Expert Review of Respiratory Medicine ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20 Management of progressive pulmonary fibrosis associated with connective tissue disease María Molina-Molina, Iván Castellví, Claudia Valenzuela, José Ramirez, José Antonio Rodríguez Portal, Tomás Franquet & Javier Narváez To cite this article: María Molina-Molina, Iván Castellví, Claudia Valenzuela, José Ramirez, José Antonio Rodríguez Portal, Tomás Franquet & Javier Narváez (2022) Management of progressive pulmonary fibrosis associated with connective tissue disease, Expert Review of Respiratory Medicine, 16:7, 765-774, DOI: 10.1080/17476348.2022.2107508 To link to this article: https://doi.org/10.1080/17476348.2022.2107508 © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 05 Aug 2022. Submit your article to this journal Article views: 4394 View related articles View Crossmark data Citing articles: 2 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierx20 EXPERT REVIEW OF RESPIRATORY MEDICINE 2022, VOL. 16, NO. 7, 765–774 https://doi.org/10.1080/17476348.2022.2107508 REVIEW Management of progressive pulmonary fibrosis associated with connective tissue disease María Molina-Molinaa, Iván Castellvíb, Claudia Valenzuelac, José Ramirezd, José Antonio Rodríguez Portale, Tomás Franquetf and Javier Narváezg a Servicio de Neumología, Hospital de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain; bServicio de Reumatología, Hospital de Santa Creu i Sant Pau, Barcelona, Spain; cServicio de Neumología, Hospital La Princesa, Madrid, Spain; dServicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Spain; eServicio de Neumología, Hospital Universitario Virgen del Rocío, Sevilla, Spain; f Servicio de Radiología, Hospital de Santa Creu i Sant Pau. Universidad Autónoma de Barcelona, Barcelona, Spain; gServicio de Reumatología, Hospital de Bellvitge, IDIBELL. Red de investigación en inflamación y enfermedades reumáticas (RIER), L’Hospitalet de Llobregat, Barcelona, Spain ABSTRACT ARTICLE HISTORY Introduction: Fibrotic interstitial lung disease (ILD) is a frequent and severe complication of connective Received 28 April 2022 tissue disease (CTD). Accepted 26 July 2022 Areas covered: In this narrative review, we update the most relevant differential characteristics of KEYWORDS fibrotic ILD associated with CTD (CTD-ILD) and propose a diagnostic and therapeutic approach based Interstitial lung disease; on a review of the articles published between 2002 and 2022 through PubMed. connective tissue disease; Expert opinion: The subset of ILD, mainly the radiological/histological pattern and the degree of progressive pulmonary fibrotic component, usually determines the prognosis and therapeutic strategy for these patients. Some fibrosis; multidisciplinary patients with CTD-ILD can develop progressive pulmonary fibrosis (PPF) with severe deterioration of consultation; diagnosis; lung function, rapid progression to chronic respiratory failure, and high mortality. PPF has been treatment described in many CTDs, mainly in systemic sclerosis and rheumatoid arthritis, and requires a multidisciplinary diagnostic and therapeutic approach to improve patient outcomes. 1. Introduction prognosis. A proportion of fibrotic CTD-ILD patients will Interstitial lung disease (ILD) has been described in almost all develop progressive pulmonary fibrosis (PPF) and rapid dete­ connective tissue diseases (CTDs) [1–12], with higher preva­ rioration of pulmonary function tests (PFTs), leading to end- lence in systemic sclerosis (SSc) [2,3], rheumatoid arthritis (RA) stage respiratory failure and high mortality [13,20–23]. [4,5], and in some groups of inflammatory myositis (dermato­ Moreover, it has been described that fibrotic ILD is character­ myositis, antisynthetase syndrome, and overlap syndromes) ized by an increased distal alveolar bacterial burden that [6–9]. might be responsible for both a rapidly deteriorating course The pathogenesis of ILD associated with CTD (CTD-ILD) is of fibrotic disease and deadly exacerbations [24,25]. It has also not completely elucidated, although the main hypothesis been shown, that RA-ILD has a higher serious infections risk, assumes that tissue fibrosis is preceded by an immune- especially pneumonia [26,27]. mediate process [1–6,13–16]. In SSc, this process seems to be