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RHEUMATOID ARTHRITIS
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Rheumatoid Arthritis

Introduction

Background

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown cause that primarily affects the peripheral joints in a symmetric pattern. Constitutional symptoms, including fatigue, malaise, and morning stiffness, are common. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can be significant. RA causes joint destruction and thus often leads to considerable morbidity and mortality. With the recent addition of new and innovative therapies, the treatment of RA is rapidly advancing.

For supplementary information, see Medscape’s Rheumatoid Arthritis Resource Center.

Pathophysiology

RA has no known cause. Although an infectious etiology has been speculated (eg, Mycoplasma organisms,Epstein-Barr virus, parvovirus, rubella), no organism has been proven responsible. RA is associated with numerous autoimmune responses, but whether autoimmunity is a secondary or primary event is still unknown.

RA has a significant genetic component, and the shared epitope of the HLA-DR4/DR1 cluster is present in up to 90% of patients with RA, although it is also present in more than 40% of controls. Synovial cell hyperplasia and endothelial cell activation are early events in the pathologic process that progresses to uncontrolled inflammation and consequent cartilage and bone destruction. Genetic factors and immune system abnormalities contribute to disease propagation.

CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, while B lymphocytes produce autoantibodies (ie, rheumatoid factors [RFs]). Abnormal production of numerous cytokines, chemokines, and other inflammatory mediators (eg, tumor necrosis factor alpha [TNF-alpha], interleukin (IL)–1, IL-6, transforming growth factor beta, IL-8, fibroblast growth factor, platelet-derived growth factor) has been demonstrated in patients with RA. Ultimately, inflammation and exuberant proliferation of synovium (ie, pannus) leads to destruction of various tissues, including cartilage, bone, tendons, ligaments, and blood vessels. Although the articular structures are the primary sites involved by RA, other tissues are also affected.

Frequency

International

Worldwide, the annual incidence of RA is approximately 3 cases per 10,000 population, and the prevalence rate is approximately 1%. RA affects all populations, although the disease is much more prevalent in some groups (eg, 5-6% in some Native American groups) and much less prevalent in others (eg, black persons from the Caribbean region). First-degree relatives of individuals with RA are at an increased risk (2- to 3-fold) of the disease. Disease concordance in monozygotic twins is approximately 15-20%, suggesting that nongenetic factors play an important role. Because the worldwide frequency of RA is relatively constant, a ubiquitous infectious agent has been postulated to play an etiologic role.

Mortality/Morbidity

RA does not usually follow a benign course. It is associated with significant morbidity, disability, and mortality.

  • Daily living activities are impaired in most individuals with RA. Spontaneous clinical remission is uncommon (approximately 5-10%). After 5 years of disease, approximately 33% of patients are unable to work; after 10 years, approximately half have substantial functional disability. Poor prognostic factors include persistent synovitis, early erosive disease, extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, family history of RA, male sex, and advanced age.
  • Life expectancy in patients with RA is shortened by 5-10 years, although the mortality rate may be lower in those who respond to therapy. Increased mortality rates are associated with poor functional status, age, male sex, socioeconomic factors (eg, level of education), positive RF findings, extra-articular disease, elevated acute-phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity (eg, more involved joints). Factors that increase the mortality risk include infections, cardiovascular disease, renal disease, GI bleeding, and lymphoproliferative disorders; these events may be directly due to the disease and its complications (eg, vasculitis, amyloidosis) or to therapy-induced adverse effects.

Race

RA affects all ethnic groups, although the disease is much more prevalent in some groups (eg, 5-6% in some Native American groups) and much less prevalent in others (eg, black persons from the Caribbean region).

Sex

RA is 2-3 times more common in females than in males.

Age

The frequency of RA increases with age and peaks in persons aged 35-50 years. Nevertheless, the disease is observed in both elderly persons and children.

