Rheumatology Advance Access published May 21, 2015

RHEUMATOLOGY

Concise report

262

doi:10.1093/rheumatology/kev129

Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience

Objectives. Tracheobronchial stenosis (TBS) is noted in 12–23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. Methods. We conducted a French nationwide retrospective study that included 47 patients with GPArelated TBS. Results. Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P = 0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose 530 mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. 1 Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, Hoˆpital Cochin, Assistance Publique-Hoˆpitaux de Paris (AP-HP), Universite´ Paris Descartes, 2 Department of Epidemiology, INSERM, U1153, Hoˆtel Dieu, AP-HP, Paris, 3Department of Internal Medicine, Hoˆpital Edouard Herriot, Lyon, 4Department of Respiratory Diseases, Hoˆpital Pontchaillou, IRSET UMR 1085, Universite´ de Rennes 1, Rennes, 5Department of Internal Medicine, Hoˆpital Foch, Suresnes, 6Department of Internal Medicine, Hoˆpital Avicenne, Bobigny, 7Department of Internal Medicine, Hoˆpital Haut-Le´veˆque, Bordeaux, 8Department of Internal Medicine, Hoˆpital Saint-Antoine, 9Department of Internal Medicine, Hoˆpital Bichat, Paris, 10Department of Internal Medicine, Hoˆpital Conception, Marseille, 11Department of Dermatology, Centre Hospitalier, Pontoise, 12Department of Internal Medicine, Hoˆpital La Timone, Marseille, 13Department of Nephrology, Hoˆpital Rangueil, Toulouse, 14Department of Internal Medicine, Hoˆpital Bretonneau, Tours, 15Department of Internal Medicine, SELARL Loire Intermed, nouvelles cliniques nantaises, 16Department of Internal Medicine, Hoˆtel Dieu, Nantes, 17Department of Rheumatology, Hoˆpital Bichat, Paris, 18Department of Internal Medicine, Hoˆpital Estaing,

Clermont-Ferrand, 19Department of Internal Medicine, Hoˆpital Henri Mondor, Cre´teil, 20Department of Internal Medicine, Hoˆpital Purpan, Universite´ de Toulouse, 21Department of Internal Medicine, Hoˆpital Lapeyronnie, Montpellier, 22Department of Internal Medicine and Clinical Immunology, Hoˆpital du Bocage, Dijon, 23Department of Pneumonology and Thoracic Surgery, Hoˆpital Foch, Suresnes and 24 Department of Otolaryngology, Hoˆpital Cochin, AP-HP, Universite´ Paris Descartes, Paris, France

Submitted 31 July 2014; revised version accepted 24 March 2015 Correspondence to: Benjamin Terrier, Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, Hoˆpital Cochin, Assistance Publique-Hoˆpitaux de Paris (AP-HP), Universite´ Paris Descartes, Hoˆpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. E-mail: [email protected] *Charlotte Girard and Ste´phane Jouneau contributed equally to this study.

! The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]

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CLINICAL SCINECE

Abstract

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Benjamin Terrier1, Agne`s Dechartres2, Charlotte Girard3,*, Ste´phane Jouneau4,*, Jean-Emmanuel Kahn5, Robin Dhote6, Estibaliz Lazaro7, Jean Cabane8, Thomas Papo9, Nicolas Schleinitz10, Pascal Cohen1, Edouard Begon11, Pauline Belenotti12, Dominique Chauveau13, Elisabeth Diot14, Thierry Ge´ne´reau15, Mohamed Hamidou16, Gilles Hayem17, Guillaume Le Guenno18, Ve´ronique Le Guern1, Marc Michel19, Guillaume Moulis20, Xavier Pue´chal1, Sophie Rivie`re21, Maxime Samson22, Franc¸ois Gonin23, Claire Le Jeunne1, Pascal Corlieu24, Luc Mouthon1 and Loic Guillevin1 , on behalf of the French Vasculitis Study Group

Benjamin Terrier et al.

Conclusion. TBS represents severe and refractory manifestations with a high rate of restenosis. Highdose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis. Key words: granulomatosis with polyangiitis, tracheobronchial involvement, subglottic stenosis, bronchial stenosis, prosthesis, dilatation.

