Lung transplantation in systemic sclerosis: A single center cohort study

Accepted Manuscript Title: Lung transplantation in systemic sclerosis: a single center cohort study Author: Andreu Fern´andez-Codina Cristina Berastegui Iago Pinal-Fern´andez Mar´ıa Guadalupe Silveira Manuel L´opez-Meseguer V´ıctor Monforte Alfredo Guill´en-del Castillo Carmen Pilar Sime´on-Aznar Vicent Fonollosa-Pl`a Joan Sol´e Carlos Bravo-Masgoret Antonio Rom´an-Broto PII: DOI: Reference:

S1297-319X(17)30075-1 http://dx.doi.org/doi:10.1016/j.jbspin.2017.03.012 BONSOI 4569

To appear in: Received date: Accepted date:

22-12-2016 15-3-2017

Please cite this article as: Fern´andez-Codina A, Berastegui C, Pinal-Fern´andez I, Silveira MG, L´opez-Meseguer M, Monforte V, Castillo AG-d, Sime´on-Aznar CP, Fonollosa-Pl`a V, Sol´e J, Bravo-Masgoret C, Rom´an-Broto A, Lung transplantation in systemic sclerosis: a single center cohort study, Joint Bone Spine (2017), http://dx.doi.org/10.1016/j.jbspin.2017.03.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Manuscript

Lung transplantation in systemic sclerosis: a single center cohort study

Andreu Fernández-Codina1, Cristina Berastegui2; Iago Pinal-Fernández1; María Guadalupe Silveira2; Manuel López-Meseguer2; Víctor Monforte2; Alfredo Guillén-del Castillo1; Carmen

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Pilar Simeón-Aznar1; Vicent Fonollosa-Plà1; Joan Solé3; Carlos Bravo-Masgoret2; Antonio

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Román-Broto2

1

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Systemic Autoimmune Diseases Unit, Hospital Universitari Vall d'Hebron, Universitat

Autònoma de Barcelona, Passeig de la Vall d’Hebron 119-129, 08035, Barcelona, Spain 2

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Lung Transplant Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de

Barcelona, Passeig de la Vall d’Hebron 119-129, 08035, Barcelona, Spain 3

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Thoracic Surgery Department; Hospital Universitari Vall d'Hebron, Universitat Autònoma

Corresponding author/reprints:

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de Barcelona, Passeig de la Vall d’Hebron 119-129, 08035, Barcelona, Spain

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Carlos Bravo-Masgoret. [email protected] Phone: (0034) 93 489 30 00 / 93 274 60 00

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Abstract: Objective: Lung transplantation (LT) has been proposed as a treatment for advanced Interstitial Lung Disease (ILD) and/or Pulmonary Hypertension (PH) associated to Systemic Sclerosis (SSc) but few studies have been reported. The aim of this study was to describe

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the clinical features, complications and survival of a single-center cohort of patients with SSc that underwent LT and to compare their survival with a group of non-SSc transplanted

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patients.

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Methods: Fifteen patients with SSc were transplanted between May 2005 and April 2015. Standard international criteria were used to determine eligibility for LT. The severity of

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gastroesophageal involvement was not considered as a major contraindication if symptoms were under control.

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Results: Eight (53.3%) patients had diffuse cutaneous SSc. Eleven (73%) underwent bilateral LT. The main indication for LT was ILD, with or associated PH in 4 cases. Acute

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cellular rejection and infections were the most frequent complications. Functional lung tests tended to keep stable after transplantation. Median survival was 2.4 years (Q1-Q3 0.7-3.7

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years). We did not find differences in survival between patients transplanted with SSc versus those transplanted due to non-SSc ILD or PH. SSc Complications were scarce with no patient developing PH after LT.

Conclusions: LT was an effective treatment for advanced ILD and/or PH associated to SSc

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in our study. Gastroesophageal reflux was not a limitation for LT in SSc in this study. Complications and survival did not differ from non-SSc patients undergoing LT.

