A Rare Cause of Multiple Cavitary Nodules
2009; Elsevier BV; Volume: 136; Issue: 1 Linguagem: Inglês
10.1378/chest.08-2354
ISSN1931-3543
AutoresRubal Patel, Sagar Naik, Alexey Amchentsev, Anthony Saleh,
Tópico(s)Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
ResumoA 62-year-old woman with a history of seropositive rheumatoid arthritis presented with a history of exertional dyspnea, a cough productive of greenish sputum, fevers, chills, and malaise for several weeks. She had experienced no weight loss, night sweats, or hemoptysis. She lived in Brooklyn, NY, had not traveled recently, and denied any contacts with sick patients. There was no history of occupational or environmental exposures, but she admitted to a remote history of smoking. She had received a diagnosis of rheumatoid arthritis 10 years prior to presentation. Her disease was nonerosive, manifested as minimal joint symptoms in her hands, and had been well controlled with prednisone, 5 mg bid, and leflunomide, 20 mg/d. A month earlier, she had been seen at another hospital for similar symptoms, at which time a CT scan of the chest revealed multiple cavitating lung nodules. A CT scan-guided biopsy specimen showed nonspecific necrotic material, and the procedure had resulted in a pneumothorax, which was successfully drained.Physical ExaminationPhysical examination findings showed an average built woman without obvious joint abnormalities, skin nodules, or lymphadenopathy. A mild fever was noted. The oxygen saturation was 98% while breathing room air, and both lung fields were clear.Laboratory Data and Radiographic FindingsLaboratory data revealed a normal CBC count and basic metabolic panel levels. C-reactive protein level, sedimentation rate, and rheumatoid factor concentration were elevated to 121 mg/L, 80 mm/h, and 152.7 IU/mL (normal concentration, ≤ 14.0 IU/mL), respectively. Cytoplasmic-staining antineutrophil cytoplasmic antibody (ANCA) and perinuclear-staining ANCA levels were < 6 units/mL. Aspergillus titers and blood cultures were negative. Three sputum samples were negative for acid-fast bacilli, mycology, Nocardia, Actinomyces, and routine bacterial cultures. Results of a purified protein derivative skin test showed no induration. A chest radiograph (Fig 1) showed bilateral nodular opacities with cavitation and thickened, irregular walls. A chest CT scan (Fig 2) revealed multiple cavitating lung nodules in varying stages of evolution, distributed both centrally and in subpleural locations. These lesions were bilateral and had a lower lobe predominance. No mediastinal or hilar adenopathy was noted, and there were no pleural effusions. A transthoracic echocardiogram revealed no vegetation. The patient subsequently underwent a video-assisted thoracoscopy with a biopsy of the right lower lobe. The pathology consisted of areas of necrosis with surrounding inflammatory infiltrates and histiocytic proliferation, consistent with necrotizing granulomatous inflammation. (Fig 3). Her initial clinical presentation of fever and productive cough, and chest CT scan findings of multiple cavitary nodules in varying stages of evolution and pathology showing necrosis strongly suggested an infectious etiology. Her relative immunosuppression increased her risk for the development of a health-care-associated infection. She was therefore started on therapy with broad-spectrum antibiotics. However, she returned a month later with subsequent worsening of her clinical symptoms as well as radiographic findings.Figure 2A 5-mm contrast-enhanced CT scan image of the chest (lung window) through the lower lobes demonstrating numerable cavitary nodules. Note the varying stages of evolution, central and subpleural distribution, and thickened peripheral walls and septations.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Right lower lobe wedge biopsy specimen showing palisading necrotizing granulomas with central fibrinoid necrosis. The necrotic center was surrounded by an inflammatory infilterate including many histiocytes. Note the lymphocytic vasculitis on the right (hematoxylin-eosin, original: right ×40, left ×20). These features are consistent with rheumatoid nodules.View Large Image Figure ViewerDownload Hi-res image Download (PPT)What is the diagnosis?Diagnosis: Rheumatoid lung nodulesClinical DiscussionSeveral pleuropulmonary manifestations are associated with rheumatoid arthritis involving the parenchyma, pleura, airways, and vasculature (Table 1).1Dawson JK Graham DR Lynch MP Lung disease in patients with rheumatoid arthritis.CPD Rheumatol. 