  • Juvenile inflammatory arthritis (JIA) is classified as polyarticular (multiple joints), pauciarticular (<5 joints), or systemic. Systemic JIA is often associated with fever, rash, and organ involvement; it is also called Still disease.
  • Polyarticular RF-positive arthritis in children generally follows a clinical course that is similar to adult RA.
  • For additional information on juvenile rheumatoid arthritis, see the article Juvenile Rheumatoid Arthritis in eMedicine’s Pediatrics: General Medicine volume.

Clinical

History

The American College of Rheumatology developed the following criteria for the classification of rheumatoid arthritis (RA).

  1. Morning stiffness: This occurs in and around the joints and lasts at least 1 hour before maximal improvement.
  2. Arthritis of 3 or more joint areas: At least 3 joint areas simultaneously have soft-tissue swelling or fluid (not bony overgrowth) observed by a physician. The 14 possible areas include the right and left proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, knee, ankle, and metatarsophalangeal (MTP) joints.
  3. Arthritis of hand joints: At least one area in a wrist, MCP, or PIP joint is swollen.
  4. Symmetric arthritis (simultaneous involvement of the same joint areas on both sides of the body): Bilateral involvement of PIPs, MCPs, and MTPs is acceptable without absolute symmetry.
  5. Rheumatoid nodules: Subcutaneous nodules are present over bony prominences or extensor surfaces or in juxta-articular regions.
  6. Serum RF: Abnormal amounts of serum RF are demonstrated by any method for which the result has been positive in fewer than 5% of healthy control subjects.
  7. Radiographic changes typical of RA on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints: Osteoarthritic changes alone do not qualify.

The presence of 4 criteria supports the diagnosis of RA. Criteria 1-4 must be present for at least 6 weeks, and a physician must observe criteria 2-5. These criteria are intended as a guideline for classification of patients, often for research purposes. They do not absolutely confirm or exclude a diagnosis of RA in a particular patient, especially in those with early arthritis.

Patients with RA often present with constitutional symptoms, including malaise, fever, fatigue, weight loss, and myalgias. They may report difficulty performing activities of daily living (eg, dressing, standing, walking, personal hygiene, using their hands).

Most patients with RA have an insidious onset. It may begin with systemic features, such as fever, malaise, arthralgias, and weakness, before the appearance of overt joint inflammation and swelling. A small percentage of patients with RA (approximately 10%) have an abrupt onset with the acute development of synovitis and extra-articular manifestations. Spontaneous remission is uncommon, especially after the first 3-6 months.

Physical

Joint involvement is the characteristic feature of RA. In general, the small joints of the hands and feet are affected in a relatively symmetric distribution. The most commonly affected joints, in decreasing frequency, include the MCP, wrist, PIP, knee, MTP, shoulder, ankle, cervical spine, hip, elbow, and temporomandibular joints. Joints show inflammation with swelling, tenderness, warmth, and decreased range of motion. Atrophy of the interosseous muscles of the hands is a typical early finding. Joint and tendon destruction may lead to deformities such as ulnar deviation, boutonnière and swan-neck deformities, hammer toes, and, occasionally, joint ankylosis.

Other commonly observed musculoskeletal manifestations include tenosynovitis and associated tendon rupture due to tendon and ligament involvement, most commonly involving the fourth and fifth digital extensor tendons at the wrist; periarticular osteoporosis due to localized inflammation; generalized osteoporosis due to systemic chronic inflammation, immobilization-related changes, or corticosteroid therapy; and carpal tunnel syndrome. Most patients with RA have muscle atrophy from disuse, which is often secondary to joint inflammation.

