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Selected Reports
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Isolated Pauciimmune Pulmonary Capillaritis Successfully Treated With Rituximab Gwen Thompson, MD; Ulrich Specks, MD; and Rodrigo Cartin-Ceba, MD
Diffuse alveolar hemorrhage (DAH) is a syndrome caused by different mechanisms, including capillary stress failure, diffuse alveolar damage, and capillaritis. Capillaritis is the most common cause and is often associated with systemic autoimmune disorders, most commonly antineutrophilic cytoplasmic antibody-associated vasculitis. The occurrence of DAH with underlying pulmonary capillaritis but without clinical or serologic findings of an associated underlying systemic disorder is known as isolated pauciimmune pulmonary capillaritis (IPPC), and only eight cases have been described in the literature. The mainstay of treatment of this rare condition has been cyclophosphamide and glucocorticoids. When cases are unresponsive to cyclophosphamide, there is no known alternative treatment. Herein, we describe a case of IPPC that failed cyclophosphamide treatment with recurrent DAH. Rituximab therapy was then initiated with no further evidence of recurrence. This case report suggests that rituximab could be considered an alternative therapy to induce remission in patients with IPPC. CHEST 2015; 147(4):e134-e136 ABBREVIATIONS: ANCA 5 antineutrophilic cytoplasmic antibody ; DAH 5 diffuse alveolar hemorrhage; IPPC 5 isolated pauciimmune pulmonary capillaritis
Diffuse alveolar hemorrhage (DAH) is a syndrome often characterized by the presence of cough, dyspnea, fever, and chest pain, with or without hemoptysis.1-3 Diagnosis is established with BAL that demonstrates progressively bloody return; hemosiderinladen macrophages are often present.3 After the diagnosis of DAH is confirmed, the etiology must be determined to guide the appropriate treatment. DAH is caused by different mechanisms, including capillary stress failure, diffuse alveolar damage, and capillaritis.2-4 Capillaritis is the most common cause and is often associated with systemic
Manuscript received July 31, 2014; revision accepted October 1, 2014. AFFILIATIONS: From the Department of Medicine (Drs Thompson, Specks, and Cartin-Ceba) and Division of Pulmonary and Critical Care Medicine (Drs Specks and Cartin-Ceba), Mayo Clinic, Rochester, MN. This study was presented in abstract form at the American Thoracic Society Annual Meeting, San Diego, CA, May 16-21, 2014.
e134 Selected Reports
autoimmune disorders, most commonly antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis.1 The occurrence of DAH with underlying pulmonary capillaritis but without clinical or serologic findings of an associated underlying systemic disorder is known as isolated pauciimmune pulmonary capillaritis (IPPC), and only eight cases have been described in the literature.5,6 Treatment of this rare condition has traditionally consisted of glucocorticoids in combination with cyclophosphamide.6 When cases are unresponsive to cyclophosphamide, there is no
CORRESPONDENCE TO: Rodrigo Cartin-Ceba, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1884
[
147#4 CHEST APRIL 2015
]
known alternative treatment. Herein, we describe a case of IPPC that failed treatment with cyclophosphamide but responded to rituximab.
Case Report A 45-year-old white man, a nonsmoker without significant past medical history, presented with hemoptysis and dyspnea on exertion. The patient endorsed fatigue and arthralgias but denied other respiratory or systemic symptoms. He was not taking medications and denied the use of illicit drugs. Examination was unremarkable. Chest CT scan showed diffuse bilateral ground-glass opacities (Fig 1). Bronchoscopy did not reveal endobronchial abnormalities. BAL showed progressively bloodier return, negative cultures, and hemosiderin-laden macrophages (. 90%). An extensive diagnostic evaluation included serum protein electrophoresis; levels of cryoglobulins, antiphospholipid antibodies, complement, anticyclic citrullinated peptide, and antiglomerular basement membrane; ANCA panel; antinuclear antibodies cascade; celiac
disease serology; immunoglobulin levels and IgG subclasses; fungal serologies, TB QuantiFERON (Quest Diagnostics Inc); and urinalysis. All tests were negative. A video-assisted thoracoscopic surgery biopsy specimen showed DAH with capillaritis and negative immunofluorescence. Therefore, a diagnosis of IPPC was reached. The patient was given oral cyclophosphamide (150 mg/d) and prednisone (60 mg/d) with subsequent gradual taper plan over 18 weeks. The patient was symptom free for 6 weeks, after which hemoptysis recurred when the prednisone taper reached 30 mg/d. Repeated evaluation with BAL, ANCA testing, urinalysis, cultures, and fungal serologies confirmed recurrence of DAH without evidence of systemic disease. Cyclophosphamide was discontinued. Weekly infusions of rituximab (375 mg/m2) for 4 weeks were given with prednisone (60 mg/d), which was tapered over 18 weeks. The patient was able to discontinue the glucocorticoids with no recurrence. Follow-up has been completed for 14 months after rituximab infusion with no evidence of recurrence 8 months after discontinuation of prednisone.