2002; 3: 38-42Google Scholar, 2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar, 3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar These usually present in patients with chronic rheumatoid arthritis but may present before the onset of articular symptoms. Lung disease caused by drugs or other agents used to treat rheumatoid arthritis may occur as a result of direct pulmonary toxicity (eg, methotrexate and gold salts) or due to infectious complications resulting from immunosuppression (eg, glucocorticoids, cyclosporine, and anticytokine therapies). The overlapping of other pulmonary diseases, including infection and malignancy, makes the diagnosis and treatment of rheumatoid lung nodules challenging.Table 1Intrathoracic Abnormalities Associated With Rheumatoid ArthritisDiseasesAssociated AbnormalitiesInterstitial lung diseaseUIP; NSIP; DIP; AIP; and LIPOrganizing pneumoniaSeen most frequently in patients with RA compared to the other rheumatic diseasesPleural diseasePleurisy with or without pleural effusionsInfectionBacterial, fungal, and mycobacterialAirway obstructionCricoarytenoid abnormalities, bronchiolitis obliterans, and bronchiectasisRheumatoid nodulesNecrobiotic nodules and Caplan syndromePulmonary vasculitisPulmonary hypertensionDrug-induced lung diseaseMethotrexate, leflunomide, anticytotoxic therapy, gold, and penicillamineUIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; DIP = desquaminative interstitial pneumonia; AIP = acute interstitial pneumonia; LIP = lymphocytic interstitial pneumonia; RA = rheumatoid arthritis. Open table in a new tab The differential diagnosis of cavitary pulmonary nodules in patients with rheumatoid arthritis is extensive, and includes infections (including septic emboli), malignancies (primary or metastatic), lymphomatoid granulomatosis, lymphoma, vasculitides, sarcoidosis, amyloidosis, drug reactions, and rheumatoid nodules.5Burke GW Carrington CB Grinnan R Pulmonary nodules and rheumatoid factor in the absence of arthritis.Chest. 1977; 72: 538-540Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 6Byrd RW Byrd RP Roy TM Rheumatoid arthritis and the pulmonary nodule.J Ky Med Assoc. 1997; 95: 19-22PubMed Google Scholar, 7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 8Hull S Mathews JA Pulmonary necrobiotic nodules as a presenting a feature of rheumatoid arthritis.Ann Rheum Dis. 1982; 41: 21-24Crossref PubMed Scopus (36) Google Scholar, 9Khazeni N Homer RJ Rubinowitz AN et al.Massive cavitary pulmonary rheumatoid nodules in a patient with HIV.Eur Respir J. 2006; 28: 872-874Crossref PubMed Scopus (3) Google Scholar, 10Walters MNI Ojeda VJ Pleuropulmonary necrobiotic rheumatoid nodules.Med J Aust. 1986; 144: 648-651PubMed Google Scholar Infection is the most likely cause and may be due to bacterial, fungal, mycobacterial or other opportunistic organisms.The initial presentation of our patient appeared to indicate an infectious disease, given the relative immunosuppression, febrile course, and radiographic findings of multiple cavitating lung nodules in varying stages of evolution. The pathology raised concern about infection; however, the microbiological data and failure of response to several broad-spectrum antibiotics went against an infectious etiology. Normal echocardiogram findings and several negative blood cultures ruled out endocarditis. There was no clinical or echocardiographic evidence of pericarditis. No malignancy was seen, and the pathology did not show nonnecrotizing granulomas with morphology typical of sarcoidosis. Serum ANCA levels were normal, and the patient did not have any of the clinical, serologic, or pathologic findings of Wegener granulomatosis. On further review, histologic examination of the lung biopsy specimen corresponded to typical features of rheumatoid nodules consisting of palisading, necrotizing granulomas with central fibrinoid necrosis. The necrotic center was surrounded by an inflammatory infiltrate including many histiocytes. The patient had failed to respond to multiple courses of antibiotics and was subsequently started on therapy with prednisone, 60 mg/d, for the treatment of presumed rheumatoid nodules. Several weeks later, she showed dramatic clinical improvement in her symptoms and an overall regression in the size of the lung nodules (Fig 4), suggesting that these were indeed rheumatoid in nature.Figure 4Contrast-enhanced CT scan images of the chest (lung window) before (A) and after (B) treatment with steroids showing a decrease in the number and size of the innumerable cavitary and solid nodules. Some changes show cavitary changes from the nodular pattern seen earlier.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Pulmonary rheumatoid nodules occur in < 1% of patients with rheumatoid arthritis. Patients are usually asymptomatic.4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar They occur more frequently in male smokers with clinical and radiographic evidence of rheumatoid arthritis, subcutaneous nodules, and high rheumatoid factor titers.2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar They may present as a manifestation of rheumatoid disease without classic arthritic changes or skin nodules. Chest radiography only detects 1% of these nodules; however, high-resolution CT scanning increases the yield of detection to 22%.11Cortet B Filipo RM Remy-Jardin M et al.Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis.Ann Rheum Dis. 1995; 54: 815-819Crossref PubMed Scopus (102) Google Scholar Necrobiotic nodules favor the middle and upper zones, can be either single or multiple, tend to be peripheral or pleural, and range from millimeters up to 7 cm in diameter; however, these nodules can be quite variable in appearance, and the natural history follows an unpredictable course.3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar They may resolve spontaneously, recur, or appear first in one lung and then in the other, with no relation to the course of the arthritis.12Eraut D Evans J Caplin M Pulmonary necrobiotic nodules without rheumatoid arthritis.Br J Dis Chest. 