Download PDF
Semin Respir Crit Care Med
DOI: 10.1055/s-0044-1782607
Review Article

Pulmonary Manifestations of Connective Tissue Diseases

Sarah Cullivan
1   Department of Respiratory Medicine and Pulmonary Hypertension, National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
,
Eleanor Cronin
1   Department of Respiratory Medicine and Pulmonary Hypertension, National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
,
Sean Gaine
1   Department of Respiratory Medicine and Pulmonary Hypertension, National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Systemic sclerosis is a multisystem connective tissue disease that is associated with substantial morbidity and mortality. Visceral organ involvement is common in patients with systemic sclerosis and occurs independently of skin manifestations. Pulmonary hypertension (PH) is an important and prevalent complication of systemic sclerosis. The clinical classification of PH cohorts conditions with similar pathophysiological mechanisms into one of five groups. While patients with systemic sclerosis can manifest with a spectrum of pulmonary vascular disease, notable clinical groups include group 1 pulmonary arterial hypertension (PAH) associated with connective tissues disease, PAH with features of capillary/venous involvement, group 2 PH associated with left heart disease, and group 3 PH associated with interstitial lung disease. Considerable efforts have been made to advance screening methods for PH in systemic sclerosis including the DETECT and ASIG (Australian Scleroderma Interest Group) composite algorithms. Current guidelines recommend annual assessment of the risk of PAH as early recognition may result in attenuated hemodynamic impairment and improved survival. The treatment of PAH associated with systemic sclerosis requires a multidisciplinary team including a PH specialist and a rheumatologist to optimize immunomodulatory and PAH-specific therapies. Several potential biomarkers have been identified and there are several promising PAH therapies on the horizon such as the novel fusion protein sotatercept. This chapter provides an overview of PH in systemic sclerosis, with a specific focus on group 1 PAH.

Keywords

systemic sclerosis - pulmonary vascular disease - pulmonary hypertension - DETECT


Publication History

Article published online:
26 March 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Launay D, Sobanski V, Hachulla E, Humbert M. Pulmonary hypertension in systemic sclerosis: different phenotypes. Eur Respir Rev 2017; 26 (145) 170056
    CrossrefPubMedGoogle Scholar
  • 2 Humbert M, Kovacs G, Hoeper MM. et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2022; 43 (38) 3618-3731
    PubMedGoogle Scholar
  • 3 Bairkdar M, Rossides M, Westerlind H, Hesselstrand R, Arkema EV, Holmqvist M. Incidence and prevalence of systemic sclerosis globally: a comprehensive systematic review and meta-analysis. Rheumatology (Oxford) 2021; 60 (07) 3121-3133
    CrossrefPubMedGoogle Scholar
  • 4 Bergamasco A, Hartmann N, Wallace L, Verpillat P. Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease. Clin Epidemiol 2019; 11: 257-273
    CrossrefPubMedGoogle Scholar
  • 5 Peoples C, Medsger Jr TA, Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord 2016; 1 (02) 177-240
    PubMedGoogle Scholar
  • 6 Weatherald J, Montani D, Jevnikar M, Jaïs X, Savale L, Humbert M. Screening for pulmonary arterial hypertension in systemic sclerosis. Eur Respir Rev 2019; 28 (153) 190023
    CrossrefPubMedGoogle Scholar
  • 7 Coghlan JG, Denton CP, Grünig E. et al; DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 2014; 73 (07) 1340-1349
    CrossrefPubMedGoogle Scholar