  • Effect of RA on organs and organ systems
    • Cutaneous: Subcutaneous nodules (rheumatoid nodules) develop in many patients with RA whose RF value is abnormal, often over pressure points (eg, olecranon). Vasculitic lesions of the skin may manifest as palpable purpura or skin ulceration.
    • Cardiac: Cardiovascular morbidity and mortality are increased in patients with RA. Nontraditional risk factors appear to play an important role. Myocardial infarction, myocardial dysfunction, and asymptomatic pericardial effusions are common; symptomatic pericarditis and constrictive pericarditis are rare. Myocarditis, coronary vasculitis, valvular disease, and conduction defects are occasionally observed.
    • Pulmonary: RA involvement of the lungs may take several forms, including pleural effusions, interstitial fibrosis, nodules (Caplan syndrome), and bronchiolitis obliterans-organizing pneumonia. Methotrexate (MTX) therapy can induce interstitial fibrosis that may be difficult to distinguish from that which naturally occurs in patients with RA.
    • GI: Intestinal involvement, as with kidney involvement, is often secondary to associated processes such as medication effects, inflammation, and other diseases. The liver is often affected in patients with Felty syndrome (ie, RA, splenomegaly, and neutropenia).
    • Renal: The kidneys are usually unaffected by RA directly. Secondary involvement is common, including that due to medications (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], gold, cyclosporin), inflammation (eg, amyloidosis), and associated diseases (eg, Sjögren syndrome with renal tubular abnormalities).
    • Vascular: Vasculitic lesions can occur in any organ but are most commonly found in the skin. Lesions may present as palpable purpura, skin ulcers, or digital infarcts.
    • Hematologic: Most active patients have an anemia of chronic disease. Several hematologic parameters parallel disease activity, including normochromic-normocytic anemia, thrombocytosis, and eosinophilia, although the latter is uncommon. Leukopenia is a finding in patients with Felty syndrome.
    • Neurologic: Nerve entrapment is common, such as with the median nerve in carpal tunnel syndrome. Vasculitic lesions, mononeuritis multiplex, and cervical myelopathy may cause serious neurologic consequences.
    • Ocular: Keratoconjunctivitis sicca is common in individuals with RA and is often the initial manifestation of secondary Sjögren syndrome. The eye may also have episcleritis, uveitis, andnodular scleritis that may lead to scleromalacia.

The American College of Rheumatology has developed criteria to aid in determining the progression, remission, and functional status of patients with RA.

  • Progression of RA (clinical and radiologic staging)
    • Stage 1 (early RA)
      • No destructive changes observed upon roentgenographic examination
      • Radiographic evidence of osteoporosis possible
    • Stage II (moderate progression)
      • Radiographic evidence of periarticular osteoporosis, with or without slight subchondral bone destruction
      • Slight cartilage destruction possible
      • Joint mobility possibly limited; no joint deformities observed
      • Adjacent muscle atrophy
      • Extra-articular soft-tissue lesions (eg, nodules, tenosynovitis) possible
    • Stage III (severe progression)
      • Radiographic evidence of cartilage and bone destruction in addition to periarticular osteoporosis
      • Joint deformity (eg, subluxation, ulnar deviation, hyperextension) without fibrous or bony ankylosis
      • Extensive muscle atrophy
      • Extra-articular soft-tissue lesions (eg, nodules, tenosynovitis) possible
    • Stage IV (terminal progression)
      • Fibrous or bony ankylosis
      • Criteria of stage III
  • Remission of RA (≥5 of conditions below for at least 2 consecutive months)
    • Duration of morning stiffness not exceeding 15 minutes
    • No fatigue
    • No joint pain
    • No joint tenderness or pain with motion
    • No soft-tissue swelling in joints or tendon sheaths
    • ESR of less than 30 mm/h in a female or less than 20 mm/h in a male
  • Functional status of patients with RA
    • Class I - Completely able to perform usual activities of daily living
    • Class II - Able to perform usual self-care and vocational activities but limited in avocational activities
    • Class III - Able to perform usual self-care activities but limited in vocational and avocational activities
    • Class IV - Limited in ability to perform usual self-care, vocational, and avocational activities

Causes

The cause of RA is unknown. Genetic, environmental, hormonal, immunologic, and infectious factors may play significant roles. Socioeconomic, psychological, and lifestyle factors may influence disease outcome.