1978; 72: 301-306Abstract Full Text PDF PubMed Scopus (24) Google ScholarRheumatoid nodules present a diagnostic dilemma since the radiographic characteristics of rheumatoid nodules are fairly nonspecific and of little diagnostic value, unless the time course is prolonged or resolution occurs. The presence of rheumatoid arthritis does not eliminate the possibility that a nodular pulmonary density may have a different etiology, including malignancy, infection, or other inflammation; therefore, histopathologic confirmation is usually necessary. Granulomatous lung disease may be seen in several entities such as sarcoidosis and vasculitis, but the clinical and or radiographic presentation as well as histopathologic findings may eliminate these entities. Rheumatoid nodules usually require no treatment unless they become quite large, infected, or cavitate with bronchopleural fistulas. There have been no controlled studies of medical therapy for pulmonary nodules, but case reports7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 13Laloux L Chevalier X Maitre B et al.Unusual onset of rheumatoid arthritis with diffuse pulmonary nodulosis: a diagnostic problem.J Rheumatol. 1999; 26: 920-922PubMed Google Scholar have suggested a response to high-dose steroids and/or methotrexate.Perhaps the most powerful evidence of the diagnosis of rheumatoid pulmonary nodules without arthritis in this case is the significant clinical and radiologic response to corticosteroid therapy. The differential diagnosis of other granulomatous diseases that might respond to such a medical regimen includes sarcoidosis and Wegener granulomatosis, but these entities were effectively excluded by clinical, serologic, and histopathologic criteria. A 62-year-old woman with a history of seropositive rheumatoid arthritis presented with a history of exertional dyspnea, a cough productive of greenish sputum, fevers, chills, and malaise for several weeks. She had experienced no weight loss, night sweats, or hemoptysis. She lived in Brooklyn, NY, had not traveled recently, and denied any contacts with sick patients. There was no history of occupational or environmental exposures, but she admitted to a remote history of smoking. She had received a diagnosis of rheumatoid arthritis 10 years prior to presentation. Her disease was nonerosive, manifested as minimal joint symptoms in her hands, and had been well controlled with prednisone, 5 mg bid, and leflunomide, 20 mg/d. A month earlier, she had been seen at another hospital for similar symptoms, at which time a CT scan of the chest revealed multiple cavitating lung nodules. A CT scan-guided biopsy specimen showed nonspecific necrotic material, and the procedure had resulted in a pneumothorax, which was successfully drained. Physical ExaminationPhysical examination findings showed an average built woman without obvious joint abnormalities, skin nodules, or lymphadenopathy. A mild fever was noted. The oxygen saturation was 98% while breathing room air, and both lung fields were clear. Physical examination findings showed an average built woman without obvious joint abnormalities, skin nodules, or lymphadenopathy. A mild fever was noted. The oxygen saturation was 98% while breathing room air, and both lung fields were clear. Laboratory Data and Radiographic FindingsLaboratory data revealed a normal CBC count and basic metabolic panel levels. C-reactive protein level, sedimentation rate, and rheumatoid factor concentration were elevated to 121 mg/L, 80 mm/h, and 152.7 IU/mL (normal concentration, ≤ 14.0 IU/mL), respectively. Cytoplasmic-staining antineutrophil cytoplasmic antibody (ANCA) and perinuclear-staining ANCA levels were < 6 units/mL. Aspergillus titers and blood cultures were negative. Three sputum samples were negative for acid-fast bacilli, mycology, Nocardia, Actinomyces, and routine bacterial cultures. Results of a purified protein derivative skin test showed no induration. A chest radiograph (Fig 1) showed bilateral nodular opacities with cavitation and thickened, irregular walls. A chest CT scan (Fig 2) revealed multiple cavitating lung nodules in varying stages of evolution, distributed both centrally and in subpleural locations. These lesions were bilateral and had a lower lobe predominance. No mediastinal or hilar adenopathy was noted, and there were no pleural effusions. A transthoracic echocardiogram revealed no vegetation. The patient subsequently underwent a video-assisted thoracoscopy with a biopsy of the right lower lobe. The pathology consisted of areas of necrosis with surrounding inflammatory infiltrates and histiocytic proliferation, consistent with necrotizing granulomatous inflammation. (Fig 3). Her initial clinical presentation of fever and productive cough, and chest CT scan findings of multiple cavitary nodules in varying stages of evolution and pathology showing necrosis strongly suggested an infectious etiology. Her relative immunosuppression increased her risk for