1032457 Musculoskeletal DiseaseM Kuwana, A Gil-Vila research-article20212021 TAB0010.1177/1759720X211032457Therapeutic Advances in Interstitial Lung Disease in Autoimmune Rheumatic Disorders Special Collection Therapeutic Advances in Musculoskeletal Disease Review Role of autoantibodies in the diagnosis and Ther Adv Musculoskel Dis 2021, Vol. 13: 1–17 prognosis of interstitial lung disease in DOI: 10.1177/ https://doi.org/10.1177/1759720X211032457 https://doi.org/10.1177/1759720X211032457 1759720X211032457 autoimmune rheumatic disorders © The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- permissions Masataka Kuwana , Albert Gil-Vila and Albert Selva-O’Callaghan Abstract: Interstitial lung disease (ILD) has been recognized as a frequent manifestation associated with a substantial morbidity and mortality burden in patients with autoimmune rheumatic disorders. Serum autoantibodies are considered good biomarkers for identifying several subsets or specific phenotypes of ILD involvement in these patients. This review features the role of several autoantibodies as a diagnostic and prognostic biomarker linked to the presence ILD and specific ILD phenotypes in autoimmune rheumatic disorders. The case of the diverse antisynthetase antibodies in the antisynthease syndrome or the anti-melanoma differentiation-associated 5 protein (MDA5) antibodies as a marker of a severe condition such as rapidly progressive ILD in patients with clinically amyopathic dermatomyositis are some of the associations herein reported in the group of myositis spectrum disorders. Specific autoantibodies such as the well-known anti-topoisomerase I (anti-Scl70) or the anti-Th/To, anti-U11/U12 ribonucleoprotein, and anti-eukaryotic initiation factor 2B (eIF2B) antibodies seems to be specifically linked to ILD in patients with systemic sclerosis. Overlap syndromes between systemic sclerosis and myositis, also have good ILD biomarkers, which are the anti-PM/Scl and anti-Ku autoantibodies. Lastly, other not so often reported disorders as being associated with ILD but recently most recognized as is the case of rheumatoid arthritis associated ILD or entities herein included in the miscellaneous disorders section, which include anti-neutrophil cytoplasmic antibody-associated interstitial lung disease, Sjögren’s syndrome or the mixed connective tissue disease, are also discussed. Keywords: autoantibodies, autoimmune rheumatic disorders, interstitial lung disease Received: 14 May 2021; revised manuscript accepted: 25 June 2021. Introduction are often unpredictable. The treatment is not Correspondence to: Interstitial lung disease (ILD) is a significant dis- required for all patients with ILD, but it is critical Masataka Kuwana Department of Allergy and ease burden in autoimmune rheumatic disorders. to identify patients with a progressive phenotype Rheumatology, Nippon In fact, ILD is a substantial morbidity and mor- early in the course of ILD and to introduce ade- Medical School Graduate School of Medicine; tality burden across many autoimmune rheumatic quate treatment in ‘high-risk’ patients timely for Scleroderma/Myositis disorders.1 Poor survival and impaired quality of improvement of outcomes.3 The mainstay of Center of Excellence (SMCE) Nippon Medical life are most notable in patients with acute or treatment of autoimmune rheumatic disorder- School Hospital, 1-1-5 chronic progressive ILD, which is often observed associated ILD is immunomodulatory regimes, Sendagi, Bunkyo-ku, Tokyo, Japan in patients with myositis spectrum disease, sys- including corticosteroids, immunosuppressants, kuwanam@nms.ac.jp temic sclerosis (SSc) or rheumatoid arthritis and molecular-targeted drugs such as rituximab Albert Gil-Vila (RA). The management of ILD in patients with and tocilizumab, while anti-fibrotic treatment has Albert Selva-O’Callaghan Systemic Autoimmune autoimmune rheumatic disorders is challenging recently been shown to prevent progression of Diseases Unit, Vall due to substantial heterogeneity in disease behav- ILD in patients with SSc and a variety of autoim- d’Hebron General Hospital, Medicine Dept, Universitat ior.2 The onset and clinical course, treatment mune rheumatic disorders with progressive fibro- Autónoma de Barcelona, responses, and outcomes are highly variable and sing ILD.4,5 There remains a critical unmet need Barcelona, Spain journals.sagepub.com/home/tab 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Musculoskeletal Disease 13 to clarify when and in whom to initiate treatment, developing ILD before costly and/or invasive and which treatment regimens to choose to examinations. General risk factors for the devel- achieve optimal outcomes. To pursue individual- opment of ILD in patients with autoimmune ized management, it is critical to predict future rheumatic disorders include older age, African clinical course, treatment response, and outcomes race, smoking and male sex.12,13 In addition, the accurately early in the course of the disease. In presence of certain autoantibodies is widely used clinical practice, the observed disease course, as diagnostic biomarkers, such as antisynthetase patient-reported outcomes, pulmonary function and anti-melanoma differentiation-associated 5 testing, ILD extent and pattern on imaging, and protein (MDA5) antibodies in myositis spectrum extra-thoracic disease activity of autoimmune disorders, anti-topoisomerase (topo) I antibodies rheumatic disorders are used to predict subse- in SSc, and high-titre rheumatoid factor (RF) and quent disease behavior. Recently, there has been anti-citrullinated protein antibodies (ACPA) in accumulating evidence for indispensable roles of RA. Chest HRCT should be considered in serum autoantibodies in predicting risk for pro- patients with those risk factors for developing gression of ILD in various autoimmune rheu- ILD in patients with autoimmune rheumatic dis- matic disorders, especially myositis spectrum orders, regardless of the presence or absence of disease.6 This review highlights how to utilise respiratory symptoms.1 serum autoantibodies as diagnostic and prognos- tic biomarkers in a patient care of autoimmune Interstitial pneumonia with autoimmune features rheumatic disorder-associated ILD. (IPAF) is a research classification of patients with ILD who have features of autoimmunity, but are not classifiable as characterizable autoimmune Autoantibodies as a useful diagnotic and rheumatic disorders, proposed by the European prognostic biomarker Respiratory Society/American Thoracic Society One of the characteristic features of autoimmune Task Force.14 The classification criteria for IPAF rheumatic disorders is the presence of circulating consist of three domains: a clinical domain autoantibodies reactive with various cellular com- (extrathoracic features), a serological domain (cir- ponents, including nuclear and cytoplasmic anti- culating autoantibodies), and a morphological gens and secreted proteins.7 Many autoantibodies domain (chest imaging, histopathological, or pul- are disease-specific, and are usually present at the monary physiological features), and at least one onset and even preceding the onset of the disease. feature from at least two of the three domains is The patients do not switch from one antibody to required for the classification. A serological domain another during the course of the disease, and includes anti-nuclear antibody (ANA) ⩾1:320 autoantibodies are almost mutually exclusive. with diffuse, speckled, and/or homogeneous pat- Thus, autoantibodies have been incorporated into terns or any titer in case of nucleolar or centromere disease classification criteria,8–10 and are conveni- pattern; RF ⩾2 × upper limit of normal; and dis- ent biomarkers for assisting in the diagnosis in ease-specific autoantibodies such as antisynthetase, many autoimmune rheumatic disorders. The anti-MDA5, anti-topo I antibodies and ACPA. autoantibodies are also useful in disease subset- ting, which offers the opportunity to predict future The clinical course of ILD in autoimmune rheu- outcomes early in the disease course, because of matic disorders is highly variable. Some patients their strong associations with disease manifesta- show rapid or slow progression leading to respira- tions, prognosis and treatment responses. There is tory insufficiency, but others have a stable course increasing awareness of autoantibodies associated with no clinically meaningful progression. Even in with more severe disease, which may benefit from patients with stable ILD, some develop acute a more aggressive treatment approach. exacerbations. Specifically, organizing pneumonia often found mainly in patients with RA resolves Current screening and diagnostic tools for ILD completely by short-course treatment with corti- include clinical assessment of respiratory symp- costeroids or even spontaneously. Acute or suba- toms, auscultation, imaging studies such as chest cute ILD in patients with dermatomyositis is X-ray and high-resolution computed tomography sometimes treatment-resistant and fatal, especially (HRCT), pulmonary function testing, and exer- in those with anti-MDA5 antibody, but those in cise-induced oxygen desaturation.3,11 A rationale patients with antisynthetase antibody usually for measuring convenient diagnostic serum bio- respond to immunosuppressive treatment, but markers is to choose patients with a high risk for recur frequently. In contrast, a worse prognosis is 2 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. observed in patients with chronic ILD with pro- are