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Rheumatoid Lung Disease. Christopher V. Tehlirian, MD Rheumatology Grand Rounds June 2, 2006. Disclosures. NONE. Objectives. Natural History of Rheumatoid lung disease Patterns of Rheumatoid lung disease Risk Factors of Rheumatoid lung disease

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rheumatoid lung disease

Rheumatoid Lung Disease

Christopher V. Tehlirian, MD

Rheumatology Grand Rounds

June 2, 2006

  • Natural History of Rheumatoid lung disease
  • Patterns of Rheumatoid lung disease
  • Risk Factors of Rheumatoid lung disease
  • Differentiating MTX lung from RA lung
  • Clinical Implications
case 1
Case 1
  • 79 yo WF with seropositive erosive nodular (RF 122, CCP 116) RA dx’d in 1960 (age 35)
  • Previous RA Treatments:
  • IM Gold
  • Prednisone (2-5mg/day)
  • MTX 7.5 mg (for 3 months in 1999)
  • Arava 20 mg (2003)
case 1 continued




Bilateral cataracts


Nondispalced pelvic fx s/p fall


Breast CA 1993

Surgical History:

s/p right mastectomy 1993

L wrist fusion 1983 with revison in 1997

L ankle fusion 1990

R TKR 1999

R 5th MTP head resection 1995

Case 1 Continued
case 1 continued6
Case 1 Continued
  • Allergies: Codeine-rash, ACEI ?
  • Medications:
  • MTX 12.5 mg +Entanercept 50 mg (12/05)
  • Prednisone 5mg
  • Raloxifen 60 mg
  • Ranitidine 300 BID
  • Atenolol 50 mg
  • Celebrex 200mg
  • Naprosyn 375 BID
  • Amlodipine 5 mg
  • Calcium +Vit D
case 1 continued7
Case 1 Continued
  • FMH:

Mother died of breast CA age 77

Father died of MI age 60

Sister has Gyn CA

  • SocH: Nun at catholic school in Dundalk

No tobacco, ETOH or Illicits

case 1 continued8
Case 1 Continued

Came to Bayview ER 1/21/06 with hip pain but was admitted with hypoxia (84% RA, PaO2 40)

case 2
Case 2
  • 84 yo WF dx’d with PMR 2002 (age 80) started on Prednisone 20 mg. RF was low positive (1:116)
  • 11/03 seen in Pulmonary Clinic with chronic dry cough and found to have bronchiectasis on Chest CT.
  • 2/05 had rheumatoid distribution of synovitis found to have RF 1500 and CCP 139.
  • 3/05 started MTX 15
case 2 continued
Case 2 Continued
  • PMH:
  • collagenous colitis
  • breast CA 1982
  • PVD
  • Osteoporosis
  • Hypercholesterolemia
  • OA
  • subclinical hypothyroidism
  • Past surgical history:

1) left second and third MCP arthroplasty 12/2003

  • Allergies: naprosyn-GI upset
  • FMH: Father died in his 30s with TB, Mother died in her 60s with colon CA.
  • SocH: 1ppd for 10 years quit in 1950.
case 2 continued14
Case 2 continued
  • 11/05 Admitted to Bayview hospital with DOE, cough, and 78-80% O2 sat on RA after 1 week febrile prodrome.
case 3
Case 3
  • 57 yo WF dx’d with Sjogrens syndrome 1985 and seropositive erosive nodular RA in 1989.
  • Previous treatments:
  • Hydroxychloroquine
  • D-penicillamine
  • IM Gold
  • Prednisone
  • MTX +Etanercept 1999
case 3 continued
Case 3 Continued
  • PMH:
  • Sjogrens syndrome 1985
  • RA 1989
  • Achilles tendon rupture
  • Allergies: NKDA
  • FMH: 5 sisters and 1 brother all essentially healthy.  Her mother died of pancreatic cancer. Father died of colorectal cancer.
  • SocH: Occ ETOH, no tobacco, no illicits. Worked as a librarian.
case 3 continued20
Case 3 Continued
  • 5/03 seen in pulmonary clinic for 3 years of non-productive cough and 5 months of worsening DOE (2 flights of stairs).
  • CXR 2002-revealed slightly increased lung volumes.
  • HRCT- reviewed by pulmonary with normal parenchyma and mild bronchial wall thickening.
  • PFTs from 09/03:

FEV1/FVC of 50 (79%)

FEV1 of 0.34 (36%)

FVC 1.7 (56%)

TLC (109%)

DLCO (86%)

rheumatoid arthritis ra
Rheumatoid Arthritis (RA)
  • Systemic chronic autoimmune inflammatory disease
  • Prevalence of RA is around 1% worldwide
  • Male : Female=1:2
  • The articular manifestations are the sine qua non of the disease.
  • Extra-articular manifestations are present in 40% of all RA patients.
rheumatoid lung disease23
Rheumatoid Lung Disease
  • On autopsy of 1246 RA pts 18% died due to lung disease (infxn 27%)1.

