Respiratory Medicine 113 (2016) 80e92

Contents lists available at ScienceDirect

Respiratory Medicine

journal homepage: www.elsevier.com/locate/rmed

Review article The use of auto-antibody testing in the evaluation of interstitial lung disease (ILD) e A practical approach for the pulmonologist

* Thomas Bahmer a, , Micaela Romagnoli b, Francesco Girelli c, Martin Claussen a, Klaus F. Rabe a a LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Woehrendamm 80, 22927 Grosshansdorf, Germany b Pulmonology Unit, S'Orsola-Malpighi Hospital, University of Bologna, via Albertoni 15, 40138 Bologna, Italy c Rheumatology Unit, Internal Medicine Department, GB Morgagni e L Pierantoni Hospital, Via Carlo Forlanini 34, 47121 Forlì, Italy article info abstract

Article history: Interstitial lung diseases (ILD), also defined as diffuse parenchymal lung diseases (DPLD) include a Received 1 June 2015 heterogeneous group of pulmonary disorders. They may be caused by an underlying connective tissue Received in revised form disease (CTD), Rheumatoid Arthritis (RA) or ANCA-associated Vasculitis (AAV). Pulmonary manifestations 27 October 2015 of these conditions may also precede systemic onset and therefore, pulmonologists may be confronted Accepted 28 January 2016 with diagnosing a systemic rheumatic disease. For the discrimination of CTD-related ILD and idiopathic Available online 1 February 2016 interstitial pneumonia (IIP), serological testing is recommended. After careful reviewing the available literature, we suggest a serologic diagnostic algorithm for pul- Keywords: CTD-ILD monologists dealing with ILD-patients. This algorithm depicts the consensus for antibody testing that IPAF was reached amongst authors. Obviously this consensus approach requires further validation in everyday IPF practice and leaves room for local adaption of the diagnostic strategy depending on the availability of Serological testing diagnostic capacity and cost. It is our hope, however, that the rational and stepwise approach of sero- Diagnostic algorithm logical testing for ILD will ultimately save unnecessary expenses associated with general laboratory ANA fluorescence pattern screening. Finally a broader consensus on the strategy for laboratory testing in ILD in general might also improve the detection level of these relatively rare diseases and this will ultimately improve manage- ment and care of patients suffering from these complex disorders. © 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction ...... 81 2. Auto-antibody tests and their clinical significance ...... 81 2.1. Antinuclear antibodies e ANA...... 81 2.1.1. t-RNA synthetase (ARS-) antibodies: inflammatory myopathy and ASS ...... 82 2.1.2. Mi-2 and CADM-140 antibodies: inflammatory myopathy ...... 83 2.1.3. PM/Scl-75/100 antibodies: overlap syndrome ...... 83 2.1.4. SSA/SSB e antibodies: Sjogren€ Syndrome ...... 83 2.1.5. Topoisomerase I (topo I/SCL-70), RNA polymerase III, Th/To and CENP-B e antibodies: systemic sclerosis ...... 83 2.1.6. Sm and ds-DNA antibodies: systemic lupus erythematodes ...... 84

2.1.7. U1-RNP antibodies: mixed connective tissue disease (MCTD) ...... 84 2.2. ANCA: ANCA-associated vasculitis ...... 85 2.3. RF and CCP-antibodies: rheumatoid arthritis ...... 85 3. Connective tissue disease-related ILD: the pulmonologists point of view ...... 85 3.1. Epidemiology ...... 85

* Corresponding author. LungenClinic Grosshansdorf, Woehrendamm 80, 22927, Grosshansdorf, Germany. E-mail address: [email protected] (T. Bahmer). http://dx.doi.org/10.1016/j.rmed.2016.01.019 0954-6111/© 2016 Elsevier Ltd. All rights reserved. T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 81

3.2. Histopathology ...... 86 3.3. Prognosis ...... 86 3.4. Diagnostic algorithm for serologic autoimmune testing e why?...... 86 4. Suggestion for a diagnostic algorithm: serological evaluation in patients with ILD ...... 87 Acknowledgment ...... 88 Glossary ...... 88 Conflict of interest ...... 89 References...... 89

