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Rheumatoid Arthritis

General Information

Description:

  • Systemic inflammatory disease characterized by symmetric, relapsing or chronic, destructive synovitis and sometimes multisystem involvement

Definitions:

  • American College of Rheumatology (ACR) definition of improvement for use in RA trials
    • ACR20 response requires both
      • 20% improvement in tender and swollen joint counts
      • 20% improvement in 3 of 5 remaining ACR core set measures
        • Patient global assessment
        • Physician global assessment
        • Self-reported physical disability
        • An acute phase reactant
        • Patient pain assessment
    • ACR response designations ACR50 and ACR70 require corresponding 50% or 70% improvements in measures
    • Reference - Arthritis Rheum 1998 Sep;41(9):1564

Organs involved:

  • Synovial joints - bilateral, symmetric
    • Small joints of hands (metacarpophalangeal joints and proximal interphalangeal joints) and feet (metatarsophalangeal joint) initially, dominant hand tends to be worse
    • Progresses to wrist, elbows, ankles, knees, shoulder, hip, cervical spine
    • Distal interphalangeal joints and lumbar spine usually spared
  • Skin, eyes, heart, lung may be involved

Who is most affected:

  • Can occur at any age, prevalence increases with age, peak incidence age 30-60 years
  • Women 2.5 times higher prevalence (but extra-articular manifestations more common in men, gender difference less pronounced among rheumatoid factor-positive patients)
RA of the Hand


RA of the HIP

Incidence/Prevalence:

United States:

  • Estimated 1.3 million adults in United States had rheumatoid arthritis in 2005, estimated 0.6% American adults aged > 18 years (Arthritis Rheum 2007 Dec 28;58(1):15)
  • Prevalence of RA 1.07% among adults aged > 35 years in Rochester, Minnesota in 1985 (Arthritis Rheum 1999 Mar;42(3):415 in Arthritis Rheum 2007 Dec 28;58(1):15)
  • Significantly lower incidence of RA in women in western United States compared to Midwest, Mid-Atlantic, and New England states
    • Based on prospective cohort of 83,546 women followed from 1976 to 2004
    • Incidence by geographic region (residence at baseline) per 100,000 person-years
      • 26 in western United States
      • 33 in Midwest states
      • 31.5 in Mid-Atlantic states
      • 35.7 in New England states
      • 30.1 in southeastern states
    • Reference - Arch Intern Med 2008 Aug 11;168(15):1664

United Kingdom:

  • About 12,000 people newly diagnosed with RA each year in United Kingdom
  • Incidence from study in Norfolk 1.5 per 10,000 males and 3.6 per 10,000 females each year

Causes and Risk Factors

Causes:

  • Initial event inciting inflammatory response is unknown, possibly autoimmune
  • Infectious etiology has been vigorously evaluated without yielding convincing evidence
  • Support for genetic predisposition comes from studies that rheumatoid arthritis clusters in families and high concordance of disease in monozygotic twins

Pathogenesis:

  • Earliest changes are injury to synovial microvasculature
    • Initial site of inflammation around blood vessels, immune complexes fix complement, cause damage to endothelial cells
    • Interleukins (IL-1, IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) involved with activation of synoviocytes and inflammatory cells
    • Occlusion of lumen, swelling of endothelial cells, and gaps between endothelial cells documented by electron microscopy
    • Usually associated with mild proliferation of superficial lining cell layer
    • Associated with congestion, edema, and fibrin exudation

