Scleroderma Highlights
Francesco Boin, M.D.
- 638 - Transgenic Expression of the Transcription Factor Fra-2 in Mice induces Progressive Vascular Injury and Fibrosis of the Skin resembling Human SSc
- 2068 - Lack of Evidence for Agonist Activity by Auto-antibodies to Platelet-derived Growth Factor (PDGF) Receptor Alpha in Systemic Sclerosis (Scleroderma)
- 1772 - Bronchoalveolar Lavage and Response to Cyclophosphamide in Scleroderma Alveolitis
- 1145 - Increased frequency of T regulatory cells in Systemic Sclerosis displaying a markedly altered phenotype and compromised regulatory capacity
- 1222 - Phase IIa Trial of Imatinib Mesylate (Gleevec) in the Treatment of Diffuse Systemic Sclerosis - An Interim Analysis
- 1224 - Systemic Sclerosis and Lung Transplantation: A Single Center Experience
Abstract 638 - Transgenic Expression of the Transcription Factor Fra-2 in Mice induces Progressive Vascular Injury and Fibrosis of the Skin resembling Human SSc
Authors:
Britta Maurer, Nicole Busch, Erwin F. Wagner, Astrid Juengel, Renate E. Gay, Georg Schett, Steffen Gay, Joerg Distler, Oliver Distler.
Background:
Microvascular damage is one of the first pathological changes in systemic sclerosis (SSc). Fra-2 is a transcription factor of the AP-1 family. The objective of our study was to investigate the role of Fra-2 in vasculopathy using recently developed Fra-2 transgenic (tg) mice which are characterized by prominent lung fibrosis and to examine the effects of Fra-2 alteration in human endothelial cells.
Methods:
Fra-2 tg and wild-type (wt) mice at 9, 12, 16/17 weeks were analyzed. In addition, paraffin embedded skin sections from SSc patients and healthy controls were used. Apoptotic cells were detected by TUNEL assay.
To study the effects of Fra-2 knock-down on tube formation, migration, proliferation (MTT), and staurosporine-induced apoptosis, cultured HUMECS were transfected with Fra-2 siRNA. Apoptotic cells were detected by Annexin-V-FLUOS/PI staining and quantified by flow cytometry.
Results:
Expression of Fra-2 by immunohistochemistry was significantly up-regulated in skin samples from SSc patients compared to healthy controls (62±14% vs. 23±12% positive cells, p=0.025, n=13 each). Fra-2 was predominantly expressed by endothelial cells and fibroblasts. The Fra-2 dimerization partner c-Jun showed a similar expression pattern and was co-expressed with Fra-2 in parallel sections. Fra-2 tg mice developed skin fibrosis at week 12 with a progressive increase in skin thickness (446±22 μm vs. 314±20 μm in wt mice, p=0.04, n=4 each). This was paralleled by the development of a severe microangiopathy in Fra-2 tg mice with a significant reduction of the capillary density starting between weeks 9 and 12 (von Willebrand-Factor positive cells 0.5±0.2/high power field vs. 5.0±0.8/high power field, p=0.008, n=4 each). Interestingly, the microangiopathy was preceded by a significant increase of apoptosis in endothelial cells at week 9 (57±6% vs. 37±6%, p=0.02, n=4 each).
The in vivo findings were confirmed by functional in vitro assays: Remarkably, Fra-2 knock-down consistently prevented HUMECs from staurosporine-induced apoptosis in a dose-dependent manner (57 vs. 67% of mock transfected cells, p=0.04, n=5). In addition, knock-down of Fra-2 improved different aspects of angiogenesis including tube formation (cumulative tube length: 6±0.6 mm vs. 1.8±0.3 mm, p=0.002, n=3; number of tubes: 42±5 vs. 12±2, p=0.002, n=3 as compared to mock transfected cells) and cell migration (1.6 ± 0.1 fold, p=0.1, n= 3), whereas proliferation was not affected.
Conclusions:
Fra-2 is operative in human SSc leading to a severe vasculopathy followed by fibrosis. Fra-2 tg mice are a promising preclinical model to study the pathogenesis and therapeutic approaches in SSc.