the development of a health-care-associated infection. She was therefore started on therapy with broad-spectrum antibiotics. However, she returned a month later with subsequent worsening of her clinical symptoms as well as radiographic findings.Figure 3Right lower lobe wedge biopsy specimen showing palisading necrotizing granulomas with central fibrinoid necrosis. The necrotic center was surrounded by an inflammatory infilterate including many histiocytes. Note the lymphocytic vasculitis on the right (hematoxylin-eosin, original: right ×40, left ×20). These features are consistent with rheumatoid nodules.View Large Image Figure ViewerDownload Hi-res image Download (PPT)What is the diagnosis?Diagnosis: Rheumatoid lung nodulesClinical DiscussionSeveral pleuropulmonary manifestations are associated with rheumatoid arthritis involving the parenchyma, pleura, airways, and vasculature (Table 1).1Dawson JK Graham DR Lynch MP Lung disease in patients with rheumatoid arthritis.CPD Rheumatol. 2002; 3: 38-42Google Scholar, 2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar, 3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar These usually present in patients with chronic rheumatoid arthritis but may present before the onset of articular symptoms. Lung disease caused by drugs or other agents used to treat rheumatoid arthritis may occur as a result of direct pulmonary toxicity (eg, methotrexate and gold salts) or due to infectious complications resulting from immunosuppression (eg, glucocorticoids, cyclosporine, and anticytokine therapies). The overlapping of other pulmonary diseases, including infection and malignancy, makes the diagnosis and treatment of rheumatoid lung nodules challenging.Table 1Intrathoracic Abnormalities Associated With Rheumatoid ArthritisDiseasesAssociated AbnormalitiesInterstitial lung diseaseUIP; NSIP; DIP; AIP; and LIPOrganizing pneumoniaSeen most frequently in patients with RA compared to the other rheumatic diseasesPleural diseasePleurisy with or without pleural effusionsInfectionBacterial, fungal, and mycobacterialAirway obstructionCricoarytenoid abnormalities, bronchiolitis obliterans, and bronchiectasisRheumatoid nodulesNecrobiotic nodules and Caplan syndromePulmonary vasculitisPulmonary hypertensionDrug-induced lung diseaseMethotrexate, leflunomide, anticytotoxic therapy, gold, and penicillamineUIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; DIP = desquaminative interstitial pneumonia; AIP = acute interstitial pneumonia; LIP = lymphocytic interstitial pneumonia; RA = rheumatoid arthritis. Open table in a new tab The differential diagnosis of cavitary pulmonary nodules in patients with rheumatoid arthritis is extensive, and includes infections (including septic emboli), malignancies (primary or metastatic), lymphomatoid granulomatosis, lymphoma, vasculitides, sarcoidosis, amyloidosis, drug reactions, and rheumatoid nodules.5Burke GW Carrington CB Grinnan R Pulmonary nodules and rheumatoid factor in the absence of arthritis.Chest. 1977; 72: 538-540Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 6Byrd RW Byrd RP Roy TM Rheumatoid arthritis and the pulmonary nodule.J Ky Med Assoc. 1997; 95: 19-22PubMed Google Scholar, 7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 8Hull S Mathews JA Pulmonary necrobiotic nodules as a presenting a feature of rheumatoid arthritis.Ann Rheum Dis. 1982; 41: 21-24Crossref PubMed Scopus (36) Google Scholar, 9Khazeni N Homer RJ Rubinowitz AN et al.Massive cavitary pulmonary rheumatoid nodules in a patient with HIV.Eur Respir J. 2006; 28: 872-874Crossref PubMed Scopus (3) Google Scholar, 10Walters MNI Ojeda VJ Pleuropulmonary necrobiotic rheumatoid nodules.Med J Aust. 1986; 144: 648-651PubMed Google Scholar Infection is the most likely cause and may be due to bacterial, fungal, mycobacterial or other opportunistic organisms.The initial presentation of our patient appeared to indicate an infectious disease, given the relative immunosuppression, febrile course, and radiographic findings of multiple cavitating lung nodules in varying stages of evolution. The pathology raised concern about infection; however, the microbiological data and failure of response to several broad-spectrum antibiotics went against an infectious etiology. Normal echocardiogram findings and several negative blood cultures ruled out endocarditis. There was no clinical or echocardiographic evidence of pericarditis. No malignancy was seen, and the pathology did not show nonnecrotizing granulomas with morphology typical of sarcoidosis. Serum ANCA levels were normal, and the patient did not have any of the clinical, serologic, or pathologic findings of Wegener granulomatosis. On further review, histologic examination of the lung biopsy specimen corresponded to typical features of rheumatoid nodules consisting of palisading, necrotizing granulomas with central fibrinoid necrosis. The necrotic center was surrounded by an inflammatory infiltrate including many histiocytes. The patient had failed to respond to multiple courses of antibiotics and was subsequently started on therapy with prednisone, 60 mg/d, for the treatment of presumed rheumatoid nodules. Several weeks later, she showed dramatic clinical improvement in her symptoms and an overall regression in the size of the lung nodules (Fig 4), suggesting that these were indeed rheumatoid in nature.Figure 4Contrast-enhanced CT scan images of the chest (lung window) before (A) and after (B) treatment with steroids showing a decrease in the number and size of the innumerable cavitary and solid nodules. Some changes show cavitary changes from the nodular pattern seen earlier.