Rheumatoid Arthritis (RA)


  • History: RA was first recognized as a multisystem disease back in 1860
  • Sex: M:F ratio is 1:2 to 1:4
  • Age of Onset: peak incidence between 5-60 y/o
    • Incidence increases into 60’s
  • Incidence: 0.2-3 per 1000 person-yrs (<0.5 per 1000 person-yrs in most studies)
  • Prevalence: similar worldwide
  • Associated with: Sarcoidosis (weak association)
  • Genetics
    • Familial association of RA and intestitial lung disease suggests genetic factors play a role in rheumatoid intestitial lung disease
    • Association between RA and HLA-DRB1
  • Hormonal Factors: may play a role, as their is a female preponderance of RA and RA has a decreased incidence during pregnancy
  • Infections and Socioeconomic Status: do not appear to play a role in incidence of RA
  • Smoking: in presence of HLA-DR suceptibility gennes, smoking is associated with the development of anti-citrulline-positive RA


  • Probably results from immunologic response to unknown antigen in genetically susceptible host
  • Alveolar macrophage dysfunction (increased release of superoxide anion, fibronectin, and neutrophil chemotactic factor, even without clinical ILD/ increased production of TNF-alpha in patients with and without ILD) precedes neutrophil and lymphocyte recruitment (suggested by BAL findings)/T-cell abnormality (may be marker of disease activity and predict progression to ILD)
  • Increased neutrophils and neutrophil type 1 collagenase: in patients with ILD
  • Rheumatoid Vasculitis: hypersensitivity (leukocytoclastic) vasculitis, mostly involving the post-capillary venules within superficial dermis
    • Probably due to immune complex deposition



  • Anemia (iron deficiency): usually present
  • Leukocytosis:

Skin Bx

  • Diagnostic


  • Rheumatoid Factor: targets IgG
    • Seropositivity is more frequent with pulmonary rheumatoid nodules
    • Presence of RF positivity does not predict development of RA-associated ILD
  • ANA: increased in cases that develop more severe pulmonary disease
  • Cryoglobulins: increased in cases that develop more severe pulmonary disease
  • Anti-DNA:
  • C3/C4/CH50:
  • ANCA:
  • Anti-GBM: negative
  • Anti-Histone: targets histone proteins
    • Positive in 5% of rheumatoid vasculitis cases


  • Usually elevated

Clinical Criteria (American Rheumatism Association)

(patient must have at least 4 of the following criteria for minimum duration of 6 wks)

  • Morning Stiffness: lasting at least 1 hr
  • Arthritis of 3 or More Joints (see [[Arthritis]]): soft tissue swelling or fluid of at least 3 joints from PIP, MCP, wrist, elbow, knee, ankle, or MTP
  • Arthritis of Hand Joints (see [[Arthritis]]): soft tissue swelling or fluid of at least 1 joint from wrist, MCP, or PIP
  • Symmetrical Arthritis (see [[Arthritis]]): simultaneous arthritis on both sides of body
  • Rheumatoid Nodules
  • Positive Serum Rheumatoid Factor: at a titer that <5% of normals are positive
  • Radiographic Hand or Wrist Changes Typical of Rheumatoid Arthritis

Lung Manifestations of RA

Interstitial Lung Disease (see [[ILD-Etiology]])

