- Email: [email protected]
Lack of evidence for intrathecal tryptase synthesis in patients with systemic mastocytosis
996 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL OCTOBER 2013
9. Reubsaet LL, Boelens JJ, Rademaker C, Smal J, Wulffraat NM. Successful cord blood transplantation in a premature and dysmature neonate of 1700 g with reticular dysgenesis. Bone Marrow Transplant 2007;39:307-8. Available online June 12, 2013. http://dx.doi.org/10.1016/j.jaci.2013.04.055
Lack of evidence for intrathecal tryptase synthesis in patients with systemic mastocytosis To the Editor: Systemic mastocytosis (SM) is a rare disorder of unknown prevalence characterized by an increased number of abnormal clonal mast cells, which can be pathologically demonstrated as multifocal infiltrates in either the bone marrow or other extracutaneous sites. Neuropsychiatric symptoms in patients with mastocytosis are not only prevalent but also important contributors to patient disability.1 An early series of 10 patients with SM used objective neuropsychometric testing, which revealed a mixed cognitive-affective symptom complex termed by the authors ‘‘mixed organic brain syndrome.’’2 Diminished attention and short-term memory, in addition to irritability, were common findings. Escribano et al noted similar neuropsychiatric symptoms in 34 (23%) of 145 patients followed prospectively.3 A recent study has revealed findings of objective memory impairment in 22 (38.6%) of 57 patients independent of antihistaminic exposure and depression.4 Anxiety, rage, anger, fatigue, difficulty with concentration, poor motivation, and sleep disruption have all been noted in this population.2,3 This constellation of symptoms might comprise what patients with SM commonly report to physicians as ‘‘brain fog.’’ A fundamental and unanswered question is whether central nervous system mast cell activity is increased in patients with SM. Routine neuroimaging and cerebrospinal fluid (CSF) indices are invariably normal in the absence of comorbid neurologic illness. To further address this question, we prospectively obtained CSF from 4 patients with SM to directly test for tryptase, a specific marker of mast cell burden and activity. All met World Health Organization diagnostic criteria for indolent SM. All patients were evaluated by both a neurologist (J.H.S.) and an allergist (C.R.W. or J.H.B.). Additional study inclusion required age of 18
years or greater and a General Health Questionnaire score of 4 or greater. Patients with SM completed the Center for Epidemiologic Studies Depression Scale and the Headache Disability Index. Magnetic resonance imaging of the head with gadolinium was performed for all patients. Laboratory evaluation included measurement of both serum and CSF tryptase levels, which were coordinated to occur sequentially within 1 hour of the other, and measurements of 24-hour urinary 11b prostaglandin F2a and N-methylhistamine excretion. Control CSF samples were obtained from 64 patients undergoing lumbar puncture for routine clinical indications. We excluded patients with suspected or confirmed multiple sclerosis given the prior report of increased CSF tryptase levels in this population.5 Tryptase measurement was performed by using a fluorescence enzyme immunoassay with the ImmunoCAP 100 (Phadia, Uppsala, Sweden). The assay measured levels of total tryptase, including a and b protryptases and mature b tryptase. The reporting detection sensitivity for this assay is set at 1 ng/mL, which is consistent with prior approval from the US Food and Drug Administration. The study was approved after Mayo Clinic Institutional Review Board review, and informed consent was obtained. The clinical features of the patients with SM are summarized in Table I. All 4 patients self-reported difficulty with concentration, sleep, and depressive symptoms. Three of the 4 patients reported chronic migraine. All patients had a normal neurologic examination and normal results on magnetic resonance imaging of the head. Control subjects had a mean age of 51.3 years (SD, 16.5 years), and 31 (48.4%) of 64 were female. Final diagnostic categories for these patients included neurodegenerative (n 5 20), primary headache disorder (n 5 12), nonneurologic (n 5 14), autoimmune/inflammatory (n 5 8), vascular (n 5 6), pseudotumor cerebri (n 5 3), and neoplastic (n 5 1) categories. Measurement of CSF tryptase levels decreased to less than the detection threshold in all patients with SM and all control subjects, except in 2 instances. One patient had an eventual diagnosis of amyotrophic lateral sclerosis (CSF tryptase level, 1.18 ng/mL), and the other had recently undergone surgical repair of a dural tear (CSF tryptase level, 1.84 ng/mL). In a small cohort of patients with prominent neuropsychological symptoms, we were unable to document evidence of