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Pulmonary rheumatoid nodules occur in < 1% of patients with rheumatoid arthritis. Patients are usually asymptomatic.4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar They occur more frequently in male smokers with clinical and radiographic evidence of rheumatoid arthritis, subcutaneous nodules, and high rheumatoid factor titers.2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar They may present as a manifestation of rheumatoid disease without classic arthritic changes or skin nodules. Chest radiography only detects 1% of these nodules; however, high-resolution CT scanning increases the yield of detection to 22%.11Cortet B Filipo RM Remy-Jardin M et al.Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis.Ann Rheum Dis. 1995; 54: 815-819Crossref PubMed Scopus (102) Google Scholar Necrobiotic nodules favor the middle and upper zones, can be either single or multiple, tend to be peripheral or pleural, and range from millimeters up to 7 cm in diameter; however, these nodules can be quite variable in appearance, and the natural history follows an unpredictable course.3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar They may resolve spontaneously, recur, or appear first in one lung and then in the other, with no relation to the course of the arthritis.12Eraut D Evans J Caplin M Pulmonary necrobiotic nodules without rheumatoid arthritis.Br J Dis Chest. 1978; 72: 301-306Abstract Full Text PDF PubMed Scopus (24) Google ScholarRheumatoid nodules present a diagnostic dilemma since the radiographic characteristics of rheumatoid nodules are fairly nonspecific and of little diagnostic value, unless the time course is prolonged or resolution occurs. The presence of rheumatoid arthritis does not eliminate the possibility that a nodular pulmonary density may have a different etiology, including malignancy, infection, or other inflammation; therefore, histopathologic confirmation is usually necessary. Granulomatous lung disease may be seen in several entities such as sarcoidosis and vasculitis, but the clinical and or radiographic presentation as well as histopathologic findings may eliminate these entities. Rheumatoid nodules usually require no treatment unless they become quite large, infected, or cavitate with bronchopleural fistulas. There have been no controlled studies of medical therapy for pulmonary nodules, but case reports7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 13Laloux L Chevalier X Maitre B et al.Unusual onset of rheumatoid arthritis with diffuse pulmonary nodulosis: a diagnostic problem.J Rheumatol. 1999; 26: 920-922PubMed Google Scholar have suggested a response to high-dose steroids and/or methotrexate.Perhaps the most powerful evidence of the diagnosis of rheumatoid pulmonary nodules without arthritis in this case is the significant clinical and radiologic response to corticosteroid therapy. The differential diagnosis of other granulomatous diseases that might respond to such a medical regimen includes sarcoidosis and Wegener granulomatosis, but these entities were effectively excluded by clinical, serologic, and histopathologic criteria. Laboratory data revealed a normal CBC count and basic metabolic panel levels. C-reactive protein level, sedimentation rate, and rheumatoid factor concentration were elevated to 121 mg/L, 80 mm/h, and 152.7 IU/mL (normal concentration, ≤ 14.0 IU/mL), respectively. Cytoplasmic-staining antineutrophil cytoplasmic antibody (ANCA) and perinuclear-staining ANCA levels were < 6 units/mL. Aspergillus titers and blood cultures were negative. Three sputum samples were negative for acid-fast bacilli, mycology, Nocardia, Actinomyces, and routine bacterial cultures. Results of a purified protein derivative skin test showed no induration. A chest radiograph (Fig 1) showed bilateral nodular opacities with cavitation and thickened, irregular walls. A chest CT scan (Fig 2) revealed multiple cavitating lung nodules in varying stages of evolution, distributed both centrally and in subpleural locations. These lesions were bilateral and had a lower lobe predominance. No mediastinal or hilar adenopathy was noted, and there were no pleural effusions. A transthoracic echocardiogram revealed no vegetation. The patient subsequently underwent a video-assisted thoracoscopy with a biopsy of the right lower lobe. The pathology consisted of areas of necrosis with surrounding inflammatory infiltrates and histiocytic proliferation, consistent with necrotizing granulomatous inflammation. (Fig 3). Her initial clinical presentation of fever and productive cough, and chest CT scan findings of multiple cavitary nodules in varying stages of evolution and pathology showing necrosis strongly suggested an infectious etiology. Her relative immunosuppression increased her risk for the development of a health-care-associated infection. She was therefore started on therapy with broad-spectrum antibiotics. However, she returned a month later with subsequent worsening of her clinical symptoms as well as radiographic findings. What is the diagnosis? Diagnosis: Rheumatoid lung nodules Clinical DiscussionSeveral pleuropulmonary manifestations are associated with rheumatoid arthritis involving the parenchyma, pleura, airways, and vasculature (Table 1).1Dawson JK Graham DR Lynch MP Lung disease in patients with rheumatoid arthritis.CPD Rheumatol. 