The diagnosis of fibrotic CTD-ILD, especially the early iden­ triggered by endothelial injury in the context of encompassing tification of patients with PPF, is complex. In these cases, immune activity [3,14,15]. In the last decades, some research a comprehensive assessment is essential, including accurate studies have suggested different pathways to be implicated in staging of the severity of the disease and extrapulmonary the development of ILD in SSc and RA, including immune- manifestations. In addition, an individualized and comprehen­ mediated alveolar epithelial damage and endothelial disor­ sive therapeutic approach is important in the treatment of ders, and the subsequent and progressive abnormal extracel­ CTD-ILD to control the autoimmune and inflammatory activity lular matrix remodeling and myofibroblast formation [17]. of the underlying disease and to prevent, when necessary, the Following the identification of these pathogenic pathways progression of fibrotic pulmonary changes [28]. For all these and implicated mediators, different future potential strategies reasons, a multidisciplinary approach is worthwhile in the are being pre-clinically evaluated in SSc-associated ILD (SSc- treatment of the different stages in CTD-ILD, for diagnosis ILD) and RA-associated ILD (RA-ILD), including the regulation and treatment (both initial and during follow-up) [29]. of some relevant overexpressed extracellular matrix proteins The aim of this article is to describe the most relevant such as COL5A2 [18,19]. differential characteristics of PPF in CTD and to propose The clinical course of CTD-ILD is variable, but patients with a diagnostic and therapeutic approach based on the pub­ evidence of pulmonary fibrosis tend to have a worse lished evidence and the clinical experience of CONTACT María Molina-Molina mariamolinamolina@hotmail.com Servicio de Neumología, Unidad Funcional de Intersticio Pulmonar (UFIP). Servicio de Neumología, Hospital Universitari de Bellvitge, IDIBELL, Carrer de la Feixa Llarga, s/n - 08907 L’Hospitalet de Llobregat, Barcelona, España, Spain © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 766 M. MOLINA-MOLINA ET AL. symptoms and auscultation is essential; ‘velcro-type’ crackles Article highlights to lung auscultation, correlates very well with the presence of ● Interstitial lung disease (ILD) is a frequent and severe complication of pulmonary fibrosis [38]. Clinically, ILD presents with repetitive connective tissue diseases (CTD), such as systemic sclerosis and dry cough and exertional dyspnea, which may progress to rheumatoid arthritis. respiratory failure. ● The diagnosis of fibrotic ILD in CTDs, especially the early identifica­ tion of patients with progressive pulmonary fibrosis, is complex, Table 1 lists those patient features that can help to identify requiring a comprehensive assessment, including accurate staging fibrotic CTD-ILD patients [17,29–31,35,39]. In case of suspected of the disease severity and extrapulmonary manifestations. ILD, a chest X-ray and PFTs including spirometry and carbon ● An individualized and comprehensive therapeutic approach is impor­ tant in the treatment of ILD associated with CTD to control the monoxide diffusing capacity (DLCO) are usually performed for autoimmune and inflammatory activity of the underlying disease initial screening. However, chest X-ray is a technique with low and to prevent, when necessary, the progression of fibrotic pulmon­ sensitivity in the early stages, when only high-resolution com­ ary changes. ● A multidisciplinary diagnostic and therapeutic approach is required to puted tomography (HRCT) detects the mild interstitial not only guarantee early diagnosis but also provide comprehensive changes, being the most sensitive imaging tool to detect and individualized treatment. ILD. The PFTs in fibrotic ILD show a restrictive ventilatory ● Antifibrotic drugs, such as nintedanib, have been shown in recent clinical trials to attenuate progressive pulmonary fibrosis in patients (decrease of total lung capacity [TLC] and forced vital capacity with CTD and may provide therapeutic benefit. [FVC]) pattern together with a decrease in DLCO. However, in early stages, a decrease in DLCO with preserved FVC may be found. Furthermore, if only a DLCO decrease is present or the severity of DLCO