TABLE I. Clinical and laboratory summary of patients with mastocytosis Case 1
Age (y) Sex WHO classification Disease duration BM involvement c-kit Asp816Val mutation status Treatment STMS CES-D HDI Serum tryptase (ng/mL; normal, <11.5 ng/mL) CSF tryptase (ng/mL) Urinary NMH, 24 h (mg/gCr; normal, 30-200 mg/gCr) Urinary 11b PGF2a (ng/24 h; normal, <1000 ng/24 h)
41 Female ISM Urticaria pigmentosa 3 33 y, ISM 3 3 y <5% Positive Aspirin, doxepin, interferon alfa 38/38 24/60 59/100 21.3 <1 229 887
Case 2
Case 3
Case 4
46 Female ISM ISM 3 11 y
48 Female ISM ISM 3 3 y
62 Female ISM ISM 3 8 y
10% Not tested Aspirin, doxepin, hydroxyzine
5% Positive Aspirin, cromolyn sodium, ketotifen
5% to 10% Not tested Aspirin, doxepin, fexofenadine
38/38 32/60 78/100 3.2 <1 111 330
38/38 22/60 50/100 28.2 <1 595 240
38/38 28/60 0/100 118 <1 1610 424
BM, Bone marrow; CES-D, Center for Epidemiologic Studies Depression Scale; gCr, grams creatinine; HDI, Headache Disability Index; ISM, indolent systemic mastocytosis; NMH, N-methylhistamine; 11b PGF2a, prostaglandin F2a; STMS, Kokmen Short Test of Mental Status; WHO, World Health Organization.
LETTERS TO THE EDITOR 997
J ALLERGY CLIN IMMUNOL VOLUME 132, NUMBER 4
increased intrathecal mast cell activity. Although mast cells are found in diverse parenchymal regions in other animals, human neuropathologic studies show localization in mainly the dura mater and regions devoid of blood-brain barrier.6 Neuropathologic studies of patients with mastocytosis are lacking. The clinical observation that disodium cromoglycate might improve brain fog7 despite its inability to penetrate the bloodbrain barrier is consistent with the hypothesis that peripheral mast cell activity is important in the pathophysiology of neuropsychological symptoms. Along these lines, a recent series of patients without mastocytosis demonstrated a high correlation between gastrointestinal mucosal mast cell density and the presence of headache.8 However, other authors have noted a lack of association between serum tryptase levels and neuropsychological measures.1 The limitations of our study include the small number of patients, inclusion of only female patients, and the limited detection threshold of our assay. Evidence for intrathecal mast cell activity might very well be detected with a higher-sensitivity technique. In the one other study that has looked at tryptase levels in CSF, differences were found in patients with multiple sclerosis that were less than the detection threshold of our assay.5 Future studies should address the penetration of peripheral mast cell mediators across the blood-brain barrier and correlations with neuropsychological measures. This would be important because mast cell degranulation has a recognized capacity to disrupt the blood-brain barrier, directly modulate neuronal function, and change behavioral states.9 Multiple mast cell–derived mediators can influence neuronal activity, including serotonin, histamine, cytokines, and lipid-derived factors.9 Jonathan H. Smith, MDa Melissa R. Snyder, PhDb Catherine R. Weiler, MDc F. Michael Cutrer, MDa Joseph H. Butterfield, MDc From the Departments of aNeurology, bLaboratory Medicine and Pathology, and cAllergic Disease, Mayo Clinic, Rochester, Minn. E-mail: [email protected]. Supported by a foundation grant awarded by the Mastocytosis Society. Disclosure of potential conflict of interest: J. H. Smith, M. R. Snyder, C. R. Weiler, and F. M. Cutrer have received a foundation grant from the Mastocytosis Society. J. H. Butterfield has received a foundation grant from the Mastocytosis Society and receives royalties according to licensing agreements with MedImmune, Amgen, Janssen Biotech, Wyeth-Ayerst, and Actelion for the use of HMC-1 cells.