2002; 3: 38-42Google Scholar, 2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar, 3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar These usually present in patients with chronic rheumatoid arthritis but may present before the onset of articular symptoms. Lung disease caused by drugs or other agents used to treat rheumatoid arthritis may occur as a result of direct pulmonary toxicity (eg, methotrexate and gold salts) or due to infectious complications resulting from immunosuppression (eg, glucocorticoids, cyclosporine, and anticytokine therapies). The overlapping of other pulmonary diseases, including infection and malignancy, makes the diagnosis and treatment of rheumatoid lung nodules challenging.Table 1Intrathoracic Abnormalities Associated With Rheumatoid ArthritisDiseasesAssociated AbnormalitiesInterstitial lung diseaseUIP; NSIP; DIP; AIP; and LIPOrganizing pneumoniaSeen most frequently in patients with RA compared to the other rheumatic diseasesPleural diseasePleurisy with or without pleural effusionsInfectionBacterial, fungal, and mycobacterialAirway obstructionCricoarytenoid abnormalities, bronchiolitis obliterans, and bronchiectasisRheumatoid nodulesNecrobiotic nodules and Caplan syndromePulmonary vasculitisPulmonary hypertensionDrug-induced lung diseaseMethotrexate, leflunomide, anticytotoxic therapy, gold, and penicillamineUIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; DIP = desquaminative interstitial pneumonia; AIP = acute interstitial pneumonia; LIP = lymphocytic interstitial pneumonia; RA = rheumatoid arthritis. Open table in a new tab The differential diagnosis of cavitary pulmonary nodules in patients with rheumatoid arthritis is extensive, and includes infections (including septic emboli), malignancies (primary or metastatic), lymphomatoid granulomatosis, lymphoma, vasculitides, sarcoidosis, amyloidosis, drug reactions, and rheumatoid nodules.5Burke GW Carrington CB Grinnan R Pulmonary nodules and rheumatoid factor in the absence of arthritis.Chest. 1977; 72: 538-540Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 6Byrd RW Byrd RP Roy TM Rheumatoid arthritis and the pulmonary nodule.J Ky Med Assoc. 1997; 95: 19-22PubMed Google Scholar, 7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 8Hull S Mathews JA Pulmonary necrobiotic nodules as a presenting a feature of rheumatoid arthritis.Ann Rheum Dis. 1982; 41: 21-24Crossref PubMed Scopus (36) Google Scholar, 9Khazeni N Homer RJ Rubinowitz AN et al.Massive cavitary pulmonary rheumatoid nodules in a patient with HIV.Eur Respir J. 2006; 28: 872-874Crossref PubMed Scopus (3) Google Scholar, 10Walters MNI Ojeda VJ Pleuropulmonary necrobiotic rheumatoid nodules.Med J Aust. 1986; 144: 648-651PubMed Google Scholar Infection is the most likely cause and may be due to bacterial, fungal, mycobacterial or other opportunistic organisms.The initial presentation of our patient appeared to indicate an infectious disease, given the relative immunosuppression, febrile course, and radiographic findings of multiple cavitating lung nodules in varying stages of evolution. The pathology raised concern about infection; however, the microbiological data and failure of response to several broad-spectrum antibiotics went against an infectious etiology. Normal echocardiogram findings and several negative blood cultures ruled out endocarditis. There was no clinical or echocardiographic evidence of pericarditis. No malignancy was seen, and the pathology did not show nonnecrotizing granulomas with morphology typical of sarcoidosis. Serum ANCA levels were normal, and the patient did not have any of the clinical, serologic, or pathologic findings of Wegener granulomatosis. On further review, histologic examination of the lung biopsy specimen corresponded to typical features of rheumatoid nodules consisting of palisading, necrotizing granulomas with central fibrinoid necrosis. The necrotic center was surrounded by an inflammatory infiltrate including many histiocytes. The patient had failed to respond to multiple courses of antibiotics and was subsequently started on therapy with prednisone, 60 mg/d, for the treatment of presumed rheumatoid nodules. Several weeks later, she showed dramatic clinical improvement in her symptoms and an overall regression in the size of the lung nodules (Fig 4), suggesting that these were indeed rheumatoid in nature.Pulmonary rheumatoid nodules occur in < 1% of patients with rheumatoid arthritis. Patients are usually asymptomatic.4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar They occur more frequently in male smokers with clinical and radiographic evidence of rheumatoid arthritis, subcutaneous nodules, and high rheumatoid factor titers.2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar They may present as a manifestation of rheumatoid disease without classic arthritic changes or skin nodules. Chest radiography only detects 1% of these nodules; however, high-resolution CT scanning increases the yield of detection to 22%.11Cortet B Filipo RM Remy-Jardin M et al.Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis.Ann Rheum Dis. 1995; 54: 815-819Crossref PubMed Scopus (102) Google Scholar Necrobiotic nodules favor the middle and upper zones, can be either single or multiple, tend to be peripheral or pleural, and range from millimeters up to 7 cm in diameter; however, these nodules can be quite variable in appearance, and the natural history follows an unpredictable course.3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar They may resolve spontaneously, recur, or appear first in one lung and then in the other, with no relation to the course of the arthritis.12Eraut D Evans J Caplin M Pulmonary necrobiotic nodules without rheumatoid arthritis.Br J Dis Chest. 1978; 72: 301-306Abstract Full Text PDF PubMed Scopus (24) Google ScholarRheumatoid nodules present a diagnostic dilemma since the radiographic characteristics of rheumatoid nodules are fairly nonspecific and of little diagnostic value, unless the time course is prolonged or resolution occurs. The presence of rheumatoid arthritis does not eliminate the possibility that a nodular pulmonary density may have a different etiology, including malignancy, infection, or other inflammation; therefore, histopathologic confirmation is usually necessary. Granulomatous lung disease may be seen in several entities such as sarcoidosis and vasculitis, but the clinical and or radiographic presentation as well as histopathologic findings may eliminate these entities. Rheumatoid nodules usually require no treatment unless they become quite large, infected, or cavitate with bronchopleural fistulas. There have been no controlled studies of medical therapy for pulmonary nodules, but case reports7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 13Laloux L Chevalier X Maitre B et al.Unusual onset of rheumatoid arthritis with diffuse pulmonary nodulosis: a diagnostic problem.J Rheumatol. 1999; 26: 920-922PubMed Google Scholar have suggested a response to high-dose steroids and/or methotrexate.Perhaps the most powerful evidence of the diagnosis of rheumatoid pulmonary nodules without arthritis in this case is the significant clinical and radiologic response to corticosteroid therapy. The differential diagnosis of other granulomatous diseases that might respond to such a medical regimen includes sarcoidosis and Wegener granulomatosis, but these entities were effectively excluded by clinical, serologic, and histopathologic criteria. Several pleuropulmonary manifestations are associated with rheumatoid arthritis involving the parenchyma, pleura, airways, and vasculature (Table 1).1Dawson JK Graham DR Lynch MP Lung disease in patients with rheumatoid arthritis.CPD Rheumatol. 2002; 3: 38-42Google Scholar, 2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar, 3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar These usually present in patients with chronic rheumatoid arthritis but may present before the onset of articular symptoms. Lung disease caused by drugs or other agents used to treat rheumatoid arthritis may occur as a result of direct pulmonary toxicity (eg, methotrexate and gold salts) or due to infectious complications resulting from immunosuppression (eg, glucocorticoids, cyclosporine, and anticytokine therapies). The overlapping of other pulmonary diseases, including infection and malignancy, makes the diagnosis and treatment of rheumatoid lung nodules challenging. UIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; DIP = desquaminative interstitial pneumonia; AIP = acute interstitial pneumonia; LIP = lymphocytic interstitial pneumonia; RA = rheumatoid arthritis. The differential diagnosis of cavitary pulmonary nodules in patients with rheumatoid arthritis is extensive, and includes infections (including septic emboli), malignancies (primary or metastatic), lymphomatoid granulomatosis, lymphoma, vasculitides, sarcoidosis, amyloidosis, drug reactions, and rheumatoid nodules.5Burke GW Carrington CB Grinnan R Pulmonary nodules and rheumatoid factor in the absence of arthritis.Chest. 1977; 72: 538-540Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 6Byrd RW Byrd RP Roy TM Rheumatoid arthritis and the pulmonary nodule.J Ky Med Assoc. 