decrease is not associated with a TLC or FVC decline, pulmonary arterial hypertension (PAH) should be con­ a multidisciplinary group of experts. Narrative literature review sidered, especially in SSc patients (PubMed Central) was used to search for the articles published To confirm ILD and to characterize its pattern, the chest between 2002 and 2022, excluding clinical cases. The terms HRCT is essential. Due to the HRCT radiologic-histologic corre­ ‘interstitial lung disease’, ‘progressive fibrosis’, and ‘connective lation pattern and the association of CTD as a cause of ILD, tissue disease’ were used in the literature search. lung biopsy is not usually required. HRCT is also useful to 2. Identification and diagnosis of CTD-ILD Table 1. Patient features and invasive and noninvasive tests useful for identify­ ILD may present as a complication during the course of ing an ILD in a CTD. a known CTD or the clinical onset of a CTD. In both scenarios, Noninvasive tests Patient history: a multidisciplinary diagnostic and therapeutic approach is ● Smoking ideally advised [29–31]. ● Medication use In patients with a known CTD, this multidisciplinary model of care has been shown to reduce the time to ILD identifica­ ● Environmental exposures (mold, feathers, animals, metal dusts, wood dusts, plant dusts, livestock, stone polishing, and cutting) tion, as well as the time between diagnosis and initiation of ● Current or recent occupations (e.g. hairdressing) and current or recent treatment [29]. In addition, assessing the severity of the ILD hobbies and associated extrapulmonary manifestations is essential for ● Family history of ILD decision making [29]. In patients with new-onset ILD, multidisciplinary assess­ Pulmonary function tests: ● FVC ment allows a specific diagnosis to be established in up to ● DLCO 80.5% of cases [17,29–33]. But, most importantly, it allows early identification of patients with an autoimmune patho­ ● If possible, total lung capacity genic substrate, either by reaching the diagnosis of Autoantibodies associated with an increased risk of developing ILD: ● Anti-cyclic citrullinated peptide at high titers a definite CTD or by establishing the initial orientation of interstitial pneumonia with autoimmune features (IPAF), ● Anti-Scl 70 which has prognostic and therapeutic implications ● Anti-Jo1, PL-7 and PL-12 [30,31,34,35]. ● Anti-Ro (SSA) The recommended composition of a multidisciplinary com­ ● Anti-MDA 5 mittee in CTD-ILD should not only include expert ILD pulmo­ ● Anti-PM/Scl nologists, radiologists, and pathologists, but also include experts in CTD (rheumatologists) [31,32]. ● Anti-Th/To Notably in CTD, some ILD may be subclinical until Imaging tests advanced stages and the detection of ILD is frequently per­ ● HRCT: reticulation, bronchiectasis and traction bronchiectasis, ‘honey­ combing’ pattern, ‘ground glass’. formed with months or even years of delay [1–12], particularly in RA [4,5,16,36,37]. Increasing data suggest that the diagnos­ Invasive tests Bronchoalveolar lavage, transbronchial criobiopsy tic delay associate a poor outcome and that ILD identification Lung biopsy can influence the therapeutic approach [17,29–35]. Therefore, CTD, connective tissue disease; DLCO, carbon monoxide diffusing capacity; FVC, the early detection of this complication is essential. forced vital capacity; HRCT, high-resolution computed tomography; ILD, inter­ Addressing this concern, regularly monitoring respiratory stitial lung disease. EXPERT REVIEW OF RESPIRATORY MEDICINE 767 Table 2. Radiological patterns and signs of fibrosis on chest HRCT [40]. Table 3. SER-SEPAR proposed screening criteria for diffuse interstitial lung Radiological patterns Radiological signs disease in patients diagnosed with rheumatoid arthritis [44]. Linear-reticular pattern ● Thickening of the intralobular septa: The following 3 clinical situations are to be screened for ILD: produces linear images of several (1) Patients with respiratory symptoms (cough and/or dyspnea) of more than centimeters in length. 