Figure 1 – CT scan demonstrating diffuse bilateral ground-glass opacities.
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Two preemptive infusions of rituximab (1,000 mg) were given 9 months after initial treatment due to reconstitution of B cells with no evidence of recurrence.
Discussion When a patient presents with DAH, the first priority is cardiopulmonary stabilization. The next step is to determine the etiology of DAH to initiate appropriate treatment.3 DAH is a syndrome with a broad differential diagnosis. DAH can be secondary to capillary stress failure (bland hemorrhage), as seen in patients with severe mitral stenosis; it could also be seen in diffuse alveolar damage, as seen in ARDS; or it can be secondary to capillaritis, as seen in autoimmune conditions such as ANCA-associated vasculitis or antiglomerular basement membrane disease. Drugs can also cause DAH, including therapeutic drugs such as d-penicillamine, amiodarone, and nitrofurantoin, and illicit drugs such as crack cocaine.2,3 IPPC is a rare cause of DAH. The diagnosis of IPPC is based on histopathologic evidence of pulmonary capillaritis in the absence of pulmonary immune deposits and clinical and serologic evidence of an underlying systemic disorder.6 Adequate follow-up is needed to ascertain that systemic signs do not develop subsequently. Whether cases of IPPC represent seronegative forms of systemic diseases such as ANCA-associated vasculitis has been considered and disputed6; seronegativity does not mean the patient would not respond to immune therapy, a phenomenon that also occurs in patients with ANCA-negative granulomatosis with polyangiitis and in seronegative patients with rheumatoid arthritis who are treated with rituximab. In analogy to severe ANCA-associated vasculitis, the combination of glucocorticoids with cyclophosphamide has been introduced empirically as therapy for IPPC and found to be effective.6 Treatment failures were only documented in smokers who were noncompliant with treatment.6 To our knowledge, this is the first reported case of a compliant nonsmoker with IPPC who failed cyclophosphamide treatment. To date, no alternative treatment has been described for IPPC when cyclophosphamide fails. We chose the rituximab regimen for induction7,8 and for maintenance of remission9-11 in analogy to the experience in ANCAassociated vasculitis. Possible mechanisms by which
e136 Selected Reports
rituximab could induce remission in this condition with no known autoantibodies are extrapolated from our knowledge in ANCA-associated vasculitis and other autoimmune conditions where rituximab has been proven beneficial. These mechanisms include the following: reduction in the number of activated B cells, decline in the levels of B-lymphocyte stimulator factors including B-cell activating factor, and secondary effects on T-cell function. To the our knowledge, this is the first case report suggesting that rituximab may be an alternative for remission induction in IPPC, and we speculate that the capillaritis in this condition is mediated by B cells.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts: Dr Specks has served as a consultant for Genentech. Drs Thompson and Cartin-Ceba have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Krause ML, Cartin-Ceba R, Specks U, Peikert T. Update on diffuse alveolar hemorrhage and pulmonary vasculitis. Immunol Allergy Clin North Am. 2012;32(4):587-600. 2. Lara AR, Schwarz MI. Diffuse alveolar hemorrhage. Chest. 2010; 137(5):1164-1171. 3. Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol. 2001;13(1):12-17. 4. Ioachimescu OC, Stoller JK. Diffuse alveolar hemorrhage: diagnosing it and finding the cause. Cleve Clin J Med. 2008;75(4):258-280. 5. Jara-Palomares L, Puig-Rullán A, Alba-García F. Pulmonary hemorrhage due to isolated pauciimmune pulmonary capillaritis and negative antineutrophil cytoplasmic antibodies [in Spanish]. Med Clin (Barc). 2008;131(3):119. 6. Jennings CA, King TE Jr, Tuder R, Cherniack RM, Schwarz MI. Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis. Am J Respir Crit Care Med. 1997;155(3): 1101-1109. 7. Jones RB, Tervaert JW, Hauser T, et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211-220. 8. Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. 9. Cartin-Ceba R, Golbin JM, Keogh KA, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): ten-year experience at a single center. Arthritis Rheum. 2012;64(11):3770-3778. 10. Charles P, Néel A, Tieulié N, et al; French Vasculitis Study Group. Rituximab for induction and maintenance treatment of ANCAassociated vasculitides: a multicentre retrospective study on 80 patients. Rheumatology (Oxford). 2014;53(3):532-539. 11. Jones RB, Ferraro AJ, Chaudhry AN, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009;60(7):2156-2168.