1997; 95: 19-22PubMed Google Scholar, 7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 8Hull S Mathews JA Pulmonary necrobiotic nodules as a presenting a feature of rheumatoid arthritis.Ann Rheum Dis. 1982; 41: 21-24Crossref PubMed Scopus (36) Google Scholar, 9Khazeni N Homer RJ Rubinowitz AN et al.Massive cavitary pulmonary rheumatoid nodules in a patient with HIV.Eur Respir J. 2006; 28: 872-874Crossref PubMed Scopus (3) Google Scholar, 10Walters MNI Ojeda VJ Pleuropulmonary necrobiotic rheumatoid nodules.Med J Aust. 1986; 144: 648-651PubMed Google Scholar Infection is the most likely cause and may be due to bacterial, fungal, mycobacterial or other opportunistic organisms. The initial presentation of our patient appeared to indicate an infectious disease, given the relative immunosuppression, febrile course, and radiographic findings of multiple cavitating lung nodules in varying stages of evolution. The pathology raised concern about infection; however, the microbiological data and failure of response to several broad-spectrum antibiotics went against an infectious etiology. Normal echocardiogram findings and several negative blood cultures ruled out endocarditis. There was no clinical or echocardiographic evidence of pericarditis. No malignancy was seen, and the pathology did not show nonnecrotizing granulomas with morphology typical of sarcoidosis. Serum ANCA levels were normal, and the patient did not have any of the clinical, serologic, or pathologic findings of Wegener granulomatosis. On further review, histologic examination of the lung biopsy specimen corresponded to typical features of rheumatoid nodules consisting of palisading, necrotizing granulomas with central fibrinoid necrosis. The necrotic center was surrounded by an inflammatory infiltrate including many histiocytes. The patient had failed to respond to multiple courses of antibiotics and was subsequently started on therapy with prednisone, 60 mg/d, for the treatment of presumed rheumatoid nodules. Several weeks later, she showed dramatic clinical improvement in her symptoms and an overall regression in the size of the lung nodules (Fig 4), suggesting that these were indeed rheumatoid in nature. Pulmonary rheumatoid nodules occur in < 1% of patients with rheumatoid arthritis. Patients are usually asymptomatic.4Walker WC Wright V Pulmonary lesions and rheumatoid arthritis.Medicine (Baltimore). 1968; 47: 501-520Crossref PubMed Scopus (182) Google Scholar They occur more frequently in male smokers with clinical and radiographic evidence of rheumatoid arthritis, subcutaneous nodules, and high rheumatoid factor titers.2Hunninghake GW Fauci AS Pulmonary involvement in the collagen vascular diseases.Am Rev Respir Dis. 1979; 119: 471-504PubMed Google Scholar They may present as a manifestation of rheumatoid disease without classic arthritic changes or skin nodules. Chest radiography only detects 1% of these nodules; however, high-resolution CT scanning increases the yield of detection to 22%.11Cortet B Filipo RM Remy-Jardin M et al.Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis.Ann Rheum Dis. 1995; 54: 815-819Crossref PubMed Scopus (102) Google Scholar Necrobiotic nodules favor the middle and upper zones, can be either single or multiple, tend to be peripheral or pleural, and range from millimeters up to 7 cm in diameter; however, these nodules can be quite variable in appearance, and the natural history follows an unpredictable course.3Helmers R Galvin J Hunninghake GW Pulmonary manifestations associated with rheumatoid arthritis.Chest. 1991; 100: 235-238Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar They may resolve spontaneously, recur, or appear first in one lung and then in the other, with no relation to the course of the arthritis.12Eraut D Evans J Caplin M Pulmonary necrobiotic nodules without rheumatoid arthritis.Br J Dis Chest. 1978; 72: 301-306Abstract Full Text PDF PubMed Scopus (24) Google Scholar Rheumatoid nodules present a diagnostic dilemma since the radiographic characteristics of rheumatoid nodules are fairly nonspecific and of little diagnostic value, unless the time course is prolonged or resolution occurs. The presence of rheumatoid arthritis does not eliminate the possibility that a nodular pulmonary density may have a different etiology, including malignancy, infection, or other inflammation; therefore, histopathologic confirmation is usually necessary. Granulomatous lung disease may be seen in several entities such as sarcoidosis and vasculitis, but the clinical and or radiographic presentation as well as histopathologic findings may eliminate these entities. Rheumatoid nodules usually require no treatment unless they become quite large, infected, or cavitate with bronchopleural fistulas. There have been no controlled studies of medical therapy for pulmonary nodules, but case reports7Fisun K Polatli M Senturk T Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis.J Clin Rheumatol. 2003; 9: 246-252Crossref PubMed Scopus (6) Google Scholar, 13Laloux L Chevalier X Maitre B et al.Unusual onset of rheumatoid arthritis with diffuse pulmonary nodulosis: a diagnostic problem.J Rheumatol. 1999; 26: 920-922PubMed Google Scholar have suggested a response to high-dose steroids and/or methotrexate. Perhaps the most powerful evidence of the diagnosis of rheumatoid pulmonary nodules without arthritis in this case is the significant clinical and radiologic response to corticosteroid therapy. The differential diagnosis of other granulomatous diseases that might respond to such a medical regimen includes sarcoidosis and Wegener granulomatosis, but these entities were effectively excluded by clinical, serologic, and histopathologic criteria.
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