  • Cellular infiltration occurs early in disease, mainly T-lymphocytes, mostly CD4 T cells which express cell-surface antigens characteristic of mature memory cells
  • Plasma cells usually found in more advanced stages of inflammation, often with multinucleated giant cells and mast cells
  • Neutrophils are major cellular component of synovial fluid
  • Pannus development
    • Granulation tissue extends to cartilage and known as pannus (thickened synovial membrane)
    • Tissue actively invades and destroys periarticular bone and cartilage
  • Joint destruction involves articular cartilage, ligaments, tendons, and bones
    • Structural damage usually begins from 1 to 2 years after onset of disease; synovitis tends to follow fluctuating pattern, structural damage progresses as linear function of amount of prior synovitis
    • Tissue destruction closely related to production of metalloproteinases and other proteinases, which are able to degrade collagen and proteoglycans
    • Major metalloproteinase-producing cells are synovial fibroblasts and monocytic phagocytes in synovial lining layer
    • Any joint subjected to prolonged immobilization loses motion because of tendon shortening and contraction of articular capsule, pain and stiffness lead to joint immobility
    • Once cartilage is lost, opposing bone surfaces may fuse when immobilized

  • Rheumatoid factor (RF)
    • Major autoantibodies in RA which recognize epitopes on immunoglobulin G Fc fragment, not present in all patients with RA and present in some persons without RA
    • RFs are associated with more severe and extra-articular disease, extra-articular manifestations seen almost exclusively in RF-positive patients
    • RF-producing B cells in RA are polyclonal, using diverse set of immunoglobulin gene segments
    • RF production is T-cell-dependent and influenced by HLA-DRB1 polymorphism
  • Review of cytokine pathways and joint inflammation can be found in N Engl J Med 2001 Mar 22;344(12):907
  • Review of genetic and immunologic mediators of rheumatoid arthritis can be found in J Musculoskel Med 2001 Oct;18(10):459

Likely risk factors:

  • Prediction rule for risk of rheumatoid arthritis in patients with undifferentiated arthritis
    • Prediction score may determine risk of rheumatoid arthritis in patients with undifferentiated arthritis (level 2 [mid-level] evidence)
      • Based on derivation in 570 patients with recent-onset undifferentiated arthritis and small validation cohort (34 patients)
      • Prediction score 0-14 derived from 9 factors
      • Rates of progression to rheumatoid arthritis in derivation cohort ranged from 0% if ≤ 3 points to 100% if ≥ 11 points
      • Rates of progression to rheumatoid arthritis in external validation cohort of 34 patients
        • 6% if score ≤ 6
        • 33% if score 6-8
        • 100% if score ≥ 8
        • results poorly described, scores of 6 and 8 appear to be counted in multiple categories
      • Reference - Arthritis Rheum 2007 Feb;56(2):433, commentary can be found in Evid Based Med 2007 Oct;12(5):154
      • Point-of-Care Guide on predicting rheumatoid arthritis risk in adults with undifferentiated arthritis can be found in Am Fam Physician 2008 May 15;77(10):1451
    • Modified predictive rule (using duration of morning stiffness instead of severity) validated for predicting progression to rheumatoid arthritis in patients with undifferentiated arthritis (level 1 [likely reliable] evidence)
      • Based on revised derivation of predictive rule and validation in 3 independent cohorts
      • Morning stiffness duration not as predictive as severity but used because duration data was available in validation cohorts
      • Prediction score 0-14 derived from 9 factors
        • Age in years x 0.02
        • Female gender - add 1 point
        • Distribution of involved joints - add 0.5 points if small joints of hands and feet, add 0.5 points if symmetric, add 1 point if upper extremities, add 1.5 points if upper and lower extremities
        • Morning stiffness duration - add 1 point if 30-59 minutes, add 2 points if ≥ 60 minutes
        • Number of tender joints - add 0.5 points if 4-10, add 1 point if ≥ 11
        • Number of swollen joints - add 0.5 points if 4-10, add 1 point if ≥ 11
        • C-reactive protein level - add 0.5 points if 5-50 mg/L, add 1.5 points if > 50 mg/L
        • Rheumatoid factor - add 1 point if positive
        • Anticyclic citrullinated peptide (anti-CCP) antibodies - add 2 points if positive
        • Score rounded to nearest integer