  • 8 Moinzadeh P, Bonella F, Oberste M. et al. Impact of systemic sclerosis-associated interstitial lung disease with and without pulmonary hypertension on survival: a large cohort study of the German Network for Systemic Sclerosis. Chest 2024; 165 (01) 132-145
    CrossrefPubMedGoogle Scholar
  • 9 Gashouta MA, Humbert M, Hassoun PM. Update in systemic sclerosis-associated pulmonary arterial hypertension. Presse Med 2014; 43 (10 Pt 2): e293-e304
    CrossrefPubMedGoogle Scholar
  • 10 Overbeek MJ, Vonk MC, Boonstra A. et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J 2009; 34 (02) 371-379
    CrossrefPubMedGoogle Scholar
  • 11 Dorfmüller P, Humbert M, Perros F. et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol 2007; 38 (06) 893-902
    CrossrefPubMedGoogle Scholar
  • 12 Dumoitier N, Lofek S, Mouthon L. Pathophysiology of systemic sclerosis: state of the art in 2014. Presse Med 2014; 43 (10 Pt 2): e267-e278
    CrossrefPubMedGoogle Scholar
  • 13 Fox BD, Shimony A, Langleben D. et al. High prevalence of occult left heart disease in scleroderma-pulmonary hypertension. Eur Respir J 2013; 42 (04) 1083-1091
    CrossrefPubMedGoogle Scholar
  • 14 Zanin-Silva DC, Santana-Gonçalves M, Kawashima-Vasconcelos MY, Oliveira MC. Management of endothelial dysfunction in systemic sclerosis: current and developing strategies. Front Med (Lausanne) 2021; 8: 788250
    CrossrefPubMedGoogle Scholar
  • 15 Rosendahl A-H, Schönborn K, Krieg T. Pathophysiology of systemic sclerosis (scleroderma). Kaohsiung J Med Sci 2022; 38 (03) 187-195
    CrossrefPubMedGoogle Scholar
  • 16 Steen V, Medsger Jr TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003; 48 (02) 516-522
    CrossrefPubMedGoogle Scholar
  • 17 Feghali-Bostwick C, Medsger Jr TA, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003; 48 (07) 1956-1963
    CrossrefPubMedGoogle Scholar
  • 18 Moll M, Christmann RB, Zhang Y. et al. Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease. J Scleroderma Relat Disord 2018; 3 (03) 242-248
    CrossrefPubMedGoogle Scholar
  • 19 Arron JR. Biomarkers in systemic sclerosis: mechanistic insights into pathogenesis and treatment. Curr Opin Rheumatol 2021; 33 (06) 480-485
    CrossrefPubMedGoogle Scholar
  • 20 Di Maggio G, Confalonieri P, Salton F. et al. Biomarkers in systemic sclerosis: an overview. Curr Issues Mol Biol 2023; 45 (10) 7775-7802
    CrossrefPubMedGoogle Scholar
  • 21 Martinović Kaliterna D, Petrić M. Biomarkers of skin and lung fibrosis in systemic sclerosis. Expert Rev Clin Immunol 2019; 15 (11) 1215-1223
    CrossrefPubMedGoogle Scholar
  • 22 Sheng XR, Gao X, Schiffman C. et al. Biomarkers of fibrosis, inflammation, and extracellular matrix in the phase 3 trial of tocilizumab in systemic sclerosis. Clin Immunol 2023; 254: 109695
    CrossrefPubMedGoogle Scholar
  • 23 Follansbee WP, Miller TR, Curtiss EI. et al. A controlled clinicopathologic study of myocardial fibrosis in systemic sclerosis (scleroderma). J Rheumatol 1990; 17 (05) 656-662
    PubMedGoogle Scholar
  • 24 Goh NSL, Desai SR, Veeraraghavan S. et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 2008; 177 (11) 1248-1254
    CrossrefPubMedGoogle Scholar
  • 25 Humbert M, Yaici A, de Groote P. et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum 2011; 63 (11) 3522-3530
    CrossrefPubMedGoogle Scholar
  • 26 Nihtyanova SI, Schreiber BE, Ong VH. et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol 2014; 66 (06) 1625-1635
    CrossrefPubMedGoogle Scholar
  • 27 Morrisroe K, Huq M, Stevens W, Rabusa C, Proudman SM, Nikpour M. Australian Scleroderma Interest Group (ASIG). Risk factors for development of pulmonary arterial hypertension in Australian systemic sclerosis patients: results from a large multicenter cohort study. BMC Pulm Med 2016; 16 (01) 134