3 months of evolution. ● Intralobular interstitial thickening: presence (2) Patients in whom velcro-type crackles are detected in respiratory ausculta­ of a fine reticular meshwork extending from tion, even if they are asymptomatic. the peribronchovascular structures of the (3) In patients without respiratory symptoms and with normal respiratory center of the lobule to the interlobular septa, auscultation, screening will be done according to the score obtained based with a ‘spider web’ morphology. on the number of risk factors present for the development of this compli­ cation. Nodular pattern ● Small nodules: > 2 mm ● Miliary nodules: 1–2 mm Any patient scoring ≥ 5 points will be considered eligible for screening: Set of variables and proposed score for each of the variables for the Score Ground-glass pattern ● Faint increase in lung density often overall score geographically distributed, which does not ● Age ≥ 60 years 2 obliterate adjacent vascular structures ● Male sex 1 Cystic pattern ● Thin-walled rounded images (generally 1 to 3 mm thick), well-defined and with air ● History of smoking (active smoker or former smoker) inside them ● ≤ 20 packs/year: 2 points 2 Condensation or ● Increased pulmonary attenuation ● > 20 packs/year: 3 points 3 consolidation pattern associated with blurring of adjacent vessel contours ● Duration of disease > 5 years 1 Usual interstitial pneumonia ● Subpleural, basal and symmetrical ● Persistently moderately-high activity: Average DAS28-VSG > 3.2 1 (UIP) localization; occasionally diffuse since disease diagnosis in baseline RA (time since diagnosis ≤ ● Apico-basal progression‘ 12 months) or DAS28-VSG > 3.2 for a minimum of 6 months in ● Ground-glass’ (minimal)Reticulation, bronch­ established RA iectasis and traction bronchiectasis‘ ● Honeycombing’ pattern ● Serology (only the criterion with the highest weighting is counted toward the total score) Nonspecific interstitial ● Variable involvement (central and pneumonia (NSIP) peripheral) ● RF positive > 3 times above ULN 1 Nonspecific interstitial ● Preference in inferior lobes pneumonia (NSIP) fibrotic* ● Patchy ‘ground-glass’ opacities associated ● ACPA positive ≤ 3 times the ULN 2 with linear, reticular and micronodular ● ACPA positive > 3 times the ULN 3 images ● Traction bronchiectasis/bronchilectasis* ● Family history of ILD 1 ● Infrequent ‘honeycombing’ pattern ACPA: anti-cyclic citrullinated peptide antibodies; ILD: interstitial lung disease; *Traction bronchiectasis/bronchilectasis refers to NSIP fibrotic. RA: rheumatoid arthritis; RF: rheumatoid factor; SEPAR: Spanish Society of Pneumology and Thoracic Surgery; SER: Spanish Society of Rheumatology; ULN: upper limit of normal. quantify the extent of parenchymal involvement, the type of Although ILD is a complication described in many CTDs, the interstitial changes (predominant fibrotic or ground-glass) and prevalence is higher in SSc and RA. The prevalence of ILD ranges pattern (usual interstitial pneumonia [UIP] vs. non-UIP), and to from 30% to 60% in SSc, and progressive pulmonary fibrosis is assess the disease progression. Table 2 shows the radiological the leading cause of death [41]. The most prevalent fibrotic patterns and signs of fibrosis on chest HRCT [40]. histologic pattern is nonspecific interstitial pneumonia (NSIP) Bronchoalveolar lavage would be recommended depend­ [2,3,42]. Systematic screening for ILD is recommended in all ing on the clinical context; to rule out infections or to better patients at diagnosis of SSc and, subsequently, on an annual approach a potential differential diagnosis (if relevant expo­ basis during follow-up based on its frequency and mortality sures for ILD development are present). Lung biopsy should [2,3,14,20]. For screening, HRCT is recommended at diagnosis be reserved for cases in which other conditions, such as of the disease, since it has been shown that initial screening by hypersensitivity pneumonitis,pneumoconiosis, or malignan­ PFT has a non-negligible percentage of false negatives [43]. cies, may be present in a patient with CTD [17,28,32]. In RA, the prevalence of symptomatic ILD diagnosed by PFTs (FVC, TLC and DLCO), 6-minutes walking test (6MWT), chest HRCT varies from 10% to 29%, being the second cause and quality of life (QoL) questionnaires are used for monitor­ of death after cardiovascular complications [4,5,16]. The radi­ ing ILD progression. HRCT is recommended during the follow- ological UIP pattern has been more frequently described than up in cases that present clinical and/or PFTs worsening, to NSIP [4,5,16]. Despite a frequent