1Toyoshina et al. Ryumachi 1993

extra articular manifestations of ra 2
Extra-articular Manifestations of RA2
  • Sicca symtpoms
  • Rheumatoid nodules
  • Pulmonary involvement
  • Cardiac involvement
  • Hematologic manifestations
  • Cervical Myelopathy
  • Opthalmologic involvement
  • Vasculitis
  • Amyloid
the history of rheumatoid lung
The History of Rheumatoid Lung
  • Ellman and Ball are the first to publish case report on RA with pulmonary involvement in 1948. 3 (3 cases of RA with ILD)
  • Caplan in 1953 describes rheumatoid nodules in coal miners suffering from RA.4
  • In 1954, rheumatoid lung nodules found in RA patients without pneumoconiosis.5
the history of rheumatoid lung28
The History of Rheumatoid Lung
  • In 1955, case series of RA patients’ autopsies demonstrate twice the incidence o pleural disease compared to normal population.6
  • In 1961, Cudkowicz et al describe the clinical, pathologic, and spirometric findings in RA patients with “rheumatoid lung” disease.7
rheumatoid lung disease29
Rheumatoid Lung Disease
  • What exactly is “Rheumatoid Lung Disease”?
rheumatoid lung
Rheumatoid Lung
  • Pleural involvement (pleurisy, effusions)
  • Pulmonary parenchymal nodules
  • Rheumatoid associated interstitial lung disease
  • Bronchiolitis obliterans organizing pneumonia
  • Obliterative bronchiolitis (obstructive lung disease/bronchiectasis)
  • Rheumatoid associated pulmonary hypertension
  • Pulmonary vasculitis/arteritis
  • Shrinking lung syndrome
  • Miscellaneous: MTX, cricoarytenoid arthritis, infxn, cancer
pleural involvement
Pleural Involvement
  • Pleural involvement is the most common pulmonary manifestation of RA. (debated)
  • Approximately 15-20% of RA patients have pleurisy.8
  • Risk factors: Men, 50s, nodules
  • It is estimated that >40% of RA patients have pleural inflammation on autopsy.9

8 Bacon, PA. Philadelphia, PA, Lea & Febiger. 1993.

9 Shannon et al.. J Thoracic Imaging 1992.

pleurisy and pleural effusions
Pleurisy and Pleural Effusions
  • Pleurisy is more common men than in women.10
  • Usually in the 4th and 5th decade of life with active arthritis and nodules.
  • Pleurisy is typically asymptomatic, it is often noticed on physical exam (pleural rub) and/or radiologic finding.11

10 Walker et al. Ann Rheum Dis 1967

11 Macfarlane et al. Br J Dis Chest 1978

pleural effusions
Pleural Effusions
  • Pleural effusions (3-5% of RA pts) are typically small and asymtpomatic.
  • The effusions are bilateral in more than 25% of cases, and 25% may precede joint disease.10
  • Effusions may be present with other RA pulmonary manifestations (nodules, ILD).
  • Pleural fluid is yellowish-green (cholesterol crystals), WBC 100-8000 cells/µl predominately lymphocytes, high LDH (>1000 U/L), low glucose (<25), low complement, and high RF.
rheumatoid lung nodules
Rheumatoid Lung Nodules
  • Pulmonary rheumatoid lung nodules (specific to RA) are also more common in men than in women, with nodules and positive RF.8
  • Frequently in the periphery of the right middle or both upper lobes (single or multiple).
  • Central cavitation occurs in 50% of the lung nodules without calcification.
  • The clinical course of lung nodule is variable, typically benign but can cause pneumothorax, hemoptysis, can get secondarily infected, or form bronhopleural fistulas.
caplan s syndrome
Caplan’s Syndrome
  • Caplan’s syndrome is pulmonary nodulosis in RA and pneumoconiosis related to exposure of coal dust, silica, or asbestos.
  • Characterized by multiple >1cm peripheral lung nodules.
  • Prevalence 2-6% of patients with RA but declining as the coal mining industry declines.
  • Spontaneous remission has been described.

