DEFINITION
Rheumatoid arthritis is a symmetrical, destructive and deforming polyarthritis affecting small and large synovial joints with associated systemic disturbances, a variety of extra articular features and the presence of circulating antiglobulin antibodies (RF).

• It is a chronic multysystem disease of unknown cause
• The characteristic feature is ‘persistent inflammatory synovitis usually involving peripheral joints in a symmetric distribution.
• The potential of the synovial inflammation to cause cartilage destruction and bone erosion and subsequent changes in joint integrity is the hall mark of the disease
• Non suppurative proliferative synovitis

EPIDEMOLOGY AND GENETICS
• Prevalence is 0.8% (Range 0.3 to 2.1%)
• Most common form of inflammatory arthropathy seen in India
• Female to male ratio-3:1
• More common in fourth and fifth decade of life
• Genetic predisposition; monozygotic twins 4 times than dizygotic twins. HLA DR3, HLA DR4 plays a vital role.
• Environmental factors also play an important role.

AETIOLOGY AND PATHOGENESIS
• Exact aetiology not known.
• Auto immune mechanism with viral infection as the triggering factor.
 Possible viral agents are
• Mycoplasma
• EBvirus
• CMV
• Parvo virus and
• Rubella.
• T Lymphocyte activation in genetically predisposed individual with defined HLA Class_II halo types HLA DR W 4.

The disease is initiated in a genetically predisposed individual, by activation of helper T lymphocytes responding to some arthritogenic  agents, possibly with microbe.
Activated CD 4 + Cells produce a number of cytokines that have two principle effects.

(1)Activation of macrophages and other cells in the joint space which release tissue destructive enzymes&other factors that  precipitate inflammation.

(2) Activation of B cell system, resulting in the production  of antibodies, some of which are directed against self constituents &the resultant autoimmune reaction damage the joints.

The rheumatoid synovium is heavily infiltrated with Activated CD4 + T Helper cells. They are well known source of cytokines which  activate other immune cells as well as macrophages. The latter in turn themselves secrete a variety of pro inflammatory & tissue degrading factors. The rheumatoid synovium is embarrassingly rich in both lymphocyte and monocyte derived cytokines. Activity of these cytokines can account for many features of rheumatoid synovitis. Not only cytokines but IL1&TGF also account for stimulation of synovial cells & chontrocytes to secrete proteolytic and matrix degrading enzymes.
Although T-cells play a primary role in the pathogenesis of RA, B cells are also involved. Approximately 80% of the patients have RF’s, which are auto antibodies directed against Fc portion of IgG, present in serum and synovial fluid. The significants of RFs in pathogenesis of RA is uncertain.

But their presence contribute to the inflammatory reaction seen in joints.
The joint damage in RA is of immune origin and appears to occur in genetically pre disposed individuals, the precise trigger that initiates these reactions are still unclear.
The environmental trigger of RA is said to be cigarette smoking.

PATHOLOGY
Swelling & congestion of synovial membrane & underlying connective tissue.
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Infiltration with lymphocytes plasma cells & macrophages
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effusion
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increase in the volume of synovial fluid& membrane
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PANNUS formation (highly vascularised inflammatory reduplicated synovium that covers the articular cartilaginous surface).

Pannus liberates proteolytic enzymes, cytokines –IL-I, IL—TNF, PDGF &These will cause destruction of the articular cartilage without regeneration.

Intra articular structures such as cruciate ligaments in the knee may also be destroyed. The bone adjacent to the joint is eroded by the intrusion of exuberant synovial membrane. It also become ostioporotic, partly because of hyperemia associated with the disease & may partly as a result of steroidal treatment. The combination of a loss of cartilage & osteoporosis may lead to rapidly progressive severe bone collapse & hence to instability & deformity of the involved joint. Immunofluresence shows that the plasma cells in the synovium &lymph nodes synthesis rheumatoid factor.

Rheumatoid subcutaneous nodules eventually appear in about one quarter of patients. The nodule usually occur along the extensor surface of the forearm or other areas subjected to mechanical pressure .They are firm nontender ,oval or rounded masses up to 2 cms in diameter .Less commonly ,these nodule appears in the achillis tendon, on the back of skull, overlying the ischial tuberosity or along the  tibia. They are characterized by a central focus fibrous tissue followed by a palisade of macrophages which in turn is rimmed by granulation tissue.

Rheumatoid nodule may also involve the viscera, including lung, spleen, pericardium, aorta &the heart valve.
Since RA is a systemic disease, a number of other structures like skin, lungs, heart, liver, CNS, & Eyes are also involved.

CLINICAL FEATURES
• RA is a chronic polyarthritis
• Onset: In approximately 2/3 of the patients, it begins
insidiously with fatigue, anorexia, generalized weakness & vague musculoskeletal symptoms until the appearance of synovitis become apparent. The prodromal symptom persists for weeks or months.
Specific symptoms starts gradually and commonly presented as chronic symmetrical poly arthritis.