and serious complication, no differentiate disease progression versus acute exacerbation or recommendations on RA-ILD screening have been published other respiratory complications such as lung cancer or respira­ until now. In order to respond to this clinical need, a joint tory infection. In patients with advanced stages of their dis­ collaboration between the Spanish societies of Rheumatology ease, or in cases with very severe DLCO decline and marked (SER) and Pneumology and Thoracic Surgery (SEPAR) have oxyhemoglobin desaturation with exercise, Doppler echocar­ recently developed a multidisciplinary proposal of selective diography is also useful to detect the development of asso­ screening criteria shown in Table 3 [44]. The main risk factors ciated PAH. for ILD development in SSc and RA are shown in Table 4. 768 M. MOLINA-MOLINA ET AL. Table 4. Main risk factors for ILD development in SSc and RA, and prognostic factors for mortality and progression of ILD. Systemic sclerosis Risk factors for ILD development ● Male gender ● African-American or Asian ethnicity ● Diffuse skin involvement ● Cardiac involvement ● Anti-Scl 70 or topoisomerase I and anti-Th/To positivity Variables associated with an increased risk of ILD progression Demographic ● Male sex ● Older age ● African-American ethnicity ● Smoking Clinical ● Diffuse skin involvement with elevated Rodnan index scores at diagnosis of ILD ● Poorly controlled gastroesophageal reflux disease ● Presence of arthritis ● Time of disease evolution (first 3 years) Laboratory ● Elevated C-reactive protein ● Anti-Scl 70 antibody positivity ● Anti-RNA polymerase III antibody positivity ● Elevated KL-6 levels Pulmonary function tests ● Low basal FVC (< 70%) ● Low basal DLCO not due to other causes (mainly pulmonary arterial hypertension) ● Deterioration of FVC ≥ 10% during follow-up or fall in its values between 5% and 9% with a deterioration of DLCO ≥ 15% HRCT ● Extent of fibrotic changes > 20% Rheumatoid arthritis Risk factors for ILD development ● Male sex ● Advanced age ● Late onset of the disease ● Duration of RA ● Smoking ● Moderate or high sustained RA activity according to DAS28 scores ● RF positive ● ACPA positive ● Antibodies directed against carbamylated proteins (anti-CarP) ● MUC5B gene mutations ● Mutations of telomerase genes leading to accelerated telomere shortening Prognostic factors Variables associated with ILD ● Radiologic pattern of UIP progression ● Elevated ACPA titers ● Degree of baseline DLCO deterioration (having been demonstrated with two cutoff points: DLCO < 45% and, in those patients with a progressive fibrosing phenotype, DLCO < 54%), decrease ≥ 10% in FVC during follow-up ● Extensive pulmonary involvement on HRCT of the chest ● Elevated serum levels of IL-6 and KL-6 Prognostic factors for mortality ● Advanced age at the time of diagnosis of ILD (> 60-65 years) ● Male sex ● Duration of RA (the longer the duration of disease at the time of ILD diagnosis, the higher the mortality) ● Moderate or high disease activity as assessed by the DAS28-VSG index ● UIP pattern* ● FVC and/or low baseline DLCO ● Decrease in FVC >10% or DLCO >15% during follow-up ● Extensive lung involvement on HRCT of the chest (>20-30%) ● Elevated serum levels of KL-6 ACPA, anti-cyclic citrullinated peptide antibodies; DLCO, carbon monoxide diffusion capacity; FVC, forced vital capacity; HRCT, high-resolution computed tomography; IL-6, interleukin-6; ILD, interstitial lung disease; KL-6, Krebs von den Lugen glycoprotein; RA, rheumatoid arthritis; RF, rheumatoid factor; SSc, systemic sclerosis; UIP, usual interstitial pneumonia. *In some studies, the radiological pattern is no longer a predictor of mortality after adjustment for confounding variables in the different multivariate analysis models. The main prognostic factors are the degree of baseline deterioration in the pulmonary functional tests (FVC and DLCO) and the magnitude of its worsening during follow-up. Finally, ILD can be the initial clinical presentation of a CTD. [48]. It is important to keep in mind that anti-Ro or SSA, anti- For example, in RA-ILD, ILD precedes joint manifestations by synthetase, and anti-Th/To antibodies may be positive, even if months or years in up to 10–14% of patients [45–47]. antinuclear antibodies are negative [29–31]. Therefore, a