Rheumatoid Lung Disease

1. Rheumatoid Lung Disease Christopher V. Tehlirian, MD Rheumatology Grand Rounds June 2, 2006

3. Objectives 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

4. Case 1 79 yo WF with seropositive erosive nodular (RF 122, CCP 116) RA dx�d in 1960 (age 35) Previous RA Treatments: NSAIDS IM Gold Prednisone (2-5mg/day) MTX 7.5 mg (for 3 months in 1999) Arava 20 mg (2003)

5. Case 1 Continued PMH: HTN RA Osteopenia Bilateral cataracts OA Nondispalced pelvic fx s/p fall GERD 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

6. 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

7. 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

8. Case 1 Continued

9. Case 1 Continued

10. Case 1 Continued

11. Case 1 Continued

12. 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

13. 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.

14. Case 2 continued

15. Case 2 Continued

16. Case 2 Continued

17. Case 2 Continued

18. 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

19. 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.

20. 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%)

21. 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.

22. 20Gabriel at al. Arthritis and Rheum 2003

23. Rheumatoid Lung Disease On autopsy of 1246 RA pts 18% died due to lung disease (infxn 27%)1.

24. 19Turesson et al. Current Opinion in Rheumatology May 2004

25. 20Gabriel at al. Arthritis and Rheum 2003

26. Extra-articular Manifestations of RA2 Sicca symtpoms Rheumatoid nodules Pulmonary involvement Cardiac involvement Hematologic manifestations Cervical Myelopathy Opthalmologic involvement Vasculitis Amyloid

27. 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

28. 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

29. Rheumatoid Lung Disease What exactly is �Rheumatoid Lung Disease�?

30. 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

31. 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

32. 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

33. 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/�l predominately lymphocytes, high LDH (>1000 U/L), low glucose (<25), low complement, and high RF.

34. Pleural Effusions

35. 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.

36. Rheumatoid Nodule

37. Rheumatoid Lung Nodules

38. 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.

39. Caplan�s Syndrome

40. 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.

41. Interstitial Lung Disease in RA 21Roschmann et al. Semin in Arthritis and Rheum 1987

42. 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 a1-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

43. 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

44. RA-ILD

45. RA-ILD 23Dawson et al. Thorax 2001.

46. RA-ILD 23Dawson et al. Thorax 2001.

47. RA-ILD

48. RA-ILD

49. RA-ILD 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.

50. 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.

51. 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.

52. BOOP

53. Bronchiolitis Obliterans Organizing Pneumonia (BOOP)

54. BOOP

55. 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

56. Obliterative Bronchiolitis

57. 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

58. Anaya et al. Semin Arth and Rheum 24;1995:242-254

59. 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.

60. 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.

61. 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.

62. Methotrexate Associated Lung Disease 17Kremer et al. Arthritis and Rheum 1997

63. 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.

64. Summary 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.

65. Conclusions 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.

66. Case 1 Revisited

67. 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

68. Case 1 Revisited 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%)

69. Case 1 Revisited

70. Methotrexate Associated Lung Disease 17Kremer et al. Arthritis and Rheum 1997

71. Case 2 Revisited

72. Case 2 Revisited 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%)

73. Case 2 Revisited 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%)

74. Case 2 Revisited

75. 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%)

76. Anaya et al. Semin Arth and Rheum 24;1995:242-254

77. References 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.

78. 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.