      • In derivation cohort of 570 patients
        • 335 of 388 patients (86%) with score ≤ 6 did not have rheumatoid arthritis
        • 86 of 114 patients (75%) with score ≥ 8 had rheumatoid arthritis
        • 60 patients (10.5%) with score 6.5-7.5 were in intermediate range
      • In British validation cohort of 99 patients
        • 54 of 65 patients (83%) with score ≤ 6 did not have rheumatoid arthritis
        • 7 of 7 patients (100%) with score ≥ 8 had rheumatoid arthritis
        • 27 patients (27%) with score 6.5-7.5 were in intermediate range
      • In German validation cohort of 155 patients
        • 78 of 94 patients (83%) with score ≤ 6 did not have rheumatoid arthritis
        • 25 of 27 patients (93%) with score ≥ 8 had rheumatoid arthritis
        • 34 patients (22%) with score 6.5-7.5 were in intermediate range
      • In Dutch validation cohort of 34 patients
        • 18 of 21 patients (86%) with score ≤ 6 did not have rheumatoid arthritis
        • 5 of 5 patients (100%) with score ≥ 8 had rheumatoid arthritis
        • 8 patients (24%) with score 6.5-7.5 were in intermediate range
      • In 3 validation cohorts combined with 288 patients
        • 150 of 180 patients (83%) with score ≤ 6 did not have rheumatoid arthritis
        • 37 of 39 patients (97%) with score ≥ 8 had rheumatoid arthritis
        • 69 patients (24%) with score 6.5-7.5 were in intermediate range
      • Reference - Arthritis Rheum 2008 Aug;58(8):2241

  • Anticyclic citrullinated peptide (anti-CCP) antibody
    • Anti-CCP antibody may predict progression to rheumatoid arthritis
      • Based on small cohort study
      • 61 patients with palindromic rheumatism followed for mean 5.4 years
      • 29 (48%) developed rheumatoid arthritis
      • Anti-CCP antibody had 83% sensitivity, 68% specificity, 71% positive predictive value, 81% negative predictive value, positive likelihood ratio 2.6, and negative likelihood ratio 0.12
      • Rheumatoid factor had 67% sensitivity, 61% specificity, 60% positive predictive value, 61% negative predictive value, positive likelihood ratio 1.7, and negative likelihood ratio 0.54
      • Both (positive anti-CCP antibody and positive rheumatoid factor) had 77% sensitivity, 84% specificity, 81% positive predictive value, 81% negative predictive value, positive likelihood ratio 4.8, and negative likelihood ratio 0.27
      • Reference - J Rheumatol 2006 Jul;33(7):1240, editorial can be found in J Rheumatol 2006 Jul;33(7):1216
    • Lower anti-CCP antibody threshold associated with more sensitive prediction of development of rheumatoid arthritis
      • Based on nested case-control study
      • 93 women with incident RA and 3 matched controls for each case from Nurses' Health Study cohorts were analyzed
      • Association of anti-CCP positivity with rheumatoid arthritis at threshold
        • > 5 units/mL had sensitivity 28% and specificity 100%
        • > 2 units/mL had sensitivity 51% and specificity 80%
      • Reference - J Rheumatol 2009 Apr;36(4):706, editorial can be found in J Rheumatol 2009 Apr;36(4):663
  • Elevated rheumatoid factor associated with increased long-term risk of RA
    • Based on prospective cohort study in Denmark
    • 9,712 white persons aged 20-100 years without rheumatoid arthritis were evaluated for plasma immunoglobulin M (IgM) rheumatoid factor level and followed up to 28 years
    • Plasma IgM rheumatoid factor levels at baseline
      • < 25 units/mL in 95.7%
      • 25-50 units/mL in 1.8%
      • 50.1-100 units/mL in 1.9%
      • > 100 units/mL in 0.6%
    • 1.9% developed RA
    • compared to plasma IgM rheumatoid factor level < 25 units/mL, risk of RA increased with rheumatoid factor level of (p < 0.0001 for trend)
      • 25-50 units/mL (adjusted hazard ratio [HR] 3.6, 95% CI 1.7-7.3)
      • 50.1-100 units/mL (adjusted HR 6, 95% CI 3.4-10)
      • > 100 units/mL (adjusted HR 26, 95% CI 15-46)
    • Reference - BMJ 2012 Sep 6;345:e5244, editorial can be found in BMJ 2012 Sep 6;345:e5841

