Anna Nowakowska-Plaza, *Joanna Werońska-Tatara, Agnieszka Forys, Małgorzata Wisłowska
Interstitial lung disease associated to systemic sclerosis – rescue treatment with tocilizumab
Śródmiąższowa choroba płuc w przebiegu twardziny układowej – leczenie ratunkowe tocilizumabem
Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
Streszczenie
Choroba śródmiąższowa płuc jest jedną z głównych przyczyn śmiertelności w przebiegu twardziny układowej. Na wczesnym etapie pacjenci nie prezentują objawów klinicznych i mogą pozostać niezdiagnozowani. Wymagają szerokiej diagnostyki, w tym tomografii komputerowej i testów czynnościowych płuc. Klasyczne opcje terapeutyczne mają ograniczoną skuteczność, dlatego choroba śródmiąższowa płuc w przebiegu twardziny układowej pozostaje ciągle wyzwaniem terapeutycznym dla klinicystów.
Praca prezentuje przypadek młodej pacjentki z ciężką twardziną układową powikłaną chorobą śródmiąższową płuc oporną na leczenie metotreksatem, cyklofosfamidem i mykofenolanem mofetilu. W leczeniu zastosowano tocilizumab jako nową opcję terapeutyczną z obiecującym wczesnym efektem.
Wykrywalność choroby śródmiąższowej płuc w przebiegu twardziny układowej i zakres możliwości terapeutycznych poprawiły się w ostatnich latach. Powstały rekomendacje diagnostyczne i terapeutyczne. Jedną z obiecujących metod wydaje się być tocilizumab, przeciwciało monoklonalne skierowane przeciwko receptorowi IL-6, zaaprobowane przez FDA w 2021 roku w tym wskazaniu.
Introduction
Systemic sclerosis (SSc) is an autoimmune connective tissue disease, characterised by progressive fibrosis and vasculopathy. It affects typically the skin and other internal organs. Some of the clinical manifestations are treatable such as gastro-oesophageal reflux, renal crisis, digital ulcers, but others like heart involvement, interstitial lung disease (ILD) are still a challenge (1, 2).
The classification criteria for SSc were revised in 2013 by European League Against Rheumatism (EULAR). The purpose was to include important clinical and immunological features of the disease and focus on the early diagnosis. The criteria have the scoring system and to meet them patients need to get a total score greater than 9 points. The sensitivity and specificity are better then the previous classification criteria (91 and 92% respectively) (3). ILD is scored for 2 points. According to EULAR Scleroderma Trials and Research (EUSTAR) SSc-related deaths were due to ILD (35%), PAH (26%) and cardiac causes, mainly heart failure and arrhythmias (26%) (4).
ILD associated to systemic sclerosis
Although any part of the respiratory system: pleura, airways, parenchyma and vessels can be involved in SSc, the most common is SSc-ILD. The factors associated with the presence of ILD are male sex, Afro American race, diffuse skin changes, nailfold capillary abnormalities, digital ulcers and longer disease duration. Specific autoantibodies are linked to the development of ILD, including anti- Scl-70, anti-Th/To, anti-PM-Scl, anti-Ro-52 and anti-NOR90 antibodies. There is an increasing role of molecular markers as predictors of SSc-ILD like cytokines: interleukin-6 (IL-6), chemokines, matrix proteins, pneumocyte products and micro-RNAs (5).
ILD is seen as the result of coexisting fibrosis, autoimmunity, inflammation, and vascular injury. The initial injury of alveolar epithelium or small vessels is followed by pathological activation of the immune system. It activates fibroblasts, which initiates replacement of normal lung tissue to fibrotic one. One of the most important factor in the pathogenesis of SSc-ILD is IL-6, which is produced by fibroblasts and stimulates lymphocytes B. Elevated serum level of IL-6 is associated with a worse prognosis of SSc (6, 7).
In the early stages of the disease, most patients are a-symptomatic. Later appear dry cough, dyspnoea and fatigue. Routinely comprehensive clinical assessment including pulmonary function tests (PFT), arterial gasometry and HRCT should be performed in all SSc patients. The highest risk of developing ILD is in the early stage of SSc and PFT should be performed every 4-6 months in the first 3 years after SSc diagnosis. Early detection of ILD and monitoring for progression is essential. After 3 years of observation annual spirometry and DLCO should be performed, more frequent testing may be done in patients with established ILD. HRCT should be performed at baseline and repeated when new symptoms appear or a decline in PFT is observed (5).
PFT in patients with SSc-ILD usually reveal a restriction changes, with reduced FVC and DLCO. However, sometimes in patients with advanced fibrosis in HRCT, FVC may remain within the normal range. Reduced DLCO should be interpreted within the entire clinical context – it may be a result of PAH, emphysema or ILD (8).
The most common pattern of ILD observed in HRCT imaging and histopathology is nonspecific ineterstinal pneumonia (NSIP). It is found in approximately in 80% of patients with SSc-ILD. This type of ILD is characterised by peripheral ground-glass opacities. A usual interstitial pneumonia (UIP) pattern characterized by honeycombing without ground-glass opacities is present in less than 10% of patients with SSc-ILD (9, 10).