9 Shannon et al. J Thoracic Imaging 1992

interstitial lung disease in ra
Interstitial Lung Disease in RA
  • Prevalence reported from 1.6% to 40% in RA pts in various studies.
  • Walker et al defines ILD by radiograph in 1.6% of 516 RA pts.12
  • Frank et al. show diminished DLCO in 40% of 41 RA pts, but only 18% of those have radiographic abnormalities.13
  • Clinical manifestations similar to idiopathic pulmonary fibrosis.
interstitial lung disease in ra41
Interstitial Lung Disease in RA

21Roschmann et al. Semin in Arthritis and Rheum 1987

interstitial lung disease in ra42
Interstitial Lung Disease in RA
  • Arthritis precedes ILD in 70-90% of cases by a mean of 37 months.14
  • Male to female ratio between 3:1 to 1:1 (debated).
  • Age of onset between 33 to 75 years of age.
  • HLA-DRB1 association as well as α1-anitrypsin phenotype.
  • >50% of RA pts with ILD have Rheumatoid nodules
  • 65% have high titer RF >1:128
  • 75% have ESR persistently above 40 mm/h
interstitial lung disease in ra43
Interstitial Lung Disease in RA
  • Smoking appears to be an additional independent risk factor.
  • BAL can show both lymphocytic or neutrophilic predominance. 25
  • Heterogenous biopsy findings in single RA patient.
  • PFTs show early restrictive pattern and DLCO drop by at least 15% predicted.
  • HRCT correlates with lung biopsy of ILD approximately 90%.24
ra ild45

23Dawson et al. Thorax 2001.

ra ild46

23Dawson et al. Thorax 2001.

ra ild49
  • Therapy consists of corticosteroids (44% response), MTX (case reports), D-penicillamine, Azathioprine, Cyclophosphamide and Cyclosporine.
  • Prognosis is variable: from spontaneous remission which has been reported, slowly progressive ILD (over 10 years), to rapidly progressive ILD (over 4 months).
  • Most commonly mean survival is 3.2 years such as idiopathic ILD
  • Survival was not related to degree of PFT impairment, RF, or ESR.
  • Survival was improved by early response to corticosteroids, less fibrosis on imaging and high cellularity on BAL.

21 Roschmann et al. Seminars in Arthritis and Rheum 1987.

bronchiolitis obliterans organizing pneumonia boop
Bronchiolitis Obliterans Organizing Pneumonia (BOOP)
  • BOOP specific interstitial pneumonitis with an unknown etiology
  • Male to female ratio 1:1 (?female predominance)
  • Mean age 56 usually between ages 45-75
  • 30% of BOOP cases preceded by febrile flu-like illness
  • Patients complain of non-productive cough and SOB.
bronchiolitis obliterans organizing pneumonia boop51
Bronchiolitis Obliterans Organizing Pneumonia (BOOP)
  • Elevated ESR
  • PFTs show restrictive pattern with reduced DLCO
  • Lymphocytic infiltrate on BAL
  • Histology is diagnostic with proliferative bronchiolitis a nonspecific reaction with an inflammatory intraluminal infiltrate with mucus in the distal alveoli.
  • BOOP is very responsive to corticosteroids and has a good prognosis.
obliterative bronchiolitis ob
Obliterative Bronchiolitis (OB)
  • OB may be a part of RA or treatment (D-penicillamine, IM Gold).
  • Presents with non-productive cough and SOB (no fever or prodrome like BOOP).
  • CXR shows hyperinflation.
  • PFTs have an obstructive defect with normal DLCO.
  • BAL has predominance of neutrophils.
  • Biopsy demonstrates constrictvie bronchiolitis with progressive concentric fibrosis.15
obliterative bronchiolitis ob57
Obliterative Bronchiolitis (OB)
  • HRCT has nonspecific findings of bronchial wall thickening, “tree in bud’, or bronchiectasis.
  • The prognosis of OB is poor
  • Aggressive treatment with high dose corticosteroids followed by Azathioprine or Cyclophosphamide may improve outcome.16
  • There is data that treatment with concurrent macrolide Abxs may be beneficial.22

22Hayakawa et al. Am J Resp Crit Care Med 1996

Kanazawa et al. Am J Respir Crit Care Med. 2004

methotrexate associated lung disease
Methotrexate Associated Lung Disease
  • MTX lung injury is an idiosyncratic reaction that has a variable clinical presentation.
  • Toxic reaction that occurs at mean of 36 weeks after initiating MTX therapy.17
  • No pleural involvement described with MTX toxicity.
  • CXR usually demonstrates a diffuse interstitial pattern that can be difficult to differentiate from infectious process or RA-ILD.