Possible risk factors:

  • Genetic predisposition
    • Estimated that first-degree relative has 16 times risk over general population
    • Twin studies have reported inconsistent results
      • Monozygotic twin concordance rate ranged from 10% to 18% depending on how RA cases were ascertained (J Rheumatol 1994 Aug;21(8):1420)
      • 15.4% monozygotic twin concordance rate was 4.3 times higher than 3.6% dizygotic twin concordance rate in United Kingdom nationwide study of 91 monozygotic and 112 dizygotic pairs; 30% monozygotic twin concordance rate quoted from a study about 30 years prior was not reproduced (Br J Rheumatol 1993 Oct;32(10):903)
      • ZERO monozygotic twin concordance rate in questionnaire study of 37,338 Danish twins with 85% response rate (BMJ 2002 Feb 2;324(7332):264), commentary can be found in BMJ 2002 May 4;324(7345):1100, BMJ 2002 Aug 17;325(7360):391
      • Interpretation of twin studies may be limited by 89% false-positive rate for self-reported diagnosis of RA (Ann Rheum Dis 1992 May;51(5):588)
    • Human leukocyte antigen (HLA) genes and gender may constitute about 30% genetic risk of RA
    • Disease-associated HLA genes modify disease expression
      • Rheumatoid arthritis associated with major histocompatibility complex (MHC) II HLA-DR4 and HLA-DR1 (hypervariable section for Ag binding - shared epitopes, associated with severe form)
      • Disease-associated HLA-DRB1 alleles determine disease progression and severity
      • Patients with extra-articular manifestations have strongest HLA-DRB1 association and often express 2 disease-associated HLA-DRB1*04 alleles
      • HLA-DRB1 alleles not associated with progression from undifferentiated arthritis to rheumatoid arthritis after adjusting for anticyclic citrullinated peptide antibodies in cohort of 570 patients (Arthritis Rheum 2006 Mar 29;54(4):1117)
    • review of genetics of rheumatoid arthritis can be found in Mayo Clin Proc 2006 Jan;81(1):94
  • Elevated soluble tumor necrosis factor receptor II (sTNFRII) inflammatory biomarker associated with increased likelihood of subsequent development of rheumatoid arthritis
    • Based on nested case-control study of 2 prospective cohorts of women (Women's Health Study and Nurses' Health Study)
    • Blood samples obtained prior to symptom onset in women later diagnosed with rheumatoid arthritis (170 incident cases) compared with blood samples of 510 matched controls
    • Mean time from blood collection to rheumatoid arthritis symptom onset 5.2 years (range 0.3-12 years)
    • sTNFRII levels significantly higher in preclinical rheumatoid arthritis cases compared with controls in pooled analysis of cohorts (relative risk 2, p = 0.004)
    • Reference - Arthritis Rheum 2009 Mar;60(3):641

  • Coffee consumption
    • Coffee consumption may be associated with increased risk for rheumatoid factor (RF)-positive rheumatoid arthritis; cross-sectional study of 6,809 subjects without arthritis; number of cups of coffee drunk daily associated with risk for RF positivity; prospective cohort study of 18,981 subjects without arthritis followed for 13 to 16 years, 126 developed rheumatoid arthritis of whom 89 had positive RF, drinking ≥ 4 cups of coffee daily associated with 2.2 times risk (95% CI 1.13-4.27) for RF-positive rheumatoid arthritis but did not predict RF-negative rheumatoid arthritis (Ann Rheum Dis 2000 Aug;59(8):631)