divided into five main types: dermatomyositis, gressive, irreversible fibrotic disease, resembling polymyositis, overlap myositis, sporadic inclusion the clinical course of idiopathic pulmonary fibro- body myositis, and immune-mediated necrotising sis (IPF).15 This phenotype is now called progres- myopathy.19 Multiple phenotypes are included sive fibrosing ILD, which is characterized by within the broad term ‘myositis’ and paradoxi- progressive pulmonary fibrosis associated with cally, some of them do not include muscle worsening respiratory symptoms, decline in pul- involvement, although from the clinical and monary function, decreased quality of life, and immunological viewpoints they are grouped in risk of early death despite treatment.16 Proportions the same box. That is why they are often referred of patients with PF-ILD are variable among to as ‘myositis spectrum disorders’. underlying autoimmune rheumatic disorders, and range from 16% to 40%.17 Two predominant Several antibodies directed against autoantigens autoimmune rheumatic disorders with progressive have been identified in myositis patients. These fibrosing ILD are RA and SSc.3 In clinical prac- are usually classified into specific (only appearing tice, detection of PF-ILD early in the course of the in patients with myositis) or associated (can disease is critical, but it is often difficult. In such appear in patients with myositis and in other simi- cases, longitudinal observation is recommended, lar conditions). Recently, the term ‘myositis- and the definition of progressive fibrosing ILD has spectrum disease antibodies’ was coined broadly been proposed as a relative decline of forced vital to define these autoantibodies.20 They are more capacity (FVC) % predicted ⩾10% alone or rela- biomarkers of certain specific features or clinical tive decline of FVC % predicted 5–10% in combi- manifestations of these conditions, such as lung nation with at least one of relative decline of involvement, than markers of myositis itself. For diffusing capacity of the lung for carbon monoxide example, as will be seen later, some patients posi- (DLCO) % predicted ⩾15%, increased extent of tive for anti-Jo1 antibody, a typical myositis-spe- fibrosis on HRCT, or worsening respiratory symp- cific autoantibody, may present with ILD alone, toms within 24 months despite standard treatment without myositis. of ILD.18 Nevertheless, it is better to predict the clinical course of ILD early in the disease course The lung is one of the organs most often affected without impaired pulmonary function. In this in patients with myositis spectrum disorders, with regard, identification of prognostic biomarkers for or without muscle involvement,21 reaching a progressive fibrosing ILD should contribute to prevalence of 41% in a recent analysis.22 early detection of progressive cases and guidance Furthermore, lung involvement is the leading of treatment decision. Therefore, clinical and bio- cause of mortality in this group of systemic dis- logical factors that predict subsequent progression eases, although it has a highly variable clinical of ILD have been extensively investigated in indi- course and prognosis, consistent with the hetero- vidual autoimmune rheumatic disorders. For this geneous characteristics of myositis patients. The purpose, serum autoantibodies are widely used as presence of several autoantibodies may be of a prognostic biomarker. value to establish an accurate diagnosis and esti- mate the prognosis of this feature. Key autoantibodies associated with ILD in auto- immune rheumatic disorders are summarised in The following sections will attempt to provide a Table 1. Autoantibodies are routinely used in comprehensive description of the various anti- patients’ care of ILD in patients with autoim- body-associated myositis phenotypes, with par- mune rheumatic disorders as a diagnostic bio- ticular focus on the diagnosis and prognosis of marker to pursue extensive ILD screening as well these conditions. as a prognostic biomarker to predict future pro- gression and prognosis and guide the manage- ment plan. Antisynthetase syndrome (ASS) In daily clinical practice, clinicians may encoun- ter a patient with several clinical manifestations, Myositis spectrum disorders such as arthritis, hiker feet [Figure 1(a)] or The group of inflammatory conditions known as mechanic’s hands [Figure 1(b)], shortness of myositis are heterogeneous disorders with an breath and perhaps, muscle weakness (e.g. when autoimmune basis in which characteristic muscle attempting to rise from a chair or combing hair). inflammation is usually present. These disorders The astute physician, after noting bibasal journals.sagepub.com/home/tab 3 Therapeutic Advances in Musculoskeletal Disease 13 Table 1. Key autoantibodies associated with interstitial lung disease. Autoantibodies Staining on ANA Prevalence of antibody Clinical associations Prevalence of ILD and its test with indirect except ILD disease behavior immunofluorescence Antisynthetase ANA negative, 15–30% in IIM, but Myositis, arthritis, 90% develop ILD, mainly cytoplasmic found in patients mechanic’s hands, ILD that stabilizes over without apparent called ASS time after treatment myositis or DM skin with immunosuppressive rashes; rare in children agents, but recurrence is common Anti-MDA5 ANA negative, 10–30% of DM, both Severe skin 80% develop ILD, often cytoplasmic classic and clinically vasculopathy, arthritis rapidly progressive ILD, amyopathic DM; also but some have mild ILD found in children resembling ASS Anti-PM/Scl Nucleolar 25% of SSc-myositis Younger age at disease 35–87% have ILD with a overlap, 3–6% of SSc onset, myositis, lcSSc, better functional outcome arthritis Anti-Ku Speckled 15% of SSc-myositis Younger age at disease Up to 76% have ILD with a overlap; 9% in myositis onset, myositis, lcSSc, better functional outcome cohort; 2% in SSc arthritis, DM skin cohort rashes, fewer vascular manifestations such as digital ulcer Anti-topo I Speckled or 20–30% of SSc dcSSc, digital ulcer early 80% develop ILD, of homogeneous in the disease course which up to 30–50% have progressive fibrosing ILD Anti-Th/To Nucleolar 2–5% of SSc lcSSc, pulmonary Up to 50% develop arterial hypertension, ILD, of which 30% have less digital ulcer progressive fibrosing ILD Anti-U11/U12 RNP Speckled 1–3% of SSc Both dcSSc/lcSSc, 80% develop ILD, which gastrointestinal is often severe and involvement, cancer associated with increased in close temporal mortality relationship to onset of SSc Anti-EIF2B ANA negative, <1% of SSc dcSSc Up to 100% have ILD cytoplasmic Anti-U1RNP Speckled 5–35% of patients Younger age at disease Up to 35% have ILD, of presenting SSc or onset, arthritis, myositis, which 20% classified as overlap syndrome; lcSSc, pulmonary severe 100% in MCTD arterial hypertension RF ANA negative 70–80% in RA Extra-articular 10–40% have ILD, manifestations, including UIP and NSIP; especially in high titer risk of acute exacerbation ACPA ANA negative 70–80% in RA Progression of joint 10–40% have ILD, destruction, MACE including UIP and NSIP; risk of acute exacerbation ANA, anti-nuclear antibody; ASS, antisynthetase syndrome; dcSSc, diffuse cutaneous systemic sclerosis; DM, dermatomyositis; IIM, idiopathic inflammatory myopathy; ILD, interstitial lung disease; lcSSc, limited cutaneous systemic sclerosis; MACE, major adverse cardiovascular events; MCTD, mixed connective tissue disease; NSIP, non-specific interstitial pneumonia; RA, rheumatoid arthritis; SSc, systemic sclerosis; UIP, usual interstitial pneumonia. 4 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. Figure 1. Hiker feet (a: arrow) and mechanic’s hands (b: arrow) observed in a patient with antisynthetase syndrome. inspiratory crackles on lung auscultation, could Table 2. Antisynthetase antibodies. suspect the diagnosis of ILD in a patient with inflammatory muscle disease. Pulmonary func- Anti-histidyl t-RNA synthetase Anti-Jo-1 tion tests showing a reduction in the FVC and Anti-threonyl-t-RNA synthetase Anti-PL-7 DLCO, HRCT scans with features of ILD (e.g. ground glass opacities, lung fibrosis, reticular pat- Anti-alanyl-t-RNA synthetase Anti-PL-12 tern), and if necessary, muscle biopsy findings Anti-isoleucyl-t-RNA synthetase Anti-OJ will confirm the suspected diagnosis. However, it is the autoantibody profile that will enable better Anti-glycyl-t-RNA synthetase Anti-EJ classification of the patient’s clinical condition. In this case, positive testing for anti-histidyl-tRNA Anti-asparaginyl-t-RNA synthetase Anti-KS synthetase (referred to as anti-Jo1 antibody) the Anti-phenylalanyl-t-RNA synthetase Anti-ZO most common antisynthetase antibody described to date, will provide relevant information regard- Anti-tyrosyl-t-RNA synthetase Anti-Ha ing the patient’s prognosis and outcome. Eight different autoantibodies against tRNA syn- When analysing the less common antisynthetase thetase have been described (Table 2) and they antibodies, we should be aware of the potential are associated with specific clinical features and for selection bias. As ASS is uncommon, the small with different outcomes regarding survival or available series may favour the bias of assigning mortality.23–25 Analysis of large multicenter some clinical features to specific autoantibodies. cohorts of patients with anti-Jo1 antibodies has This was the case of anti-threonyl-tRNA syn- enabled depiction of the long-term clinical out- thetase, known as anti-PL7 (PL stands for pre- come. In a retrospective longitudinal study cipitation