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Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting diarthrodial joints and frequently a variety of other

organs.

RHEUMATOID ARTHRITIS

RA occurs worldwide in all ethnic groups. Prevalence rates range from 0.3 to 1.5% in most

EPIDEMIOLOGY

populations, but frequencies of 3.5 to 5.3% have been found in several Native American tribes (Yakima, Chippewa, Inuit).

The peak incidence of onset is between the 4th and 6th decades, but RA may begin at any time from childhood ( Juvenile Chronic Arthritis) to later life. Females are two to three times more likely to be affected than males.

ETIOLOGY
Despite intensive research over many

decades, the cause of RA remains unknown. Three areas of interrelated research are currently most promising: (1) host genetic factors, (2) immunoregulatory abnormalities and autoimmunity, and (3) a triggering or persisting microbial infection.

ETIOLOGY
Genetic susceptibility to RA has been clearly

demonstrated. The disease clusters in families and is more concordant in monozygotic (30%) than dizygotic (5%) twins. Certain major histocompatibility complex (MHC) class II alleles (and their encoded HLA, or human leukocyte antigens) occur with increased frequency in affected individuals.

ETIOLOGY
Among white people of western European

origin, HLA-DR4 occurs in 60 to 70% of seropositive patients with RA as compared with 25 to 30% of normal individuals. HLA-DR1 is found in the majority of HLADR4-negative patients and is most strongly associated with the disease in several other ethnic groups (Israelis, Asian Indians).

ETIOLOGY
Only certain HLA-DR4 subtypes predispose to RA (Dw4 or DRB1*0401, Dw14 or DRB1*0404, and Dw15 or DRB1*0405), whereas others do not (Dw10 or DRB1*0402 and Dw13 or DRB1*0403). HLA-DR4 subtypes result from only a few amino

acid differences in the 3rd hypervariable region of the HLA-DR beta-chain. HLA-DR1 shares this same amino acid sequence, as do several other HLA alleles that have more recently been associated with RA in some populations .

ETIOLOGY
. Thus a "shared epitope" among several MHC

class II molecules appears to predispose to RA. Moreover, homozygosity for the amino acid sequence, especially if carried on HLADR4 molecules, has been shown to correlate with disease severity, including more destructive joint disease, subcutaneous nodules, and extra-articular manifestations, especially rheumatoid lung disease and Felty's syndrome.

ETIOLOGY
The crucial region for the shared epitope on

HLA-DR molecules appears to be a combining site for the T-cell antigen receptor (TCR). Because MHC class II molecules present processed antigen to the TCR on helper (CD4+) T lymphocytes it appears likely that an abnormal antigen-specific cellular and/or humoral immune response is inherent to the etiology of RA.

ETIOLOGY
The nature of the antigen, whether self or

foreign, remains unknown, although candidates include type II collagen, microbial antigens or heat shock proteins, and immunoglobulins. Other genes are also necessary for RA, and genome mapping studies are in progress.

ETIOLOGY
RA appears to be an "autoimmune" disease, similar to other MHC class II-associated disorders

Autoantibodies to the Fc portion of IgG molecules, or rheumatoid factors are present in the blood and synovial tissues of 80% of RA patients. Such cases are termed "seropositive." High titers of serum rheumatoid factor typically of the IgM isotype, are associated with more severe joint disease and with extra-articular manifestations, especially subcutaneous nodules.

ETIOLOGY
Despite the extremely strong association of rheumatoid factors with RA, they clearly do not

cause the disease. Production of rheumatoid factor commonly occurs in other disorders characterized by chronic antigenic stimulation, such as bacterial endocarditis, tuberculosis, syphilis, kala-azar, viral infections, intravenous drug abuse, and cirrhosis. Normal individuals occassionally produce rheumatoid factor, especially with increasing age.

ETIOLOGY
An infectious origin for RA has been a

continuing hypothesis. A variety of bacterial and viral candidates have been proposed and later discarded because of lack of definitive evidence. Viral infections such as rubella, Ross River virus, and parvovirus B19 have been shown to produce an acute polyarthritis, but no evidence exists that they initiate chronic RA..

ETIOLOGY
Epstein-Barr virus (EBV) remains a viable but

unproven candidate for a pathogenetic role because several unusual immune responses to it are found in patients with RA. An EBV protein has also been shown to share the same five amino acids as the HLA-DR4 (Dw14) and HLADR1 molecules, which are implicated in susceptibility to RA, thus raising the possibility of "molecular mimicry" as a mechanism. A similar homology with an Escherichia coli heat shock protein has also been found

PATHOGENESIS
The pathologic hallmark of RA is synovial membrane proliferation and outgrowth

associated with erosion of articular cartilage and subchondral bone. Often likened to a malignant tumor, proliferating inflammatory tissue (pannus) may subsequently lead to destruction of intraarticular and periarticular structures and result in the joint deformities and dysfunction seen clinically. The events initiating the process are unknown .