REFERENCES 1. Hermine O, Lortholary O, Leventhal PS, Catteau A, Soppelsa F, Baude C, et al. Case-control cohort study of patients’ perceptions of disability in mastocytosis. PLoS One 2008;3:e2266. 2. Rogers MP, Bloomingdale K, Murawski BJ, Soter NA, Reich P, Austen KF. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med 1986;48:437-47. 3. Escribano L, Alvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514-21. 4. Moura DS, Sultan S, Georgin-Lavialle S, Barete S, Lortholary O, Gaillard R, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012;7:e39468. 5. Rozniecki JJ, Hauser SL, Stein M, Lincoln R, Theoharides TC. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol 1995;37: 63-6. 6. Dropp JJ. Mast cells in the human brain. Acta Anatomica 1979;105:505-13. 7. Soter NA, Austen KF, Wasserman SI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med 1979;301:465-9.
8. Yeom JS, Choi MB, Seo JH, Park JS, Lim JY, Park CH, et al. Relationship between headache and mucosal mast cells in pediatric Helicobacter pylori-negative functional dyspepsia. Cephalalgia 2013;33:323-9. 9. Nautiyal KM, Ribeiro AC, Pfaff DW, Silver R. Brain mast cells link the immune system to anxiety-like behavior. Proc Natl Acad Sci U S A 2008;105:18053-7. Available online June 27, 2013. http://dx.doi.org/10.1016/j.jaci.2013.04.060
Efficacy and safety of thalidomide in patients with inflammatory manifestations of chronic granulomatous disease: A retrospective case series To the Editor: The prognosis of patients with chronic granulomatous disease (CGD) has improved in recent years thanks to earlier recognition and prevention of infectious complications.1 In this context an important concern remains the management of inflammatory manifestations (ie, colitis, interstitial pneumonitis, cystitis, or neutrophilic dermatosis). Gastrointestinal tract disorders, the prevalence of which can be as high as 60% and mimic Crohn disease (fistulae, perforations, and aseptic abscesses),2 can affect the quality of life and prognosis of these patients. Immunosuppressive agents (corticosteroids and azathioprine) are associated with significant adverse effects, mostly infections. Moreover, in a series of 5 patients treated with anti–TNF-a agents,3 infections were more frequent, and 2 deaths occurred despite effectiveness in severe colitis, thus raising concerns regarding their safety in such patients. The alternative in severe cases is allogeneic hematopoietic stem cell transplantation (HSCT).4 However, this procedure can be associated with significant mortality. In this retrospective study we report the clinical efficacy and safety profile of thalidomide, an immunomodulatory agent with TNF-a antagonist properties, in the inflammatory manifestations of CGD. Of 119 patients followed in the Centre de Reference des Deficits Immunitaires Hereditaires5 between 1968 and 2011, 70 (58.8%) experienced at least 1 inflammatory manifestation. Eight patients (7 male patients with mutations in CYBB and 1 female patient with a mutation in NCF1) received thalidomide for inflammatory manifestations (Table I). Their median age at diagnosis of CGD was 13 months (range, 1-188 months). Inflammatory conditions were colitis (n 5 6, see Fig E1 in this article’s Online Repository at www.jacionline.org), interstitial lung disease or nodular consolidation (n 5 4), neutrophilic dermatosis (n 5 1), and histologically proved granulomatous hepatitis (n 5 1). Inflammatory lung disease presented with 2 distinct patterns: mass-like nodular consolidation (patients 3 and 6, see Figs E2 and E3 in this article’s Online Repository at www. jacionline.org) and interstitial lung disease (patients 4 and 5, see Fig E4 in this article’s Online Repository at www. jacionline.org). The nodular consolidations corresponded to granuloma pathologically, and no evidence of infectious pneumonia was found at the time of their occurrence. Overall, 4 patients had only 1 inflammatory manifestation (colitis, n 5 3; granulomatous hepatitis, n 5 1), and 4 patients presented with 2 manifestations (colitis and pneumonia, n 5 3; pneumonia and neutrophilic dermatosis, n 5 1), leading to a total of 12 inflammatory flares.