Key words: transplantation; systemic sclerosis; lung diseases

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Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by the presence of specific autoantibodies and the activation of an inflammatory cascade, which ultimately

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leads to fibrosis and vascular injury. In the last three decades, the main mortality causes in SSc shifted from scleroderma renal crisis (SRC) to interstitial lung disease (ILD), pulmonary

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arterial hypertension (PAH) and cardiac involvement [1, 2] Effective therapeutic

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management of SRC with angiotensin converter enzyme inhibitors led to that change. Current medical treatment for ILD and PAH (Group 1) or secondary pulmonary

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hypertension (PH) rather slows disease progression than heals patients. In the last twenty years, lung transplantation (LT) has emerged as a possible therapeutic tool against these

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two deadly manifestations of SSc in refractory cases [3,4]. Some centers may avoid LT in

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this group of patients due to concerns about short and long term outcomes [5]. To our knowledge, only a few studies, with a small number of patients enrolled, have focused in

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SSc LT [3]. Idiopathic pulmonary fibrosis (IPF) and SSc-ILD share similar pathologic alterations but long-term survival is greater in the second [6]. Idiopathic pulmonary arterial hypertension (IPAH) currently has a similar prognosis to SSc-PAH. In the setting of endstage respiratory failure and LT, ILD and IPAH patients have been compared with patients

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with SSc. Selected patients with SSc who received a lung transplant experienced rates of survival similar to those of patients with ILD or IPAH [3]. Still, there is controversy in whether LT in SSc is really indicated and when, if it may give patients a better quality of life or if it could increase survival [7]. We conducted single-center a cohort study to assess the clinical characteristics, mortality and evolution of pulmonary function tests over time in SSc LT, and compared the survival of these patients with subjects who underwent LT due to other causes. 3 Page 3 of 27

Methods Patient selection

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Patients with and without SSc were selected from a third level teaching hospital (Hospital Universitari Vall d’Hebron, Barcelona, Spain) with a lung transplantation program. Patients

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were included from February 2005 to April 2015. All individuals diagnosed with SSc fulfilled

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LeRoy and Medsger’s classification [8]. Subjects who underwent LT were referred from our own center or peripheral institutions. Patients were evaluated for LT in accordance with the

gastroesophageal

involvement

(GI),

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international guidelines for selection of LT candidates [9]. The presence of severe especially

gastroesophageal

reflux,

was

not

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considered an absolute contraindication for LT, providing that symptoms were controlled

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medically prior to surgery. During the pre-transplantation assessment, GI was not systematically studied in any patient unless symptoms were present (whether patients had

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SSc or not). If symptoms appeared, investigations were made according to the clinicians’ choice, including: upper gastrointestinal endoscopy, esophageal manometry and pH metry. Then, patients underwent specialized evaluation and intensive medical treatment with proton pump inhibitors, prokynetics, anti-acid drugs and postural measures. No pre or post-

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transplant gastrojejunal tube placement or antirreflux surgery definite protocols were adopted. The non-SSc cohort was obtained from our LT database, including 500 patients who underwent LT in our center from January 2005 to April 2015. These patients were transplanted mainly due to ILD and chronic obstructive pulmonary disease (COPD). The study period ended in June 2015 for both groups. The Vall d’Hebron Hospital Ethics committee considered the study ethically and scientifically suitable (Session 275). The

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International Society of Heart and Lung Transplantation (ISHLT) ethics code was met. No external financial support was received.

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Clinical assessment A standardized data collection form was fulfilled for every patient including: sex, race,

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date of birth, date of transplantation, smoking habit, toxic exposure, previous treatments,

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date of decease and cause of death.

Two groups of SSc patients were established according to the extent of skin sclerosis [8]: Limited cutaneous SSc (lcSSc), when skin sclerosis was absent or confined distally

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•

to elbows and knees or face.

Diffuse cutaneous SSc (dcSSc) when skin thickening extended proximally to elbows

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•

and knees or included trunk.

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The SSc clinical features evaluated were: presence of Raynaud phenomenon (RP); digital ulcers (DU) at physical examination; musculoskeletal involvement, including arthritis,

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arthralgia and tendon friction rubs; gastro-esophageal involvement, that consisted in hypomotility of the lower two thirds of the esophagus and/or decreased peristalsis or gastroesophageal reflux, assessed clinically and confirmed by manometry, radioscopy, pHmetry or endoscopic studies; ILD, when a pulmonary interstitial pattern was evidenced by

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High-Resolution Computerized Tomography; cardiac involvement, defined as having any of the manifestations included by Desai et al. [10]; PH, when the mean pulmonary arterial pressure was found to be equal or higher than 25 mmHg by right–sided heart catheterization; SRC as defined by Traub et al [11].