line where the antibody was first including 148 patients with anti-Jo1 ASS and a identified in the laboratory).27 In a study includ- follow-up of 78.3 months, the authors found that ing a small case series, anti-PL7 seemed to be a the disease mainly acted as a chronic condition in marker of pericardial disease, but the association terms of lung involvement.26 Only a small per- disappeared when large patient cohorts were centage of patients reached the composite analysed. endpoint defined ad-hoc for the study: death due to respiratory failure directly related to ASS, A recent study including the largest cohort of long-term oxygen therapy requirement, or lung patients with ASS analysed to date has shed light transplantation. on this topic.28 In total, 828 ASS patients from journals.sagepub.com/home/tab 5 Therapeutic Advances in Musculoskeletal Disease 13 10 countries and 63 hospitals were included in that the coexistence of Ro52 with anti-Jo1 the study, which provided relevant data regarding was associated with more severe disease and a the rarer antisynthetase antibodies, such as anti- poorer prognosis. EJ (38 patients included) and anti-OJ (18 patients included). Comparisons between the different groups with antisynthetase antibodies found that The anti-PM/Scl phenotype arthritis was more frequent in those with anti-Jo1 The anti-PM/Scl autoantibody is directed against than in those without. Moreover, in some anti- a multi-subunit nucleolar protein complex known body specificities, such positive status to anti-PL7 as exosomes. These are endocytic vesicles con- or anti-PL12, the diagnostic delay was greater taining RNA and proteins that are involved in than in the anti-Jo1 antibodies group, likely RNA degradation and processing. Although the because certain atypical forms of the syndrome PM/Scl antigen is a particle with 11 different pol- had been misdiagnosed. The acute form, which is ypeptides, it is believed that the autoantibodies unusual in patients with ASS, was more frequent recognize the 75-kD or preferentially, the 100-kD in patients positive for anti-EJ antibodies. In addi- protein. Thus, most commercial tests for anti- tion, the authors stated that the clinical presenta- PM/Scl antibodies contain the 100-kD antigen. tion was quite similar between the various antibody specificities at the end of follow-up (i.e. The clinical phenotype of patients with anti-PM/ it did not differ from one specificity to another). Scl may resemble that of patients with ASS, prob- Finally, and most importantly, survival was not ably because of a shared genetic background.35,36 influenced by the underlying antisynthetase anti- At times manifestations of myositis, arthritis, and body (at least after 5 years of follow-up), which even scleroderma features such as Raynaud’s agrees with findings from other studies.29,30 The phenomenon and specific capillaroscopy findings cumulative 10-year survival rate of the ASS may make it difficult to differentiate between patients is estimated at nearly 75%.24,26 ASS and the anti-PM/Scl scleromyositis pheno- type until the immunological profile results are Although most patients with ASS will develop a obtained. Lung involvement in anti-PM/Scl- chronic form of ILD that stabilizes over time positive patients is common, documented in after treatment with immunosuppressive agents, 35-87% of patients in the reported series.37,38 But some factors associated with the syndrome have the main point to keep in mind is that ILD seems been recognized as indicators of a poor progno- to have a better functional outcome in these sis. Older age, and several serological factors, patients. Two studies have addressed this topic. such as increased ferritin concentration, coexist- The first, carried out by researchers in Barcelona,39 ence of other autoantibodies (e.g. anti-Ro52 or analysed progression-free survival in patients with anti-Ro60), or a phenotype without muscle systemic sclerosis and ILD according to positive involvement, seem to be related to a poorer lung status to anti-PM/Scl antibodies. Progression- function outcome. Coexistence of antisynthetase free survival in the study was defined as the time autoantibodies (mainly anti-Jo1) and anti-Ro52 period in which ILD was stable up to the point antibodies has been identified as marker of more when an FVC decrease of at least 10% from base- severe ILD and a poorer prognosis for lung func- line or death occurred over follow-up. When tion outcome in adults and in juvenile forms. patients positive for anti-PM/Scl antibody were Researchers in France analysed a cohort of 89 compared with SSc patients negative for anti- consecutive anti-Jo1 patients with ASS and PM/Scl but positive for anti-topo I, progression- found that those who also tested positive for free survival at 10 years’ follow-up was higher in anti-Ro52 more commonly exhibited sympto- anti-PM/Scl-positive than anti-topo I-positive matic ILD and higher fibrosis scores on HRCT.31 patients (76% versus 29%, respectively). Other Similar results were found by Váncsa et al.32 studies focused on the clinical features of patients Other researchers have reported that the pres- with anti-PM/Scl antibodies have reported similar ence of the Ro52-Jo1 complex is a biomarker of results,40–42 thus defining a characteristic pheno- a more acute form of ILD and of refractoriness type in which ILD is present and has a good out- to conventional immunosuppressive therapy, but come. The second study, a recent multicenter not to rituximab,33 although these data have not report from the EUSTAR database, comple- been replicated by other groups. Lastly, in an mented with a case–control study from another analysis of a large cohort of 302 patients with center, found that lung function outcome was juvenile dermatomyositis, Sabbagh et al.34 found better in ILD patients positive for anti-PM/Scl.43 6 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. Anti-Ku syndrome China concluded that detection of anti-MDA5 Patients with anti-Ku syndrome may also develop antibodies was a valuable tool to identify dermato- a type of overlap condition between SSc and myositis patients (mainly those with the amyo- myositis. A recent cluster analysis in a cohort of pathic form) who will develop rapidly progressive 42 consecutive patients positive for anti-Ku anti- ILD with a poor prognosis.52 bodies disclosed a high prevalence of ILD when associated with myositis (high creatine kinase The next question is whether all anti-MDA5- levels).44 Data from a large cohort of Chinese positive dermatomyositis patients will develop patients with myositis revealed that only 1.73% this severe condition, and the answer is no. Some were anti-Ku positive, but 76.2% of the anti-Ku- researchers have found that the clinical spectrum positive patients developed ILD.45 As occurs in in patients with anti-MDA5 antibodies may anti-PM/Scl-positive patients, it seems that the expand to other features or that some patients ILD that accompanies anti-Ku antibodies is not may develop a milder form of ILD similar to that severe; nonetheless, the short reported series pre- seen in the anti-PM/Scl phenotype or ASS,50,51 clude strong statements. discussed above. Moreover, arthritis and skin lesions can be a hallmark of other phenotypes of the disease. Researchers from the French Myositis Anti-MDA5-positive, dermatomyositis- Network recently reported a study53 characteriz- associated, rapidly progressive ILD ing several phenotypes related to anti-MDA5. In 2005 Sato et al.46 described a new autoanti- The main phenotype (only 18% of the total cases body in patients with dermatomyositis. The reported) corresponded to the severe condition of autoantibody was found to be a good biomarker rapidly progressive ILD, but two additional phe- of severe disease; that is, the rapidly progressive notypes were defined, one in which patients only ILD that can develop in patients with the amyo- have skin lesions and arthritis/arthralgia with a pathic or hypomyopathic form of dermatomy- good prognosis (55%), and the other character- ositis. The target antigen recognized by this ized by severe skin vasculopathy and myositis, autoantibody was later identified as MDA5, also with an intermediate prognosis. known as interferon-induced helicase C domain- containing protein 1 (IFIH1), which participates At this point we must face the challenge of how to in a well-recognized innate antiviral response, manage a dermatomyositis patient testing positive triggering the production of type I interferons on for anti-MDA5 antibodies. We first need to know detection of viral double-stranded RNA at the whether or not the patient will develop rapidly cytosol. MDA5 is a member of the retinoic-acid progressive ILD. Some reported data may help in inducible gene (RIG)-I-like helicases, which act addressing this difficult topic. The anti-MDA5 as cytoplasmic RNA sensors.47 antibody level,54,55 ferritin concentration,56 and presence of anti-Ro52 antibodies57,58 should all The clinical relevance of anti-MDA5 antibodies be considered. Focusing on the coexistence of resides in their capacity to identify patients with anti-Ro52 antibodies, a well-known situation in dermatomyositis – to date the only myositis sub- patients with ASS, the available data indicate a type related with the antibody – who may have rap- role of this biomarker for determining the prog- idly progressive ILD and a poor prognosis. Up to nosis in patients with anti-MDA5 antibodies. 