J ALLERGY CLIN IMMUNOL OCTOBER 2013
9. Reubsaet LL, Boelens JJ, Rademaker C, Smal J, Wulffraat NM. Successful cord blood transplantation in a premature and dysmature neonate of 1700 g with reticular dysgenesis. Bone Marrow Transplant 2007;39:307-8. Available online June 12, 2013. http://dx.doi.org/10.1016/j.jaci.2013.04.055
Lack of evidence for intrathecal tryptase synthesis in patients with systemic mastocytosis To the Editor: Systemic mastocytosis (SM) is a rare disorder of unknown prevalence characterized by an increased number of abnormal clonal mast cells, which can be pathologically demonstrated as multifocal infiltrates in either the bone marrow or other extracutaneous sites. Neuropsychiatric symptoms in patients with mastocytosis are not only prevalent but also important contributors to patient disability.1 An early series of 10 patients with SM used objective neuropsychometric testing, which revealed a mixed cognitive-affective symptom complex termed by the authors ‘‘mixed organic brain syndrome.’’2 Diminished attention and short-term memory, in addition to irritability, were common findings. Escribano et al noted similar neuropsychiatric symptoms in 34 (23%) of 145 patients followed prospectively.3 A recent study has revealed findings of objective memory impairment in 22 (38.6%) of 57 patients independent of antihistaminic exposure and depression.4 Anxiety, rage, anger, fatigue, difficulty with concentration, poor motivation, and sleep disruption have all been noted in this population.2,3 This constellation of symptoms might comprise what patients with SM commonly report to physicians as ‘‘brain fog.’’ A fundamental and unanswered question is whether central nervous system mast cell activity is increased in patients with SM. Routine neuroimaging and cerebrospinal fluid (CSF) indices are invariably normal in the absence of comorbid neurologic illness. To further address this question, we prospectively obtained CSF from 4 patients with SM to directly test for tryptase, a specific marker of mast cell burden and activity. All met World Health Organization diagnostic criteria for indolent SM. All patients were evaluated by both a neurologist (J.H.S.) and an allergist (C.R.W. or J.H.B.). Additional study inclusion required age of 18
years or greater and a General Health Questionnaire score of 4 or greater. Patients with SM completed the Center for Epidemiologic Studies Depression Scale and the Headache Disability Index. Magnetic resonance imaging of the head with gadolinium was performed for all patients. Laboratory evaluation included measurement of both serum and CSF tryptase levels, which were coordinated to occur sequentially within 1 hour of the other, and measurements of 24-hour urinary 11b prostaglandin F2a and N-methylhistamine excretion. Control CSF samples were obtained from 64 patients undergoing lumbar puncture for routine clinical indications. We excluded patients with suspected or confirmed multiple sclerosis given the prior report of increased CSF tryptase levels in this population.5 Tryptase measurement was performed by using a fluorescence enzyme immunoassay with the ImmunoCAP 100 (Phadia, Uppsala, Sweden). The assay measured levels of total tryptase, including a and b protryptases and mature b tryptase. The reporting detection sensitivity for this assay is set at 1 ng/mL, which is consistent with prior approval from the US Food and Drug Administration. The study was approved after Mayo Clinic Institutional Review Board review, and informed consent was obtained. The clinical features of the patients with SM are summarized in Table I. All 4 patients self-reported difficulty with concentration, sleep, and depressive symptoms. Three of the 4 patients reported chronic migraine. All patients had a normal neurologic examination and normal results on magnetic resonance imaging of the head. Control subjects had a mean age of 51.3 years (SD, 16.5 years), and 31 (48.4%) of 64 were female. Final diagnostic categories for these patients included neurodegenerative (n 5 20), primary headache disorder (n 5 12), nonneurologic (n 5 14), autoimmune/inflammatory (n 5 8), vascular (n 5 6), pseudotumor cerebri (n 5 3), and neoplastic (n 5 1) categories. Measurement of CSF tryptase levels decreased to less than the detection threshold in all patients with SM and all control subjects, except in 2 instances. One patient had an eventual diagnosis of amyotrophic lateral sclerosis (CSF tryptase level, 1.18 ng/mL), and the other had recently undergone surgical repair of a dural tear (CSF tryptase level, 1.84 ng/mL). In a small cohort of patients with prominent neuropsychological symptoms, we were unable to document evidence of