Editorial:
Fra-2 transgenic mice represent a new intriguing animal model to study scleroderma. The authors showed that, similarly to the human disease, the progressive development of skin and lung fibrosis is preceded, in these transgenic mice, by the institution of a severe diffuse microangiopathy, and is associated with pulmonary vascular obliterative disease. Moreover, experiments on HUMECs indicate a pro-apoptotic and anti-angiogenic function for Fra-2. Intriguingly, in the skin of scleroderma patients Fra-2 was upregulated in endothelial cells and fibroblasts compared to normal controls. Previous literature suggests that osteopontin, a pro-fibrotic factor, may be a relevant downstream effector of the Fra-2 and the AP-1 family. This pathway should be further explored in this animal model as well as in patients with scleroderma for potential new targeted therapy.
Abstract 2068 - Lack of Evidence for Agonist Activity by Auto-antibodies to Platelet-derived Growth Factor (PDGF) Receptor Alpha in Systemic Sclerosis (Scleroderma)
Authors
Nick Loizos, Jami Weiner, Heather Griffin, Francesco Boin, Laura K. Hummers, Fredrick M. Wigley, Paul Kussie
Background
Fibrosis in scleroderma, as well as in other fibrotic diseases, involves the proliferation of mesenchymal cells and excessive deposition of collagen and other extracellular matrix proteins by these cells causing scarring and loss of organ function. PDGFRs are expressed on cells of mesenchymal origin and the upregulation of PDGFRα by TGF-β1 is thought to have an important role in promoting hyperplastic growth of scleroderma fibroblasts. Autoantibodies specific to PDGF receptors (PDGFRs) have been reported in the serum of scleroderma patients. These autoantibodies displayed agonist activity as demonstrated by inducing PDGF receptor phosphorylation in cultured fibroblasts. The present study sought to confirm the presence of PDGFRα-specific autoantibodies in scleroderma and evaluate their potential agonist activity using cell-based assays.
Methods
Serum was obtained from 35 normal (i.e. disease-free healthy) individuals and 49 scleroderma patients (55% diffuse and 45% limited). Detection of serum autoantibodies to Platelet-derived growth factor receptor alpha (PDGFRα), PDGFRβ, Epidermal growth factor receptor (EGFR) and Colony stimulating factor receptor 1 (CSF1R) was carried out using an electrochemiluminescense binding assay. Immunoglobulin (Ig) from serum was purified using protein A/G chromatography. To assess Ig agonist activity, PDGFRα-expressing cells were incubated with pure Ig and the level of receptor phosphorylation determined in an enzyme-linked immunoassay as well as by western blotting. Ig agonist activity was also assessed in a mitogenic assay and by MAP Kinase activation in PDGFRα-expressing cell line.
Results
Serum from 34.3% normal individuals and 32.7% scleroderma patients contained detectable autoantibodies to PDGFRα and PDGFRβ, but not EGFR and CSF1R. The Ig from these serums were purified and shown to retain the PDGFR-binding activity. Pure Ig at 200-1000 μg/ml showed no agonist activity in a cell-based PDGFRα phosphorylation assay. Pure Ig did not stimulate a mitogenic response nor MAP Kinase activation in a PDGFRα-expressing cell line. Two pure Ig samples unable to bind PDGFRα did show binding activity to a non-glycosylated form of PDGFRα.
Conclusions
Although approximately a third of sera from scleroderma patients contained detectable autoantibodies to PDGFRs, these antibodies are not specific for scleroderma and do not demonstrate PDGFRα agonist activity. These data do not support a pathological role for autoantibodies against PDGFRs.
Editorial
The presence of agonistic anti-PDGF receptor (PDGFR) antibodies in scleroderma has been reported in 2006 and their role in the pathogenesis of this disease has been proposed. However, since the original work no other study has been published addressing this issue. The present investigation adopts a very thorough and comprehensive experimental approach and shows that these autoantibodies are not found in 100% of scleroderma patients as previously reported, and that they can be detected with the same frequency (one third) in healthy individuals. After affinity purification, the anti-PDGF antibodies did not exhibited agonistic activity in a cellular-based assay measuring receptor phosphorilation as well as downstream molecular activation. Even if the initial study on anti-PDGF antibodies employed different cell lines and detection methods, the data provided by this new investigation do not support the conclusion that autoantibodies to PDGFR are pathologically relevant in scleroderma.
Abstract 1772 - Bronchoalveolar Lavage and Response to Cyclophosphamide in Scleroderma Alveolitis
Authors
Michele Colaci, Marco Sebastiani, Andreina Manfredi, Dilia Giuggioli, Veronica Malagoli, Clodoveo Ferri
Purpose
Systemic sclerosis (SSc) is an autoimmune connective tissue disease, characterised by abnormal fibrosis of the skin and internal organs, particularly of the lungs. Recently, some Authors reported the lack of correlation between bronchoalveolar lavage (BAL) variations and response to therapy in patients with overt SSc alveolitis.Our study aimed to evaluate whether the normalization of BAL fluid cellularity may correlate with long-term response to cyclophosphamide (CYC) in SSc-related alveolitis.