complete evaluation for the presence of a CTD, Repeating the autoimmunity study during the follow-up of including serological autoimmunity study and physical exam, ILD patients is relevant because approximately 10–25% of is recommended in all patients with new-onset ILD (Table 5) cases that are initially idiopathic evolve into a CTD by clinical- EXPERT REVIEW OF RESPIRATORY MEDICINE 769 Table 5. Panel of antibodies to be requested in the evaluation of an ILD to include a decrease in FVC between 5–10% with worsening assess its possible association with a CTD. DLCO >15% [54]. In the initial evaluation of all patients PPF has been described in many CTDs [13,23], but this ● Antinuclear antibodies (detection by indirect immunofluorescence) progressive feature is more frequent in SSc and RA. In SSc- ● Rheumatoid factor and anti-cyclic citrullinated peptide antibodies (ACPA) ILD, 67% of patients will present pulmonary progression at If rheumatoid arthritis is suspected 5 years. Of these, 32–33% have PPF [20]. Different variables ● Anti-citrullinated peptide antibody (ACPA) associated with an increased risk of progression in SSc-ILD ● Rheumatoid factor have been identified and are summarized in Table 4 [55–57]. If systemic sclerosis is suspected Two simple algorithms have also been proposed to stratify the ● Anti-Scl70/topoisomerase I ● Anti-U3RNP (anti- fibrillarin) prognosis of these patients (Goh et al. and the SPAR model), which are shown in Figure 1 [58,59]. ● Anti-centromere ● Anti-Th/To In RA-ILD, 53% of patients will progress, with an estimated ● Anti-RNA polymerase III ● Anti-PM/Scl 40% of patients meeting criteria for progressive fibrosing RA- ● Anti-U1RNP ● Anti-Ku ILD at 5 years of evolution [13,23,60]. The main prognostic ● Anti-NOR 90 factors for pulmonary progression and mortality in RA-ILD are If inflammatory myopathy is suspected also shown in Table 4 [61]. The usefulness of the gender, age, ● Anti-synthetase (Jo-1, PL-7, PL-12, EJ, OJ and ● Anti-HMG-CoA reductase physiology (GAP) and composite physiological index (CPI) in KS) predicting the risk of mortality in these patients has been ● Anti-MDA5 ● Anti-SAE demonstrated [21,62,63]. ● Anti-Mi-2 ● Anti-U1RNP Knowledge of the prognostic factors in these two entities ● Anti-NXP2 ● Anti-PM/Scl75 (SSc-ILD and RA-ILD) allows early identification of patients ● Anti-TIF1-γ ● Anti-PM/Scl100 with a potentially higher severity profile who are candidates for intensive targeted treatment as soon as the diagnosis of ● Anti-SRP ● Anti-Ku ILD is established and for close clinical follow-up. If primary Sjögren’s syndrome is suspected ● Anti-SSA/Ro60 ● Anti-SSB/La ● Anti-TRIM21/Ro52 ● Rheumatoid factor 4. Treatment and follow-up If ANCA vasculitis is suspected* The treatment of CTD-ILD should be individualized and com­ ● Anti-neutrophil cytoplasm antibody (ANCA) prehensive and should be planned considering the underlying HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; MDA5: melanoma differen­ tiation-associated protein 5; NXP2: nuclear matrix protein 2; PM/Scl: polymyo­ CTD, the patient’s comorbidities, and the severity of extrapul­ sitis/scleroderma; RNP: ribonucleoprotein; SAE: small ubiquitin-related monary manifestations. In any case, the choice of treatment modifier-activating enzyme; SRP: signal recognition particle; SSA/Ro: Sjögren- should always seek a balance between the preservation of specific antibody A; SSB/La: Sjögrens-specific antibody B; TRIM: Tripartite Motif Containing 21;TIF1-: transcriptional intermediary factor 1 gamma. pulmonary function and the risk of adverse events. *10-11% of patients with idiopathic pulmonary fibrosis develop ANCA (anti- So far, low-dose glucocorticoids are usually used as initial myeloperoxidase or anti-proteinase 3), in most cases in the absence of treatment in monotherapy or in combination with immunosup­ symptoms of systemic vasculitis [50,51]. pressants agents. There are no randomized controlled trials (RCTs) that have evaluated the efficacy of glucocorticoids in CTD- ILD and the evidence supporting their use is based primarily on onset or autoimmunity positivity (although there is no con­ clinical experience and real-life data. Glucocorticoids should be sensus on what should be the frequency of serial testing for used with caution in SSc since their use, especially