Rheumatoid Arthritis

Overview
  • Rheumatoid Arthritis (RA) is a systemic chronic auto-inflammatory disease of unknown etiology whose primary manifestation is a progressive symmetric distal erosive inflammatory polyarthritis. Extra-articular disease primarily affects the skin, vasculature, heart, lungs, and blood.
Etiology and Pathogenesis
  • The ultimate etiology of RA is unknown and likely involves an as yet unknown environmental, possibly microbial, trigger in a genetically susceptible individual. Currently, it is thought that auto-reactive CD4+ T-cells are responsible for initiating a cascade of inflammation by stimulating macrophages and synoviocytes within joint spaces to release highly inflammatory cytokines such as TNF-alpha. These auto-reactive T-cells are also thought to release RANK within the inflamed synovium, resulting in activation of nearby osteoclasts and thus stimulating the erosive resorption of adjacent bone characteristic of RA.
  • B-cell hyperactivity and auto-antibody generation is also a component of RA pathogenesis and is likely secondary to hyper-stimulation of humoral immunity by the auto-reactive CD4+ T-cells already discussed. The primary auto-antibody of RA is Rheumatoid Factor (RF) which represents an IgM to the Fc Region of IgG. The presence of RF appears to generate large immune complexes that deposit in tissues, fix complement, and attract inflammatory neutrophils. Systemic deposition of these complexes may account for some of the systemic symptomology of RA and their deposition in joints can certainly exacerbate the already ongoing inflammation. While Rheumatoid Factor can be observed in a variety of other autoimmune diseases, the presence of antibodies to Cyclic Citrullinated Peptides (Anti-CCP) are highly specific to RA and now account for an important part of the diagnostic work-up.
Pathology
  • The morphological hallmark of RA is the pannus, a thickened collagenous synovial membrane burdened by a heavy inflammatory infiltrate. The pannus forms from hyperplasia of synoviocytes and infiltration of lymphocytes, macrophages, and neutrophils. In some cases inflammatory cells can begin to organize into recognizable lymphoid follicles. The pannus can grow into and fill the joint space as well as invade into adjacent cartilage and bone. Inflammatory cytokines generated by immune cells within the pannus are believed to stimulate nearby chondrocytes and osteoclasts, resulting in significant erosion of adjacent articular cartilage and bone. Over time, the pannus can become increasingly fibrotic, resulting in permanent deformity of the affected joint.
Clinical Consequences
  • Overview
    • RA is thought to affect nearly 1% of the world population with a predilection for women. Onset is typically in adulthood and following an insidious onset the clinical course is usually chronic, progressive, with waxing-waning intensity and occasional flares. Prior to the advent of disease-modifying therapeutics, RA was a highly debilitating disorder with almost universal progression to severe disability. The clinical manifestations of RA can be divided into articular and extra-articular and these are discussed below. Prior to flares of arthritis patients may complain of constitutional symptoms including fever, night sweats, and profound fatigue.
  • Joints
    • The classic presentation of RA is with symmetrical arthritis. The wrists, ankles, small joints of the hands, particularly the MCP and PIP, as well as the feet, particularly the MTP, are most frequently affected initially although the disease can spread to involve the large joints of the knees, elbows, and shoulders. RA typically does not affect the spine except at the C1-C2 level, the only level of the spine surrounded by synovium, and can render this level prone to "atlanto-axial" subluxation.
    • Joint are characteristically sore and stiff for greater than 1 hour in the morning, with gradual improvement during the course of the day. This contrasts with osteoarthritis in which pain is better in the morning and worsens during the day. Joints will also appear swollen and upon palpation can display a doughy consistency, representing the presence of the rheumatoid pannus described above.
    • Radiography can support the diagnosis of RA and will classically show symmetric erosion of sub-chondral bone and narrowing of joint spaces, representing inflammation-mediated destruction of local cartilage and bone.
    • Over time, progressive destruction of joints and tendons can lead to irreversible deformities several of which are so classic in RA that they have received monickers. These include "Ulnar Deviation" of the the fingers at the MCP joints, the "Swan-Neck Deformity", and the "Boutonnière Deformity".
  • Rheumatoid Nodules
    • Rheumatoid Nodules are a common feature of RA and are most frequently encountered in the skin as painless, firm, sub-cutaneous nodules especially on the extremities. These nodules represent foci of fibrinoid necrosis surrounded by macrophages and can also occur in visceral organs especially the lungs, spleen, and heart.
  • Heart and Lungs
    • RA can be complicated by inflammation of the serosa which can manifest either as an exudative pleural effusions or pericarditis. Rheumatoid nodules can develop in the heart and lungs as discussed above. Finally, In a small subset of patients an interstitial lung disease can develop.
  • Vasculature
    • Rarely, patients can develop a vasculitis syndrome with primarily cutaneous manifestations as well as peripheral neurological deficits.
  • Blood
    • In keeping with a chronic systemic inflammatory environment, patients with RA frequently display a normocytic anemia representing Anemia of Chronic Disease. Rarely, patients may develop "Felty's Syndrome" characterized by the the presence of neutropenia and splenomegaly in the context of RA.