Methods
We studied 26 consecutive SSc patients (M/F 6/20, mean age 47.8±10.5 years, mean disease duration 5.6±6.2 years) with alveolitis, diagnosed by BAL (neutrophils > 3%; eosinophils > 2%), performed in the ground-glass opacification areas on high-resolution computed tomography scans. Then, we evaluated the variations of pulmonary function tests (PFTs) and BAL cellularity before/after CYC therapy (cumulative dosage 26.5±11.7g; 21.1±8.9 months of treatment). Finally, we re-evaluated PFTs after one year of follow-up in 18 patients.
Results
BAL fluid cell counts normalized after CYC therapy in 12/26 (46.2%) SSc patients (group 1), while remained abnormal in 14/26 (53.8%) subjects (group 2). Variations of PFTs, namely forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), are summarised in the table. FVC and DLCO of group 1 slightly increased after CYC therapy (p=0.012; p=0.07; respectively) and remained stable at one-year follow-up, whereas in group 2 they did not change at the end of treatment and slightly worsened at one-year follow-up (p= 0.04; p=0.17; respectively). In particular, FVC and/or DLCO showed a clinical improvement/stabilization in 8/9 patients of group 1 versus 3/9 of group 2; on the contrary, they worsened in 1/9 of group 1 versus 6/9 of group 2 (Fisher’s p<0.05).
Conclusions
In our patients, BAL fluid normalization after CYC therapy correlated with long-term response to treatment, compared to subjects with persistent alveolitis. Although previous studies have questioned the value of BAL in the monitoring of CYC therapy, our findings suggested that BAL variations could reflect the evolution of scleroderma alveolitis, especially when done in selected ground-glass areas. However, it remains to be further investigated why SSc patients with comparable alterations of BAL and PFTs may show a different response to CYC therapy.
Editorial
The value of BAL fluid analysis in assessing active interstitial lung disease (ILD) or presence of “alveolitis” in scleroderma patients has been controversial. Some studies failed to show that an abnormal BAL has a predictive value in term of response to therapy or survival. The present investigation evaluates prospectively patients with active lung disease and abnormal BAL cell count at baseline. The Authors found that in scleroderma patients with better long term outcome after therapy with cyclophosphamide, the BAL cell counts normalized. However, the follow-up period was relatively short (1 year). Without further immunosuppressive treatment a sizable number of patients with ILD tend to relapse. Therefore, it would be interesting to determine whether the BAL cell count, normalized in response to therapy, will subsequently become abnormal during exacerbated lung inflammation.
Two major issues remain: 1) the bronchoscopic approach and the BAL cell count protocols often differ among clinical centers, making the comparison of different studies difficult; 2) the definition of “positive” BAL cell counts (>3% neutrophils and/or >2% eosinophils) is based on “surrogate” markers. In fact, these cells are not considered pathogenic for ILD. No study to date has shown significant association between the number of lymphocytes in BAL and active ILD (only one limited study showed an association with higher CD8 T cell counts). The identification of cell types or biomarker in BAL more correlated with the pathogenesis of lung injury is warranted.
Abstract 1145 - Increased frequency of T regulatory cells in Systemic Sclerosis displaying a markedly altered phenotype and compromised regulatory capacity
Authors
Timothy R. Radstake, Lenny van Bon, Jasper Broen, Yanhui Deng, William Cruikshank, Robbert Lafyatis.
Purpose
The identification of CD4+CD25+ regulatory T cells as a crucial component of self-tolerance has opened a major area of investigation and numerous studies have demonstrated the potent influence of T reg cells in suppressing autoimmunity. SSc is an autoimmune disease that displays high levels of TGFb, IL-6 and IL-17, all cytokines involved in skewing T cell priming. Therefore, it is conceivable that T reg development is aberrant in SSc.
Methods
In total, thirty-six SSc patients were included in the study. All of the patients met the ACR preliminary criteria for SSc and were subdivided as having limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). A further subdivision was made between early dcSSc and late dcSSc based upon the duration of disease listing early dcSSc as a disease duration < 2 years. From the peripheral blood, T cells were isolated using the pan T cell marker CD3. Subsequently, several markers for T cell activation (GITR, CD62L and CD69) and T regulatory function (CD4, CD25, FoxP3 and CD127) were measured. Next, CD25highCD127 negative cells were sorted and proliferation assays were implemented to investigate the suppressive potential of CD25highCD127 negative cells from SSc patients with different disease phenotypes.