ETIOPATHOGENESIS
The stages of rheumatoid arthritis are proposed to be an 1. initiation phase of nonspecific inflammation, followed by 2. an amplification phase resulting from T cell activation, and 3. finally a stage of chronic inflammation with tissue injury.

ETIOPATHOGENESIS
The earliest findings include microvascular

injury and proliferation of synovial cells, accompanied by interstitial edema and perivascular infiltration by mononuclear cells, predominantly T lymphocytes.

ETIOPATHOGENESIS
Continuation of the process leads to further hyperplasia of lining cells, both DR-positive type

A (macrophage-like) and DR-negative type B (fibroblast-like), and the normally acellular subsynovial stroma becomes engorged with mononuclear inflammatory cells, which may collect into aggregates or follicles, especially around post-capillary venules. The proliferating synovium (pannus) becomes villous and is vascularized by arterioles, capillaries, and venules.

ETIOPATHOGENESIS
Roles for both cellular and humoral immune

mechanisms in the rheumatoid synovium are supported by molecular and immunopathologic findings. T lymphocytes, chiefly of the TH 1 type, appear to be activated, presumably by some unknown antigen(s) presented by DR-positive cells (type A synoviocytes, macrophages, dendritic cells, B lymphocytes).

ETIOPATHOGENESIS
Collectively, these interacting immune cells produce a variety of cytokines that promote

further synovial proliferation and inflammation, as well as bone and cartilage destruction. Important pro-inflammatory cytokines appear to be linked in a cascade, with tumor necrosis factor alpha (TNF-alpha) at the apex promoting the subsequent elaboration of interleukin-1 (IL-1), IL-6, IL-8, and granulocyte-macrophage colonystimulating factor (GM-CSF)..

ETIOPATHOGENESIS
IL-1 induces the production of

metalloproteinases (collagenase and stromelysin) and prostaglandin E2 by synoviocytes. This cytokine also promotes the degradation and inhibits the synthesis of proteoglycan by chondrocytes, as well as enhances resorption of calcium from bone.

ETIOPATHOGENESIS
There appears to be an attempt by

unregulated anti-inflammatory cytokines, such as soluble TNF receptor, transforminggrowth factor beta (TGF-beta), IL-10, and IL-1 receptor antagonist, to counterbalance these destructive effects.

ETIOPATHOGENESIS
Humoral mechanisms are supported by the

demonstration of local rheumatoid factor production within the synovium, the formation of IgM-activated B cells and IgG immune complexes, and activation and consumption of complement via the classic pathway. The sequelae of complement activation include increased vascular permeability and phagocytosis of the immune complexes by phagocytic cells. Aggregates of immune complexes within polymorphonuclear leukocytes are often seen in rheumatoid synovial fluid and have been termed "RA cells" or "ragocytes."

ETIOPATHOGENESIS
Antigen-antibody complexes formed within

the joint cavity can become trapped in hyaline cartilage and fibrocartilage, where they cause changes in matrix macromolecules. Within the synovial fluid, immune complexes activate the complement system, kinins, phagocytic cells, and the release of lysosomal enzymes and oxygen free radicals.

ETIOPATHOGENESIS
Mediators produced in this process stimulate

synovial cells to proliferate and produce proteinases and prostaglandins. These products cause dissolution of connective tissue macromolecules, as well as articular cartilage. They may also activate fibroblasts to produce a denser connective tissue matrix (fibrosis). The ultimate destruction of cartilage, bone, tendons, and ligaments probably results from a combination of proteolytic enzymes, metalloproteinases, and soluble mediators. Collagenase, produced at the interface of pannus and cartilage, is probably largely responsible for the typical bony erosions.

C/F
SMALL JTS OF HAND-PAIN/STIFFNESS >

1HR. The pattern of joint involvement is typically polyarticular and symmetrical and involves the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, shoulder, knee, ankle, and MTP joints. The distal interphalangeal (DIP) joints of the fingers are usually spared.

C/F
FEVER/MALAISE/HEADACHE JT SWELLING/TENDER With persistent inflammation, a variety of

characteristic joint changes develop.