17Kremer at al. Arthritis and Rheum 1997

methotrexate associated lung disease60
Methotrexate Associated Lung Disease
  • The histopathology may help differentiate RA-ILD vs. MTX lung injury.
  • MTX lung histology should demonstrate an acute hypersensitivity pneumonitis with type II pneumocyte hyperplasia, fibroblastic proliferations, and eosinophilia.
methotrexate associated lung disease61
Methotrexate Associated Lung Disease
  • Questionable whether pre-existing lung disease is a risk factor for developing MTX lung injury (No evidence)
  • Fatality rate in literature is 17.2% from MTX lung injury.
  • Patients that are re-challenged with MTX after initial lung injury are at higher mortality risk.
  • With symptoms, empirically hold MTX and treat with combination of Abx and corticosteroids.
methotrexate associated lung disease62
Methotrexate Associated Lung Disease

17Kremer et al. Arthritis and Rheum 1997

rare ra lung manifestations
Rare RA Lung Manifestations
  • Pulmonary vasculitis -rarely limited only to lungs, bx with immunoflorescence is diagnostic (IgA, IgG).
  • Pulmonary Hypertension -uncommonly arterial in origin, rather secondary to interstitial process
  • Bronchiectasis - along with non-specific have been found to be more common in RA than general population on autopsy.18
  • Apical Emphysematous bullae
  • Cricoarytenoid arthritis- sore throat, hoarseness, discomfort while speaking and breathing.
  • Shrinking Lung Syndrome -upper lobe fibrosis with rise of diaphragms.
  • Variety of lung manifestations in RA of which the natural history is not understood.
  • Difficult to differentiate medication induced vs. infection induced vs. RA induced lung injury.
  • The tools for screening lung disease have changed.
  • Difficult to screen lung disease in RA as most of the manifestations are asymptomatic or too insidious in onset.
  • Examine each RA patient during each visit thoroughly.
  • Pulmonary nodules and pleural involvement is more common in men but not true for RA-ILD, BOOP or OB.
  • If pulmonary involvement suspected, get PFTs and HRCT (most sensitive early).
  • Need further epidemiologic studies to further characterize RA lung disease.

Biederer et al. Eur Radiology 2004.

Gabbay et al. Am J Resp Crit Care 1997

case 1 revisited67
Case 1 Revisited
  • Transbronchial bx:

1) normal fragments of alveolated lung

2) thickened septa

3) Increased reactive alveolar macrophages

4) No pulmonary edema

5) Special stains negative for fungi, viruses and amyloid

  • BAL- culture negative
case 1 revisited68
PFTs 2/20/06:

FEV1 1.84 (89%)

FVC 2.33 (87%)

TLC 4.20 (93%)

DLCO 11.7 (71%)

PFTs 3/20/06:

FEV1 1.95(97%)

FVC 2.31(89%)

TLC 4.32(98%)

DLCO 13(82%)

Case 1 Revisited

MTX and Enbrel held 1/21/06. Prednisone 60 mg and Levaquin started.

Arava restarted after 1 month for RA tx.

methotrexate associated lung disease70
Methotrexate Associated Lung Disease

17Kremer et al. Arthritis and Rheum 1997

case 2 revisited72
Acute on chronic DOE

Female +/-

Febrile prodrome

Dry cough

Squeaks on pulm exam

Infiltrate on Chest CT

ESR 114

BAL negative for infxn.