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147#4 CHEST APRIL 2015
]
Selected Reports
]
Isolated Pauciimmune Pulmonary Capillaritis Successfully Treated With Rituximab Gwen Thompson, MD; Ulrich Specks, MD; and Rodrigo Cartin-Ceba, MD
Diffuse alveolar hemorrhage (DAH) is a syndrome caused by different mechanisms, including capillary stress failure, diffuse alveolar damage, and capillaritis. Capillaritis is the most common cause and is often associated with systemic autoimmune disorders, most commonly antineutrophilic cytoplasmic antibody-associated vasculitis. The occurrence of DAH with underlying pulmonary capillaritis but without clinical or serologic findings of an associated underlying systemic disorder is known as isolated pauciimmune pulmonary capillaritis (IPPC), and only eight cases have been described in the literature. The mainstay of treatment of this rare condition has been cyclophosphamide and glucocorticoids. When cases are unresponsive to cyclophosphamide, there is no known alternative treatment. Herein, we describe a case of IPPC that failed cyclophosphamide treatment with recurrent DAH. Rituximab therapy was then initiated with no further evidence of recurrence. This case report suggests that rituximab could be considered an alternative therapy to induce remission in patients with IPPC. CHEST 2015; 147(4):e134-e136 ABBREVIATIONS: ANCA 5 antineutrophilic cytoplasmic antibody ; DAH 5 diffuse alveolar hemorrhage; IPPC 5 isolated pauciimmune pulmonary capillaritis
Diffuse alveolar hemorrhage (DAH) is a syndrome often characterized by the presence of cough, dyspnea, fever, and chest pain, with or without hemoptysis.1-3 Diagnosis is established with BAL that demonstrates progressively bloody return; hemosiderinladen macrophages are often present.3 After the diagnosis of DAH is confirmed, the etiology must be determined to guide the appropriate treatment. DAH is caused by different mechanisms, including capillary stress failure, diffuse alveolar damage, and capillaritis.2-4 Capillaritis is the most common cause and is often associated with systemic
Manuscript received July 31, 2014; revision accepted October 1, 2014. AFFILIATIONS: From the Department of Medicine (Drs Thompson, Specks, and Cartin-Ceba) and Division of Pulmonary and Critical Care Medicine (Drs Specks and Cartin-Ceba), Mayo Clinic, Rochester, MN. This study was presented in abstract form at the American Thoracic Society Annual Meeting, San Diego, CA, May 16-21, 2014.
e134 Selected Reports
autoimmune disorders, most commonly antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis.1 The occurrence of DAH with underlying pulmonary capillaritis but without clinical or serologic findings of an associated underlying systemic disorder is known as isolated pauciimmune pulmonary capillaritis (IPPC), and only eight cases have been described in the literature.5,6 Treatment of this rare condition has traditionally consisted of glucocorticoids in combination with cyclophosphamide.6 When cases are unresponsive to cyclophosphamide, there is no
CORRESPONDENCE TO: Rodrigo Cartin-Ceba, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1884
[
147#4 CHEST APRIL 2015
]
known alternative treatment. Herein, we describe a case of IPPC that failed treatment with cyclophosphamide but responded to rituximab.
Case Report A 45-year-old white man, a nonsmoker without significant past medical history, presented with hemoptysis and dyspnea on exertion. The patient endorsed fatigue and arthralgias but denied other respiratory or systemic symptoms. He was not taking medications and denied the use of illicit drugs. Examination was unremarkable. Chest CT scan showed diffuse bilateral ground-glass opacities (Fig 1). Bronchoscopy did not reveal endobronchial abnormalities. BAL showed progressively bloodier return, negative cultures, and hemosiderin-laden macrophages (. 90%). An extensive diagnostic evaluation included serum protein electrophoresis; levels of cryoglobulins, antiphospholipid antibodies, complement, anticyclic citrullinated peptide, and antiglomerular basement membrane; ANCA panel; antinuclear antibodies cascade; celiac
disease serology; immunoglobulin levels and IgG subclasses; fungal serologies, TB QuantiFERON (Quest Diagnostics Inc); and urinalysis. All tests were negative. A video-assisted thoracoscopic surgery biopsy specimen showed DAH with capillaritis and negative immunofluorescence. Therefore, a diagnosis of IPPC was reached. The patient was given oral cyclophosphamide (150 mg/d) and prednisone (60 mg/d) with subsequent gradual taper plan over 18 weeks. The patient was symptom free for 6 weeks, after which hemoptysis recurred when the prednisone taper reached 30 mg/d. Repeated evaluation with BAL, ANCA testing, urinalysis, cultures, and fungal serologies confirmed recurrence of DAH without evidence of systemic disease. Cyclophosphamide was discontinued. Weekly infusions of rituximab (375 mg/m2) for 4 weeks were given with prednisone (60 mg/d), which was tapered over 18 weeks. The patient was able to discontinue the glucocorticoids with no recurrence. Follow-up has been completed for 14 months after rituximab infusion with no evidence of recurrence 8 months after discontinuation of prednisone.