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Immunologically,

anticentromere

autoantibodies

(ACA)

were

detected

by

immunofluorescence assay on Hep-2 cell substrate; and antitopoisomerase-I antibodies (ATA) were detected by immunoblotting. The different pathologies that led to LT were recorded in the non-SSc LT group, which was

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used as a control. Non-SSc ILD was considered when patients had a pulmonary interstitial pattern by High-Resolution Computerized Tomography or if a biopsy specimen confirmed

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the disease. IPAH was defined according to the European guidelines [12]. Patients were

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diagnosed with IPAH only when pulmonary arterial pressure was ≥25 mmHg by right-heart

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catheterization and after discarding all the other known causes of secondary PH.

Pulmonary assessment

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Lung function was tested when patients underwent evaluation for LT for the first time and after LT at 6, 12, 24, 32 and 44 months. Single LT was assigned to those patients with only

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ILD. Patients with ILD and PH or only with PH received bilateral LT. The immunosuppressive regime included in first line tacrolimus, mycophenolate mophetil and

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methylprednisolone. Second line drugs available were everolimus and rapamicine. All patients received individualized antibacterial prophylaxis, ganciclovir, amphotericine B and cotrimoxazole. During follow-up, when infections or rejection were suspected, directed cultures and image techniques or fiber optic-flexible bronchoscopy with bronchoalveolar

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lavage and transbronchial biopsies were performed. Infections were diagnosed once cultures or viral polymerase chain reaction kits were positive. Acute rejection was described using the ISHLT criteria, and graded from 1 to 4 [13]. Treatment of acute rejection was based on methylprednisolone boluses and high doses of oral or endovenous corticosteroids. Chronic lung allograft dysfunction (CLAD) was considered when bronchiolitis obliterans or restrictive allograft syndrome appeared, as previously described

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[14]. The cause of death was established by chart review, case by case, by two expert physicians.

Scleroderma assessment:

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SSc-related complications and flares were recorded during the follow-up after LT. PH screening was made with transthoracic echocardiography (if pulmonary systolic arterial

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pressure was estimated to be above 40 mmHg, diagnosis was confirmed through right

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heart catheterization). Supplementary treatments added to LT-related immunosuppression were also recorded.

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Statistical analysis

Categorical variables were expressed as percentages and absolute frequencies, while

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continuous parameters were expressed as medians and first and third quartiles (Q1-Q3). Univariate comparisons between groups were made using the Wilcoxon rank-sum test for

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continuous variables and Fisher’s exact test for categorical variables. The Kaplan–Meier method was used to calculate survival estimates, and Cox proportional-

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hazards regression analysis was used to estimate unadjusted hazard ratios (HR). Mixed effects linear regression was used to calculate the unbiased evolution of the pulmonary function tests over time.

Statistical analyses were performed with Stata v.13. P-values less than 0.05 were

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considered statistically significant.

Results: Patients Fifteen patients with SSc underwent LT at our center during the study period. Seven patients (46.6%) presented lcSSc and 8 (53.3%) dcSSc, with female predominance (67%). 7 Page 7 of 27

Nine subjects (60%) had been smokers in the past and one had been exposed to silica while working. These patients, before referral for LT, had been under treatment with: nacetylcysteine 8 (53.3%), corticosteroids 13 (86.6%), d-penicillamine 2 (13.3%), mofetil mycophenolate 8 (53.3%), cyclophosphamide 11 (73.3%), methotrexate 1 (6.6%),

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azathioprine 9 (60%), rituximab 3 (20%), 7 (46.6%) sildenalfil, 5 (33.3%) bosentan, and 4 (26.6%) prostaglandins. Only one patient with PAH and another with ILD associated to

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silicosis did not receive disease modifying antirheumatic drugs. All subjects but one

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required home oxygen therapy. The baseline characteristics and manifestations regarding their connective tissue disease are shown in Table 1. All patients had upper gastrointestinal

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tract symptoms including hiatal hernia in two, severe esophagus hypomotility in four and Barrett’s' esophagus in one.