  • Epidemiology
    • M:F ratio = 3:1
    • CT-diagnosed fibrosis is found in as many as 1-19% of RA patients
      • Fibrosis may be seen on biopsy in as many as 60% of RA patients
      • Decreased DLCO may be seen in as many as 40% of RA patients
    • Risk Factors for Development of Interstitial Lung Disease in RA: smoking, high titer of rheumatoid factor, presence of rheumatoid nodules
  • Time of Onset
    • Interstitial pulmonary fibrosis and arthritis usually begin within 5 yrs of each other (but their severities are not correlated)
    • Interstitial lung disease symptoms usually follow arthritis onset (however, in 20% of cases, ILD precedes arthritis)
  • Diagnosis
    • ABG: elevated A-a gradient hypoxemia, Hypo- or normocapnia
    • CT/HRCT: lower-lobe predominance of reticular or reticulonodular infiltrates (pattern mimics that of Idiopathic Pulmonary Fibrosis
      • Ground-glass infiltrates: likely reflects inflammatory histology in these regions
      • Interstitial infiltrates may follow recurrent Diffuse Alveolar Hemorrhage episodes, as well
      • Occasional: patchy or focal alveolar infiltrates
      • Honeycombing may be seen late in course (radiographic honeycombing correlates well with pathologic honeycombing)
    • PFT’s: restriction, deceased DLCO, decreased compliance
      • PFT’s do not necessarily correlate with radiographic or biopsy findings
      • However, smoking is actually the most common cause of any PFT abnormality observed in RA patients
    • Exercise Testing: exercise-associated desaturation
    • FOB
      • Increased BAL inflammatory cells (increased macrophages and neutrophils) may be seen in cases without other clinical evidence of interstitial lung disease
        • However, note that BAL macrophages and eosinophils are increased in smokers (take this into account in analysis)
      • BAL histamine level: increased (especially in those with active lung disease)
      • BAL procollagen peptide and collagenase activity: increased in patients with established interstitial lung disease (greater than that in early disease)
      • BAL superoxide anion: correlates with percentage of neutrophils in BAL
      • BAL ratio of local immune complex: albumin: increased in cases with established interstitial lung disease
    • OLB: resembles that of idiopathic pulmonary fibrosis with usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) patterns
      • Early: lymphocytic intersitial infiltrate, peribronchiolar follicles with aggregates of lymphocytes with germinal center
      • Late: fibrosis with cystic changes and honeycombing
  • Clinical Features (resembles idiopathic pulmonary fibrosis)
    • Dyspnea and Dry Cough: may precede CXR abnormalities
    • Chest Pain/Fever/Hemoptysis: less common
    • Tachypnea:
    • Bibasilar Crackles:
    • Clubbing (75% of cases, more common than in other connective tissue disease-associated ILD cases): however, full hypertrophic osteoarthropathy is rare
  • Treatment: gnerally aimed at preventing progression of interstitial lung disease
  • Prognosis
    • Average survival of RA after development of interstitial lung disease: 3.5-4.9 years (however, course is variable)
    • 5-Yr Survival in Presence of Severe Interstitial Disease Requiring Hositalization: <50%
    • UIP pattern is associated with better outcome in association with connective tissue disease than it is in idiopathic pulmonary fibrosis
    • Best Predictor of Decline: DLCO <55% pred at time of presentation

Cryptogenic Organizing Pneumonia (COP) (see [[Cryptogenic Organizing Pneumonia]])

  • Epidemiology: COP is more common in RA than in most other connective tissue diseases (with the exception of polydermatomyositis)
  • Diagnosis
    • CXR/Chest: alveolar and ground-glass infiltrates (predominantly sublpleural, but may be bronchovascular), <1 cm nodules (common)
    • OLB: plugs of granulation tissue in air spaces distal to and including terminal bronchioles, lymphocytic infiltration, preserved bronchiolar walls and interstitium
  • Clinical Presentation: pneumonia-like presentation with multifocal consolidation (with restrictive PFT’s)
  • Treatment: most cases respond to steroid therapy
  • Prognosis: RA-associated COP has better prognosis than RA-associated BO

Lymphocytic Intersitial Pneumonia (see [[Lymphocytic Interstitial Pneumonia]])

  • Occasionaly found in OLB specimens in RA
  • Variable response to steroid therapy

Acute Lung Injury-ARDS (see [[Acute Lung Injury-ARDS]])

  • Diagnosis
    • HRCT: diffuse ground-glass infiltrates and/or consolidation, reticular infiltrates, honeycombing (mimics accelerated idiopathic pulmonary fibrosis)
    • OLB: diffuse alveolar damage
  • Clinical: acute respiratory deterioration
    • May occur as the initial presentation of the disease (without pre-existing lung manifestations)
  • Treatment and Prognosis: most cases die within months, despite steroid therapy
    • Case reports describe treatment with cyclosporin A + either prednisolone or cyclophosphamide