    CrossrefPubMedGoogle Scholar
  • 28 Thakkar V, Stevens WM, Prior D. et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther 2012; 14 (03) R143
    CrossrefPubMedGoogle Scholar
  • 29 Smith V, Vanhaecke A, Vandecasteele E. et al. Nailfold videocapillaroscopy in systemic sclerosis-related pulmonary arterial hypertension: a systematic literature review. J Rheumatol 2020; 47 (06) 888-895
    CrossrefPubMedGoogle Scholar
  • 30 Dumitrescu D, Nagel C, Kovacs G. et al. Cardiopulmonary exercise testing for detecting pulmonary arterial hypertension in systemic sclerosis. Heart 2017; 103 (10) 774-782
    CrossrefPubMedGoogle Scholar
  • 31 Humbert M, McLaughlin V, Gibbs JSR. et al. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J 2023; 61 (01) 2201347
    CrossrefPubMedGoogle Scholar
  • 32 Hoeper MM, Badesch DB, Ghofrani HA. et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med 2023; 388 (16) 1478-1490
    CrossrefPubMedGoogle Scholar
  • 33 Frantz RP, Benza RL, Channick RN. et al. TORREY, a phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension. Pulm Circ 2021; 11 (04) 20 458940211057071
    CrossrefPubMedGoogle Scholar
  • 34 Frost AE, Barst RJ, Hoeper MM. et al. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant 2015; 34 (11) 1366-1375
    CrossrefPubMedGoogle Scholar
  • 35 Gillies HM, Chakinala M, Dake BEN. et al. Inhaled imatinib for pulmonary arterial hypertension clinical trial: design of the impact phase 2B/3 study design. Chest 2022; 162 (04) A2325-A2329
    CrossrefPubMedGoogle Scholar
  • 36 Bohdziewicz A, Pawlik KK, Maciejewska M. et al. Future treatment options in systemic sclerosis-potential targets and ongoing clinical trials. J Clin Med 2022; 11 (05) 1310
    CrossrefPubMedGoogle Scholar
  • 37 Khanna D, Allanore Y, Denton CP. et al. Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial. Ann Rheum Dis 2020; 79 (05) 618-625
    CrossrefPubMedGoogle Scholar
  • 38 Nagaraja V, Spino C, Bush E. et al. A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers. Arthritis Res Ther 2019; 21 (01) 202
    CrossrefPubMedGoogle Scholar
  • 39 Spiera RF, Gordon JK, Mersten JN. et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis 2011; 70 (06) 1003-1009
    CrossrefPubMedGoogle Scholar
  • 40 Waxman A, Restrepo-Jaramillo R, Thenappan T. et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 2021; 384 (04) 325-334
    CrossrefPubMedGoogle Scholar
  • 41 Raman L, Stewart I, Barratt SL. et al. Nintedanib for non-IPF progressive pulmonary fibrosis: 12-month outcome data from a real-world multicentre observational study. ERJ Open Res 2023; 9 (02) 00423-02022
    CrossrefPubMedGoogle Scholar
  • 42 Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005; 14 (1, Suppl 1) s2-s8
    CrossrefPubMedGoogle Scholar
  • 43 Tashkin DP, Roth MD, Clements PJ. et al; Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016; 4 (09) 708-719
    CrossrefPubMedGoogle Scholar
  • 44 Suzuki C, Takahashi M, Morimoto H. et al. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats. Biochem Biophys Res Commun 2006; 349 (02) 781-788
    CrossrefPubMedGoogle Scholar
  • 45 Zheng Y, Li M, Zhang Y, Shi X, Li L, Jin M. The effects and mechanisms of mycophenolate mofetil on pulmonary arterial hypertension in rats. Rheumatol Int 2010; 30 (03) 341-348
    CrossrefPubMedGoogle Scholar
  • 46 Saketkoo LA, Lammi MR, Gordon JK. et al. Does mycophenolate mofetil (MMF) have an effect on pulmonary hemodynamics? Observations from the pulmonary hypertension assessment and recognition of outcomes in scleroderma (PHAROS) cohort. A2580. 2013 ACR/ARHP Annual Meeting 2013.