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The main indication for LT in the SSc group was ILD, with or without associated PH (ILD 8 patients, ILD+PH 4 cases, PH 3 cases). Only one patient was transplanted because of

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genuine PAH without lung fibrosis, the other two had minor ILD. Bilateral LT was the preferred modality of transplantation (Table 2). The main complications during the

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immediate period after surgery and the complications appeared at long term are shown in Table 3. Gastric and diaphragmatic palsy were transitory in all but one patient, who persisted with severe gastric palsy and required percutaneous endoscopic gastrostomy. Regarding bronchial stenosis, one patient required bronchial stenting. Acute cellular

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rejection occurred in nine (60%) patients, with stages from A1 to A3, and one patient himself presented 3 episodes. The mean time from the moment of the surgery to the first acute cellular rejection episode was 16 days (Q1-Q3: 15-42 days). Two patients who developed skin cancer were switched from mofetil mycophenolate to everolimus or sirolimus. One patient was diagnosed with a preexisting lung cancer in the explant, which went undetected in the initial screening. The non-SSc-LT cohort was composed mainly of

8 Page 8 of 27

patients with ILD and COPD. The whole composition of the non-SSc ILD group and the non-SSc PH group are shown in Table 4. Their main characteristics are shown on Table 2. SSc-LT group had a higher percentage of females than the non-SSc cohort. The rest of

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comparisons did not reach statistical signification.

Survival and follow-up

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Within the 15 patients with SSc that underwent LT, five died. None of them died in the first

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30 days after LT. Two passed away within the first year after transplantation. Four deceases (80%) where caused by sepsis and another one due to a pre-existing pulmonary

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neoplasm (seven months after transplantation). Taking into consideration the SSc subsets, 3 patients with lcSSc and 2 with dcSSc dyed. In the non-SSc group, mortality in the first 30

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days after LT was 7.61%. The causes of death did not differ between SSc and non SSc patients. In both groups, sepsis was the leading cause of death. Median time from LT to

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death and follow-up were similar between the SSc group and the rest of the patients (Table 2). Kaplan Meier curves comparing SSc versus the non-SSc group (Figure 1), SSc patients

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versus the subgroup of individuals transplanted due to non-SSc ILD (Figure 2, panel A), and SSc patients versus the subgroup of subjects transplanted because of non-SSc PH (Figure 2, panel B), did not show statistically significant differences. Patients with non-SSc PH had a higher mortality rate (43%) during the first year than SSc patients (15%).

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However, after the first year of follow-up, mortality in this group converged with SSc. In summary, cumulative survivals at 1 and 3 years were 80% and 65% in the SSc LT group, and 78% and 63% in the non-SSc group. Regarding evolution and follow-up, patients with SSc reached their best lung functional tests 9 months (range 6-12 months) after LT. Median Forced Vital Capacity (FVC) before transplantation was 38% (95% CI 36-62%), increasing to 58.7% (95% CI 50-72%) 6 months

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after LT. FVC remained stable for the 1st (59% [95% CI 54%-73%]), 2nd (58% [95% CI 5470%]) and 3rd (66% [95% CI 47-78%]) years of follow-up. A random mixed effects model showed stability over time in the values of FVC (the slope of the regression line was not significantly different from 0). One year after LT, all the surviving patients were able to

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cease home oxygen therapy.

Systemic Sclerosis evolution

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One patient developed digital ulcerations and another developed panniculitis, but both responded well to sildenalfil and hydroxychloroquine, respectively. Regarding GI, one

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patient had already required a gastrojejunal tube. Only one patient developed new significant gastric palsy but symptoms were finally controlled with medical treatment. No

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patients developed again PH or ILD, after performing a yearly screening with a transthoracic echocardiography and a chest computerized tomography scan. No other disease

Discussion

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activity was reported.

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We have described the largest monocentric cohort of patients with SSc who underwent LT in Europe. Manifestations of the autoimmune disease before LT were severe and multiple. These patients presented the usual complications during and after LT, already described in the literature. We compared these subjects with a large cohort of patients that required LT during the same period, mainly because of ILD and COPD, as well as PH and we found no differences regarding survival. The leading cause of mortality in all groups was sepsis.

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Moreover, lung functional tests seemed stable during follow-up and disease activity was low in the SSc group.

