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Challenges in Lung Transplantation for Anti-Synthetase Syndrome Associated Interstitial Lung Disease

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Hrishikesh S. Kulkarni, MD
Chad Witt, MD
Faculty Sponsor
Washington University in St. Louis
St. Louis, MO, USA

35-65% of patients with connective tissue diseases (CTD) such as scleroderma, rheumatoid arthritis, myositis, systemic lupus erythematosus and mixed connective tissue disease develop interstitial lung disease (ILD), depending on patient selection and detection methods [1]. According to the 2014 Report from the International Society for Heart and Lung Transplantation Registry, 1.4% of total transplants between January 1995 to June 2013 were done for CTD (586/41900) [2]. However, while grouped together under the "CTD-ILD" umbrella, each of these diseases presents unique challenges in the management of a potential lung transplant recipient [3]. Antisynthetase syndrome is one such distinct clinical phenotype comprised of inflammatory myopathy, ILD, Raynaud phenomenon, hyperkeratotic skin changes (mechanic's hands), and non-erosive arthritis in patients who have antibodies against aminoacyl transfer RNA synthetases [4]. The myositis in these patients ranges from being amyopathic to fulminant. Historically, many centers have been hesitant to perform lung transplants in this patient population due to existing comorbidities, risk of recurrence in the allograft, and poor long-term outcomes.

Patients with anti-synthetase syndrome may have sub-clinical cardiac involvement including myocarditis and conduction abnormalities that may be unmasked in the perioperative period [4]. In patients with end-stage lung disease, pulmonary hypertension is often a concomitant risk factor and may require the patient to be on cardiopulmonary bypass during transplantation, thus increasing the risk for primary graft dysfunction [1,5]. Some of these patients are malnourished, and may have muscle weakness due to their myositis superimposed on deconditioning, all of which can predispose them to hypoventilation [5]. Esophageal involvement in connective tissue diseases may also increase the risk for gastroesophageal reflux and thus the risk of developing chronic lung allograft dysfunction. Additionally, patients with antisynthetase syndrome are at an increased risk for malignancy, which one needs to be mindful of prior to listing for transplantation [3,5].

A major challenge in this population is refractory underlying disease. Many patients have progressed to end-stage lung disease despite being treated with prednisone, azathioprine or mycophenolate mofetil, cyclophosphamide, plasmapheresis and/or rituximab [1,6]. More recently, tacrolimus has also been used for steroid-refractory anti-synthetase syndrome [7]. Patients can develop diffuse alveolar hemorrhage or diffuse alveolar damage, and some of them have needed extracorporeal life support for refractory hypoxemia [8,9]. If the underlying disease cannot be adequately controlled prior to transplant, the successful prevention of recurrent disease in the allograft remains questionable. Unfortunately, there are no accurate markers of disease activity. A high creatine phosphokinase or aldolase level certainly incites caution, but patients have had successful short-term and intermediate outcomes despite high levels [6].

Most of the outcomes of transplanting patients with anti-synthetase syndrome have been reported as case reports or a part of a larger cohort of patients who have been transplanted for CTD-ILD [9,10]. A 2012 report of 284 lung transplant recipients with CTD-ILD revealed that 5 year post-transplant survival for these patients was lower than that for COPD but comparable with IPF (73% versus 83% for COPD, 78% for IPF) [1]. More recently, data from the Leuven Transplant Cohort revealed that among 5 patients with pulmonary polymyositis (disease duration before lung transplant ranging from 2 months to 10 years), only 1 patient experienced acute rejection [6]. While the sample size was limited, none of these patients developed chronic rejection during follow-up (28-36 months). However, the length of hospital stay was longer in these patients compared to IPF and non-IPF non-IIM (idiopathic inflammatory myopathy) ILD cohorts. Both studies show that the increased complication risk appears to be mainly within the first 6-12 months after transplantation. Once beyond this period, the long-term outcomes are similar to the patients with other interstitial lung diseases.

Pulmonary and extrapulmonary recurrences of anti-synthetase syndrome are a major area of concern in this recipient population, complicating the recipient management and balance between augmenting immunosuppression and increasing the risk of infection. Recurrent diffuse alveolar hemorrhage and antibody-mediated allograft injury may delay extubation, increase the length of ICU, hospital or long-term acute care facility stay, or may even be fatal [1,8]. Worsening myopathy from myositis or intractable gastroesophageal reflux are also potential complications.

The abovementioned, limited reports suggest that lung transplantation may be successfully performed in patients with anti-synthetase syndrome. However, future research to identify accurate biomarkers is necessary to more clearly identify underlying disease activity. In the meanwhile, an organized, disease-specific multi-system evaluation must be performed in patients with antisynthetase syndrome who are being considered for lung transplantation. ■

Disclosure Statement: The author is funded by the Principles in Pulmonary Research grant T32HL007317 from the National Heart, Lung and Blood Institute (NHLBI), and the Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH).


  1. Takagishi T, Ostrowski R, Alex C, Rychlik K, Pelletiere K, Tehrani R. Survival and extrapulmonary course of connective tissue disease after lung transplantation. J Clin Rheum. 2012;18:283-289.
  2. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report--2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:1009-1024.
  3. de Lauretis A, Veeraraghavan S, Renzoni E. Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ? Chr Resp Dis 2011;8:53-82.
  4. Kulkarni HS, Gutierrez FR, Despotovic V, Russell TD. A 43-year-old man with antisynthetase syndrome presenting with acute worsening of dyspnea. Chest 2015;147:e215-219.
  5. Hadley R, Chan KM. Lung Transplantation for Connective Tissue Disease-Associated Lung Disease. In: Paul F. Dellaripa AF, Kevin R. Flaherty, ed. Pulmonary Manifestations of Rheumatic Disease: A Comprehensive Guide. New York: Springer; 2014:179-191.
  6. Ameye H, Ruttens D, Benveniste O, Verleden GM, Wuyts WA. Is lung transplantation a valuable therapeutic option for patients with pulmonary polymyositis? Experiences from the Leuven transplant cohort. Transpl Proc 2014;46:3147-3153.
  7. Labirua-Iturburu A, Selva-O'Callaghan A, Martinez-Gomez X, Trallero-Araguas E, Labrador-Horrillo M, Vilardell-Tarres M. Calcineurin inhibitors in a cohort of patients with antisynthetase-associated interstitial lung disease. Clin Exp Rheum 2013;31:436-439.
  8. Arboleda R, Gonzalez O, Cortes M, Perez-Cerda F. Recurrent polymyositis-associated lung disease after lung transplantation. Interact Cardiovasc Thorac Surg 2015;20:560-562.
  9. Hayes D, Jr., Galantowicz M, Preston TJ, et al. Cross-country transfer between two children's hospitals of a child using ambulatory extracorporeal membrane oxygenation for bridge to lung transplant. Pediatr Transplant 2013;17:E117-118.
  10. Broome M, Palmer K, Schersten H, Frenckner B, Nilsson F. Prolonged extracorporeal membrane oxygenation and circulatory support as bridge to lung transplant. Ann Thorac Surg 2008;86:1357-1360.

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