Rheumatology key messages Cumulative incidence of endoscopic treatment failure of tracheobronchial stenoses in granulomatosis with polyangiitis reaches 50% at 1 year. . Shorter time from granulomatosis with polyangiitis diagnosis to procedure is associated with higher endoscopic treatment failure of tracheobronchial stenosis. . Prednisone 530 mg/day is associated with lower cumulative incidence of endoscopic treatment failure of tracheobronchial stenoses in granulomatosis with polyangiitis. .

Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis affecting predominantly smallsized vessels [1], usually involving the ENT, lungs and kidneys. GPA is associated with ANCA, most frequently directed against proteinase 3 [1]. GPA may also involve the tracheobronchial tree in 12–23% of cases [2–4], including subglottic stenosis, ulcerating tracheobronchitis with or without inflammatory pseudotumours and/or bronchial stenosis [5]. These stenoses may occur as the first manifestation of GPA, but more frequently appear during the course of the disease [3, 6]. Subglottic stenosis and/or bronchial stenosis can be life-threatening and/or associated with significant morbidity [6, 7]. The course of subglottic stenosis and bronchial stenosis seems to be independent of systemic disease activity [3, 5]. Along this line, distinguishing stenoses due to active disease from those caused by tissue scarring is challenging [8]. Previous studies demonstrated that systemic treatments were frequently disappointing and that patients required repeated bronchoscopic interventions in half of cases [3]. However, the optimal systemic treatments and endoscopic interventions providing the best efficacy, and the best timing for such interventions, remain unclear, explaining why, in the 2010s, subglottic stenosis and bronchial stenosis remain a therapeutic challenge in the management of GPA patients. In the present work we analyse the endoscopic management of tracheobronchial stenosis (TBS) in GPA patients and the factors associated with the efficacy of endoscopic interventions.

Methods Selection of patients This retrospective and multicentre cohort study was conducted in French departments of internal medicine, nephrology and pulmonology, members of the French Vasculitis Study Group (FVSG), to collect cases fulfilling

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the following inclusion criteria: diagnosis of GPA satisfying the ACR [9] and/or responding to the definitions of the Chapel Hill nomenclature [1], with TBS and requiring one or more endoscopic interventions. We also compared these TBS patients with GPA patients without TBS (n = 615) included in the FVSG database. This study was conducted in compliance with the protocol of Good Clinical Practices and the Declaration of Helsinki principles and conforms to standards currently applied in France. In accordance with French law, formal approval from an ethics committee was not required for this type of study.

Clinical, laboratory and endoscopic assessment For each patient, data were recorded at the time of initial evaluation, at the time of each endoscopic intervention, during follow-up and at the end of follow-up. All features of GPA diagnosis, tracheobronchial involvement and events related to endoscopic interventions were noted. All data were collected using a standardized form. Disease activity was evaluated using the BVAS for GPA (BVAS/GPA) [10]. Laboratory assessment included routine analyses, in particular ANCA status. Endoscopic parameters included interventions, acute complications during procedures and late events attributable to endoscopic procedures. Infectious events and death were also recorded.

Response to endoscopic intervention Results of endoscopic interventions were recorded by analysing the time to treatment failure, defined as the time from intervention to restenosis, to endoscopy or stenosis-related event and/or death attributable to TBS. Endoscopy or stenosis-related events included haemorrhages, alveolar hypoventilation, airway obstruction and/ or pneumothorax for early complications, and restenosis, periprosthetic stenosis and/or prosthesis migration or expulsion for late complications. Restenosis was defined as the reappearance of clinical signs (i.e. dyspnoea) in the

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Introduction

Tracheobronchial stenoses in GPA

presence of endoscopic signs of TBS leading to new endoscopic intervention.

Statistical analysis

Results Characteristics of patients Forty-seven GPA patients were included, among whom three patients exhibited an overlap form with relapsing polychondritis. The characteristics of the 47 patients are shown in Table 1. TBS was present at the time of GPA diagnosis in 24 patients (51%) and after GPA diagnosis in the remaining 23 patients (49%), with a median interval of 44 months (range 20–71). Compared with patients without TBS, patients with TBS were younger at diagnosis of GPA [mean age 41.0 years (S.D. 15.0) vs 51.4 (16.0), P < 0.0001], more frequently female (62% vs 42%, P = 0.014) and more frequently of Arabic (10.9% vs 4.0%, P = 0.050) and sub-Saharan Africa or West Indian origin (8.7% vs 3.0%, P = 0.064). GPA patients with TBS also less frequent had kidney (28% vs 58%, P < 0.0001), ocular (15% vs 32%, P = 0.014) and gastrointestinal involvement (2.1% vs 11%, P = 0.049) and mononeuritis multiplex (11% vs 21%, P = 0.092) compared with GPA patients without TBS. ENT involvement and pulmonary nodules did not significantly differ between the two groups.