80% of these patients do not survive even after a Ro52 is an interferon-inducible protein of the prompt diagnosis and intensive immunosuppres- tripartite motif family (TRIM21), usually located sive therapy.48 The anti-MDA5 antibody currently in the cytoplasm, that regulates inflammation detected by commercial tests enables the identifica- induced by the interferon pathway.59 The associa- tion dermatomyositis patients at risk of rapid lung tion of anti-Ro52 with anti-MDA5, which is not a function impairment: worsening of radiological rare occurrence, seems to identify a more aggres- interstitial changes with progressive dyspnoea and sive phenotype (i.e. rapidly progressive ILD), as hypoxemia within 1 month after the onset of res- has been reported in a study investigating piratory symptoms.49 Imaging detection of reticular 83 patients with anti-MDA5-positive, clinically opacities, ground-glass opacities, or a honeycomb amyopathic ILD.57 Coexistence of anti-Ro52 in pattern may assist the diagnosis. Several studies these patients was significantly associated with a worldwide have confirmed the role of these autoan- high percentage of rapidly progressive ILD cases. tibodies as a biomarker of this severe condition.50–52 The same results were observed in a retrospective A meta-analysis carried out by researchers from analysis of a cohort of Japanese patients with journals.sagepub.com/home/tab 7 Therapeutic Advances in Musculoskeletal Disease 13 myositis: those with anti-MDA5 plus anti-Ro52 lower lobes, is typical of SSc-ILD, while cellular antibodies had a poor prognosis.58 Although the NSIP or usual interstitial pneumonia (UIP) pat- association of anti-Ro52 with anti-MDA5 and terns are observed in a small number of cases.12 with ASS has been described in juvenile forms of Despite the apparent association of ILD and mor- dermatomyositis, data on its contribution as a bidity and mortality in patients with SSc, screening marker of a poor prognosis are not available in for ILD and monitoring for disease progression is this population.34 still challenging in the clinical setting. Anti-SAE antibodies Autoantibodies in SSc In 2007, Betteridge et al.60 described a new auto­ Anti-nuclear antibodies detected by the indirect antibody in a few dermatomyositis patients. It was immunofluorescence technique are a hallmark of directed against a 40-kD and 90-kD doublet of SSc and are found in >95% of the patients. At least bands on protein immunoprecipitation and was 12 autoantibody specificities associated with SSc later identified as small ubiquitin-like modifier 1 have been reported and well characterized, and activating enzyme A (SAE), a protein involved in >80% of SSc patients have one of these autoanti- post-translational changes. Two of 20 dermatomy- bodies.68 These include anti-topo I or anti-Scl-70; ositis patients who were positive for anti-SAE anti- anticentromere antibody (ACA); anti-RNA poly- body had associated non-specific ILD. In two merase (RNAP) III; anti-U3 ribonucleoprotein reported case series,61,62 57–71% of anti-SAE- (RNP); anti-Th/To; anti-U11/U12 RNP; anti- positive dermatomyositis patients had ILD. In our centriole; anti-eukaryotic initiation factor 2B hospital dermatomyositis cohort, 5% of patients are (eIF2B); anti-U1 RNP; anti-Ku, anti-PM/Scl; anti-SAE positive and all have some degree of ILD. anti-RuvBL1/2 antibodies. SSc-related autoanti- Although this factor has not been studied in large bodies target various nuclear or cytoplasmic com- cohorts, it seems that anti-SAE could be a marker ponents involved in essential cellular processes, of a dermatomyositis phenotype in which ILD is such as cell division and transcription. These not rare and does not have a poor outcome. autoantibodies are rarely seen in patients with other connective tissue diseases without SSc features and thus are important diagnostic markers. The detec- Systemic sclerosis (SSc) tion of SSc-related autoantibodies is clinically use- SSc is a systemic autoimmune disease character- ful in classifying SSc patients into subtypes that are ized by microvasculopathy, immune dysregulation, almost exclusively associated with characteristic and excessive fibrosis, but detailed pathogenesis clinical phenotypes. The main autoantibodies asso- still remains unclear.63 In addition to characteristic ciated with ILD include anti-topo I, anti-Th/To, skin and peripheral vascular involvement, SSc can anti-U11/U12 RNP and anti-eIF2B antibodies, affect multiple organ systems, including the lung, while antibodies associated with SSc overlap syn- heart, kidney, and gastrointestinal tract. ILD is one drome, mainly with myositis, occasionally have of the most important causes of mortality in SSc ILD. Anti-PM/Scl and anti-Ku syndromes are cov- patients along with pulmonary arterial hyperten- ered in a section of myositis spectrum disorders. sion.64 Disease behavior of SSc-ILD is highly vari- ous, and only <30% of the patients have progressive fibrosing ILD, leading to respiratory insuffi- Anti-topo I antibodies ciency.65–67 Most patients who develop severe Anti-topo I antibody is detected in 20–30% of restrictive lung disease experience ILD progres- SSc patients in many ethnic groups. Approximately sion prominently in the first 5 years following the two-thirds of anti-topo I-positive patients have onset of SSc. The most common initial symptoms diffuse cutaneous systemic sclerosis (dcSSc), but of SSc-ILD are exertional dyspnea and dry cough, progression of skin thickening is slower than in although early SSc-ILD can be asymptomatic. those with anti-RNAP III antibody.69 Anti-topo I Therefore, recent evidence-based European con- antibody is associated with a high risk of severe sensus statements for SSc-ILD recommend chest ILD, cardiomyopathy and peripheral vascular HRCT for screening of ILD at diagnosis of SSc.11 complications, such as digital ulcer and gangrene, A HRCT pattern suggestive of fibrotic non-spe- particularly early in the disease course.70,71 Anti- cific interstitial pneumonia (NSIP), which shows topo I antibody is considered to be a marker for bilateral ground-glass opacities, reticulation, and poor prognosis, and patients with severe ILD die traction bronchiectasis most prominent in the of this complication at an average of 10 years after 8 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. the onset of SSc. The prevalence of ILD is com- prevalence was ~1% in the United Kingdom parable between dcSSc and limited cutaneous cohort,78 but 7% in the North American cohort.79 systemic sclerosis (lcSSc) patients with anti-topo The majority of patients with anti-eIF2B antibod- I, but survivals are worse in dcSSc than in lcSSc ies are classified as having dcSSc and have ILD. patients.71,72 In SSc patients with anti-topo I, the concomitant presence of IgM isotype of anti-topo I antibodies is associated with subsequent disease Screening and diagnosis of SSc-ILD progression.73 The prevalence of ILD in SSc patients varies depending on detection methods or tools; the prevalence using HRCT is estimated at 47–84%,12 Anti-Th/To antibodies while the prevalence is <30% using auscultation, Anti-Th/To antibody occurs in patients with chest X-ray, or pulmonary function testing (FVC lcSSc, although its frequency overall in SSc % predicted).80,81 A number of demographic and patients is only 2–5%.74 Like ACA-positive clinical characteristics are associated with a higher patients, anti-Th/To-positive patients are pre- risk of developing ILD in SSc patients. Patients dominantly Caucasians, but tend to have a shorter with SSc are routinely divided into lcSSc and duration of Raynaud’s phenomenon before the dcSSc based on the extent of skin thickening, and onset of other symptoms such as puffy fingers. ILD was more common in dcSSc than in lcSSc Digital ulcer and digital gangrene are infrequent, subset.82 African American race and male sex but patients with anti-Th/To antibody can have were also reported to be associated with ILD.82 significant ILD or pulmonary arterial hyperten- Risk factors for the development of ILD also sion, the latter often independent of ILD, which include anti-topo I antibody. Multivariate analy- often occurs early in the disease course. This ses suggest that the risk of developing ILD is increased frequency and severity of pulmonary more closely associated with anti-topo I antibody complications result in a decreased survival com- rather than the dcSSc/lcSSc subset.82 Anti-topo pared with lcSSc patients without this antibody. I-positive patients have the highest incidence of ILD (>80%) independent of dcSSc/lcSSc sub- sets.70,83 A novel autoantibody targeting U11/ Anti-U11/U12 RNP antibodies U12 RNP is associated with severe ILD and Anti-U11/U12 RNP antibody is a rare antibody decreased survival.75 Other antibodies associated specificity found in 1–3% of patients with SSc.75 with ILD include anti-Th/To in the case of a This antibody recognizes RNA binding region nucleolar pattern on routine ANA assay74 and containing 3 (RNPC-3) associated with U11/U12 anti-eIF2B in the case of a cytoplasmic pattern (a RNA, and produces speckled nuclear staining on negative ANA).78 In the context of lcSSc with indirect immunofluorescence. Patients with this severe ILD, anti-U11/U12 RNP and anti-Th/To antibody are classified as having either dcSSc or are the most common autoantibodies. In con- lcSSc. A characteristic feature of patients with trast, the presence of ACA, anti-RNA polymerase this antibody is a high frequency of ILD (>80%), III, and anti-U3RNP were associated with a low which is often severe and progressive, and associ- risk of ILD.71 