A systematic review conducted in 2012 by Khan et al. [3] found that only 186 cases of LT in

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SSc had been reported in the literature from 1986 to 2012. A multicenter retrospective study [15] has reported 299 patients with SSc who underwent LT in the USA from 2005 to

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2014, from a total number of 3673 lung transplants performed. Recently, the largest

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monocentric study to the date has been published, including 72 American patients with SSc [4]. Experience with this treatment in SSc is still limited and data is scarce. In Europe, there

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is only one previous experience with 13 French patients transplanted in a single center [16]. Our cohort included 15 patients that developed multiple complications related to SSc

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including ILD and PH before LT. They had been treated with many drugs without a maintained satisfactory response. This severity is also supported by the predominance of

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the dcSSc subset, related with worse survival and pulmonary fibrosis, which may be rapidly progressive. The high percentage of lcSSc patients with severe lung involvement in our

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sample is explained by an enrichment in such patients due to the LT process selecting preferentially individuals with end-stage respiratory insufficiency. The assessment before LT in patients with SSc has not been completely elucidated. Patients with connective tissue diseases have been accepted for LT since the ISHLT recommended in 2006 [9] to

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individualize the indication in every case. The same year, Schachna et al. reported a cohort of patients with SSc that underwent LT, using restrictive selection criteria, with promising results [17]. These criteria excluded individuals with severe renal, skin, gastrointestinal and cardiac involvement. Focusing on the gastroesophageal reflux (GER) in connective tissue diseases in the context of LT, two studies raised concerns on this issue because of higher rejection rates and worse survival [18, 19]. An American study including 22 patients,

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identified and aggressively treated (medically or surgically) patients with severe GER with similar complications and survival than patients with non-connective-tissue-related ILD. Thus, severe GER may not be a limiting factor to promote LT within patients with SSc [20]. Likely, we included patients with severe GER but without a definite study protocol during

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the pretransplantation assessment, which was led to clinicians’ criteria. Forcing medical treatment and postural measures, we were able to control symptoms in all of our patients.

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Early and late complications, including postoperative complications, rejection rates and

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infections after LT were similar to the ones reported in other recent studies [4, 16, 20, 21]. Lung functional tests were also stable along time after LT.

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Mortality rates in the first months after LT were higher (67.6%) in the first studies in the early 2000s' [22]. Probably, the improvement in LT surgical technique, postoperative care

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and drug treatment, as well as the development of highly specialized centers that concentrated most of the transplantations have contributed to limit the mortality at this stage

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[3]. Thus, we decided to use a non-SSc LT comparison group, which underwent LT since 2005. The abovementioned French study [16] presented high precocious mortality rates at

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1 year after LT but 8 patients were transplanted due to isolated PAH and 5 over 13 received heart and lungs transplantation, making comparisons difficult. Oppositely, Crespo et al. [4] found that 1-year cumulative survival for SSc LT receivers was 81% and that scleroderma was not an independent mortality risk factor in the 1-year survival multivariate analysis. In

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our study, only one patient died six months after surgery in relation with LT (the other died because of a pre-existing pulmonary neoplasm in the receptor). Our 1-year survival rate was 80%. The main cause of death in our study, in accordance with the Pittsburgh group [4], was sepsis in both the SSc group and in the non-SSc LT group. The survival study comparing the Kaplan Meier curves of both groups did not show statistically significant differences. As in other studies, we compared SSc patients that underwent LT with some

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definite subgroups that seemed comparable due to the nature of the baseline diseases. Patients transplanted due to ILD and PH obtained similar results to those offered by the latest survival studies performed [3, 4], without finding differences when comparing these populations versus the SSc-LT group (1-year survival 73-93.4% and 81% versus 80%; 3-

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year survival 73-68% and 73% versus 65%). Crespo et al. [4] found that LT receivers with SSc were younger than controls, and hypothesized that this may play a role in the outcome

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of the study. We found no age-related differences, what may emphasize the resemblance in

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survival between SSc and ILD or PH, when receiving LT. A nationwide retrospective study made in the USA [15] and published in 2015 included 229 patients with SSc, 201 with PAH

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and 3333 with ILD, transplanted from 2005 to 2012. Authors pointed a 48% multivariableadjusted relative increase in the 1-year mortality rate in the SSc patients that underwent LT

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compared to those with non-SSc-related ILD (HR 1.48, 95% CI 1.01-2.17). These differences disappeared after a follow-up of three years. They stated that mortality in

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patients undergoing LT during the first year after the procedure was in a middle position between survival seen in patients with ILD and survival seen in patients with PAH (not