at medium or CTD) [49–51]. high doses, is an independent risk factor for the development of scleroderma renal crisis [64]. The efficacy of glucocorticoids in fibrotic patterns (UIP and fibrosing NSIP) is inconclusive. On the contrary, there is accumulating evidence about the detrimental 3. Progressive pulmonary fibrosis associated with effect of steroids as treatment of PPF [65,66]. CTD Cytotoxic immunosuppressive drugs that are commonly Different definitions of progressive pulmonary fibrosis have used to treat CTD and CTD-ILD include cyclophosphamide, been used, based on expert consensus, definitions used in mycophenolate, azathioprine, calcineurin inhibitors (especially clinical trials, and recently the definition published in the in ILD associated with inflammatory myopathies) and lefluno­ recent international guide, based on functional, clinical, and mide (in RA). Despite their use in all CTDs, their efficacy has radiological parameters [52]. The INBUILD randomized clinical only been demonstrated in RCTs in the case of cyclophospha­ trial [53] used the following criteria to define progression in mide and mycophenolate for the treatment of SSc-ILD [67,68], patients with fibrosing ILD: 1) a decrease in baseline FVC with none of them having a therapeutic indication. >10%; 2) a decrease in FVC between 5–10% with evidence of Methotrexate has classically been discouraged in patients fibrosing progression on HRCT of the chest; 3) a decrease in with RA-ILD because of the risk of causing acute pneumonitis. FVC between 5–10% with worsening respiratory symptoms However, the literature confirms that the actual risk of drug- (dyspnea and dry cough); or 4) worsening dyspnea with pro­ induced pneumonitis is very low (0.3%) [69–71]. There is no gression of fibrosis on HRCT in the previous 24 months despite confirmation that methotrexate increases the risk of develop­ treatment. As a definition of progression, some experts also ing ILD in patients with RA, but recent studies suggest that RA 770 M. MOLINA-MOLINA ET AL. Figure 1. Proposed algorithms to stratify the prognosis of patients with interstitial lung disease associated with systemic sclerosis (SSc-ILD). (a). Algorithm proposed by Goh et al. [58] (b). SPAR model [59] FVC, forced vital capacity; HRCT, high-resolution computed tomography. control achieved with this drug is associated with a delay in There are currently two antifibrotic agents on the market: the onset of ILD and a better prognosis [36,72–76]. nintedanib and pirfenidone. At present, only nintedanib has In case of ILD progression, despite initial treatment with been approved by the FDA and the European Medicines glucocorticoids and immunosuppressants, there are several Agency (EMA) for the treatment of fibrosing SSc-ILD, based options: rescue therapy with biologic drugs (rituximab, tocili­ on data from the phase III RCT SENSCIS [90], and for the zumab or abatacept) particularly in ILDs with inflammatory treatment of other progressive fibrosing ILD, including CTD- features or patterns. Antifibrotic treatment can be used in ILD, based on results from the phase III RCT INBUILD [53]. CTD-ILD patients with PPF despite previous management . In Pirfenidone does not have data in CTD-ILD with fibrosis and SSc, the option of autologous hematopoietic stem cell trans­ a progressive phenotype but only in a few disease entities that plantation is also available, although its effect on the lung are under the designation of CTD. The published experience remains controversial [77–80]. with pirfenidone in CTD-ILD is so far limited to two phase II Regarding evidence for the efficacy of biologic agents in RCTs (LOTUSS and RELIEF) [91,92]. Ongoing studies include the treatment of CTD-ILD, only tocilizumab has confirmed a phase III RCT in SSc-ILD (Scleroderma lung study III) [93] effectiveness in RCTs, specifically in SSc-ILD [81–83]. and a phase II in RA-ILD (TRAIL 1) [94]. Although the trials only included patients with mild-to- Equally relevant non-pharmacological measures within the moderate ILD, tocilizumab has recently been approved by comprehensive approach include smoking cessation, respira­ the Food and Drug Administration (FDA) for the treatment tory rehabilitation, prevention and treatment of gastroesopha­ of SSc-ILD. There are several ongoing RCTs with rituximab