Rheumatoid Arthritis (RA)

Epidemiology

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

Physiology

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

Diagnosis

CBC

Anemia (iron deficiency): usually present
Leukocytosis:

Skin Bx

Diagnostic

Serology

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

ESR

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

Amyloidosis

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

Other Manifestations of RA

Lymphadenopathy:
Splenomegaly:
Felty’s syndrome:

Treatment

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

Steroids

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

Cytotoxics

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]])

Prognosis

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

References

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Yousem, 1985
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Liu, et al; Anesth Analg, 2001: 92: 783-784
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Intrapulmonary rheumatoid nodules in a patient with long-standing rheumatoid arthritis treated with leflunomide. Pathol Oncol Res. 2008 Mar;14(1):101-4
Cunnane G, Warnock M, Fye KH, et al. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum 2002; 47:445-449
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