TABLE I. Clinical and laboratory summary of patients with mastocytosis Case 1
Age (y) Sex WHO classification Disease duration BM involvement c-kit Asp816Val mutation status Treatment STMS CES-D HDI Serum tryptase (ng/mL; normal, <11.5 ng/mL) CSF tryptase (ng/mL) Urinary NMH, 24 h (mg/gCr; normal, 30-200 mg/gCr) Urinary 11b PGF2a (ng/24 h; normal, <1000 ng/24 h)
41 Female ISM Urticaria pigmentosa 3 33 y, ISM 3 3 y <5% Positive Aspirin, doxepin, interferon alfa 38/38 24/60 59/100 21.3 <1 229 887
Case 2
Case 3
Case 4
46 Female ISM ISM 3 11 y
48 Female ISM ISM 3 3 y
62 Female ISM ISM 3 8 y
10% Not tested Aspirin, doxepin, hydroxyzine
5% Positive Aspirin, cromolyn sodium, ketotifen
5% to 10% Not tested Aspirin, doxepin, fexofenadine
38/38 32/60 78/100 3.2 <1 111 330
38/38 22/60 50/100 28.2 <1 595 240
38/38 28/60 0/100 118 <1 1610 424
BM, Bone marrow; CES-D, Center for Epidemiologic Studies Depression Scale; gCr, grams creatinine; HDI, Headache Disability Index; ISM, indolent systemic mastocytosis; NMH, N-methylhistamine; 11b PGF2a, prostaglandin F2a; STMS, Kokmen Short Test of Mental Status; WHO, World Health Organization.
LETTERS TO THE EDITOR 997
J ALLERGY CLIN IMMUNOL VOLUME 132, NUMBER 4
increased intrathecal mast cell activity. Although mast cells are found in diverse parenchymal regions in other animals, human neuropathologic studies show localization in mainly the dura mater and regions devoid of blood-brain barrier.6 Neuropathologic studies of patients with mastocytosis are lacking. The clinical observation that disodium cromoglycate might improve brain fog7 despite its inability to penetrate the bloodbrain barrier is consistent with the hypothesis that peripheral mast cell activity is important in the pathophysiology of neuropsychological symptoms. Along these lines, a recent series of patients without mastocytosis demonstrated a high correlation between gastrointestinal mucosal mast cell density and the presence of headache.8 However, other authors have noted a lack of association between serum tryptase levels and neuropsychological measures.1 The limitations of our study include the small number of patients, inclusion of only female patients, and the limited detection threshold of our assay. Evidence for intrathecal mast cell activity might very well be detected with a higher-sensitivity technique. In the one other study that has looked at tryptase levels in CSF, differences were found in patients with multiple sclerosis that were less than the detection threshold of our assay.5 Future studies should address the penetration of peripheral mast cell mediators across the blood-brain barrier and correlations with neuropsychological measures. This would be important because mast cell degranulation has a recognized capacity to disrupt the blood-brain barrier, directly modulate neuronal function, and change behavioral states.9 Multiple mast cell–derived mediators can influence neuronal activity, including serotonin, histamine, cytokines, and lipid-derived factors.9 Jonathan H. Smith, MDa Melissa R. Snyder, PhDb Catherine R. Weiler, MDc F. Michael Cutrer, MDa Joseph H. Butterfield, MDc From the Departments of aNeurology, bLaboratory Medicine and Pathology, and cAllergic Disease, Mayo Clinic, Rochester, Minn. E-mail: [email protected]. Supported by a foundation grant awarded by the Mastocytosis Society. Disclosure of potential conflict of interest: J. H. Smith, M. R. Snyder, C. R. Weiler, and F. M. Cutrer have received a foundation grant from the Mastocytosis Society. J. H. Butterfield has received a foundation grant from the Mastocytosis Society and receives royalties according to licensing agreements with MedImmune, Amgen, Janssen Biotech, Wyeth-Ayerst, and Actelion for the use of HMC-1 cells.