Other less common presentations are,
• a/c poly arthritis (10—15%)
• Oligo arthritis
• a/c monoarticular arthritis
• c/c monoarticular arthritis
• More insidious systemic onset with fever, sweating, wt loss, fatigue, malaise, leukocytes, lymphadinopathy, & pleural effusion in addition to arthritis.

SIGNS & SYMPTOMS OF ARTICULAR DISEASE
Morning pain in joints initially but rest pain & early morning stiffness are characteristic of all inflammatory arthritis.
Typical cases, lesion starts on the small joints of the fingers and toes (proximal interphalangeal joints, metacarpophalangial joints, metatarsophalangial joints).
The affected joints are warm, painful and swollen.
Spindled appearance of the finger may result from swelling of the proximal but not distal interphalangeal joints.
The swelling of the metatarsophalangial joints results in broadening of the fore foot. In the forefoot, subluxation of the metatarso-phalangeal joints is followed by clawing of the toes, callosities over the exposed metatarsal heads and a painful sensation of ‘walking on pebbles’.
As the disease progresses, it spreads to involve the wrist, elbow, shoulder, knee, ankle joints, sub talar and mid tarsal joints.
Axial involvement is usually limited to the upper cervical spine.Atlanto axial subluxation leading to neck pain and stiffness, clucking sound on flexion of the neck heard. Involvement of lumbar spine not seen.

Hip, sacroiliac and dorso lumbar involvement only in severe cases.
The temperomandibular, acromioclavicular, sternoclavicular & Cricoaratinoid joints are sometimes affected.

As the disease advances a variety of characteristic joint changes develop. These can be attributed to a number of pathological events; involving laxity of supporting soft tissue, weakening of ligaments, tendons & joint capsule; cartilage degradation ;muscle imbalance.

Characteristic deformities
Flexion contracture of the small joints of the hands and feet, knees &elbow.
In the hand, anterior subluxation of the metacarpophalangial joints is common with ulnar deviation of fingers.
‘Swan neck deformity’ –hyper extension of the proximal inter phalangeal joints with flexion of the distal inter phalangeal joints
Button hole deformity (boutonnière deformity) -- flexion of the proximal inter phalangeal joints with hyper extension of the distal inter phalangeal joints.
Dropped fingers.
Hitch –haker thumb/ ‘Z’ shaped deformity of the thumb.
In the fore foot, subluxation of the metacarpo-phalangeal joints is followed by clawing of the toes, callosities over the exposed metatarsal heads& a painful sensation of walking on pebble sensation.
In the hind foot calcaneal erosions may develop at the tendo achillis
Hammer toes -- flexion of the proximal inter phalangeal joints with hyper extension of the meta tarso phalangeal joints.
Hallus valgus—lateral deviation of the big toe.
The arches of feet may be lost due to the affection of the joints& ligaments.
Callosities develop over the prominent bony parts.

Teno sinuvitis and bursitis are integral part of RA.
Triggering of the finger may be associated with nodule in the flexor tendon sheaths which can progress to prominent flexion contractures or tendon rupture if left untreated.
Bakers cyst—cyst developing in the popliteal fossa
Lateral subluxation of knee joint is also very common.

EXTRA ARTICULAR MANIFESTATIONS
These manifestations occur in individuals with high titers of auto antibodies to the Fc component of IgG (Rheumatoid factor).
Skin: Rheumatoid nodules develop in 20-30% of persons .They are painless and nontender subcutaneous nodules
Musculoskeletal: Muscle weakness/wasting
Teno synovitis

Osteoporosis
• Periarticular
• Generalized

Vasculitis: Raynauds disease

• Necrotizing vasculitis

Respiratory/pleuropulmonary:

• Fibrosing alveolitis
• Cor pulmonale
• R/c pleural effusion
•Rheumatoid nodule in lung—when rheumatoid nodule appears in individuals with pneumoconiosis, a diffuse nodular fibrotic process may develop(Caplan’s syndrome)

Cardiac:
• Asymptomatic pericarditis
• Pericardial effusion
• Constrictive pericarditis
• Heart block
• Cardio myopathy
• Coronary artery occlusion
• Aortic regurgitation

Neurological:
• Peripheral neuropathy (glove stocking sensory loss)
• Cervical cord compression
• Entrapment neuropathy
. Carpal tunnel syndrome
. Tarsal tunnel syndrome

• Symmetrical polyneuropathy
• Mononeuritis multiples

Ocular:
• Episcleritis
• Scleritis
• Scleromalasia performance
• Kerato conjunctivitis sicca (Sjogrens syndrome)

Hematological: Normocytic normochromic anemia
Thrombocytosis
Lymphadenopathy
Amyloidosis
Septic arthritis

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