ated with a 2.25-fold greater risk of death in comparison with anti-U11/U12 RNP-negative patients with ILD.75 A relationship between anti- Prediction of progression of SSc-ILD U11/U12 RNP antibody and severe ILD has Once ILD has been diagnosed in patients with been replicated in an independent cohort, which SSc, it is important to identify which patients are has additionally found the association of this anti- likely to progress, because some patients experi- body with moderate to severe gastrointestinal ence progressive loss of pulmonary function, and involvement.76 Recently, anti-U11/U12 RNP others progress slowly or exhibit stable disease. antibodies were found in patients with cancer in The prediction of subsequent progression of SSc- close temporal relationship to the onset of SSc.77 ILD should be considered as a first step in the management of the patients. However, at present, there are no reliable prediction models for pro- Anti-eIF2B antibodies gression of SSc-ILD. In clinical practice, the Anti-eIF2B antibody is a novel anti-cytoplasmic severity of SSc-ILD is staged based on the extent antibody identified in SSc sera negative for of ILD on HRCT and FVC.84 A number of other all known SSc-related autoantibodies.78 The clinical factors associated with the progression of journals.sagepub.com/home/tab 9 Therapeutic Advances in Musculoskeletal Disease 13 SSc-ILD have been reported and include older RA is characterized by the presence of RF, which age, smoking history, early dcSSc, progression of is reactive with the Fc portion of IgG, and skin thickening, history or presence of arthritis, antibodies reactive to autoantigens undergoing desaturation after 6-minute walk test, and post-translational modifications, mainly by citrul- decreased DLCO.12,85–87 Serum biomarkers have lination (in this case, a term ACPA is used) but also been extensively investigated, and elevated also other modifications.98 These antibodies are levels of C-reactive protein, Krebs von den included in the classification of RA because Lungen (KL)-6, chemokine ligand 18 are shown of adequate disease sensitivity and specificity, to be associated with a subsequent decline of whereas ACPA has greater specificity than RF FVC and/or development of end-stage of ILD or with similar sensitivity.8 These autoantibodies are death.66,88–90 Several studies have reported that thought to be pathogenic, because they might anti-topo I antibody may be associated with the directly induce stimulatory signals by ligating key faster progression of SSc-ILD in the short term.91 citrullinated cell surface molecules or, alterna- However, its utility as a prognostic biomarker to tively, act as immune complexes on Fc recep- predict the future progression of ILD still remains tors.98 A number of studies have revealed controversial as many observational studies did pathogenic processes to the onset of synovitis in not support this finding. RA, and production of RA autoantibodies pre- cedes the onset of RA.99 Specifically, in a geneti- cally predisposed host, environmental insults, Rheumatoid arthritis (RA) epigenetic modifications and post-translational RA is a systemic autoimmune disease primarily modifications can lead to loss of immune toler- affecting synovial joints, but also involves other ance with subsequent production of autoantibod- organ systems including the lung.92 The lung ies, including RF and ACPA. This ultimately involvement is the most common extra-articular leads to clinically overt arthritis. Therefore, the manifestation, and includes a variety of respira- onset of arthritis is thought to be the last step of a tory complications, such as ILD, airway disease, series of pathogenic events lasting years. Mucosal pleuritis, nodulosis and vasculitis.93 Infections surfaces, such as oral and airway mucosa, are and drug hypersensitivity are important differen- major sites for initiating this autoantibody tial diagnoses and should be considered in the dif- response.100 Several risk factors, such as smoking, ferential diagnosis of RA patients presenting with dust inhalation, bacterial colonization, and pre- respiratory symptoms. ILD is one of the major ceding lung diseases such as ILD are known as causes of morbidity and mortality,94 and is associ- environmental triggers. Interestingly, ILD may ated with a significantly shortened survival in precede the development of articular manifesta- patients with RA, compared to those patients tions, and 14% of patients with RA-ILD had been without ILD.95 In addition, the presence of ILD diagnosed with ILD 1 to 5 years before the RA often interferes with outcomes of a treat-to-target diagnosis.94 In this regard, the association with strategy for synovitis by influencing choices of MUC5B promoter variant, which was observed disease-modifying anti-rheumatic drugs. The in patients with IPF, was also found in patients prevalence of ILD in RA patients varies from with RA-ILD and more specifically in patients 10% to 40%, depending on the definition of with the UIP pattern on HRCT.101 ILD,95 but it is a major proportion of autoim- mune rheumatic disorder-associated ILD in clini- There are a number of risk factors for the devel- cal practice because RA is the most common opment of ILD in RA patients, including older autoimmune rheumatic disorder. Another feature age, male sex, and history of smoking, and high- of RA-ILD is high variability in HRCT patterns titre RF and ACPA are also recognized as diag- and lung histopathology. The most common nostic biomarkers for ILD.102 The risk of HRCT patterns in RA-ILD are UIP and NSIP, developing ILD increases with prolonged dura- while organizing pneumonia (OP) is less com- tion of RA, especially sustained disease activity.103 mon.96 Disease behavior is also highly heteroge- RF and ACPA, especially high levels and the IgA neous, and some patients show progressive isotype, are associated with the occurrence of fibrosing ILD, but others have a stable course. ILD in RA patients, but it is difficult to assess if Even in patients with stable ILD, some develop they are independent risks due to many con- acute exacerbations, which is more common than founding factors, such as smoking, age, and other ILD associated with autoimmune rheu- sex.104–106 Interestingly, up to 15% of patients matic disorders.97 with idiopathic ILD without synovitis have 10 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. ACPA. Among them, serum ACPA positivity is association between anti-Ro60/Ro52 positive sta- predictive of developing RA in the following tus and ILD.116 Nonetheless in this latter study, a 5 years, suggesting common genetic and environ- significant percentage of anti-Ro52-positive mental predisposing factors between RA and patients developed a non-usual interstitial pneu- ILD, especially IPF.107,108 Alternatively, ILD monia pattern. contributes to the onset of RA as one of the trig- gers for production of RA autoantibodies. ANCA vasculitis In terms of risk factors for progression of RA-ILD, The association between anti-neutrophil cyto- the UIP pattern is associated with higher mortal- plasmic antibody (ANCA)-positive vasculitis and ity rates, similar to IPF.109 The prediction model ILD has been recognized since the 1990s, specifi- combining the extent of ILD on HRCT and cally in older patients.117,118 Two phenotypes have FVC, which was described in patients with SSc- been identified. The first comprises patients with ILD, was also useful to predict mortality in ANCA-positive vasculitis, mainly microscopic patients with RA-ILD.110 RF is also listed as a polyangiitis with p-ANCA-positive antibodies prognostic biomarker. In this integrated analysis (myeloperoxidase (MPO)-ANCA), that develop of 2331 patients with early RA, RF was associated ILD.119 The second includes ANCA-positive with all-cause mortality as well as ILD-related patients with no clinical features of vasculitis, but death, independent of other autoantibodies, with ILD.120 Patients within the second pheno- including ACPA.111 type may develop full-blown ANCA-associated vasculitis on follow-up, but this is not always the rule. The outcome appears to depend on the Miscellaneous diseases fibrosis pattern, with a poorer outcome in those This section describes other systemic autoim- with UIP than in those with non-specific intersti- mune diseases that can progress with some degree tial pneumonia.121 ANCA testing should be of ILD, in which associated autoantibodies may included in the diagnostic work-up of ILD. be of help to identify the phenotype. Mixed connective tissue disease Systemic lupus erythematosus Mixed connective tissue disease (MCTD) was ILD is uncommon112 in patients with systemic lupus described in 1972 by Sharp et al.122 ILD is a fea- erythematosus (SLE) to such an extent that if a ture in up to 48% of MCTD patients.123,124 patient diagnosed with SLE develops ILD, an alter- Several autoantibodies have been related with the native diagnosis should be sought (e.g. mixed con- ILD in MCTD, such as anti-Sm125 and anti-U1 nective tissue disease or Sjögren’s syndrome). In this RNP antibodies,124,126 both of which are included line, certain autoantibodies, such as anti-Ro/SSA, in the spliceosome, a cytoplasmic macromolecule anti-La/SSB, and anti-U1 RNP may test positive in responsible for processing pre-messenger RNA the rare SLE patients with ILD, whereas the most by removing intronic sequences to obtain mature specific SLE antibodies, anti-DNA antibodies, are RNA that can be translated into proteins. This is not associated with ILD.113 One