  • Genetic
    • Approximately 60% of US patients with RA carry a shared epitope of the HLA-DR4 cluster, which constitutes one of the peptide-binding sites of certain HLA-DR molecules associated with RA (eg, HLA-DR beta *0401, 0404, or 0405); in addition, HLA-DR1 (HLA-DR beta *0101) also carries this shared epitope and confers risk, particularly in certain southern European areas.
    • Other HLA-DR4 molecules (eg, HLA-DR beta *0402) do not share the same epitope and do not confer risk. Genes other than those of the major histocompatibility complex are also involved, and results from sequencing genes of RA families suggest the presence of several susceptibility genes and several resistance genes.
  • Environmental
    • For many decades, numerous infectious agents have been suggested to induce RA. Among these are Mycoplasma organisms, Epstein-Barr and rubella viruses, and others.
    • This supposition is further supported indirectly by the following:
      • Occasional reports of flulike disorders preceding the start of arthritis
      • The inducibility of arthritis in experimental animals with different bacteria or bacterial products (eg, streptococcal cell walls)
      • The presence of bacterial products including bacterial RNA in patients' joints
      • The activity of several agents that have antimicrobial effects as disease-modifying drugs (eg, gold salts, antimalarials, minocycline)
  • Hormonal
    • Sex hormones may play a role, as evidenced by the disproportionate number of females with RA, its amelioration during pregnancy, its recurrence in the early postpartum period, and its reduced incidence in women using oral contraceptives.
    • Hyperprolactinemia may be a risk factor for RA.
  • Immunologic
    • All of the major immunologic elements play fundamental roles in the initiation, propagation, and maintenance of the autoimmune process of RA. The exact orchestration of the cellular and cytokine events that lead to pathologic consequences, such as synovial proliferation and subsequent joint destruction, is complex. It involves T and B lymphocytes, antigen-presenting cells (eg, B cells, macrophages, dendritic cells), and numerous cytokines. Aberrant production and regulation of both pro-inflammatory and anti-inflammatory cytokines and cytokine pathways are found in RA.
    • T cells are assumed to play a pivotal role in the initiation of RA, and the key player in this respect is assumed to be the Th1 CD4 cells. (T helper 1 cells produce IL-2 and interferon gamma.)
    • These cells may subsequently activate macrophages and other cell populations, including synovial fibroblasts. Macrophages and synovial fibroblasts are the main producers of the proinflammatory cytokines TNF-alpha and IL-1.
    • B cells are important in the pathologic process and may serve as antigen-presenting cells. B cells also produce numerous autoantibodies (eg, RF, to citrullinated proteins) and secrete cytokines. Elimination of populations of B cells with monoclonal antibodies (eg, rituximab) offers another effective therapeutic option. While rituximab may be used as a sole agent, it is often used in combination with MTX. Rituximab has been shown to be effective in reducing the signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF-antagonist therapies.1,2,3
    • Experimental models suggest that synovial macrophages and fibroblasts may become autonomous and thus lose responsiveness to T-cell activities in the course of the disease.
    • The hyperactive and hyperplastic synovial membrane is ultimately transformed into pannus tissue and invades cartilage and bone, the latter being degraded by activated osteoclasts.
    • The major difference between RA and other forms of inflammatory arthritis, such as psoriatic arthritis, does not lie in their cytokine patterns but rather in the highly destructive potential of the RA synovial membrane and in the local and systemic autoimmunity. Whether these two events are linked is unclear; however, the autoimmune response conceivably leads to the formation of immune complexes that activate the inflammatory process to a much higher degree than normal. This theory is supported by the much worse prognosis of RA among patients with positive RF results.
    • In patients with RA, autoantibodies are directed not only against immunoglobulin G (IgG), ie, RFs, but also against various other antigens, such as nuclear antigens (RA 33, EBNA), citrullinated proteins (anti-CCP antibodies), collagen, and glucose-6-phosphate isomerase.
  • Differential Diagnoses