    PubMed
  • 47 Tashkin DP, Elashoff R, Clements PJ. et al; Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354 (25) 2655-2666
    CrossrefPubMedGoogle Scholar
  • 48 Ranchoux B, Günther S, Quarck R. et al. Chemotherapy-induced pulmonary hypertension: role of alkylating agents. Am J Pathol 2015; 185 (2, suppl 59): 356-371
    CrossrefPubMedGoogle Scholar
  • 49 Kuzumi A, Ebata S, Fukasawa T. et al. Long-term outcomes after rituximab treatment for patients with systemic sclerosis: follow-up of the DESIRES trial with a focus on serum immunoglobulin levels. JAMA Dermatol 2023; 159 (04) 374-383
    CrossrefPubMedGoogle Scholar
  • 50 Zamanian RT, Badesch D, Chung L. et al. Safety and efficacy of B-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension: a multicenter, double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2021; 204 (02) 209-221
    CrossrefPubMedGoogle Scholar
  • 51 Khanna D, Lin CJF, Furst DE. et al; focuSSced investigators. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2020; 8 (10) 963-974
    CrossrefPubMedGoogle Scholar
  • 52 Moraes DA, Oliveira MC. Life after autologous hematopoietic stem cell transplantation for systemic sclerosis. J Blood Med 2021; 12: 951-964
    CrossrefPubMedGoogle Scholar
  • 53 Bagnato G, Versace AG, La Rosa D. et al. Autologous haematopoietic stem cell transplantation and systemic sclerosis: focus on interstitial lung disease. Cells 2022; 11 (05) 843
    CrossrefPubMedGoogle Scholar
  • 54 Grünig E, MacKenzie A, Peacock AJ. et al. Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial. Eur Heart J 2021; 42 (23) 2284-2295
    CrossrefPubMedGoogle Scholar
  • 55 Grünig E, Eichstaedt C, Barberà J-A. et al. ERS statement on exercise training and rehabilitation in patients with severe chronic pulmonary hypertension. Eur Respir J 2019; 53 (02) 1800332
    CrossrefPubMedGoogle Scholar
  • 56 Pradère P, Tudorache I, Magnusson J. et al; Working Group on Heart/Lung Transplantation in Systemic Sclerosis. Lung transplantation for scleroderma lung disease: An international, multicenter, observational cohort study. J Heart Lung Transplant 2018; 37 (07) 903-911
    CrossrefPubMedGoogle Scholar
  • 57 Cullivan S, Lennon D, Meghani S, Minnock C, McCullagh B, Gaine S. Incidence and outcomes of pulmonary hypertension in the Ireland. BMJ Open Respir Res 2022; 9 (01) e001272
    CrossrefPubMedGoogle Scholar
  • 58 Gall H, Felix JF, Schneck FK. et al. The Giessen pulmonary hypertension registry: survival in pulmonary hypertension subgroups. J Heart Lung Transplant 2017; 36 (09) 957-967
    CrossrefPubMedGoogle Scholar
  • 59 Chen X, Quan R, Qian Y. et al. 10-year survival of pulmonary arterial hypertension associated with connective tissue disease: insights from a multicentre PAH registry. Rheumatology (Oxford) 2023; 62 (11) 3555-3564
    CrossrefPubMedGoogle Scholar
  • 60 Gupta S, Gupta A, Rehman S. et al. Pulmonary veno-occlusive disease is highly prevalent in scleroderma patients undergoing lung transplantation. ERJ Open Res 2019; 5 (01) 00168-2018
    CrossrefPubMedGoogle Scholar
  • 61 Günther S, Jaïs X, Maitre S. et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64 (09) 2995-3005
    CrossrefPubMedGoogle Scholar
  • 62 Holcomb Jr BW, Loyd JE, Ely EW, Johnson J, Robbins IM. Pulmonary veno-occlusive disease: a case series and new observations. Chest 2000; 118 (06) 1671-1679 (In eng)
    PubMedGoogle Scholar
  • 63 Wille KM, Sharma NS, Kulkarni T. et al. Characteristics of patients with pulmonary venoocclusive disease awaiting transplantation. Ann Am Thorac Soc 2014; 11 (09) 1411-1418
    CrossrefPubMedGoogle Scholar
  • 64 Montani D, Lau EM, Dorfmüller P. et al. Pulmonary veno-occlusive disease. Eur Respir J 2016; 47 (05) 1518-1534
    CrossrefPubMedGoogle Scholar