Rheumatoid Pleural Effusion (see [[Pleural Effusion-Exudate]])

  • Epidemiology
    • Prevalence
      • 38-73% of all RA cases have pleural involvement by autopsy
      • 20% of all RA cases have history of pleuritic chest pain
      • Only 5% of all RA cases develop pleural effusion
    • Sex Predominance: M:F = 4:1
      • Rheumatoid pleuritis is present in >10% of males with RA
      • Only 2% of females with RA develop pleural effusion
    • Typically occurs in male patient with high RF, rheumatoid nodules, and moderate-severe arthritis about 5-10 years after disease onset
    • Time of Onset: pleural disease may precede onset of arthritis in few cases or may occur >20 yrs after
      • However, there are case reports of rheumatoid pleural effusion in the absence of arthritis
  • Diagnosis
    • CXR/Chest CT Pattern
      • Effusion usually occurs with otherwise normal CXR (with normal cardiac size)
        • However, clinical rheumatoid pleuritis accompanies pulmonary fibrosis in 20% of cases
      • Size of Effusion: typically small-moderate
      • Side of Effusion: 75% are unilateral, 25% are bilateral
    • Thoracentesis
      • Appearance: serous, turbid, or yellow-green/may have debris
      • pH: decreased (usually <7.2), due to impaired transfer of acidic anerobic metabolites across the inflammed pleura
      • Exudate: LDH usually >700-1000 U/L and total protein usually >35 g/L
      • Glucose <30 mg/dL (in 70-80% of cases)
        • Glucose may be normal early in course: due to selectively impaired glucose transport from blood into the pleural space
      • Cell Count/Diff: few hundred to 15k nucleated cells (PMN-predominant early -> may develop into lymphocyte-predominant later)
        • Macrophages, spindle-shaped cells, granular debris, and multi-nucleated giant cells are seen (epithelioid cells are similar to those seen in rheumatoid synovitis and are specific for rheumatoid pleuritis)
      • Mesothelial cells are usually absent (due to rheumatoid process replacing the mesothelium)
      • Gram Stain/Culture: negative (important to distinguish this from complicated parapneumonic effusion)
      • Empyema (predisposed by BPF due to necrotic necrobiotic nodule) may occur also
      • Pleural Immune Complexes: increased when compared to serum
      • Pleural Fluid RF: positive (at >1:320), usually higher than serum titer
        • However, this is not specific for rheumatoid pleural effusion
      • Pleural C4: decreased (<0.03 g/L), as compared to serum
      • In contrast, TB and malignant effusions have 10-fold higher C4 levels
      • Cholesterol: elevated >55-60 mg/dL (seen in all exudates, but may be especially high with crystals in RA pleuritis)
      • Pleural: Serum Cholesterol Ratio: elevated (seen in all exudates)
  • Clinical
    • Symptomatic: dyspnea, pleuritic chest pain, absence of fever
    • Asymptomatic (seen in some cases):
  • Prognosis: may progress to pleural thickening and trapped lung in some cases

Rheumatoid Pseudochylothorax (see [[Pleural Effusion-Pseudochylothorax]])

  • Thoracentesis: usually thick, opalescent, whitish or coffee-colored (due to high fat content)

Rheumatoid (Necrobiotic) Nodules (see [[Lung Nodule or Mass]])