possible exception consistent with the higher prevalence of ILD is lupus pneumonitis. This rare manifestation (<1% found in MCTD with epitope spreading during of lupus patients), which usually appears in the con- follow-up; that is, recognition of a new epitope text of a disease flare, may progress to chronic ILD (e.g. Sm) which is spatially related with another due to long-term lung damage. epitope for which the patient had autoantibodies previously (e.g. U1 RNP).127 Anti-Ro52 antibod- ies are also reported to be a biomarker of ILD in Sjögren’s syndrome MCTD patients.124,128 All three autoantibodies The prevalence of ILD in Sjögren’s syndrome is are considered risk factors for developing ILD in nearly 20%, with non-specific interstitial pneu- patients diagnosed with MCTD. monia being the most common pattern.114 The role of anti-Ro antibodies is not well understood in these patients. Whereas anti-Ro52 antibodies Conclusions are a recognized risk factor for ILD and screen- Autoantibodies are a characteristic feature of the ing by HRCT in these patients is recommended autoimmune rheumatic disorders, and are conveni- by some authors,115 others have reported no ent, useful diagnostic and prognostic biomarkers in journals.sagepub.com/home/tab 11 Therapeutic Advances in Musculoskeletal Disease 13 clinical practice of ILD associated with autoim- 6. Gono T and Kuwana M. Inflammatory mune rheumatic disorders. Measurement of rele- myopathies: choosing the right biomarkers to vant autoantibodies contributes to precision predict ILD in myositis. Nat Rev Rheumatol 2016; medicine because of their utility in the prediction of 12: 504–506. future progression and prognosis of ILD and poten- 7. Mulhearn B, Tansley SL and McHugh NJ. tial guidance of treatment decision. Although the Autoantibodies in connective tissue disease. Best measurement of ANA, RF, ACPA, and ANCA in Pract Res Clin Rheumatol 2020; 34: 101462. patients with ILD lacking overt features of autoim- 8. Aletaha D, Neogi T, Silman AJ, et al. 2010 mune rheumatic disorders is generally recom- Rheumatoid arthritis classification criteria: an mended, we suggest a more comprehensive testing American College of Rheumatology/European for antibodies including the myositis spectrum dis- League Against Rheumatism collaborative ease autoantibodies and SSc-related autoantibodies initiative. Arthritis Rheum 2010; 62: 2569–2581. because a good correlation with cytoplasmic stain- 9. van den Hoogen F, Khanna D, Fransen J, et al. ing is not always observed. However, as autoanti- 2013 Classification criteria for systemic sclerosis: bodies are just surrogate biomarkers, a clinical an American College of Rheumatology/European decision should be made based on comprehensive League against Rheumatism collaborative assessments, including physical findings, pulmonary initiative. Arthritis Rheum 2013; 65: 2737–2747. function and imaging studies. In addition, there are 10. Lundberg IE, Tjärnlund A, Bottai M, et al. 2017 a number of methods for the measurement of European League against Rheumatism/American autoantibodies each with their own inherent limita- College of Rheumatology Classification Criteria tions. Physicians should understand them best to for Adult and Juvenile Idiopathic Inflammatory interpret results in the clinical context. Myopathies and their Major Subgroups. Arthritis Rheumatol 2017; 69: 2271–2282. Conflict of interest statement 11. Hoffmann-Vold AM, Maher TM, Philpot EE, The authors declare that there is no conflict of et al. The identification and management of interest. interstitial lung disease in systemic sclerosis: evidence-based European consensus statements. Funding Lancet Rheumatol 2020; 2: e71–e83. The authors received no financial support for the 12. Distler O, Assassi S, Cottin V, et al. Predictors research, authorship, and/or publication of this of progression in systemic sclerosis patients with article. interstitial lung disease. Eur Respir J 2020; 55: 1902026. ORCID iD Masataka Kuwana https://orcid.org/0000- 13. Cottin V and Brown KK. Interstitial lung disease 0001-8352-6136 associated with systemic sclerosis (SSc-ILD). Respir Res 2019; 20: 13. 14. Fischer A, Antoniou KM, Brown KK, et al. References ERS/ATS Task Force on Undifferentiated 1. Mathai SC and Danoff SK. Management of Forms of CTD-ILD. An official European interstitial lung disease associated with connective Respiratory Society/American Thoracic Society tissue disease. BMJ 2016; 352: h6819. research statement: interstitial pneumonia with 2. Castelino FV and Moua T. Detection and autoimmune features. Eur Respir J 2015; 46: management of interstitial lung diseases 976–987. associated with connective tissue diseases. ACR 15. Wells AU, Brown KK, Flaherty KR, et al.; IPF Open Rheumatol. Epub ahead of print 28 March Consensus Working Group. What’s in a name? 2021. DOI: 10.1002/acr2.11253 That which we call IPF, by any other name 3. Wijsenbeek M and Cottin V. Spectrum of fibrotic would act the same. Eur Respir J 2018; 51: lung diseases. N Engl J Med 2020; 383: 958–968. 1800692. 4. Distler O, Highland KB, Gahlemann M, et al. 16. Cottin V, Wollin L, Fischer A, et al. Fibrosing Nintedanib for systemic sclerosis-associated interstitial lung diseases: knowns and unknowns. interstitial lung disease. N Engl J Med 2019; 380: Eur Respir Rev 2019; 28: 180100. 2518–2528. 17. Wijsenbeek M, Kreuter M, Olson A, et al. 5. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib Progressive fibrosing interstitial lung diseases: in progressive fibrosing interstitial lung diseases. current practice in diagnosis and management. N Engl J Med 2019; 381: 171817–171827. Curr Med Res Opin 2019; 35: 2015–2024. 12 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. 18. George PM, Spagnolo P, Kreuter M, function in a cohort of patients with interstitial et al. Progressive fibrosing interstitial lung lung disease and positive for antisynthetase disease: clinical uncertainties, consensus antibodies. J Rheumatol 2020; 47: 415–423. recommendations, and research priorities. 30. Marie I, Josse S, Decaux O, et al. Comparison Lancet Respir Med 2020; 8: 925–934. of long-term outcome between anti-Jo1 and 19. Selva-O’Callaghan A, Pinal-Fernández I, anti-PL7/PL12 positive patients with antisynthetase Trallero-Araguás E, et al. Classification and syndrome. Autoimmun Rev 2012; 11: 739–745. management of adult inflammatory myopathies. 31. Marie I, Hatron PY, Dominique S, et al. Short- Lancet Neurol 2018; 17: 816–828. term and long-term outcome of anti-Jo1-positive 20. McHugh NJ and Tansley SL. Autoantibodies in patients with anti-Ro52 antibody. Semin Arthritis myositis. Nat Rev Rheumatol 2018; 14: 290–302. Rheum 2012; 41: 890–899. 21. Barba T, Mainbourg S, Nasser M, et al. Lung 32. Váncsa A, Csípo I, Németh J, et al. diseases in inflammatory myopathies. Semin Characteristics of interstitial lung disease in SS-A Respir Crit Care Med 2019; 40: 255–270. positive/Jo-1 positive inflammatory myopathy patients. Rheumatol Int 2009; 29: 989–994. 22. Sun KY, Fan Y, Wang YX, et al. Prevalence of interstitial lung disease in polymyositis and 33. Bauhammer J, Blank N, Max R, et al. Rituximab dermatomyositis: a meta-analysis from 2000 to in the treatment of jo1 antibody-associated 2020. Semin Arthritis Rheum 2021; 51: 175–191. antisynthetase syndrome: anti-Ro52 positivity as a marker for severity and treatment response. J 23. Hervier B, Devilliers H, Stanciu R, et al. Rheumatol 2016; 43: 1566–1574. Hierarchical cluster and survival analyses of 34. Sabbagh S, Pinal-Fernandez I, Kishi T, et al.; antisynthetase syndrome: phenotype and outcome Childhood Myositis Heterogeneity Collaborative are correlated with anti-tRNA synthetase Study Group. Anti-Ro52 autoantibodies are antibody specificity. Autoimmun Rev 2012; 12: associated with interstitial lung disease and more 210–217. severe disease in patients with juvenile myositis. 24. Shi J, Li S, Yang H, et al. Clinical profiles and Ann Rheum Dis 2019; 78: 988–995. prognosis of patients with distinct antisynthetase 35. Lega JC, Cottin V, Fabien N, et al. Interstitial autoantibodies. J Rheumatol 2017; 44: 1051– lung disease associated with anti-PM/Scl or 1057. anti-aminoacyl-tRNA synthetase autoantibodies: 25. Pinal-Fernández I, Casal-Domínguez M, a similar condition? J Rheumatol 2010; 37: Huapaya JA, et al. A longitudinal cohort study of 1000–1009. the anti-synthetase syndrome: increased severity 36. Rothwell S, Chinoy H, Lamb JA, et al. of interstitial lung disease in black patients Focused HLA analysis in Caucasians with and patients with anti-PL7 and anti-PL12 myositis identifies significant associations with autoantibodies. Rheumatology 2017; 56: autoantibody subgroups. Ann Rheum Dis 2019; 999–1007. 78: 996–1002. 26. Trallero-Araguas E, Grau-Junyent JM, Labirua- 37. Mahler M and Raijmakers R. Novel aspects of Iturburu A, et al. Clinical manifestations and autoantibodies to the PM/Scl complex: clinical, long-term outcome of anti-Jo1 antisynthetase genetic and diagnostic insights. Autoimmun Rev patients in a large cohort of Spanish patients from 2007; 6: 432–437. the GEAS-IIM group. Semin Arthritis Rheum 2016; 46: 225–231. 