Figure 1 – CT scan demonstrating diffuse bilateral ground-glass opacities.
journal.publications.chestnet.org
e135
Two preemptive infusions of rituximab (1,000 mg) were given 9 months after initial treatment due to reconstitution of B cells with no evidence of recurrence.
Discussion When a patient presents with DAH, the first priority is cardiopulmonary stabilization. The next step is to determine the etiology of DAH to initiate appropriate treatment.3 DAH is a syndrome with a broad differential diagnosis. DAH can be secondary to capillary stress failure (bland hemorrhage), as seen in patients with severe mitral stenosis; it could also be seen in diffuse alveolar damage, as seen in ARDS; or it can be secondary to capillaritis, as seen in autoimmune conditions such as ANCA-associated vasculitis or antiglomerular basement membrane disease. Drugs can also cause DAH, including therapeutic drugs such as d-penicillamine, amiodarone, and nitrofurantoin, and illicit drugs such as crack cocaine.2,3 IPPC is a rare cause of DAH. The diagnosis of IPPC is based on histopathologic evidence of pulmonary capillaritis in the absence of pulmonary immune deposits and clinical and serologic evidence of an underlying systemic disorder.6 Adequate follow-up is needed to ascertain that systemic signs do not develop subsequently. Whether cases of IPPC represent seronegative forms of systemic diseases such as ANCA-associated vasculitis has been considered and disputed6; seronegativity does not mean the patient would not respond to immune therapy, a phenomenon that also occurs in patients with ANCA-negative granulomatosis with polyangiitis and in seronegative patients with rheumatoid arthritis who are treated with rituximab. In analogy to severe ANCA-associated vasculitis, the combination of glucocorticoids with cyclophosphamide has been introduced empirically as therapy for IPPC and found to be effective.6 Treatment failures were only documented in smokers who were noncompliant with treatment.6 To our knowledge, this is the first reported case of a compliant nonsmoker with IPPC who failed cyclophosphamide treatment. To date, no alternative treatment has been described for IPPC when cyclophosphamide fails. We chose the rituximab regimen for induction7,8 and for maintenance of remission9-11 in analogy to the experience in ANCAassociated vasculitis. Possible mechanisms by which
e136 Selected Reports
rituximab could induce remission in this condition with no known autoantibodies are extrapolated from our knowledge in ANCA-associated vasculitis and other autoimmune conditions where rituximab has been proven beneficial. These mechanisms include the following: reduction in the number of activated B cells, decline in the levels of B-lymphocyte stimulator factors including B-cell activating factor, and secondary effects on T-cell function. To the our knowledge, this is the first case report suggesting that rituximab may be an alternative for remission induction in IPPC, and we speculate that the capillaritis in this condition is mediated by B cells.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts: Dr Specks has served as a consultant for Genentech. Drs Thompson and Cartin-Ceba have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Krause ML, Cartin-Ceba R, Specks U, Peikert T. Update on diffuse alveolar hemorrhage and pulmonary vasculitis. Immunol Allergy Clin North Am. 2012;32(4):587-600. 2. Lara AR, Schwarz MI. Diffuse alveolar hemorrhage. Chest. 2010; 137(5):1164-1171. 3. Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol. 2001;13(1):12-17. 4. Ioachimescu OC, Stoller JK. Diffuse alveolar hemorrhage: diagnosing it and finding the cause. Cleve Clin J Med. 2008;75(4):258-280. 5. Jara-Palomares L, Puig-Rullán A, Alba-García F. Pulmonary hemorrhage due to isolated pauciimmune pulmonary capillaritis and negative antineutrophil cytoplasmic antibodies [in Spanish]. Med Clin (Barc). 2008;131(3):119. 6. Jennings CA, King TE Jr, Tuder R, Cherniack RM, Schwarz MI. Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis. Am J Respir Crit Care Med. 1997;155(3): 1101-1109. 7. Jones RB, Tervaert JW, Hauser T, et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211-220. 8. Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. 9. Cartin-Ceba R, Golbin JM, Keogh KA, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): ten-year experience at a single center. Arthritis Rheum. 2012;64(11):3770-3778. 10. Charles P, Néel A, Tieulié N, et al; French Vasculitis Study Group. Rituximab for induction and maintenance treatment of ANCAassociated vasculitides: a multicentre retrospective study on 80 patients. Rheumatology (Oxford). 2014;53(3):532-539. 11. Jones RB, Ferraro AJ, Chaudhry AN, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009;60(7):2156-2168.
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147#4 CHEST APRIL 2015
]