Results
In line with previous observations, all 36 SSc patients had higher frequencies of CD4 + cells and CD4/CD8 ratios compared with healthy controls. In contrast with that observed in RA and SLE, further analysis revealed that all SSc patients had significantly higher numbers of CD4+CD25+ cells when compared with that observed in healthy controls. Further analysis revealed that the percentage of CD25+FoxP3 expressing cells was significantly increased in lcSSc (17.5% ± 2.4, P = 0.0007), ldSSc (15.4% ± 1.1, P = 0.0006) and edSSc 22.0% ± 1.7, P = 0.003) compared to that observed in healthy controls (3.1% ± 0.3). Whereas the mean fluorescence intensity (MFI) of FoxP3 and CD127 on CD4CD25 and CD25FoxP3 expressing cells respectively was similar in all individuals, the expression of CD62L and CD69 was significantly lower in SSc patients showing a gradual decrease when lcSSc, ldSSc and edSSc were compared subsequently. Since these observations suggested an altered activation state of T regulatory cells in SSc we conducted T cell suppressor assays. As expected, the CD25highCD127 negative T cells from healthy controls (n=3) efficiently inhibited the proliferation of stimulated CD3+ cells (80-90%) whereas CD25lowCD127high cells were less efficient (15-20%). In contrast, the inhibitory capacity of CD25highCD127neg cells was decreased in patients with lcSSc (40-50%, n=2), ldSSc (40-45%, n=3) and edSSc (25-30%, n=2).
Conclusions
We demonstrate for the first time that the T regulatory compartment is clearly expanded but dysfunctional in SSc. Further research is warranted to understand the pathways that underlie these aberrances.
Editorial
This study addresses the role of T regulatory cells (Tregs) in scleroderma. There is no previous publication focusing on this topic. The authors report that despite a strikingly increased number of circulating Tregs, their function in scleroderma patients is somehow impaired with a decreased inhibitory capacity. Intriguingly, this mismatch is more pronounced in “early” diffuse scleroderma patients. This may suggest that during the early phases of the disease, there is an attempt of suppressing or controlling the ongoing pro-inflammatory autoimmune response (higher number of Tregs), but that this process is not effective. Another interesting speculation arising from this study is that these defective Tregs, while failing to inhibit the mounting autoimmune process, they still could contribute to the generation of a pro-fibrotic microenvironment in virtue of their ability to secrete TGF-β. Further studies are needed to investigate the cytokine repertoire secreted by these dysfunctional Tregs.
Abstract 1222 - Phase IIa Trial of Imatinib Mesylate (Gleevec) in the Treatment of Diffuse Systemic Sclerosis - An Interim Analysis
Authors
Robert F. Spiera, Jessica K. Gordon, Mansi Mehta, Kyriakos A. Kirou, Stephen Lyman, Stacey A. Kloiber, Mary K. Crow.
Background
Imatinib mesylate (IM), a selective tyrosine kinase inhibitor, has been a drug of interest for the treatment of systemic sclerosis. Preclinical mechanistic data suggest that it inhibits PDGF and TGF-β mediated signaling and fibrosis in vitro and in vivo. IM is known to have an acceptable safety and tolerability profile in the treatment of malignancy.
Purpose
A single center phase IIa open label trial of IM in the treatment of diffuse systemic sclerosis (DSSc) is ongoing. The primary outcome is safety and tolerability as assessed by adverse events (AEs) and severe adverse events (SAEs.) Secondary outcomes are modified Rodnan Skin Score (mRSS) and indices of pulmonary function. Tertiary outcomes include quality of life indices, skin thickness based on blinded assessment of pre- and post-treatment biopsies, and biomarkers of disease activity. We present here our interim data.
Methods
IM 400 mg daily is given to patients with DSSc who meet eligibility criteria. Target recruitment is 20 patients with < 4 years of disease and 10 patients with 4 to 10 years of disease. Patients are evaluated monthly with detailed histories, physical examinations, SF-36s, sHAQs, and laboratory analyses including CK determinations. Skin biopsies, PFTs, chest x-rays, and echocardiograms are obtained at baseline and after one year of treatment. mRSS are evaluated quarterly.