    Amyloidosis, Overview
    Myelodysplastic Syndrome
    Calcium Pyrophosphate Deposition Disease
    Osteoarthritis
    Cryoglobulinemia
    Paraneoplastic Syndromes
    Fibromyalgia
    Polychondritis
    Hepatitis B
    Polymyalgia Rheumatica
    Hypothyroidism
    Psoriatic Arthritis
    Inflammatory Bowel Disease
    Sarcoidosis
    Lyme Disease
    Sjogren Syndrome
    Mediterranean Fever, Familial
    Systemic Lupus Erythematosus
    Multicentric Reticulohistiocytosis
    Whipple Disease

    Other Problems to Be Considered

    • Infectious arthritis - Bacteria (eg, Lyme disease), fungi, mycobacteria, viruses (eg, hepatitis B, rubella, parvovirus, human T-cell leukemia virus 1)
    • Autoimmune connective tissue diseases (eg, systemic lupus erythematosus, progressive systemic sclerosis, mixed connective tissue disease, Sjögren syndrome, vasculitis, cryoglobulinemias)
    • Other rheumatic diseases (eg, polyarticular gout, seronegative spondyloarthropathy [eg, ankylosing spondylitis, reactive arthritis])
    • Subacute bacterial endocarditis
    • Hemoglobinopathies
    • Angioimmunoblastic lymphadenopathy

    Workup

    Laboratory Studies

    No pathognomonic test is available to help confirm the diagnosis of rheumatoid arthritis (RA); instead, the diagnosis is made using clinical, laboratory, and imaging features.

    • Markers of inflammation, such as ESR and CRP, are associated with disease activity; additionally, the CRP value over time correlates with radiographic progression.
    • Hematologic parameters include a CBC count and synovial fluid analysis.
      • Complete blood cell count
        • Anemia of chronic disease is common and correlates with disease activity; it improves with successful therapy.
        • Hypochromic anemia suggests blood loss, commonly from the GI tract (associated with NSAIDs).
        • Anemia may also be related to disease-modifying antirheumatic drug (DMARD) therapy.
        • Thrombocytosis is common and is also associated with disease activity.
        • Thrombocytopenia may be a rare adverse event of therapy and may occur in patients with Felty syndrome.
        • Leukocytosis may occur but is usually mild.
        • Leukopenia may be a consequence of therapy or a component of Felty syndrome, which may then respond to DMARD therapy.
      • Synovial fluid analysis
        • Inflammatory synovial fluid (WBC count >2000/µL) is present with WBC counts generally from 5,000-50,000/µL.
        • Usually, neutrophil predominance (60-80%) is observed in the synovial fluid (in contrast with mononuclear cell predominance in the synovium).
        • Because of a transport defect, the glucose levels of pleural, pericardial, and synovial fluids in patients with RA are often low compared to serum glucose levels.
    • Immunologic parameters include autoantibodies (eg RF, anti-RA33, anti-CCP, antinuclear antibodies).
      • Rheumatoid factor
        • RF is present in approximately 60-80% of patients with RA over the course of their disease but is present in fewer than 40% of patients with early RA.
        • RF values fluctuate somewhat with disease activity, although high-titered RF generally remains present even in patients with drug-induced remissions.
      • Antinuclear antibodies: These are present in approximately 40% of patients with RA, but test results for antibodies to most nuclear antigen subsets are negative.
      • Newer antibodies (eg, anti-RA33, anti-CCP): Recent studies of anti-CCP antibodies suggest a sensitivity and specificity equal to or better than those of RF, with an increased frequency of positive results in early RA. The presence of both anti-CCP antibodies and RF is highly specific for RA. Additionally, anti-CCP antibodies, as do RF, indicate a worse prognosis.

