC count of 2,000 to 50,000 plus cells/mm3. RA begins with early changes limited to the soft tissues appearing first as fusiform swelling and joint effusion. As the disease progresses juxta-articular osteoporosis may become more apparent. Cartilage destruction ensues manifested by joint space narrowing. Erosion of bone are the hallmark of RA and occur characteristically in the metaphyseal region underlying collateral ligament attachments. Structural damage to the joints usually begins between the first and second year of the disease. Synovitis tends to come and go intermittently but the structural damage tends to be progressive and related to the amount of prior synovitis. End-stage rheumatoid disease is marked by mal-alignment, displacement, and finally ankylosis of the joint.

The course of RA varies considerably. About 10% of patients undergo spontaneous remission. Most cases of long-term remission occur within the first 2 years of disease presentation. Additionally, close to 90% of the joints that will ultimately be involved in a given patient declare themselves clinically within the first year of disease presentation. Patients who undergo remission within the first year can become virtually symptom free. However, once structural damage occurs, there will be permanent disability. Recurrent synovitis is usually treated pharmacologically, whereas structural deformity requires activity restriction, or reconstructive surgery. Structural damage is characterized by pain that occurs with activity but is relieved by rest. Structural deformity is often easily evaluated radiographically with joint space narrowing. As in OA, there is periarticular cysts and diffuse subchondral osteopenia

Because RA is a systemic autoimmune disease that attacks other tissue besides its favorite target of the synovium, there are multiple associated extra articular manifestations. These extra-articular manifestations are associated with a higher mortaility rate as well as more severe disability. Extra-articular manifestations are also more common with a high-titer of rheumatoid factor. Some of these associations include (19): 
A) Sjögren’s syndrome which occurs in about 15% of RA patients. Sjögren’s is due to infiltration of the lacrimal and saliva exocrine glands w/ lymphocytes. Keratoconjunctivitis and xerostomia as well as lymphoid infiltration of parenchymal organs may ensue. These patients are at increased risk for developing lymphoid malignancies.
B) Multiple subcutaneous nodules. If these nodules involve the heart pericarditis, cardiomyopathy, interstitial fibrosis and valvular incompetence can devolve. vasculitis, pericarditis, pulmonary nodules and interstitial fibrosis, mononeuritis multiplex, episcleritis, and Sjögren's and Felty's syndromes. 
C) The eyes can demonstrate scleritis, and occasionally scleromalacia perforans. However the incidence of iritis in RA is no greater than that found in general population.
D) The nervous system will occasionally develop mononeuritis multiplex, and peripheral compression syndromes such as carpal tunnel and medial cubital tunnel syndromes.
E) The kidneys often suffer from amyloid deposition.
F) Hematopoietic system involvement can demonstrate Felty's syndrome which is characterized by anemia, splenomegaly, and leucopenia. 
G) Vasculitis is not uncommon. It is usually is a non necrotizing arteritis of the small terminal arterials, but occasionally will take the form of a fulminating arteritis with skin lesions, leg ulcers, necrotizing arteritis of the viscera, digital infarctions, and fever. 
 
The differential diagnosis for RA includes many other autoimmune disorders and inflammatory arthropathies:
A) polyarticular crystal deposition disease 
B) polyarticular septic arthritis
C) systemic lupus erythematosus
D) scleroderma
E) dermatomyositis
F) seronegative arthritis including:
 psoriatic arthritis
 Reactive arthritis formerly know as Reiter's syndrome;
 Ankylosing spondylitis
  arthritis of chronic inflammatory bowel disease
Since these diagnoses are inflammatory in nature, they often mimic features of RA in clinical presentation as well as radiographic and laboratory evaluation.

Because RA is a complex systemic disease the American College of Rheumatology has developed several objective criteria to establish a standardized diagnosis. Criteria have also been established to monitor disease progression and remission in a standardized fashion. Diagnostic Criteria For RA described by Arnett et al in 1987 (16) and accepted by the American College of Rheum. Diagnosis requires at least 4 of the seven criteria for at least 6 weeks

1 Morning stiffness for at least 1 hour and present for at least 6 weeks..
2. Swelling of 3 or more joints for at least 6 weeks.
3. Swelling of wrist, MCP, or PIP for 6 or more weeks.
4. Symmetrical joint swelling.
5. Hand xray typical of RA that must include erosions or unequivocal bony decalcification.
6. Rheumatoid nodules.
7. Serum rheumatoid factor by a method that is positive in less than 5% of normals.

Criteria for clinical remission of RA accepted by the American College of Rheum (17) Remission requires 5 or more criteria for at least 2 consecutive months. There must be no clinical manifestation of active VASCULITIS, PERICARDITIS, PLEURITIS, or MYOSITIS or unexplained recent weight loss or fever attributable to RA.

1. Duration of morning stiffness not to exceed 15 minutes.
2. No fatigue.
3. No symptoms of joint pain.
4. No joint tenderness or pain on motion.
5. No soft tissue swellin in joints or tendon sheaths
6. ESR < 30 (FEMALE) and <20 (MALE)

Criteria for determination staging and progression of RA (18).