    • Decaffeinated coffee consumption but not caffeinated coffee or tea associated with increased risk in another study; 31,366 women aged 55-69 years followed for 11 years, 158 developed rheumatoid arthritis, subjects drinking > 3 cups of decaffeinated coffee per day had increased risk (relative risk [RR] 2.58) and subjects drinking > 3 cups of tea per day had decreased risk (RR 0.24), no association with caffeinated coffee or daily caffeine intake (Arthritis Rheum 2002 Jan;46(1):83)
  • Smoking associated with increased risk of rheumatoid arthritis, especially in rheumatoid factor-positive men and heavy smokers
    • Based on systematic review
    • Systematic review of 16 observational studies evaluating association between smoking history and risk of developing rheumatoid arthritis
    • Significantly increased risk of rheumatoid arthritis in
      • Male smokers
        • Ever (odds ratio [OR] 1.89)
        • Current (OR 1.87, 95% CI 1.49-2.34)
        • Past (OR 1.76, 95% CI 1.33-2.31)
      • Rheumatoid factor-positive males
        • Ever (OR 3.02, 95% CI 2.35-3.88)
        • Current (OR 3.91, 95% CI 2.78-5.5)
        • Past (OR 2.46, 95% CI 1.74-3.47)
      • Males with ≥ 20 pack-year history smoking (OR 2.31, 95% CI 1.55-3.41)
      • Female smokers
        • Ever (OR 1.27, 95% CI 1.12-1.44)
        • Current (OR 1.31, 95% CI 1.12-1.54)
        • Past (OR 1.22, 95% CI 1.06-1.4)
      • females with ≥ 20 pack-year history smoking (OR 1.75, 95% CI 1.52-2.02)
    • Reference - Ann Rheum Dis 2010 Jan;69(1):70
  • Low vitamin D intake associated with increased risk of RA; cohort of 29,368 women aged 55-69 years followed for 11 years, 152 developed RA; intake of vitamin D (food and supplement) inversely related to development of RA (Arthritis Rheum 2004 Jan;50(1):72)

Factors not associated with increased risk:

  • No evidence supporting association of silicone breast implants and any connective tissue disorders in meta-analysis of 20 studies (N Engl J Med 2000 Mar 16;342(11):781), commentary can be found in ACP J Club 2000 Nov-Dec;133(3):118
  • Association with interferon-gamma gene polymorphism implicated in 1 study but not found in 3 subsequent studies
    • HLA-DR microsatellite polymorphism within first intron of interferon-gamma gene with 126 base-pair allele found in 44 (73%) of 60 patients with severe rheumatoid arthritis, compared with 8 (21%) of 39 with mild rheumatoid arthritis (odds ratio [OR] 10.66, 95% CI 4.1-24.9) and with 8 (12%) of 65 normal controls (OR 19.59, 95% CI 7.7-49.9) (Lancet 2000 Sep 2;356(9232):820)

    • This finding NOT confirmed in study of 93 patients with early rheumatoid arthritis and 128 controls (Lancet 2001 Jul 14;358(9276):122
    • Interferon-gamma receptor 1 polymorphisms NOT associated with rheumatoid arthritis in case-control study with 364 Europeans (Arthritis Research & Therapy 2006 Mar 23;8(3)
  • C-reactive protein levels NOT associated with risk of incident rheumatoid arthritis
    • Based on prospective cohort of 27,939 women followed mean 9.9 years
    • 398 developed rheumatoid arthritis
    • Reference - Arch Intern Med 2006 Dec 11;166(22):2490, commentary can be found in Arch Intern Med 2007 Jul 23;167(14):1552

  • Long-term breastfeeding might be associated with reduced risk for rheumatoid arthritis in mother
    • Based on case-control study
    • 136 women with rheumatoid arthritis were matched to 544 controls without rheumatoid arthritis
    • Lifestyle factors evaluated via self-administered questionnaire
    • Breastfeeding for ≥ 13 months was associated with reduced risk (OR 0.46, 95% CI 0.24-0.91) compared to never breastfeeding
    • Reference - Ann Rheum Dis 2009 Apr;68(4):526
  • Lower incidence of rheumatoid arthritis in people with schizophrenia (Acta Psychiatr Scand 2007 Nov;116(5):317)

 

Complications and Associated Conditions

Complications:

  • General joint manifestations
    • Joint destruction
    • Deformities
      • Boutonniere - flexed proximal interphalangeal (PIP) joints and hyperextended distal interphalangeal (DIP) joints, considerable damage from PIP synovitis
      • Swan-neck - hyperextended PIP and flexed DIP, metacarpophalangeal (MCP) joint inflammation stimulates spasm in hand's intrinsic muscles
      • Grasshopper thumb - hyperextended
      • Ulnar deviation at MCP joints
    • Ankylosis (fibrosis and bony obliteration leading to fused joint)
    • Tendon rupture
  • Manifestations in specific joints
    • Cervical spine involvement
      • Atlantoaxial subluxation or subaxial subluxation
        • Tenosynovitis of transverse ligament of C1 may produce C1-C2 instability (atlantoaxial subluxation)
        • Subluxation of C4-C5 or C5-C6 may also occur due to apophyseal joint destruction (subaxial subluxation)
        • 28.6% of patients with rheumatoid arthritis may have cervical spine involvement
          • Based on cohort of 1,120 Korean patients with rheumatoid arthritis and neck pain
          • 28.6% had cervical spine involvement (of whom 90% had atlantoaxial subluxation and 15% had subaxial subluxation)
          • Risk factors for cervical spine involvement were erosion in hand or foot radiographs and RA diagnosis before age 45 years
          • Reference - Rheumatol Int 2011 Oct;31(10):1363
        • Prevalence of cervical spine instabilities increased from 47.6% to 70.4% over 5-year follow-up of 267 patients with RA in Japan (Spine (Phila Pa 1976) 2011 Apr 15;36(8):647)
        • 12% prevalence of atlantoaxial subluxation in 1 cohort, associated with erosive disease on x-ray
          • Based on cohort of 736 patients with RA and available cervical radiographs
          • 88 (12%) had anterior atlantoaxial subluxation
          • Atlantoaxial subluxation associated with disease onset before age 50 years, number of prior disease-modifying antirheumatic drugs (DMARDs), and Larsen score > 50
          • No significant association with rheumatoid factor
          • Reference - Clin Exp Rheumatol 2004 Jul-Aug;22(4):427
        • Lateral neck x-rays in flexion and extension needed to demonstrate instability

      • Cervical myelopathy
        • May develop from spinal cord or nerve compression due to erosion of odontoid process, ligament laxity, or ligament rupture
        • Symptoms typically gradual in onset
        • Bilateral sensory paresthesias of hands and motor weakness over weeks to months
        • Often unrelated to neck pain
        • Lhermitte sign is sudden development of tingling paresthesias that descend thoracolumbar spine as cervical spine is flexed
        • Physical exam may show Babinski sign, Hoffmann sign, hyperactive deep-tendon reflexes
        • Magnetic resonance imaging or computed tomography (CT) can document spinal cord compression
      • Neck pain without neurologic features usually improves, even if radiographic evidence of joint destruction
      • Review of cervical spine complications in RA can be found in Postgrad Med 2000 Jan;107(1):199
    • Adhesive capsulitis (frozen shoulder) can develop rapidly
    • Ulnar nerve compression at elbow (cubital tunnel syndrome)