38. Selva-O’Callaghan A, Labrador-Horrillo M, Solans-Laque R, et al. Myositis-specific and 27. Labirua-Iturburu A, Selva-O’Callaghan A, myositis-associated antibodies in a series of Vincze M, et al. Anti-PL-7 (anti-threonyl-tRNA eighty-eight Mediterranean patients with synthetase) antisynthetase syndrome: clinical idiopathic inflammatory myopathy. Arthritis manifestations in a series of patients from a Rheum 2006; 55: 791–798. European multicenter study (EUMYONET) and review of the literature. Medicine (Baltimore) 39. Guillen-Del Castillo A, Pilar Simeón-Aznar 2012; 91: 206–211. C, Fonollosa-Pla V, et al. Good outcome of interstitial lung disease in patients with 28. Cavagna L, Trallero-Araguas E, Meloni F, et al. scleroderma associated to anti-PM/Scl antibody. Influence of antisynthetase antibodies specificities Semin Arthritis Rheum 2014; 44: 331–337. on antisynthetase syndrome clinical spectrum 40. Ussavarungsi K, Nugent K, Gerke AK, et al. time course. J Clin Med 2019; 8: 2013. Interstitial lung disease associated with anti-PM-Scl 29. Gonzalez-Perez MI, Mejía-Hurtado JG, antibody: a single center experience. Autoimmun Perez-Roman DI, et al. Evolution of pulmonary Rev 2019; 18: 102355. journals.sagepub.com/home/tab 13 Therapeutic Advances in Musculoskeletal Disease 13 41. De Lorenzo R, Pinal-Fernández I, Huang W, 51. Moghadam-Kia S, Oddis CV, Sato S, et al. et al. Muscular and extramuscular clinical features Anti-melanoma differentiation-associated gene 5 of patients with anti-PM/Scl autoantibodies. is associated with rapidly progressive lung disease Neurology 2018; 90: e2068–e2076. and poor survival in US patients with amyopathic and myopathic dermatomyositis. Arthritis Care 42. D’Aoust J, Hudson M, Tatibouet S, et al. Res (Hoboken) 2016; 68: 689–694. Clinical and serologic correlates of anti-PM/Scl antibodies in systemic sclerosis: a multicenter 52. Chen Z, Cao M, Plana MN, et al. Utility of study of 763 patients. Arthritis Rheumatol 2014; anti-melanoma differentiation-associated gene 5 66: 1608–1615. antibody measurement in identifying patients with dermatomyositis and a high risk for developing 43. Lazzaroni MG, Marasco E, Campochiaro C, rapidly progressive interstitial lung disease: a et al. The clinical phenotype of systemic sclerosis review of the literature and a meta-analysis. patients with anti-PM/Scl antibodies: results from Arthritis Care Res (Hoboken) 2013; 65: 1316–1324. the EUSTAR cohort. Rheumatology (Oxford). Epub ahead of print 12 February 2021. DOI: 53. Allenbach Y, Uzunhan Y, Toquet S, et al. 10.1093/rheumatology/keab152 Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: study of 44. Spielmann L, Nespola B, Séverac F, et al. 121 cases. Neurology 2020; 95: e70–e78. Anti-Ku syndrome with elevated CK and anti-Ku syndrome with anti-dsDNA are two distinct 54. Matsushita T, Mizumaki K, Kano M, et al. entities with different outcomes. Ann Rheum Dis Antimelanoma differentiation-associated protein 2019; 78: 1101–1106. 5 antibody level is a novel tool for monitoring disease activity in rapidly progressive interstitial 45. Yang H, Li W, Tian X, et al. Immune-mediated lung disease with dermatomyositis. Br J Dermatol necrotizing myopathies and interstitial lung 2017; 176: 395–402. disease are predominant characteristics in anti-Ku positive patients with idiopathic 55. Sato S, Kuwana M, Fujita T, et al. Anti- inflammatory myopathies. Ann Rheum Dis. Epub CADM-140/MDA5 autoantibody titer correlates ahead of print 20 February 2020. DOI: 10.1136/ with disease activity and predicts disease annrheumdis-2020-217096 outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease. Mod 46. Sato S, Hirakata M, Kuwana M, et al. Rheumatol 2013; 23: 496–502. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically 56. Hoa S, Troyanov Y, Fritzler MJ, et al. Describing amyopathic dermatomyositis. Arthritis Rheum and expanding the clinical phenotype of anti- 2005; 52: 1571–1576. MDA5-associated rapidly progressive interstitial lung disease: case series of nine Canadian 47. Wang DP, Zhang HY, Liao BW, et al. SRP54 patients and literature review. Scand J Rheumatol. negatively regulates IFN-beta production and Epub ahead of print 25 October 2017. DOI: antiviral response by targeting RIG-I and MDA5. 10.1080/03009742.2017.1334814 Virol Sin. Epub ahead of print 7 August 2020. DOI: 10.1007/s12250-020-00267-6 57. Xu A, Ye Y, Fu Q, et al. Prognostic values of anti-Ro52 antibodies in anti-MDA5-positive 48. Vuillard C, Pineton de Chambrun M, de Prost N, clinically amyopathic dermatomyositis associated et al. Clinical features and outcome of patients with interstitial lung disease. Rheumatology with acute respiratory failure revealing anti- (Oxford). Epub ahead of print 17 December synthetase or anti-MDA-5 dermato-pulmonary 2020. DOI: 10.1093/rheumatology/keaa786 syndrome: a French multicenter retrospective study. Ann Intensive Care 2018; 8: 87. 58. Temmoku J, Sato S, Fujita Y, et al. Clinical significance of myositis-specific autoantibody 49. Romero-Bueno F, Díaz Del Campo P, Trallero- profiles in Japanese patients with polymyositis/ Araguás E, et al. Recommendations for the dermatomyositis. Medicine (Baltimore) 2019; 98: treatment of anti-melanoma differentiation- e15578. associated gene 5-positive dermatomyositis- associated rapidly progressive interstitial lung 59. Kong HJ, Anderson DE, Lee CH, et al. Cutting disease. Semin Arthritis Rheum 2020; 50: 776–790. edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances 50. Labrador-Horrillo M, Martínez MA, Selva- cytokine expression in macrophages. J Immunol O’Callaghan A, et al. Anti-MDA5 antibodies in 2007; 179: 26–30. a large Mediterranean population of adults with dermatomyositis. J Immunol Res 2014; 2014: 60. Betteridge Z, Gunawardena H, North J, et al. 290797. Identification of a novel autoantibody directed 14 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. against small ubiquitin-like modifier activating outcome-based disease classification in systemic enzyme in dermatomyositis. Arthritis Rheum sclerosis. Arthritis Rheumatol 2020; 72: 465–476. 2007; 56: 3132–3137. 72. Kranenburg P, van den Hombergh WM, 61. Peterson LK, Jaskowski TD, La’ulu SL, et al. Knaapen-Hans HK, et al. Survival and organ Antibodies to small ubiquitin-like modifier involvement in patients with limited cutaneous activating enzyme are associated with a diagnosis systemic sclerosis and anti-topoisomerase-I of dermatomyositis: results from an unselected antibodies: determined by skin subtype or auto- cohort. Immunol Res 2018; 66: 431–436. antibody subtype? A long-term follow-up study. Rheumatology (Oxford) 2016; 55: 2001–2008. 62. Fujimoto M, Matsushita T, Hamaguchi Y, et al. Autoantibodies to small ubiquitin-like 73. Boonstra M, Bakker JA, Grummels A, et al. modifier activating enzymes in Japanese patients Association of anti-topoisomerase I antibodies with dermatomyositis: comparison with a UK of the IgM isotype with disease progression in Caucasian cohort. Ann Rheum Dis 2013; 72: anti-topoisomerase I-positive systemic sclerosis. 151–153. Arthritis Rheumatol 2020; 72: 1897–904. 63. Varga J, Trojanowska M and Kuwana M. 74. Mitri GM, Lucas M, Fertig N, et al. A Pathogenesis of systemic sclerosis: recent insights comparison between anti-Th/To-and of molecular and cellular mechanisms and anticentromere antibody-positive systemic therapeutic opportunities. J Scleroderma Relat sclerosis patients with limited cutaneous Disord 2017; 2: 137–152. involvement. Arthritis Rheum 2003; 48: 203–209. 64. Elhai M, Meune C, Boubaya M, et al. Mapping 75. Fertig N, Domsic RT, Rodriguez-Reyna T, and predicting mortality from systemic sclerosis. et al. Anti-U11/U12 RNP antibodies in systemic Ann Rheum Dis 2017; 76: 1897–1905. sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 2009; 61: 65. Man A, Davidyock T, Ferguson LT, et al. 958–965. Changes in forced vital capacity over time in systemic sclerosis: application of group-based 76. McMahan ZH, Domsic RT, Zhu L, et al. Anti- trajectory modelling. Rheumatology (Oxford) RNPC-3 (U11/U12) antibodies in systemic 2015; 54: 1464–1471. sclerosis in patients with moderate-to-severe gastrointestinal dysmotility. Arthritis Care Res 66. Kuwana M, Shirai Y and Takeuchi T. Elevated (Hoboken) 2019; 71: 1164–1170. serum Krebs von den Lungen-6 in early disease predicts subsequent deterioration of pulmonary 77. Shah AA, Xu G, Rosen A, et al. Anti-RNPC-3 function in patients with systemic sclerosis and antibodies as a marker of cancer-associated interstitial lung disease. J Rheumatol 2016; 43: scleroderma. Arthritis Rheumatol 2017; 69: 1825–1831. 1306–1312. 67. Hoffmann-Vold AM, Allanore Y, Alves M, et al. 78. Betteridge ZE, Woodhead F, Lu H, et al. Anti- Progressive interstitial lung disease in patients eukaryotic initiation factor 2B autoantibodies are with systemic sclerosis-associated interstitial lung associated with interstitial lung disease in patients disease in the EUSTAR database. Ann Rheum Dis with systemic sclerosis. Arthritis Rheumatol 2016; 2021; 80: 219–227. 68: 2778–2783. 