REFERENCES 1. Hermine O, Lortholary O, Leventhal PS, Catteau A, Soppelsa F, Baude C, et al. Case-control cohort study of patients’ perceptions of disability in mastocytosis. PLoS One 2008;3:e2266. 2. Rogers MP, Bloomingdale K, Murawski BJ, Soter NA, Reich P, Austen KF. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med 1986;48:437-47. 3. Escribano L, Alvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514-21. 4. Moura DS, Sultan S, Georgin-Lavialle S, Barete S, Lortholary O, Gaillard R, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012;7:e39468. 5. Rozniecki JJ, Hauser SL, Stein M, Lincoln R, Theoharides TC. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol 1995;37: 63-6. 6. Dropp JJ. Mast cells in the human brain. Acta Anatomica 1979;105:505-13. 7. Soter NA, Austen KF, Wasserman SI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med 1979;301:465-9.
8. Yeom JS, Choi MB, Seo JH, Park JS, Lim JY, Park CH, et al. Relationship between headache and mucosal mast cells in pediatric Helicobacter pylori-negative functional dyspepsia. Cephalalgia 2013;33:323-9. 9. Nautiyal KM, Ribeiro AC, Pfaff DW, Silver R. Brain mast cells link the immune system to anxiety-like behavior. Proc Natl Acad Sci U S A 2008;105:18053-7. Available online June 27, 2013. http://dx.doi.org/10.1016/j.jaci.2013.04.060
Efficacy and safety of thalidomide in patients with inflammatory manifestations of chronic granulomatous disease: A retrospective case series To the Editor: The prognosis of patients with chronic granulomatous disease (CGD) has improved in recent years thanks to earlier recognition and prevention of infectious complications.1 In this context an important concern remains the management of inflammatory manifestations (ie, colitis, interstitial pneumonitis, cystitis, or neutrophilic dermatosis). Gastrointestinal tract disorders, the prevalence of which can be as high as 60% and mimic Crohn disease (fistulae, perforations, and aseptic abscesses),2 can affect the quality of life and prognosis of these patients. Immunosuppressive agents (corticosteroids and azathioprine) are associated with significant adverse effects, mostly infections. Moreover, in a series of 5 patients treated with anti–TNF-a agents,3 infections were more frequent, and 2 deaths occurred despite effectiveness in severe colitis, thus raising concerns regarding their safety in such patients. The alternative in severe cases is allogeneic hematopoietic stem cell transplantation (HSCT).4 However, this procedure can be associated with significant mortality. In this retrospective study we report the clinical efficacy and safety profile of thalidomide, an immunomodulatory agent with TNF-a antagonist properties, in the inflammatory manifestations of CGD. Of 119 patients followed in the Centre de Reference des Deficits Immunitaires Hereditaires5 between 1968 and 2011, 70 (58.8%) experienced at least 1 inflammatory manifestation. Eight patients (7 male patients with mutations in CYBB and 1 female patient with a mutation in NCF1) received thalidomide for inflammatory manifestations (Table I). Their median age at diagnosis of CGD was 13 months (range, 1-188 months). Inflammatory conditions were colitis (n 5 6, see Fig E1 in this article’s Online Repository at www.jacionline.org), interstitial lung disease or nodular consolidation (n 5 4), neutrophilic dermatosis (n 5 1), and histologically proved granulomatous hepatitis (n 5 1). Inflammatory lung disease presented with 2 distinct patterns: mass-like nodular consolidation (patients 3 and 6, see Figs E2 and E3 in this article’s Online Repository at www. jacionline.org) and interstitial lung disease (patients 4 and 5, see Fig E4 in this article’s Online Repository at www. jacionline.org). The nodular consolidations corresponded to granuloma pathologically, and no evidence of infectious pneumonia was found at the time of their occurrence. Overall, 4 patients had only 1 inflammatory manifestation (colitis, n 5 3; granulomatous hepatitis, n 5 1), and 4 patients presented with 2 manifestations (colitis and pneumonia, n 5 3; pneumonia and neutrophilic dermatosis, n 5 1), leading to a total of 12 inflammatory flares.