Results
Eighteen patients have initiated treatment. 3 month data is available on 10 patients and 6 month data on 5 patients. 53 AEs have occurred in 15 patients. The most common AEs include CK elevations (n = 7), edema (n = 7), periorbital edema (n = 7), nausea (n = 7), and myalgias (n = 2.) CK elevations have required dose adjustments in 7 patients. Two SAEs have occurred, neither of which was felt to be related to study medication. One patient was hospitalized for nephrolithiasis (a preexisting problem), and one patient was hospitalized with a pulmonary contusion and aspiration after a fall. Two patients have discontinued study medication: one secondary to nausea and malaise and one after the fall. Efficacy is presented in Table 1. The mean change in mRSS was -1.4 at three months and -1.6 at six months.
Table 1. Change in mRSS. |
|||||
Patient Id |
Disease |
Total time on |
Baseline |
Month 3 |
Month 6 mRSS |
G1 |
1.5 years |
7 months |
21 |
26 |
28 |
G2 |
3 years |
7 months |
30 |
29 |
27 |
G3 |
<4 years |
3 months* |
26 |
20 |
24 |
G4 |
<3 years |
7 months |
24 |
24 |
24 |
G5 |
6 years |
6 months |
20 |
15 |
10 |
G6 |
<1 year |
5 months |
43 |
40 |
|
G7 |
7 years |
1 month** |
31 |
27 |
|
G8 |
<1 year |
3 months |
25 |
21 |
|
G9 |
3.5 years |
3 months |
46 |
45 |
|
G10 |
<1 year |
3 months |
41 |
46 |
|
MEAN (S.D.) |
30.7 (9.4) |
29.3 (10.8) |
|||
MEAN (S.D.) |
24.2 (4.0) |
22.8 (5.4) |
22.6 (7.3) |
||
*Patient G3 discontinued study medication because of nausea and malaise. |
|||||
Summary
In our interim analysis, IM has shown acceptable tolerability in patients with DSSc. AEs are common but generally mild. CK elevations are the most common AE resulting in the need to adjust dosage. There is a modest improvement in mRSS that does not yet reach statistical significance.
Conclusion
Imatinib mesylate continues to be an interesting candidate therapeutic agent for diffuse systemic sclerosis with an acceptable safety and tolerability profile.
Editorial
The detection that imatinib mesilate (gleevec) exerts specific anti-fibrotic properties has generated significant expectations for a potential scleroderma-specific disease modifying treatment. Data in vitro and in animal models have been quite promising. Different phase II clinical trials are now underway.
This abstract presents an interim analysis conducted after a relatively short treatment period (1 to 7 months) of 18 scleroderma patients. While the tolerability of the medication was generally acceptable (except for recurrent edema and CPK elevation) no apparent clinical benefit could yet be identified. In particular, the skin fibrosis had minimal improvement measured by mRSS. This appears in line with the expected natural history of the disease. Longer follow-up intervals are needed to better explore benefit from treatment with imatinib. It is possible that the dosing or the thyrosine kinase inhibition was not adequate to effectively suppress fibrosis. In fact, new trials employing more potent and broader thyrosine kinase inhibitors (i.e. dasatinib) have been initiated.
Abstract 1224 - Systemic Sclerosis and Lung Transplantation: A Single Center Experience
Authors
Rajeev Saggar, Rajan Saggar, Dinesh Khanna, Daniel E. Furst, John Belperio, Sam Weigt, David A. Zisman, Philip J. Clements, Abbas Ardehali, Bernard Kubak, Aric Gregson, Joseph P. Lynch, 3rd, David Ross
Purpose
To evaluate the outcomes of lung transplant recipients (LTR) with underlying systemic sclerosis (SSc) as compared to idiopathic pulmonary fibrosis (IPF). Both diseases can result in endstage lung disease with pulmonary fibrosis and pulmonary hypertension.
Methods
We retrospectively selected only bilateral LTRs with underlying SSc or IPF at our center between 1/2003 and 12/2007. The primary endpoint was all cause mortality at 1yr post-LT. Secondary endpoints included assessments of acute rejection (AR), lung function, infection, and renal function. All SSc patients were placed on metoclopramide, ACE inhibition, and high dose proton-pump inhibition, immediately post-LT (lung transplantation).