68. Kuwana M. Circulating anti-nuclear antibodies in 79. Pauling JD, Salazar G, Lu H, et al. Presence systemic sclerosis: utility in diagnosis and disease of anti-eukaryotic initiation factor-2B, anti- subsetting. J Nippon Med Sch 2017; 84: 56–63. RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative 69. Wirz EG, Jaeger VK, Allanore Y, et al. systemic sclerosis. Rheumatology (Oxford) 2018; Incidence and predictors of cutaneous 57: 712–717. manifestations during the early course of 80. Steele R, Hudson M, Lo E, et al.; Canadian systemic sclerosis: a 10-year longitudinal study Scleroderma Research Group. Clinical decision from the EUSTAR database. Ann Rheum Dis rule to predict the presence of interstitial lung 2016; 75: 1285–1292. disease in systemic sclerosis. Arthritis Care Res 70. Kuwana M, Kaburaki J, Okano Y, et al. Clinical 2012; 64: 519–524. and prognostic associations based on serum 81. Suliman YA, Dobrota R, Huscher D, et al. antinuclear antibodies in Japanese patients with Pulmonary function tests: high rate of false- systemic sclerosis. Arthritis Rheum 1994; 37: 75–83. negative results in the early detection and 71. Nihtyanova SI, Sari A, Harvey JC, et al. Using screening of scleroderma-related interstitial lung autoantibodies and cutaneous subset to develop disease. Arthritis Rheumatol 2015; 67: 3256–3261. journals.sagepub.com/home/tab 15 Therapeutic Advances in Musculoskeletal Disease 13   82. Walker UA, Tyndall A, Czirják L, et al. Clinical remains a challenge for clinicians. J Clin Med risk assessment of organ manifestations in 2019; 8: 2038. systemic sclerosis: a report from the EULAR   94. Hyldgaard C, Hilberg O, Pedersen AB, et al. Scleroderma Trials and Research group A population-based cohort study of rheumatoid database. Ann Rheum Dis 2007; 66: 754–763. arthritis-associated interstitial lung disease:   83. Peoples C, Medsger TA Jr, Lucas M, et al. comorbidity and mortality. Ann Rheum Dis Gender differences in systemic sclerosis: 2017; 76: 1700–1706. relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord 2016;   95. Olson AL, Swigris JJ, Sprunger DB, et al. 1: 177–240. Rheumatoid arthritis-interstitial lung disease- associated mortality. Am J Respir Crit Care Med   84. Goh NS, Desai SR, Veeraraghavan S, et al. 2011; 183: 372–378. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care   96. Kelly CA, Saravanan V, Nisar M, et al. Med 2008; 177: 1248–1254. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and   85. Morisset J, Vittinghoff E, Elicker BM, et al. physiological and radiological characteristics – a Mortality risk prediction in scleroderma-related large multicentre UK study. Rheumatology interstitial lung disease: the SADL model. Chest (Oxford) 2014; 53: 1676–1682. 2017; 152: 999–1007.   97. Hozumi H, Nakamura Y, Johkoh T, et al. Acute   86. Wu W, Jordan S, Becker MO, et al. Prediction exacerbation in rheumatoid arthritis-associated of progression of interstitial lung disease in interstitial lung disease: a retrospective case patients with systemic sclerosis: the SPAR control study. BMJ Open 2013; 3: e003132. model. Ann Rheum Dis 2018; 77: 1326–1332.   98. Catrina A, Krishnamurthy A and Rethi B.   87. Wu W, Jordan S, Graf N, et al. Progressive Current view on the pathogenic role of anti- skin fibrosis is associated with a decline in citrullinated protein antibodies in rheumatoid lung function and worse survival in patients arthritis. RMD Open 2021; 7: e001228. with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research   99. Smolen JS, Aletaha D and McInnes IB. (EUSTAR) cohort. Ann Rheum Dis 2019; 78: Rheumatoid arthritis. Lancet 2016; 388: 648–656. 2023–2038.   88. Liu X, Mayes MD, Pedroza C, et al. Does 100. Lucchino B, Spinelli FR, Iannuccelli C, et al. C-reactive protein predict the long-term Mucosa–environment interactions in the progression of interstitial lung disease and pathogenesis of rheumatoid arthritis. Cells 2019; survival in patients with early systemic sclerosis? 8: 700. Arthritis Care Res 2013; 65: 1375–1380. 101. Juge PA, Lee JS, Ebstein E, et al. MUC5B   89. Salazar GA, Kuwana M, Wu M, et al. KL-6 but promoter variant and rheumatoid arthritis with not CCL-18 is a predictor of early progression interstitial lung disease. N Engl J Med 2018; in systemic sclerosis-related interstitial lung 379: 2209–2219. disease. J Rheumatol 2018; 45: 1153–1158. 102. Doyle TJ, Patel AS, Hatabu H, et al. Detection   90. Elhai M, Hoffmann-Vold AM, Avouac J, et al. of rheumatoid arthritis-interstitial lung disease is Performance of candidate serum biomarkers enhanced by serum biomarkers. Am J Respir Crit for systemic sclerosis-associated interstitial lung Care Med 2015; 191: 1403–1412. disease. Arthritis Rheumatol 2019; 71: 972–982. 103. Sparks JA, He X, Huang J, et al. Rheumatoid   91. Assassi S, Sharif R, Lasky RE, et al. Predictors arthritis disease activity predicting incident of interstitial lung disease in early systemic clinically apparent rheumatoid arthritis-associated sclerosis: a prospective longitudinal study of the interstitial lung disease: a prospective cohort GENISOS cohort. Arthritis Res Ther 2010; 12: study. Arthritis Rheumatol 2019; 71: 1472–1482. R166. 104. Aubart F, Crestani B, Nicaise-Roland P, et al.   92. Turesson C, O’Fallon WM, Crowson CS, High levels of anti-cyclic citrullinated peptide et al. Extra-articular disease manifestations in autoantibodies are associated with co-occurrence rheumatoid arthritis: incidence trends and risk of pulmonary diseases with rheumatoid arthritis. factors over 46 years. Ann Rheum Dis 2003; 62: J Rheumatol 2011; 38: 979–982. 722–727. 105. Kokkonen H, Mullazehi M, Berglin E, et al.   93. Bendstrup E, Møller J, Kronborg-White S, et al. Antibodies of IgG, IgA and IgM isotypes Interstitial lung disease in rheumatoid arthritis against cyclic citrullinated peptide precede the 16 journals.sagepub.com/home/tab M Kuwana, A Gil-Vila et al. development of rheumatoid arthritis. Arthritis 117. Nada AK, Torres VE, Ryu JH, et al. Pulmonary Res Ther 2011; 13: R13. fibrosis as an unusual clinical manifestation of a pulmonary-renal vasculitis in elderly patients. 106. Rocha-Muñoz AD, Ponce-Guarneros M, Mayo Clin Proc 1990; 65: 847–856. Gamez-Nava JI, et al. Anti-cyclic citrullinated peptide antibodies and severity of interstitial 118. Katsumata Y, Kawaguchi Y and Yamanaka H. lung disease in women with rheumatoid Interstitial lung disease with ANCA-associated arthritis. J Immunol Res 2015; 2015: 151626. vasculitis. Clin Med Insights Circ Respir Pulm Med 2015; 9 (Suppl. 1): 51–56. 107. Fischer A, Solomon JJ, du Bois RM, et al. Lung disease with anti-CCP antibodies but 119. Alba MA, Flores-Suárez LF, Henderson not rheumatoid arthritis or connective tissue AG, et al. Interstitial lung disease in ANCA disease. Respir Med 2012; 106: 1040–1047. vasculitis. Autoimmun Rev 2017; 16: 722–729. 108. Katsumata M, Hozumi H, Yasui H, et al. 120. Sun X, Peng M, Zhang T, et al. Clinical Frequency and clinical relevance of anti-cyclic features and long-term outcomes of interstitial citrullinated peptide antibody in idiopathic lung disease with anti-neutrophil cytoplasmic interstitial pneumonias. Respir Med 2019; 154: antibody. BMC Pulm Med 2021; 21: 88. 102–108. 121. Maillet T, Goletto T, Beltramo G, et al. Usual 109. Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in ANCA-associated interstitial pneumonia in rheumatoid arthritis- vasculitis: a poor prognostic factor. J Autoimmun associated interstitial lung disease. Eur Respir J 2020; 106: 102338. 2010; 35: 1322–1328. 122. Sharp GC, Irvin WS, Tan EM, et al. Mixed 110. Jacob J, Hirani N, van Moorsel CHM, et al. connective tissue disease – an apparently Predicting outcomes in rheumatoid arthritis distinct rheumatic disease syndrome associated related interstitial lung disease. Eur Respir J with a specific antibody to an extractable 2019; 53: 1800869. nuclear antigen (ENA). Am J Med 1972; 52: 148–159. 111. Ajeganova S, Humphreys JH, Verheul MK, et al. Anticitrullinated protein antibodies 123. Saito Y, Terada M, Takada T, et al. Pulmonary and rheumatoid factor are associated with involvement in mixed connective tissue disease: increased mortality but with different causes of comparison with other collagen vascular death in patients with rheumatoid arthritis: a diseases using high resolution CT. J Comput longitudinal study in three European cohorts. Assist Tomogr 2002; 26: 349–357. Ann Rheum Dis 2016; 75: 1924–1932. 124. Reiseter S, Gunnarsson R, Mogens Aaløkken T, 112. Weinrib L, Sharma OP and Quismorio FP Jr. et al. Progression and mortality of interstitial A long-term study of interstitial lung disease in lung disease in mixed connective tissue disease: systemic lupus erythematosus. Semin Arthritis a long-term observational nationwide cohort Rheum 1990; 20: 48–56. study. Rheumatology (Oxford) 2018; 57: 255–262. 113. Amarnani R, Yeoh SA, Denneny EK, et al. Lupus and the lungs: the assessment and 125. Narula N, Narula T, Mira-Avendano I, management of pulmonary manifestations et al. Interstitial lung disease in patients with of systemic lupus erythematosus. Front Med mixed connective tissue disease: pilot study (Lausanne) 2021; 7: 610257. on predictors of lung involvement. Clin Exp Rheumatol 2018; 36: 648–651. 114. Luppi F, Sebastiani M, Silva M, et al. Interstitial lung disease in Sjögren’s syndrome: 126. Lhote R, Grenier P, Haroche J, et al. a clinical review. Clin Exp Rheumatol 2020; 38 Characterization of interstitial lung disease (Suppl. 126): 291–300. associated with anti-ribonucleoprotein antibodies. J Clin Rheumatol 2020; 26: 327–333. 115. Buvry C, Cassagnes L, Tekath M, et al. Anti-Ro52 antibodies are a risk factor for 127. Escolà-Vergé L, Pinal-Fernández I, Fernández- interstitial lung disease in primary Sjögren Codina A, et al. Mixed connective tissue disease syndrome. Respir Med 2020; 163: 105895. and epitope spreading: an historical cohort study. J Clin Rheumatol 2017; 23: 155–159. 116. Zhang T, Yuan F, Xu L, et al. Characteristics of patients with primary Sjögren’s syndrome 128. Gunnarsson R, El-Hage F, Aaløkken TM, et al. Visit SAGE journals online associated interstitial lung disease and relevant Associations between anti-Ro52 antibodies and journals.sagepub.com/ home/tab features of disease progression. Clin Rheumatol lung fibrosis in mixed connective tissue disease. 2020; 39: 1561–1568. Rheumatology (Oxford) 2016; 55: 103–108. SAGE journals journals.sagepub.com/home/tab 17