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reaching statistical signification). In our study, survival was reduced in the PH control group during the first year (65% survival versus 80% in SSc), but the overall survival rate was not statistically different to SSc, like in the French cohort. In the light of these results, the role of GER in selected patients with SSc may be questionable. Focusing on controlling GER

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symptoms (medically or surgically) may be enough to allow SSc patients into transplantation. Other factors not identified to the date may play a role in the incidence of complications and survival of LT patients with SSc. Once more, the presence of specialized centers in LT and in SSc may play a significant role. It seems clear now that middle term survival in LT (3 years) has evolved from 45.9% in 2005 [22] to nearby 70% [4], and that is similar between SSc and ILD or PAH, nearby 65%. The latest long-term study suggests that

13 Page 13 of 27

survival at 5 years may be identical [4]. More long term studies are warranted in order to explore survival, to assess quality of life in these patients, and to identify factors that may modify survival and the incidence of complications. Regarding the evolution of SSc-LT patients from the scleroderma point of view, only the

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French cohort reported 2 patients that developed severe digital ulcers in the 3 months after transplantation and one patient that developed a SRC 44 months after LT. In our cohort,

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one patient developed digital ulcers that healed with sildenalfil. None of the patients with

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SSc and PH or PAH showed indirect signs of PH under echocardiographic control after LT. All patients kept only with the per protocol immunosuppressive treatment associated to LT.

complications, although they seem infrequent.

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It is important to keep the scleroderma follow-up after LT in order to avoid new

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Our study has a number of limitations. First, the single center study design may have limited the external validity of our study. This factor may have underpowered some of the

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statistical analysis and thus, it is possible that clinically relevant differences may have passed unnoticed. Second, the number of SSc patients that underwent LT was limited both

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by the rarity of the disease and by the low number of patients where lung involvement was severe enough to require LT. However, the single center design of the study also increased the homogeneity of patient management and the number of SSc patients with LT included in the study is the largest single center sample in Europe. Moreover, our center has

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performed 34 to 59 LT per year between 2009 and 2015. The limited follow-up period, the retrospective nature of the study, the absence of per protocol gastrointestinal studies during the pretransplant assessment and the lack of more extensive autoantibody determinations in order to identify prognostic factors may have also limited the study. In conclusion, compared with other series, LT in patients with SSc at our center, had a similar incidence of complications. Acute rejection and infections were the most common

14 Page 14 of 27

ones. Regardless the gradation of esophageal involvement, survival study showed no differences regarding mortality and cumulative survival at 3 years compared with patients that underwent LT due to non-SSc-related ILD or PH. LT may be a valid treatment for terminal ILD or PH in SSc. This promising outcomes in our study seem to be related with a

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strict selection process among potential recipients.

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Conflicts of interest:

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The authors declare that they have no competing interest.

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2. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic

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sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010;69:1809-15.

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3. Khan IY, Singer LG, de Perrot M, et al. Survival after lung transplantation in systemic sclerosis. A systematic review. Respir Med 2013;107:2081-7

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4. Crespo MM, Bermudez CA, Dew MA, et al. Lung Transplantation in Patients with

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Scleroderma Compared with Pulmonary Fibrosis: Short and Long-term Outcomes in a Single Institution. Ann Am Thorac Soc 2016;13:784-92.

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5. Rosas V, Conte JV, Yang SC, et al. Lung Transplantation and systemic sclerosis. Ann Transplant 2000;5:38-43.

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6. Wells AU, Cullinan P, Hansell DM, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1994;149:1583-90. 7. De Cruz S, Ross D. Lung transplantation in patients with scleroderma. Curr Opin

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Rheumatol 2013;25:714-8. 8. LeRoy EC, Medsger TA, Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573-6. 9. Orens JB, Estenne M, Arcasoy S, et al. Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from

16 Page 16 of 27

the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745-55. 10. Desai CS, Lee DC, Shah SJ. Systemic sclerosis and the heart: current diagnosis and management. Curr Opin Rheumatol 2011;23:545-54.

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11. Traub YM, Shapiro AP, Rodnan GP, et al. Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Medicine (Baltimore)

cr

1985;62:335-52.

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12. Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International

an

Society of Heart and Lung Transplantation (ISHLT), Galiè N, Hoeper MM, Humbert

Respir J 2009;34:1219-63.