C/F
1) radial deviation at the wrist with ulnar deviation of

the digits, often with palmar subluxation of the proximal phalanges (Z deformity); (2) hyperextension of the proximal interphalangeal joints, with compensatory flexion of the distal interphalangeal joints (swan-neck deformity); (3) flexion contracture of the proximal interphalangeal joints and extension of the distal interphalangeal joints (boutonnire deformity); and (4) hyperextension of the first interphalangeal joint and flexion of the first metacarpophalangeal joint with a consequent loss of thumb mobility and pinch.

C/F
KNEE-BAKERS CYST/BULGE SIGN WRIST-MEDIAN NERVE COMPRESSION. FEET & ANKLE-MTP JTS INVOLVED. NECK-Atlantoaxial subluxation (C1 on C2) can

be seen radiographically in up to 30% of cases Spinal cord compression with neurologic manifestations occurs infrequently

C/F
Occipital and/or frontal headache is a

common premonitory sign of weakness in the extremities, bladder or bowel incontinence, or frank quadriplegia. Vertebral arteries may also be compressed and lead to vertebrobasilar insufficiency with vertigo or syncope, especially on downward gaze. Head tilt may occur from lateral mass collapse of the C1 and C2 vertebrae.

C/F
HIP/SHOULDER JTS/CRICOARYTENOID JTS. EXTRA-ARTICULAR FEATURES1. SKIN-RHEUMATOID NODULES,PALMAR

ERYTHEMA,SKIN FRAGILITY 2. CVS-PERICARDITIS/NODULES 3. LUNGS-PLEURAL INV./PULM.NODULES./DIFFUSE INTERSTITIAL FIBROSIS.

C/F
NERVOUS SYSTEM-PER.

NEUROPATHY/VASCULITIS. EYES-SJOGRENS/SCLERITIS/EPISCLERITIS. FELTYS-CHRONIC RA,SPLENOMEGALY/NEUTROPENIA.

DIAGNOSIS
CLINICAL. X-RAYS. SYNOVIAL FLUID ASPIRATION ANEMIA,RAISED ESR SEROLOGICAL TESTS.

DIAGNOSIS
Guidelines for classification

a. Four of seven criteria are required to classify a patient as having rheumatoid arthritis (RA). b. Patients with two or more clinical diagnoses are not excluded.

DIAGNOSIS
Criteriaa

a. Morning stiffness: Stiffness in and around the joints lasting 1 h before maximal improvement. b. Arthritis of three or more joint areas: At least three joint areas, observed by a physician simultaneously, have soft tissue swelling or joint effusions, not just bony overgrowth. The 14 possible joint areas involved are right or left proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, and metatarsophalangeal joints.

DIAGNOSIS
c. Arthritis of hand joints: Arthritis of wrist, metacarpophalangeal joint, or proximal

interphalangeal joint. d. Symmetric arthritis: Simultaneous involvement of the same joint areas on both sides of the body.

e. Rheumatoid nodules: Subcutaneous nodules over bony prominences, extensor surfaces, or juxtaarticular regions observed by a physician.

DIAGNOSIS
f. Serum rheumatoid factor: Demonstration of abnormal amounts of serum rheumatoid factor

by any method for which the result has been positive in less than 5% of normal control subjects. g. Radiographic changes: Typical changes of RA on posteroanterior hand and wrist radiographs that must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints.

TREATMENT
The goals of therapy of RA are (1) relief of pain,

(2) reduction of inflammation, (3) protection of articular structures, (4) maintenance of function, and (5) control of systemic involvement. Since the etiology of RA is unknown, the pathogenesis is not completely delineated, and the mechanisms of action of some of the therapeutic agents employed are uncertain, therapy remains somewhat empirical.

TREATMENT
None of the therapeutic interventions is curative, and therefore all must be viewed as

palliative, aimed at relieving the signs and symptoms of the disease. The various therapies employed are directed at nonspecific suppression of the inflammatory or immunologic process in the hope of ameliorating symptoms and preventing progressive damage to articular structures. Rest is an impt part of treatment.

TREATMENT OPTIONS
NSAIDS STEROIDS IMMUNOMODULATORS/IMMUNOSUPPRESSIVE

AGENTSMTX,HCQ,LEFLONEMIDE,SULPHASALAZINE,CYCLOPHO SPHAMIDE,AZATHIOPRINE, MYCOPHENOLATE.. ANTICYTOKINE DRUGS-TNF INHETANERCEPT,INFLIXIMAB,ADALIMUMAB IL1 INH-ANAKINRA. DO NOT COMBINE THE IL1 AND TNF INH.-SEVERE SEPSIS. PLASMAPHERESIS -A new approach, pheresis across a column bound with staphylococcal protein A, the Prosorba column, has been approved for treatment of RA.