  • Epidemiology
    • Present in <1% of all RA cases
    • Specific for RA
    • Nodules typically wax and wane in concert with subcutaneous nodules and systemic disease activity -> nodules may become thin-wallled and disappear with remission of RA
      • However, nodules may precede the onset of arthritis in some cases
  • Diagnosis
    • CXR/Chest CT Features of Nodules
      • Shape: usually well-circumscribed (3 mm-7 cm)
      • Location: usually basilar and sublpleural-predominant
      • Number: multiple >> single nodules
      • Cavitation: common (with thick wall and smooth inner lining)
      • Calcification: only occurs in Caplan’s syndrome-type nodules
  • Clinical Presentations
    • Nodules may be asymptomatic
    • Nodules may rupture into pleural space, causing pneumothorax
    • Nodules may cavitate, causing hemoptysis
    • Diffuse infiltration by numerous small nodules may result in respiratory failure
    • Caplan’s Syndrome (rheumatoid nodules in setting of inhaled coal dust exposure in [[Coal Workers Pneumoconiosis]]): rapidly appearing in crops, cavitate, typically 0.5-5.0 cm, may calcify

Bronchiolitis Obliterans (BO) (see [[Bronchiolitis Obliterans]])

  • Epidemiology
    • Increased prevalence of HLA B40 and DR1 in RA-related BO cases (but not in non-RA-related cases)
    • Risk Factors: presence of co-existent Sjogrens syndrome, use of penicillamine
      • Gold therapy is not associated with an increased risk of RA-associated BO
  • Diagnosis
    • CXR: usually normal
    • Chest CT: may demonstrate mosaic perfusion (patchy areas of decreased lung density) -> reflects hypoxic vasoconstriction in areas of BO
    • PFT’s: obstruction
    • ABG: moderate hypoxemia with respiratory alkalosis
    • OLB: inflammatory exudate -> destruction of bronchiolar wall by granulation tissues and effacement of bronchiolar lumen -> replacement of bronchiole by fibrous tissue
  • Clinical Features
    • Abrupt Onset of Dyspnea + Dry Cough: typical presentation in middle-aged female with positive RF
    • Inspiratory Rales:
    • Mid-Inspiratory Squeak:
  • Treatment: poor steroid-response
  • Prognosis: generally poor, but some patients have an indolent course

Follicular Bronchiolitis (see [[Follicular Bronchiolitis]])

  • Epidemiology: follicular bronchiolitis is more commonly associated with RA than with other connetcive tissue diseases
  • Diagnosis
    • CXR: reticular or reticulonodular infiltrates
    • Chest CT: centrilobular or peribronchial nodules with patchy bronchocentric ground-glass infiltrates
    • PFT’s: restrictive or obstructive
    • OLB: external compression of brochioles by hyperplastic lymphoid follicles, variable lymphocytic infiltration of bronchiolar wall
  • Clinical: similar presentation to that of interstitial pulmonary fibrosis
  • Treatment: steroids
  • Prognosis: better response than with BO

Bronchiectasis (see [[Bronchiectasis]])

  • Epidemiology
    • More common in RA than in other connective tissue diseases
    • In one case series, respiratory symptoms preceded systemic manifestations in 90% of cases
  • Diagnosis: bronchiectasis was found on CT in 30% of RA cases with normal CXR’s
  • Clinical: usually clinically silent
  • Prognosis: less progressive course than with bronchiectasis from other causes

Apical Fibrobullous Disease (see [[Cystic-Cavitary Lung Lesions]])

  • Mimics that seen in ankylosing spondylitis
  • Reported in RF-positive cases
  • Sometimes precedes the onset of arthritis (without HLA-B27)
  • May follow a fulminant course in some cases

Pulmonary Infection

  • RA increases the risk of pulmonary infection (even without immunosuppressive treatment) -> infection is the cause of death in 15-20% of RA cases
  • Bacterial Pneumonia (see [[Pneumonia]])
  • Tuberculosis (see [[Tuberculosis]])

Empyema (see [[Pleural Effusion-Parapneumonic]])

  • Likely increased risk in RA

Diffuse Alveolar Hemorrhage (see [[Diffuse Alveolar Hemorrhage]] and [[Pulmonary Vasculitis]])

  • Epidemiology
    • Pulmonary vasculitis is rare in RA (although may be occasionally seen on autopsy)
    • Most cases of pulmonary vasculitis are associated with co-existing systemic vasculitis (although a few cases have been reported with isolated pulmonary vasculitis)
  • Diagnosis
    • OLB: pulmonary capillaritis (however, pulmonary angiitis was found in only 40% of specimens from patients with diffuse alveolar hemorrhage)

Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

  • Incidence of pulmonary hypertension increases with time from diagnosis
  • Histologic changes include vascular medial hypertrophy with intimal fibrosis (resembles [[Idiopathic Pulmonary Arterial Hypertension]])

Secondary Pulmonary Hypertension Due to RA-Associated Interstitial Pulmonary Fibrosis

  • In the presence of advanced ILD

Thoracic Cage Immobility

  • Contributing factors include fibrothorax, pleural involvement, myopathy, and increased thoracic rigidity

Lung Cancer (see [[Lung Cancer]])

  • Increased risk in RA


  • Cases have been reported

Drug-Induced Induction or Exacerbation of Rhematoid Arthritis-Associated Lung Disease

  • Etanercept: may accelerate progression of rheumatoid pulmonary nodules
  • Etanercept/Infliximab: can worsen pre-existing RA-associated interstitial lung disease
  • Methorexate: pneumonitis can be precipitated by addition of infliximab
  • Leflunomide: may induce rheumatoid pulmonary nodules

Upper Airway Manifestations of RA

Atlantoaxial Subluxation (C1-C2 Instability)

  • May pose difficulties during endotracheal intubation -> spinal cord injury or cerebral artery impingement
  • Screen for with C-spine films prior to endotracheal intubation

TMJ Dysfunction

  • TMJ is affected in 0.3-70% of all RA cases
  • Manifested by dull deep TMJ pain, limited ability to open the mouth, tenderness to palpation, crepitation, and anterior openbite
  • May result in inability to open jaw during endotracheal intubation

Cricoarytenoid Arthritis

  • Occurs in 25% of RA cases (especially common in advanced RA)
  • Sex-Predominance: more common and more severe in female cases
  • Clinical Features:
    • Globus Sensation/Sore Throat:
    • Hoarseness:
    • Exertional Dyspnea:
    • Otalgia:
    • Nocturnal or Daytime Stridor:
    • Dysphagia/Odynophagia:
    • Acute Upper Airway Obstruction: narrowed glottic orifice may pose difficulties during endotracheal intubation

Laryngeal Rheumatoid Nodules

  • May result in upper airway obstruction

Arteritis of Vasa Vasorum of Recurrent Laryngeal and Vagus Nerves

  • May result in upper airway obstruction

Cardiac Manifestations of RA

  • Pericarditis:

Rheum Manifestations of RA

  • Arthritis: symmetric/involving small joints
  • Rheumatoid Vasculitis (of small and medium-sized arteries, venues)
    • Usually confined to skin (but may progress to PAN-like syndrome)
    • Derm: nodules, ulcers, palpable purpura (of LE)
    • Neuro: acute neuropathy, digital infarcts, gangrene
    • Pulmonary: DAH
    • Ocular
    • GI: may occur in some cases

Derm Manifestations of RA

  • Subcutaneous nodules:
  • Ulceration: as above

Ocular Manifestations of RA

  • xxx

Other Manifestations of RA

  • Lymphadenopathy:
  • Splenomegaly:
  • Felty’s syndrome:


Treatment of Rheumatoid Pleuritis

  • Steroids work in some cases (but no controlled trials)
  • Pleuritis usually takes 3 weeks-months to resolve
  • Some patients require decortication for extensive pleural thickening


  • Useful for interstitial lung disease anecdotally (but no controlled trials)


  • Includes cyclophosphamide, methotrexate, D-penicillamine, azathioprine, hydroxychloroquine sulfate
  • Few case reports of efficacy in interstitial lung disease

Anti-TNF Therapy (infliximab, etanercept, adalimumab)

  • Efficacious
  • However, these agents have been reported to have both infectious and non-infectious complications (see [[Anti-TNF Therapy]])


  • Age-matched mortality rate for RA is 2x higher than that of the geberal population
  • Most excess mortality is attributed to cardiopulmonary complications


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