Characteristics of TBS and endoscopic procedures The characteristics of tracheobronchial involvement are summarized in Table 1. The 47 patients underwent a total of 173 endoscopic procedures because of New York Heart Association classes II–IV dyspnoea, in the absence of other cause of dyspnoea, with a median number of two interventions per patient (1–20). The median interval between GPA diagnosis and first endoscopic intervention was 22 months (range 0.5–273). Endoscopic procedures included 137 tracheal and 50 bronchial interventions.

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Variable

Value

Demographics Age at GPA diagnosis, median 40 (range), years Female, n (%) 29 Ethnicity, n (%) Caucasian 37 Arab 5 Sub-Saharan African 4 Asian 1 Missing data 1 Characteristics of GPA at diagnosis, n (%) ENT 39 Pulmonary 29 Nodules 24 Intra-alveolar haemorrhage 9 Arthralgia/arthritis 19 GN 13 Skin 12 Eye 7 Myalgia 6 Mononeuritis multiplex 5 Orbital tumour 1 Gastrointestinal 1 GPA disease activity at diagnosis BVAS/GPA, median (range) 5 Severe disease/flare, n (%) 21 Limited disease/flare, n (%) 26 Persistent disease, n (%) 0 Positive ANCA, n (%) 38 Anti-PR3 specificity, n (%) 34 Anti-MPO specificity, n (%) 4 Tracheobronchial involvement, n (%) Stenosis present at diagnosis of GPA 24 Stenosis occurring after diagnosis of GPA 23 Subglottic stenosis 35 Bronchial stenosis 6 Tracheal and bronchial stenosis 6 GPA disease activity at endoscopic procedures BVAS/GPA, median (range) 1 Severe disease/flare, n (%) 5 Limited disease/flare, n (%) 53 Persistent disease, n (%) 115 Positive ANCA, n (%) 54/158

(16–78) (62) (78) (11) (9) (2)

(83) (62) (51) (19) (40) (28) (26) (15) (13) (11) (2) (2) (1–21) (45) (55) (0) (81) (89) (11) (51) (49) (74) (13) (13) (1–12) (3) (32) (65) (34)

BVAS/GPA: BVAS for GPA; GPA: granulomatosis with polyangiitis.

The most frequently performed interventions to treat subglottic stenosis were tracheal dilatation (n = 101), local steroid injection (n = 38), conservative laser surgery (n = 23) and stenting (n = 9), whereas bronchial stenoses were mainly treated by endoscopic dilatation (n = 48), and less frequently by silicone or metal stenting (n = 10) or conservative laser surgery (n = 9). After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years.

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Descriptive statistics included frequencies for categorical variables and mean (S.D.) or median (range) for continuous variables. Analysis included chi-square or Fisher’s exact test as appropriate to compare categorical variables and the non-parametric Mann–Whitney test to compare continuous variables. We assessed factors associated with time to treatment failure, taking into account correlation of observations for the same patient and stratification according to the rank of the event, with a conditional Cox model recommended to analyse multiple events per subjects [11]. In a first step, we identified all factors potentially associated with time to recurrence of stenosis or complications by performing univariate models to test each variable. Then we introduced in a multivariate Cox conditional model all factors associated with a P-value 30 mg/day of prednisone, AZA in 66 cases (38%), MTX in 33 cases (19%), IVIGs in 23 cases (13%), i.v. CYC in 17 cases (10%), oral CYC in 13 cases (7.5%), MMF in 13 cases (7.5%), rituximab as maintenance therapy in 11 cases (6.4%), rituximab as induction therapy in 10 cases (5.8%) and infliximab in 9 cases (5.2%).