    • Wrist and hand
      • Carpal tunnel syndrome
      • Guyon canal syndrome (ulnar nerve compression at wrist)
      • Tendon rupture
        • Inflammatory tenosynovitis may erode through tendon, most common in extensor muscle of interphalangeal joint of thumb
        • Attrition rupture of extensor tendons in third, fourth, and fifth fingers occurs with abrasion over ulnar styloid
        • tendon ruptures present with abrupt, usually painless, loss of specific active motion without affecting passive range of motion
    • popliteal cyst in knee
    • tarsal tunnel syndrome (compression neuritis of posterior tibial nerve) produces burning paresthesias of sole of foot, worsened with standing or walking
  • extra-articular manifestations (see also under Associated Conditions below)
    • rheumatoid nodules
      • develop in up to 50% RA patients
      • almost all patients with rheumatoid nodules are rheumatoid factor (RF)-positive
      • Tend to develop in crops during active phases of disease
      • Occur most commonly subcutaneously, in bursae and along tendon sheaths, but may occur in viscera or in any region
      • Typically located over pressure points
        • Extensor surface of forearm
        • Achilles tendon
        • Ischial area
        • Over metatarsophalangeal (MTP) joint
        • Flexor surface of fingers
      • Methotrexate may accelerate development of rheumatoid nodules
      • Rheumatoid nodules of cervix and vagina in case report (Obstet Gynecol 2010 Aug;116 Suppl 2:501)
    • Dermal vasculitis
      • Most commonly leukocytoclastic vasculitis and palpable purpura (see Hypersensitivity angiitis), not generally associated with systemic vasculitis
      • Ischemic ulcers often occur with systemic involvement
      • Treatment of malignant rheumatoid arthritis (which includes rheumatoid arthritis associated with rheumatoid vasculitis) may include antirheumatic drugs, glucocorticoid, immunosuppressants, D-penicillamine, plasmapheresis, anticoagulants, and biological drugs (Circ J 2011;75(2):474)
      • Evidence for treatment of cutaneous vasculitis in rheumatoid arthritis appears limited to case reports and case series
        • Sulfasalazine reported to be effective in 2 cases of cutaneous rheumatoid vasculitis (Int J Dermatol 1979 Jun;18(5):394)
        • minocycline 100 mg twice daily plus prednisone 5 mg once daily maintained control of rheumatoid-associated leukocytoclastic vasculitis in case report (Arch Dermatol 1997 Jan;133(1):15)
        • topical nerve growth factor appeared effective for chronic vasculitic ulcers in uncontrolled trial of patients with rheumatoid arthritis (Lancet 2000 Nov 18;356(9243):1739

