Diseases

Rheumatoid arthritis (RA) : Causes, Pathogenesis, Symptoms, Diagnosis, Treatment

By Dr Daya

Posted on December 25, 2016

Rheumatoid Arthritis (RA)

Introduction

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disease affecting many tissues but
principally attacking the joints.
It causes a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis.
When extraarticular involvement develops—for example, of the skin, heart, blood vessels, muscles, and lungs—
RA may resemble lupus or scleroderma.

Incidence

RA is a relatively common condition, with a prevalence of approximately 1%; it is three to five times more common in women than in men.
The peak incidence is in the second to fourth decades of life, but no age is immune.

Pathogenesis

Rheumatoid arthritis is an autoimmune disease involving complex, and still poorly understood, interactions of genetic risk factors, environment, and the immune system.
The pathologic changes are caused mainly by cytokine-mediated inflammation, with CD4+ T cells being the principal source of the cytokines.
Many patients also produce antibodies against cyclic citrullinated peptides (CCPs), which may contribute to the joint lesions. CCPs are derived from proteins in which arginine residues are converted to citrulline residues posttranslationally.
In RA, antibodies to citrullinated fibrinogen, type II collagen, α-enolase, and vimentin are the most important and may form immune complexes that deposit in the joints. These antibodies are a diagnostic marker for the disease and may be involved in tissue injury.
Like other autoimmune diseases, RA is a disorder in which genetic and environmental factors contribute to the breakdown of tolerance to self-antigens.
• Genetic factors: It is estimated that 50% of the risk of developing RA is related to genetic factors. Susceptibility to rheumatoid arthritis is linked to the HLA-DRB1 locus. Recent linkage and genome-wide association studies have revealed a large number of non-HLA genes in which polymorphisms are associated with RA. There is a strong association with a polymorphism in the PTPN22 gene, which encodes a tyrosine phosphatase that is postulated to inhibit T cell activation.
• Environmental factors: Many candidate infectious agents whose antigens may activate T or B cells have been considered, but none has been conclusively implicated. As mentioned above, in at least 70% of patients the blood contains anti-CCP antibody, which may be produced during inflammation. Inflammatory and environmental insults such as smoking and infections may induce the citrullination of some self proteins, creating new epitopes that trigger autoimmune reactions.

Morphology

A broad spectrum of morphologic alterations are seen in RA; the most severe occur in the joints.
Rheumatoid arthritis typically manifests as symmetric arthritis, principally affecting the small joints of the hands and feet, ankles, knees, wrists, elbows, and shoulders.
Most often, the proximal interphalangeal and metacarpophalangeal joints are affected, but distal interphalangeal joints are spared.
Axial involvement, when it occurs, is limited to the upper cervical spine; similarly, hip joint involvement is extremely uncommon.
On histologic examination, the affected joints show chronic papillary synovitis, characterized by (1) synovial cell hyperplasia and proliferation; (2) dense perivascular inflammatory cell infiltrates (frequently forming lymphoid follicles) in the synovium composed of CD4+ T cells, plasma cells, and macrophages; (3) increased vascularity due to angiogenesis; (4) neutrophils and aggregates of organizing fibrin on the synovial surface and in the joint space; and (5) increased osteoclast activity in the underlying bone, leading to synovial penetration and periarticular bone erosion.
The classic appearance is that of a pannus, formed by proliferating synovial lining cells admixed with inflammatory cells, granulation tissue, and fibrous connective tissue; the overgrowth of this tissue is so exuberant that the usually thin, smooth synovial membrane is transformed into lush, edematous, frondlike (villous) projections.
With full-blown inflammatory joint involvement, periarticular soft tissue edema usually develops, classically manifested first by fusiform swelling of the proximal interphalangeal joints. With progression of the disease, the articular cartilage subjacent to the pannus is eroded and, in time, virtually destroyed. The subarticular bone also may be attacked and eroded. Eventually the pannus fills the joint space, and subsequent fibrosis and ossification may cause permanent ankylosis.
The radiographic hallmarks are joint effusions and juxtaarticular osteopenia with erosions and narrowing of the joint space and loss of articular cartilage. Destruction of tendons, ligaments, and joint capsules produces the characteristic deformities, including radial deviation of the wrist, ulnar deviation of the fingers, and flexion-hyperextension abnormalities of the fingers (swan-neck deformity, boutonnière deformity).
Rheumatoid subcutaneous nodules develop in about one fourth of patients, occurring along the extensor surface of the forearm or other areas subjected to mechanical pressure; rarely, they can form in the lungs, spleen, heart, aorta, and other viscera.
Rheumatoid nodules are firm, nontender, oval or rounded masses as large as 2 cm in diameter. They are characterized microscopically by a central focus of fibrinoid necrosis surrounded by a palisade of macrophages, which in turn is rimmed by granulation tissue and lymphocytes.
Patients with severe erosive disease, rheumatoid nodules, and high titers of rheumatoid factor are at risk of developing vasculitic syndromes; acute necrotizing vasculitis may involve small or large arteries. Serosal involvement may manifest as fibrinous pleuritis or pericarditis or both. Lung parenchyma may be damaged by progressive interstitial fibrosis. Ocular changes such as uveitis and keratoconjunctivitis (similar to those seen in Sjögren syndrome) may be prominent in some cases.

Clinical Features

Although Rheumatoid arthritis is basically a symmetric polyarticular arthritis, there also may be constitutional symptoms such as weakness, malaise, and low-grade fever.
Many of the systemic manifestations result from the same mediators that cause joint inflammation (e.g., IL-1, TNF). The arthritis first appears insidiously, with aching and stiffness of the joints, particularly in the morning. As the disease advances, the joints become enlarged, motion is limited, and in time complete ankylosis may appear. Vasculitic involvement of the extremities may give rise to Raynaud phenomenon and chronic leg ulcers. Such multisystem involvement must be distinguished from lupus, scleroderma, polymyositis, dermatomyositis, and Lyme disease, as well as other forms of arthritis.
Helpful in making the correct diagnosis are (1) characteristic radiographic findings; (2) sterile, turbid synovial fluid with decreased viscosity, poor mucin clot formation, and inclusion-bearing neutrophils; and (3) anti-CCP and rheumatoid factor (80% of patients).
The clinical course of Rheumatoid arthritis is highly variable. In a minority of patients, the disease may stabilize or even regress; in most patients, however, it pursues a chronic, remittingrelapsing course.
Historically, the natural history of the disease has been one of progressive joint destruction leading to disability after 10 to 15 years. The outcome has been dramatically improved by recent advances in therapy, including aggressive treatment of early RA and the introduction of highly effective biologic agents that antagonize TNF. RA is an important cause of reactive amyloidosis, which develops in 5% to 10% of these patients, particularly those with long-standing severe disease.

Variants

There are a few variant forms of RA:

Juvenile RA found in adolescent patients under 16 years of age is characterised by acute onset of fever and
predominant involvement of knees and ankles. Pathologic changes are similar but RF is rarely present.
Felty’s syndrome consists of polyarticular RA associated with splenomegaly and hypersplenism and consequent haematologic derangements.
Ankylosing spondylitis or rheumatoid spondylitis is rheumatoid involvement of the spine, particularly sacroiliac joints, in young male patients. The condition has a strong HLA-B27 association and may have associated inflammatory diseases such as inflammatory bowel disease, anterior uveitis and Reiter’s syndrome.