Deviations in arterial gasometry appear late in the disease course and indicate hypoxemic respiratory failure. In routine clinical practice a 6-minute walk test (≤ 94%) is used to predict the prognosis of SSc ILD (5).
The clinical course of SSc-ILD is variable, most of patients have a slow decline in PFT and increase of fibrosis in imaging, some have rapid progression of the lung disease. Independent factors of mortality are a low FVC and extent of fibrosis on HRCT (11, 12).
The staging system proposed by Goh et al. (13) predicts mortality. The threshold of minimal disease involvement is fibrosis less than 10% on HRCT. The extensive disease is defined if extent of fibrosis is more than 30%. If the lung lesions range is between 10 and 30%, than the FVC value below 70% predicts advanced disease.
Management of SSc-ILD
The recent EULAR guidelines recommend the use of cyclophosphamide (CYC) or hematopoietic stem cell transplantation (HSCT) in SSc-ILD (14). Data for a positive influence on SSc-ILD are also available for mycophenolate mofetil (MMF) and biologic therapies. Because of the pathophysiological similarities to idiopathic pulmonary fibrosis, the use of the antifibrotic agents: nintedanib and pirfenidone are a promising therapeutic strategy (15). Moreover experts from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research group were asked to establish treatment algorithms of organ manifestations of SSc. For ILD 69% of experts agreed that for induction therapy, treatment options were MMF, CYC IV, and rituximab, respectively. For maintenance the first-line treatment was MMF (16).
Powyżej zamieściliśmy fragment artykułu, do którego możesz uzyskać pełny dostęp.
Mam kod dostępu
- Aby uzyskać płatny dostęp do pełnej treści powyższego artykułu albo wszystkich artykułów (w zależności od wybranej opcji), należy wprowadzić kod.
- Wprowadzając kod, akceptują Państwo treść Regulaminu oraz potwierdzają zapoznanie się z nim.
- Aby kupić kod proszę skorzystać z jednej z poniższych opcji.
Opcja #1
24 zł
Wybieram
- dostęp do tego artykułu
- dostęp na 7 dni
uzyskany kod musi być wprowadzony na stronie artykułu, do którego został wykupiony
Opcja #2
59 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 30 dni
- najpopularniejsza opcja
Opcja #3
119 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 90 dni
- oszczędzasz 28 zł
Piśmiennictwo
1. Denton CP, Khanna D: Systemic sclerosis. Lancet 2017; 390(10103): 1685-1699.
2. Cutolo M, Soldano S, Smith V: Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol 2019; 15(7): 753-764.
3. Van den Hoogen F, Khanna D, Fransen J et al.: 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 2013; 72(11): 1747-1755.
4. Tyndall AJ, Bannert B, Vonk M et al.: Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010; 69(10): 1809-1815.
5. Perelas A, Silver RM, Arrossi AV et al.: Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med 2020; 8(3): 304-320.
6. Cottin V, Brown K: Interstitial lung disease associated with systemic sclerosis (SSc-ILD). Respir Res 2019; 20(1): 13.
7. Martinović Kaliterna D, Petrić M: Biomarkers of skin and lung fibrosis in systemic sclerosis. Expert Rev Clin Immunol 2019; 15(11): 1215-1223.
8. Suliman YA, Dobrota R, Huscher D et al.: Brief report: pulmonary function tests: high rate of false-negative results in the early detection and screening of scleroderma-related interstitial lung disease. Arthritis Rheumatol 2015; 67: 3256-3261.
9. Desai SR, Veeraraghavan S, Hansell DM et al.: CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology 2004; 232(2): 560-567.
10. Daimon T, Johkoh T, Honda O et al.: Nonspecific interstitial pneumonia associated with collagen vascular disease: analysis of CT features to distinguish the various types. Intern Med 2009; 48(10): 753-761.
11. Wu W, Jordan S, Becker MO et al.: Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model. Ann Rheum Dis 2018; 77(9): 1326-1332.
12. Hoffmann-Vold AM, Allanore Y, Alves M et al.: Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021; 80(2): 219-227.
13. Goh NS, 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.
14. Kowal-Bielecka O, Fransen J, Avouac J et al.: Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017; 76(8): 1327-1339.
15. Prasse A, Bonella F, Müller-Ladner U et al.: Treatment of systemic sclerosis-associated interstitial lung disease. Z Rheumatol 2020; 79(3): 294-303.
16. Fernández-Codina A, Walker KM, Pope JE: Scleroderma Algorithm Group Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis Rheumatol 2018; 70(11): 1820-1828.
17. Tashkin DP, Elashoff R, Clements PJ et al.: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354(25): 2655-2666.
18. Tashkin DP, Roth MD, Clements PJ et al.: 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(9): 708-719.
19. Burt RK, Shah SJ, Dill K et al.: Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 2011; 378(9790): 498-506.
20. Elhai M, Boubaya M, Distler O et al.: Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis 2019; 78(7): 979-987.
21. Khanna D, Lin CJF, Furst DE et al.: Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2020; 8(10): 963-974.
22. Distler O, Highland KB, Gahlemann M et al.: Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med 2019; 380(26): 2518-2528.
23. Hachulla E, Agard C, Allanore Y et al.: French recommendations for the management of systemic sclerosis. Orphanet J Rare Dis 2021; 16(Suppl 2): 322.