Results
The two cohorts included 14 SSc and 38 IPF LTRs. SSc patients were younger (p=0.02), otherwise the groups were well matched (Table). The median DeMeester score pretransplant was elevated at 42.6 (32.3-52.7); [normal 0-22]. 3 SSc (one immediate postoperative death) and 11 IPF LTRs died over the 1yr followup period (p=0.73; Figure). Moderate to severe AR (>A2) rates were increased for the SSc group after adjusting for age (HR 2.91; CI95% (1.0-8.4), p=0.05). Creatinine clearance from LT to 1yr post-LT for the SSc group was decreased. Other secondary endpoints including infection and lung function showed no significant differences.
IPF |
PSSc |
p-value |
|
Baseline Demographic |
|||
Number of Patients |
38 |
14 |
- |
Female Gender |
9 (24%) |
4 (29%) |
0.73 |
Limited Disease |
- |
11 (79%) |
- |
Age |
58.8 (53.6-62.3) |
53.2 (42.6-58) |
0.02* |
Patient followup days |
757.6 + 420.4 |
759 + 452.2 |
0.99 |
DeMeester Score |
- |
42.6 (32.3-52.7) |
- |
Mean PAP PreLT |
23.5 (20-32.5) |
29 (23-45) |
0.11 |
Echo RVSP |
51 (37-62) |
61 (40-82) |
0.43 |
Lung Allocation Score |
42.5 (36.7-45.3) |
42 (35.9-46.7) |
0.98 |
# Bronchoscopies |
5 (4-6) |
6 (4-7.5) |
0.19 |
Infection (Bronch 12 mo) |
|||
Bacteria |
0.17 (0-0.5) |
0.2 (0-0.5) |
0.54 |
Fungus |
0 (0-0.25) |
0 (0-0.25) |
0.39 |
Virus |
0 (0-0) |
0 (0-0) |
0.91 |
AFB |
0 (0-0) |
0 (0-0.13) |
0.22 |
Rejection (TBBx 12 mo) |
|||
Any Acute Rejection Grade 2 |
21.6% |
62% |
0.01* |
Never Rejection |
62.2% |
31% |
0.05* |
Acute Rejection (Average) |
0 (0-0.4) |
0.5 (0-0.67) |
0.05* |
Lung Function (12 mo) |
|||
FEV1 (% pred) |
77 (69.5-85.5) |
74.5 (65.5-99.5) |
1 |
FVC (% pred) |
73 (63.5-80) |
68.5 (58-99) |
0.85 |
FEV1/FVC (%) |
80 (73-86) |
83 (76-84.5) |
0.93 |
Renal Function |
|||
Creat Clearance (pre transplant) |
- |
92.2 (64.8-118) |
- |
Creat Clearance (12 mo) |
- |
63.2 (55.5-78.5) |
- |
Survival |
|||
# Deaths at 12 months |
11 |
3 |
0.73 |
* p value is statistically significant. All values are median (25th-75th percentile), except Patient follow up days (mean + SD).RVSP (right ventricular systolic pressure); MPAP (mean pulmonary artery pressure).TBBx (transbronchial biopsies) |
|||
Conclusions
LTRs with SSc experience similar rates of survival over a 1yr followup when compared to a matched IPF cohort. Acute rejection rates are higher in the SSc group. Pre-LT, GERD was common in the SSc LTRs. There were no differences in lung function to suggest an earlier onset of bronchiolitis obliterans syndrome (BOS) (ie. chronic rejection) which is the most common cause of late mortality post-LT. GERD and AR are prominent in the SSc group and are accepted risk factors for BOS. However, in carefully selected patients with SSc, LT remains a viable treatment option with acceptable outcomes at 1yr. Longer-term followup is still necessary.
Editorial
Lung transplantation is considered in scleroderma patients with end-stage interstitial lung disease (ILD). However, this condition is considered at higher risk for allograft dysfunction due to significant gastrointestinal problems, such as upper GI dysmotility and decreased intestinal absorption. In fact, some report has linked the presence of severe gastroesophageal reflux (GERD) with higher incidence of bronchiolitis obliterans syndrome (BOS) after lung transplant. The present study shows that mortality at 1 year after bilateral lung transplant did not differ between patients with scleroderma and those with IPF. In particular, it is remarkable that survival as well as onset of BOS was comparable in the two groups despite GERD and acute rejection rates were more frequent in scleroderma. Longer follow-up periods are needed to define what the real benefit of lung transplant is. However, this study, in line with previous publications, suggests that scleroderma patients don’t have a worse outcome compared to IPF when undergoing lung transplant. Therefore, this represents a viable option that should always be explored in patients with end-stage scleroderma lung disease.