M

M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur

13. Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. Registry of

ed

the International Society for Heart and Lung transplantation: twenty-second official adult lung and heart-lung transplant report--2005. J Heart Lung Transplant

ce pt

2005;24:956-67.

14. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297-310. 15. Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with systemic sclerosis

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following lung transplantation: A nationwide cohort study. Arthritis Rheumatol 2015;67:1314-22.

16. Launay D, Savale L, Berezne A, et al. Working Group on Heart/Lung transplantation in systemic sclerosis of the French Network on Pulmonary Hypertension. Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience

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of 13 patients, review of the literature and position paper of a multidisciplinary Working Group. Presse Med 2014;43(10 Pt 2):e345-63. 17. Schachna L, Medsger TA Jr, Dauber JH, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial

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hypertension. Arthritis Rheum 2006;54:3954-61. 18. D'Ovidio F, Singer LG, Hadjiliadis D, et al. Prevalence of gastroesophageal reflux in

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end-stage lung disease candidates for lung transplant. Ann Thorac Surg

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2005;80:1254-60.

19. Gasper WJ, Sweet MP, Golden JA, et al. Lung transplantation in patients with tissue

disorders

and

esophageal

dysmotility.

Dis

Esophagus

an

connective

2008;21:650-5.

M

20. Sottile PD, Iturbe D, Katsumoto TR, et al. Outcomes in systemic sclerosis-related lung disease after lung transplantation. Transplantation 2013;95:975-80.

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21. Shitrit D, Amital A, Peled N. Lung transplantation in patients with scleroderma: case series, review of the literature, and criteria for transplantation. Clin Transplant

ce pt

2009;23:178-183.

22. Massad MG, Powell CR, Kpodonu J, al. Outcomes of lung transplantation in patients with scleroderma. World J Surg 2005;29:1510-5.

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

18 Page 18 of 27

FIGURES:

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Figure 1:

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Kaplan-Meier curves describing the survival of patients with Systemic sclerosis (SSc) who

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underwent lung transplantation versus the non-SSc transplantation group

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Figure 2:

A: Kaplan-Meier curves describing the survival of patients with Systemic sclerosis (SSc)

ed

non-SSc Interstitial Lung Disease (ILD)

M

who underwent lung transplantation versus the subgroup of individuals transplanted due to

B: Kaplan-Meier curves describing the survival of patients with Systemic sclerosis (SSc)

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who underwent lung transplantation versus the subgroup of subjects transplanted because of non-SSc Pulmonary Hypertension (PH)

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

19 Page 19 of 27

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ce

pt

ed

M

an

us

cr

i

Figure 1

Page 20 of 27

Ac ce p

te

d

M

an

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Figure 2

Page 21 of 27

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Table 1

Sex

SSc

Raynaud

Digital

subset

phenomenon

ulcers

Ostheomuscular

Esophageal

ILD

PH

mPAP

SRC

ANA

ACA

ATA

+

+

-

13

-

+

+

-

+

+

+

47

-

+

-

-

+

+

+

35

-

+

-

-

+

+

+

-

NA

-

+

-

-

+

+

+

+

28

-

+

+

-

+

+

+

+

75

-

+

-

-

+

+

+

+

-

NA

-

+

+

-

+

+

+

+

+

36

-

+

-

-

-

-

+

+

-

22

-

+

-

-

-

-

+

+

+

43

-

+

+

-

an

Patient

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Table 1: Baseline characteristics of patients with SSc that underwent LT.

F

lcSSc

+

-

+

2

M

lcSSc

+

+

-

3

F

lcSSc

+

+

+

4

F

dcSSc

+

-

5

M

dcSSc

+

+

6

F

lcSSc

+

-

7

F

dcSSc

+

8

F

dcSSc

+

9

F

lcSSc

+

10

F

dcSSc

+

11

F

dcSSc

+

+

+

+

+

+

30

-

+

+

-

12

M

dcSSc

+

-

-

+

+

+

25

-

-

-

-

13

M

lcSSc

+

-

-

+

-

+

62

-

+

-

+

14

F

dcSSc

+

+

-

+

+

+

33

-

+

-

+

15

M

lcSSc

+

+

+

+

+

-

19

-

+

-

-

Ac c

ep te

d

M

1

Page 22 of 27

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Ac c

ep te

d

M

an

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SSc (systemic sclerosis); LT (lung transplantation); ILD (interstitial lung disease); PH (pulmonary hypertension); mPAP (mean pulmonary artery pressure); SRC (scleroderma renal crisis); ANA (antinuclear autoantibodies); ACA (anticentromere autoantibodies); ATA (antitopoisomerase I autoantibodies); F (female); M (male); lcSSc (limited cutaneous systemic sclerosis); dcSSc (diffuse cutaneous systemic sclerosis)