Adverse events related to endoscopic interventions and outcome Per-endoscopic events were noted in only 5/173 cases (2.9%) and included haemorrhage (n = 4), alveolar hypoventilation (n = 1) and airway obstruction (n = 1). Adverse

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events occurring after the procedure were noted in 132/173 cases (76%) and included restenosis (n = 125), periprosthetic stenosis (n = 12), prosthesis migration (n = 4; 2 for subglottic stenosis and 2 for bronchial stenoses) and prosthesis expulsion (n = 1). After a median follow-up of 112 months (range 10–324), the median BVAS/GPA was 1 (range 0–5). Thirty-six patients (77%) had persistent TBS, including subglottic stenosis in 27 and bronchial stenoses in 11. Persistent stenoses were considered, based on subjective endoscopic characteristics, to be fibrous and scarring in 33 cases (92%) and inflammatory in 3 cases (8%). Thirtysix patients (77%) remained under long-term CS therapy, at a median prednisone dose of 7.25 mg/day (range 4–30), while 34 patients (72%) remained on immunosuppressive agents. Finally, 13 patients (28%) experienced recurrent bacterial bronchopulmonary infections as late complications of TBS, which were fatal in 2 cases (4%). No other deaths occurred.

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Demographics Agea Male GPA characteristics at the time of the procedure BVAS/GPA Severe and systemic flare (vs persistent disease) Mild flare (vs persistent disease) Positive ANCA (vs negative) Systemic treatment at the time of the procedure Prednisone doseb Prednisone dose >30 mg/day CYC, i.v. CYC, oral CYC, i.v. or oral RTX induction regimen CYC or RTX induction regimen RTX maintenance regimen Conventional IS (MTX, AZA) IVIG Infliximab Characteristics of endoscopic procedures Time from GPA diagnosis to procedurec Bronchial intervention (vs tracheal intervention alone) Tracheal and bronchial intervention (vs tracheal intervention alone) Local dilatation Local steroid injection Conservative laser surgery Endoprothesis Endoscopic resection of granulomatous lesions

Univariate analysis, HR (95% CI)

Tracheobronchial stenoses in GPA

Factors associated with the efficacy of endoscopic interventions We analysed factors potentially associated with time to endoscopic treatment failure. The results of the univariate and multivariate analyses are shown in Table 2. In multivariate analysis, a shorter time from GPA diagnosis to endoscopic procedure and bronchial stenosis were associated with a higher cumulative incidence of treatment failure, whereas a prednisone dose 530 mg/day was associated with a lower cumulative incidence of treatment failure.

Discussion

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Acknowledgements Conception and design: B.T., L.G.; analysis and interpretation: B.T., A.D., C.G., S.J., J.E.K., R.D., E.L., J.C., T.P., N.S., P.C., E.B., P.B., D.C., E.D., T.G., M.H., G.H., G.L.G.,V.L.G., M.M., G.M., X.P., S.R., M.S., F.G., C.L.J., P.C., L.M., L.G.; drafting the manuscript for important intellectual content: B.T., L.G. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: L.G. received fees from Roche Pharma in 2012. Roche Pharma provided rituximab for prospective academic trials in ANCA-associated vasculitides. All other authors have declared no conflicts of interest.

References 1 Jennette JC, Falk RJ, Bacon PA et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1–11.

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In the era of highly effective induction and maintenance therapeutic regimens in GPA, TBS remains a therapeutic challenge in the management of patients. Most of the previous studies on this topic are in agreement on the benefits of endoscopic procedures [3, 12, 13]. However, few data are available on the long-term outcomes of these patients and the ways to prevent restenosis and reduce the need for additional procedures. We observed that patients with TBS exhibit more a granulomatous grumbling phenotype rather than a vasculitis phenotype, which could explain why these patients remained under long-term CSs and immunosuppressive agents. Various endoscopic procedures have been used in GPA patients with TBS. Local dilatation and conservative laser surgery have been widely used in subglottic stenosis as well as in bronchial stenosis [12, 14, 15]. However, the use of local steroid injections was restricted to subglottic stenosis, whereas stenting represented a frequent endoscopic therapeutic option in patients with bronchial stenosis. In contrast, topical mitomycin and cryotherapy have rarely been used [16, 17]. Overall, this seems to be a consensus in studies on the use of these therapeutic options for treating subglottic stenosis and bronchial stenosis, with a favourable safety profile for both strategies. However, besides the low rate of per-procedure complications, we observed high rates of treatment failure, demonstrating the need to identify characteristics associated with a better efficacy of endoscopic interventions. We analysed and identified some factors associated with a better event-free survival after endoscopic intervention in GPA patients. In agreement with a previous study [3], our data confirm that the outcome of TBS is independent of GPA-related features, such as disease activity or ANCA status. In contrast, we observed that a shorter time from GPA diagnosis to endoscopic procedure was associated with a higher cumulative incidence of treatment failure, which suggests that endoscopic procedures should be performed long after maximal inflammatory activity of tracheobronchial stenoses. Regarding systemic treatments, we found that CS at a dose 530 mg/day in combination with endoscopic intervention was associated with a better event-free survival, whereas the use of immunosuppressive agents did not seem to impact on the risk of restenosis and/or complications. These findings