    • Ocular manifestations
      • keratoconjunctivitis sicca with associated Sjogren syndrome
      • episodes of episcleritis common, usually benign and self-limited
      • scleritis has worse prognosis, inflammation may erode through sclera into choroid causing scleromalacia perforans
      • review of ocular manifestations of rheumatoid arthritis can be found in J Musculoskel Med 2002 Dec;19(12):508
      • review of ocular manifestations of autoimmune disease can be found in Am Fam Physician 2002 Sep 15;66(6):991
    • Tespiratory manifestations
      • inflammation of cricoarytenoid joint
        • symptoms usually episodic with laryngeal pain, hoarseness, dysphonia, occasionally odynophagia
        • laryngeal obstruction rare but may occur after extubation for endotracheal anesthesia
      • interstitial lung disease
        • present histologically in most patients, but may be asymptomatic
        • mortality from pulmonary disease in RA twice that for general population
        • interstitial fibrosis tends toward basal involvement and nodules in lung parenchyma
        • rarely subpleural nodule may rupture leading to bronchopleural fistula, which may progress to pneumothorax or empyema
        • RA associated with increased risk of interstitial lung disease
          • based on case-control study of 582 patients with RA followed for mean 16.4 years and 603 matched healthy controls followed for mean 19.3 years
          • lifetime risk of developing interstitial lung disease 7.7% for RA patients vs. 0.9% for controls (hazard ratio [HR] 8.96, 95% CI 4.02-19.94)
          • RA with interstitial lung disease associated with increased risk of death compared to RA without interstitial lung disease (HR 2.86, 95% CI 1.98-4.12)
          • risk factors for interstitial lung disease in patients with RA
            • older age at time of disease onset
            • male sex
            • severe RA
          • Reference - Arthritis Rheum 2010 Jun;62(6):1583
        • interstitial lung disease has been reported following use of DMARDs, including both biologic and nonbiologic DMARDs
      • Bronchiolitis obliterans
      • Pleural inflammation (pleuritis)
        • typical symptoms of pleurisy usually self-limited
        • small pleural effusions may be noted incidentally on chest x-ray
        • pleural fluid has markedly low glucose and white blood cell count usually < 5000/mm3
        • case presentation of rheumatoid pleuritis can be found in N Engl J Med 2002 Mar 14;346(11):843
    • Cardiac manifestations
      • echocardiography shows pericardial abnormality in almost 50% RA patients who have no symptoms of cardiac involvement
      • symptomatic pericarditis rare
        • usually during generalized disease flare
        • pericardial effusions are exudative with increased protein and decreased glucose
        • occasionally may progress to chronic constrictive pericarditis
        • case presentation of rheumatoid pericarditis can be found in N Engl J Med 2003 Jan 16;348(3):243
      • Inflammatory lesions may develop on myocardium and valve leaflets and may cause valvular dysfunction, embolism, conduction defects, cardiomyopathy
      • Aortitis has been described and may lead to aortic insufficiency related to dilation of aortic root or aneurysmal rupture
    • Neurologic manifestations
      • cervical myelopathy described above
      • peripheral nerve entrapment (compression neuropathy)
        • carpal tunnel syndrome
        • ulnar nerve compression at wrist or elbow
        • posterior interosseous nerve in antecubital fossa
        • femoral nerve anterior to hip joint
        • peroneal nerve adjacent to fibular head
        • interdigital nerve at MTP joint
    • RA associated with increased risk for myocardial infarction
      • Based on cohort study
      • 4.3 million persons ≥ 16 years old from Danish health registries were followed for 10 years
      • 10,477 developed RA, of these 265 had myocardial infarction
      • RA associated with increased risk for myocardial infarction
        • incidence rate ratio (IRR) 1.7 (95% CI 1.5-1.9) overall
        • IRR 2 (95% CI 1.9-2.1) for women
        • IRR 1.5 (95% CI 1.5-1.6) for men
      • Reference - Ann Rheum Dis 2011 Jun;70(6):929, editorial can be found at Ann Rheum Dis 2011 Jun;70(6):881
    • Rheumatoid arthritis associated with increased cardiovascular mortality, especially if parental history of cardiovascular death
      • cohort of 10,805 Swedish patients aged 16-67 years with rheumatoid arthritis followed for 10 years
      • standardized mortality ratio (relative risk of death compared to general population) for cardiovascular death was
        • 1.7 (95% CI 1.2-2.3) for rheumatoid patients without parental history of cardiovascular death
        • 2.9 (95% CI 2.5-3.4) for rheumatoid patients with parental history of cardiovascular death
      • Reference - Ann Rheum Dis 2006 Jun;65(6):741
    • inflammatory polyarthritis associated with increased cardiovascular mortality
      • based on cohort of 1,098 patients diagnosed with inflammatory polyarthritis from 1990 to 1994 and followed for median 11.4 years
      • standardized mortality ratios for cardiovascular death for patients compared to general population
        • 1.25 (95% CI 1.01-1.54) overall
        • 1.19 (95% CI 0.83-1.65) at 5 years
        • 1.2 (95% CI 0.95-1.5) at 10 years
        • 2 (95% CI 1.41-2.74) in RF-positive patients overall
        • 1.93 (95% CI 1.08-3.19) in RF-positive patients at 5 years
        • 2 (95% CI 1.37-2.8) in RF-positive patients at 10 years
      • Reference - Arthritis Rheum 2008 Apr;58(4):985
    • Rheumatoid arthritis associated with increased mortality in patients with heart failure within first year of heart failure diagnosis
      • based on prospective case-control study
      • 103 patients with rheumatoid arthritis and heart failure were compared to 852 patients with heart failure without rheumatoid arthritis
      • comparing heart failure patients with and without rheumatoid arthritis
        • 30-day mortality after heart failure diagnosis 15.5% vs. 6.5% (p = 0.001)
        • 1-year mortality after heart failure diagnosis 35% vs. 19.3% (p = 0.01)
      • no difference in overall survival if patient survived > 1 year after heart failure diagnosis
      • fewer typical signs and symptoms in patients with rheumatoid arthritis
        • paroxysmal nocturnal dyspnea (odds ratio [OR] 0.62)
        • hepatojugular reflux (OR 0.5)
        • dyspnea on exertion (OR 0.64)
        • orthopnea (OR 0.53)
      • Reference - Arthritis Rheum 2008 Sep;58(9):2603