Transbronch bx was non-diagnostic. (no alveolated lung seen)

PFTs 1/17/06:

FEV1 1.38(89%)

FVC 1.56(75%)

TLC 3.09(81%)

DLCO 2.7(21%)

Case 2 Revisited
case 2 revisited73
PFTs 1/17/06:

FEV1 1.38(89%)

FVC 1.56(75%)

FEV1/FVC 88%

TLC 3.09(81%)

DLCO 2.7(21%)

PFTs 5/3/06:

FEV1 0.89(58%)

FVC 1.37(67%)

FEV1/FVC 65%

DLCO 5.7(45%)

Case 2 Revisited

1)MTX and Etanercept held

2) Given 60 mg Prednisone slow taper

case 3 revisited
PFTs 09/03:

FEV1/FVC of 50 (79%)

FEV1 of 0.34 (36%)

FVC 1.7 (56%)

TLC (109%)

DLCO (86%)

PFTs 11/05:

FEV1/FVC 54%

FEV1 1.04 (43%)

FVC 1.9 (63%)

TLC 5.39 (109%)

DLCO (107%)

Case 3 Revisited

BAL culture negative

Transbronchial bx:Alveolar Macrophges present

Epithelials 6

Macrophages 56

Neutrophils 213

Lymphocytes 11

Eosinophils 14

  • Toyoshina et al. Cause of death in autopsied rheumatoid arthritis patients. Ryumachi 1993;33:209-214
  • Anaya et al. Pulmonary involvement in rheumatoid arthritis. Semin Arth and Rheum 24;1995:242-254
  • Ellman et al. Rheumatoid disease with joint and pulmonary manifestations. BMJ 1948;2:816-820.
  • Caplan, A. Certain unusual radiologic appearances in the chest of coal miners suffering from rheumatoid arthritis. Thorax 1953;8:29-37.
  • Mahler , JA. Dural nodules in rheumatoid arthritis. Arch Pathol 1954;58:354-359.
  • Sinclair et al. Clinical and pathologic study of sixteen cases of rheumatoid arthritis with extensive visceral involvement. Q J Med 1955;25:313-332.
  • Cudkowicz et al. Rheumatoid lung disease. Br J Dis Chest 1961;55:35-39
  • Bacon, PA. Extra-articular rheumatoid arthritis: Arthritis and Allied Conditions (ed 20). Philadelphia, PA, Lea & Febiger. 1993;811-840.
  • Shannon et al. Noncardiac manifestations of rheumatoid arthritis in the thorax. J Thorac Imaging 1992;7:19-29.
  • Walker et al. Rheumatoid pleuritis. Ann Rheum Dis 1967;26:467-474.
references continued
References Continued

11. Macfarlane et al. Pulmonary and pleural lesions in rheumatoid disease. Br J Dis Chest 1978;72:288-300.

12 Walker et al. Pulmonary lesions and rheumatoid arthritis. Medicine 1968;47:501-520.

13 Frank et al. Pulmonary dysfunction in rheumatoid disease. Chest 1973;63:27-34.

14 Brannan et al. Pulmonary disease associated with rheumatoid arthritis. J AM Med Assoc 1964;189:914-918.

15 Colby et al. Clinical and histopathological spectrum of bronchiolitis obliterans, including bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Semin Resp Med 1992;13:119-133.

16 Penny et al. Obliterative bronchiolitis in Rheumatoid arthritis. Ann Rheum Dis 1992;41:469-472.

17 Kremer at al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis. 1997;40:1829-1837.

18 Aronoff et al. Lung lesions in rheumatoid arthritis. Br Med J 1955;4933:228-232.

19 Turesson et al. Extraarticular management in Rheumatoid arthritis. Current Opinion in Rheumatology May 2004;16:206-211.

20 Gabriel et al. Survival in Rheumatoid Arthritis. A population based study over 40 years. Arthritis and Rheumatism. Jan 2003;48:54-58.

21 Roschmann et al. Pulmonary fibrosis in Rheumatoid Arthritis: A Review of the clinical features and Therapy. Seminars in Arthritis and Rheum Feb 1987;16:174-185.

22 Hayakawa et al. Bronchiolar Disease in Rheumatoid Arthritis. Am J Resp Crit Care Med 1996; 154:1531

23 Dawson et al. Fibrosing alveolitis inpatients with rheumatoid arthritis as assessed by high resolution computed tomography, and pulmonary function test. Thorax 2001;56:622-627.

24 Mathieson et al. Chronic diffuse infiltrative lung disease: comparison of diagnostic accuracy of CT and chest radiography. Radiology 1989;171:111-116.

25 Kolarz et al. Bronchoalveolar lavage in rheumatoid arthritis. British Journal of Rheumaotolgy July 1993;7:556-561.