suggest that CS should be increased (>30 mg/day) at the time of the procedure in order to decrease the risk of restenosis. The use of new tools that could assess inflammatory activity of tracheobronchial stenoses could be of critical interest in the therapeutic management of these patients. Klink et al. [18] evaluated the ability of MRI and demonstrated that MRI was able to detect and grade subglottic stenosis in patients with GPA and to assess the status of inflammatory activity. 18F-fluorodeoxyglucose PET/CT could also represent an interesting tool to assess the inflammatory activity of lesions in GPA [19, 20], as it was suggested in relapsing polychondritis [21]. Thoracic CT scan could also be useful, in particular the presence (or not) of peritracheal and/or peribronchial infiltration and the characteristics of tracheal and/or bronchial thickness, but only a minority of patients had a CT scan, which does not allow any conclusions from our series on its use. Finally, our study has some limitations. Although it represents a large series of GPA patients with TBS requiring endoscopic interventions, it is limited by the retrospective design and the sample size. However, we used as judgement criteria the requirement for new endoscopic interventions based on the reappearance of clinical and/or endoscopic signs of TBS, which represents a relevant criterion in daily practice. In addition, we were unable to evaluate the impact of histological data on the rate of restenosis, as well as the impact of colonization by bacteria. In conclusion, our data suggest that high-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenoses.

Benjamin Terrier et al.

2 Monach PA. L25. Medical treatment of subglottic stenosis in granulomatosis with polyangiitis (Wegener’s). Presse Med 2013;42:575–6. 3 Langford CA, Sneller MC, Hallahan CW et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis. Arthritis Rheum 1996;39:1754–60. 4 Hoffman GS, Kerr GS, Leavitt RY et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488–98. 5 Daum TE, Specks U, Colby TV et al. Tracheobronchial involvement in Wegener’s granulomatosis. Am J Respir Crit Care Med 1995;151:522–6.

7 Lebovics RS, Hoffman GS, Leavitt RY et al. The management of subglottic stenosis in patients with Wegener’s granulomatosis. Laryngoscope 1992;102: 1341–5. 8 Hernandez-Rodriguez J, Hoffman GS, Koening CL. Surgical interventions and local therapy for Wegener’s granulomatosis. Curr Opin Rheumatol 2010;22:29–36. 9 Bloch DA, Michel BA, Hunder GG et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Patients and methods. Arthritis Rheum 1990;33:1068–73.

13 Hoffman GS, Thomas-Golbanov CK, Chan J, Akst LM, Eliachar I. Treatment of subglottic stenosis, due to Wegener’s granulomatosis, with intralesional corticosteroids and dilation. J Rheumatol 2003;30:1017–21. 14 Rasmussen N. L24. Local treatments of subglottic and tracheal stenoses in granulomatosis with polyangiitis (Wegener’s). Presse Med 2013;42:571–4. 15 Wolter NE, Ooi EH, Witterick IJ. Intralesional corticosteroid injection and dilatation provides effective management of subglottic stenosis in Wegener’s granulomatosis. Laryngoscope 2010;120:2452–5. 16 Arebro J, Henriksson G, Macchiarini P, Juto JE. New treatment of subglottic stenosis due to Wegener’s granulomatosis. Acta Otolaryngol 2012;132:995–1001. 17 Krimsky WS, Rodrigues MP, Malayaman N, Sarkar S. Spray cryotherapy for the treatment of glottic and subglottic stenosis. Laryngoscope 2010;120:473–7. 18 Klink T, Holle J, Laudien M et al. Magnetic resonance imaging in patients with granulomatosis with polyangiitis (Wegener’s) and subglottic stenosis. MAGMA 2013;26:281–90. 19 Ito K, Minamimoto R, Yamashita H et al. Evaluation of Wegener’s granulomatosis using 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Ann Nucl Med 2013;27:209–16.

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6 Gluth MB, Shinners PA, Kasperbauer JL. Subglottic stenosis associated with Wegener’s granulomatosis. Laryngoscope 2003;113:1304–7.

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Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience.

Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronc...
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