Page 23 of 27

Table 2

Table 2: Features of the patients who underwent LT by groups. Percentages are expressed as % (n) and continuous variables as median (Q1-Q3).

Non-SSc Total (N=515)

SSc (N=15)

p (N=500)

Female % (N)

67% (n=10)

39 (194)

ILD

41 (210)

80 (12)

40 (198)

PH

4 (18)

47 (7)

36 (185)

0 (0)

Cystic fibrosis

9 (46)

0 (0)

9 (46)

ns

Others

10 (53)

0 (0)

11 (53)

ns

52 (48-57)

54 (44-59)

ns

0.4 (0.2-1.3)

0.5 (0.2-1.1)

ns

Time in the waiting list (years)

0.5 (0.2-1.1)

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<0.001

37 (185)

0.002

64.6 (333)

73.3 (11)

64.4 (322)

ns

Time of follow-up (years)

2.3 (0.7-4.7)

2 (1-4)

2 (1-5)

ns

Time from LT to death (years)

ed

Bilateral LT

54 (44-59)

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Age at LT (years)

M

COPD

<0.001

4 (18)

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Cause of LT

0.04

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40 (204)

0.8 (0.1-2.5)

2.6 (0.7-3.7)

0.8 (0.1-2.4)

ns

40 (204)

33 (5)

40 (199)

ns

27 (56)

80 (4)

26 (52)

ns

23 (47)

0 (0)

24 (47)

0.02

8 (16)

20 (1)

8 (15)

ns

Suture dehiscence

4 (9)

0 (0)

5 (9)

ns

Pulmonary embolism

3 (7)

0 (0)

4 (7)

ns

Primary allograft failure

1 (3)

0 (0)

2 (3)

ns

Humoral rejection

1 (3)

0 (0)

2 (3)

ns

Others

8 (17)

0 (0)

9 (17)

ns

Unknown

21 (44)

0 (0)

22 (44)

ns

Death

Sepsis CLAD

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Malignancy

ce pt

Cause of death

Page 24 of 27

LT (lung transplantation); SSc (systemic sclerosis); ILD (interstitial lung disease); PH (pulmonary hypertension); COPD (chronic obstructive pulmonary disease); CLAD (chronic lung

Ac

ce pt

ed

M

an

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allograft dysfunction)

Page 25 of 27

Table 3

Table 3: Composition by diagnosis of the non-SSc ILD group and the non-SSc PH group.

ILD % (N)

100 (198) 52.5 (104)

Usual interstitial pneumonia

33.8 (67)

Nonspecific interstitial pneumonia

11.1 (22)

Sarcoidosis

2.5 (5)

PH

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18 (100)

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Unspecified fibrosis

Idiopathic pulmonary arterial hypertension

94.4 (17) 5.6 (1)

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Secondary pulmonary hypertension

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ce pt

ed

M

an

SSc (systemic sclerosis); ILD (interstitial lung disease); PH (pulmonary hypertension)

Page 26 of 27

Table 4

Table 4: Complications in patients with SSc that underwent LT.

40% (6)

Reoperation

6.6% (1)

Gastric palsy

60% (9)

Diaphragmatic palsy

40% (6)

Bronchial stenosis

26.6% (4)

Suture dehiscence

6.6% (1)

Rejection 60% (9)

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Acute cellular rejection

13.3% (2)

Chronic allograft dysfunction

26.6% (4)

an

Antibody mediated rejection

Infections

60% (9)

M

Bacterial Viral

33.3% (5) 26.6% (4)

Mycobacterial Malignancy

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Skin cancer

ed

Fungal

Other

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Extracorporeal circulation

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Early complications (<30 days after LT)

Pulmonary embolism

40% (6)

13.3% (2)

13.3% (2)

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SSc (systemic sclerosis); LT (lung transplantation)

Page 27 of 27