geal reflux, systematic vaccination against respiratory and abatacept (RECITAL and EVER-ILD in SSc-ILD, and APRIL pathogens such as influenza, pneumococcus and SARS-CoV in RA-ILD) [84–86]; currently, however, their use is only -2, adequate and early treatment of coexisting respiratory supported by real-life observational studies demonstrating infections, psychosocial support, and long-term home oxygen their usefulness in stabilizing or improving lung function, therapy in the presence of chronic respiratory failure. particularly in patients with a non-UIP radiological pattern, When PPF does not show stabilization, despite the measures including cases in which ILD worsened despite previous taken, lung transplantation should always be considered in candi­ treatment with glucocorticoids and classic synthetic dis­ date patients and the case should be referred to Lung Transplant ease-modifying antirheumatic drugs (DMARDs) or immuno­ Units before reaching an advanced stage of respiratory suppressants [87–89]. involvement. EXPERT REVIEW OF RESPIRATORY MEDICINE 771 5. Conclusion I. Castellví has received support for research and presentation at congresses from Roche, Boehringer Ingelheim, Bristol Myers-Squibb, and CTD-ILD especially those with progressive pulmonary fibrosis Janssen-Cilag. have a high morbidity and mortality rate. In order to reverse C. Valenzuela has received research and presentation support from this situation and improve the prognosis and QoL of patients, Roche, Boehringer Ingelheim, and Bristol Myers Squibb. J. Ramírez has received research and presentation support from Roche, a multidisciplinary diagnostic and therapeutic approach is Boehringer Ingelheim, and Pfizer. necessary as the best model of care to guarantee early diag­ J.A. Rodríguez-Portal has received research and presentation support nosis and comprehensive and individualized treatment. from Roche, Boehringer Ingelheim, Janssen, and Bristol Myers Squibb. Antifibrotic drugs are considered for those presenting progres­ T. Franquet has received research and presentation support from sive pulmonary fibrosis. Roche and Boehringer Ingelheim. J. Narváez has received funding for meetings and congresses and course attendance from Roche, Bristol Myers Squibb, Kern, Pfizer, Lilly, and Sanofi; speaking fees from Roche, Bristol Myers Squibb, Lilly, AbbVie, 6. Expert opinion Pfizer, Boehringer Ingelheim, Sanofi, GSK, Gebro pharma, Kern, and Sobi; There are still unmet needs in PPF-CTD, including the need for and consulting for a pharmaceutical company/other technologies from Roche, Bristol Myers Squibb, Lilly, AbbVie, Pfizer, Boehringer Ingelheim, reliable prognostic biomarkers for early identification and Sanofi, GSK, Gebro pharma, Kern, and Sobi. tools to select the most appropriate comprehensive treatment strategy for each patient. It is desirable that, in the coming years, through the identification of biomarkers, genetic poly­ Reviewer disclosures morphisms and other molecular classification techniques, pro­ Peer reviewers on this manuscript have no relevant financial or other gress will be made in personalized precision medicine. There relationships to disclose. are also high expectations for new drugs that could expand the therapeutic arsenal for PPF, such as JAK kinase inhibitors, pentraxin 2, pamrevlumab, and autotaxin inhibitors [95–99]. Geolocation information It is also essential to know the long-term safety and efficacy This article has been developed by experts from different cities in Spain: of combined immunosuppressant and antifibrotic therapy, L’Hospitalet de Llobregat, Barcelona, Madrid, and Seville. and to have methods for evaluating the response to treatment that provide a more comprehensive and multifaceted vision, including patient-reported outcomes, because patients should References be increasingly empowered in decision-making. 1. Atzeni F, Gerardi MC, Barilaro G, et al. Interstitial lung disease in Another area for improvement is the diagnostic delay systemic autoimmune rheumatic diseases: a comprehensive experienced by these patients, which leads to a delay in review. Expert Rev Clin Immunol. 2018 Jan;14(1):69–82. treatment initiation. The origin of this delay is usually multi­ 2. Perelas A, Silver RM, Arrossi AV, et al. 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