    Imaging Studies

    • Radiography: Note that erosions may be present in the feet, even in the absence of pain and in the absence of erosions in the hands.
      • Extremities - Hands, wrists, knees, feet, elbows, shoulders, hips, cervical spine
      • Others when indicated
    • MRI: This modality is used primarily in patients with abnormalities of the cervical spine; early recognition of erosions based on MRI images has been sufficiently validated.
    • Ultrasonography: This allows recognition of effusions in joints that are not easily accessible (eg, hip joints, shoulder joints in obese patients) and cysts (Baker cysts). High-resolution sonograms may allow visualization of tendon sheaths, changes and degree of vascularization of the synovial membrane, and even erosions; however, this needs further validation. Ultrasonography may be used as an office-based procedure.
    • Bone scanning: Findings may help to distinguish inflammatory from noninflammatory changes in patients with minimal swelling.
    • Densitometry: Findings are useful for helping diagnose changes in bone mineral density indicative of osteoporosis.

    Other Tests

    • HLA-DR4 (shared epitope) may constitute a helpful marker in early undifferentiated arthritis.

    Procedures

    • Joint aspiration, diagnostic arthroscopy (histology), and biopsies (eg, skin, nerve, fat, rectum, kidney) may be considered if vasculitis or amyloidosis is suggested.

    Histologic Findings

    The lymphoplasmacytic infiltration of the synovium with neovascularization seen in RA is similar to that seen in other conditions characterized by inflammatory synovitis. Early rheumatoid nodules are characterized by small-vessel vasculitis and later by granulomatous inflammation.

    Complications

    • RA itself is not fatal, but complications of the disease may shorten survival by years in some individuals. In general, RA is progressive and cannot be cured; in some, the disease gradually becomes less aggressive and symptoms may even improve. However, if bone and ligament destruction and any deformities have occurred, the effects are permanent.
    • Joint disability and pain with daily life are common. Affected joints can become deformed, and the performance of even ordinary tasks may be very difficult or impossible. According to one survey, 70% of patients with RA believe the disease prevents them from living a fully productive life. In 2000, a study in England found that approximately one third of individuals stop working within 5 years of the onset of disease.
    • RA is a systemic disease that can affect other parts of the body in addition to joints. These effects include the following:
      • Peripheral neuropathy: This condition affects nerves, most often those in the hands and feet. It can result in tingling, numbness, or burning.
      • Anemia
      • Scleritis: This is an inflammation of the blood vessels in the eye that can result in corneal damage, scleromalacia, and, in severe cases of nodular scleritis, perforation.
      • Infections: Patients with RA have a higher risk for infections. The immunosuppressive drugs required for treatment further increase that risk.
      • GI problems: Although patients with RA may experience stomach and intestinal distress, lower rates of stomach and colorectal cancers have been reported among patients with RA.
      • Osteoporosis: Osteoporosis is more common than average in postmenopausal women with RA. The hip is particularly affected. The risk for osteoporosis also appears to be higher than average in men with RA who are older than 60 years.
      • Lung disease: One small study found a very high prevalence of lung disease (pulmonary inflammation and fibrosis) in patients newly diagnosed with RA. However, the association between a history of smoking and a higher risk for RA may at least partially account for this finding. Cigarette smoking, in any case, may increase the severity of the disease.
      • Heart disease: RA can affect the blood vessels and independently increases the risk for coronary ischemic heart disease.
      • Sjögren syndrome: Keratoconjunctivitis sicca is a common complication of RA. Oral sicca and salivary gland enlargement are less common.
      • Felty syndrome: This condition is characterized by the combination of splenomegaly, leukopenia (neutropenia), and recurrent bacterial infections. Felty syndrome sometimes responds to DMARD therapy.
      • Lymphoma and other cancers: Alterations in the immune system associated with RA may play a role in the higher risk for lymphoma observed in patients with RA. Aggressive treatments for RA that suppress the immune system may help prevent this cancer, but more research is needed to evaluate this possibility. Other cancers that may occur with increased frequency in patients with RA include prostate and lung cancers.
      • Macrophage activation syndrome: This is a life-threatening complication of RA and requires immediate treatment with high-dose steroids and cyclosporin A. Patients with RA should be aware of symptoms, which include persistent fever, weakness, drowsiness, and lethargy.
 
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