1. Introduction In this article, we therefore suggest a diagnostic algorithm for autoantibody testing, based on a current literature screen. This al- Interstitial lung disease (ILD), also defined as diffuse paren- gorithm shall give the pulmonologist, being first contacted by a chymal lung disease (DPLD) include a heterogeneous group of patient with ILD of unknown origin, a pragmatic and clinically pulmonary diseases, sharing several clinical, functional, radiologic orientated code of practice for serological testing. While autoanti- and pathologic similarities [1e3] but also presenting with many bodies are fundamental diagnostic tools, it is important to differences [4], including prognosis and response to treatment. ILDs emphasize that auto-antibody results do not definitvely prove or are usually classified on the basis of aetiology, being defined as disprove a disease. This algorithm is meant to assist current diag- “idiopathic” [5], or secondary to known causes, e.g. connective nostic guidelines on the detection of ILD and CTD, which may be tissue disease, infections, drugs and radiation-induced lung disease found elsewhere. We believe that the use of such an algorithm in or occupational and environmental exposure. daily clinical practice can be associated with a reduction in the One of the main known causes of ILDs is an underlying con- number of second-level tests and a higher cost-effectiveness in nective tissue disease (CTD) [5], or ANCA-associated Vasculitis laboratory testing [20,21]. Furthermore, there is a growing appre- (AAV) [6]. The pulmonary manifestation of a connective tissue ciation that a multidisciplinary approach to CTD-ILDs can further disease or vasculitis can precede the systemic onset [7,8]. Therefore, enhance the diagnostic performance [22]. the physician being primarily involved in diagnosing a systemic rheumatic disease might be a pulmonologist [9]. Recognition of an 2. Auto-antibody tests and their clinical significance underlying CTD is particularly challenging when ILD is its first or lone manifestation [10]. The discrimination is important, as the 2.1. Antinuclear antibodies e ANA prognosis of patients with connective tissue disease-related ILD (CTD-ILD) tends to be less severe than that of idiopathic ILDs The most commonly used technique for ANA determination is e [11 13] - although still controversial [14] - and therapeutic options indirect immunofluorescence (IIF). The antigens of Human are different. Epithelial cell line-2 (HEp-2), derived from human larynx carci- In clinical practice, pulmonologists dealing with ILD patients are noma cells, are used to detect relevant autoantibodies [23]. The confronted with patients presenting with subtle clinical features ANA-test by immunofluorescence is preferred as screening method suggesting an underlying autoimmune process, though not because of its high sensitivity [25]. The cut-off for positive test re- meeting established criteria for a distinct connective tissue disease sults is suggested to be 1:160 [24], although this cannot be gener- (CTD). Criteria and terms to describe this subset of patients differed alized because of the high variability of the test itself and local, “ between various research groups: undifferentiated CTD associated technician-dependant differences. High autoantibody titers ” “ ” “ ILD (UCTD-ILD) [15], lung dominant CTD [16] or autoimmune- (>1:160) can be detected in sick subjects, but in only 5% of healthy ” featured ILD [17]. Recently, an ERS/ATS Task Force introduced the people [25]. Low antibody titers (1:40) can be detected in about fi “ concept and de nition of interstitial pneumonia with autoimmune 25e30% of healthy controls [26] and should therefore be consid- ” fi features (IPAF) [18], offering harmonized classi cation criteria ered as negative test result. The frequency of unspecificANA- based on clinical, serological and morphological features. This positivity in [27] healthy controls seems to increase with consensus approach is important to raise the awareness for this increasing age [26]. In a study by Tan et al. (1997), however, the patient subgroup, to uniform clinical approach and to guide future frequency of ANA positivity in healthy subjects did not differ e research recommendations for diagnostic testing, clinical care significantly across the 4 age subgroups spanning 20e60 years of and management of patients, however, may not yet be derived from age [25]. this concept and are still left to the individual health care provider The autoantibodies detected in the ANA-test are generally [18]. referred to as antinuclear antibodies owing to their predominant The current international guidelines on the diagnosis of IPF reactivity with nuclear antigens. However, the ANA-test also de- recommend excluding the presence of CTD [19], which inevitably tects some antigens that are located in the cytoplasm [28]. should involve the assessment of extra-thoracic features of CTD The type of distribution pattern observed in IIF on human (medical history and physical examination by a dedicated physi- epithelial cell line-2 (HEp-2) cells in interphase is correlated with cian), testing for circulating auto-antibodies and integrating antibody specificity, and the signals can originate from nuclear, fi radiological and histopathological ndings [18,19]. However, the mitotic or cytoplasmatic domains [28] (see Table 1). Anti-Ro/SSA diagnostic value of autoantibody testing in excluding connective and anti-t-RNA synthetases, however, are not readily detected tissue disease-related ILD, remains sometimes unclear and rec- owing to the scarcity of antigen in HEp-2 cells and/or leaching and fi ommendations regarding the signi cance of the single auto- denaturation secondary to fixation procedures [28,31]. antibody tests or the necessity to repeat auto-antibody testing af- The ANA-test is performed in the majority of patients with an fi ter some time are lacking. Especially the emerging eld of anti- ILD of unknown origin in order to exclude an underlying CTD [29]. synthetase autoantibodies is challenging for an evidence-based ANA-positivity at baseline visit may be up to 56% in patients with diagnostic approach. unclear ILD and performed ANA-test [30]. The probability to 82 T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 develop an overt CTD is significantly higher in initially ANA- in the absence of myositis [43]. Regarding the OJ and KS antibodies, positive patients compared to initially ANA-negative patients, and clear recommendations concerning the use of these antibodies in in younger patients compared to elderly patients [29,30]. A nega- patients with ILD are hardly possible because of the low frequency tive ANA-test, however, should be repeated at a future time, as the and the low level of evidence. test might turn positive with change of the clinical course and Interstitial lung disease is commonly found in patients with proceeding time [31]. Furthermore, even a negative ANA-test may myositis and especially those with positive anti-synthetase anti- justify further rheumatologic evaluation in case of a suspicious bodies [44e46]. The prevalence of ILD varies widely (40e80%) clinical picture. The range of newly diagnosed CTDs in patients among case series of patients with polymyoisitis (PM) and der- referred to a specialized clinic for evaluation of unclear ILD varies matomyositis (DM) [47e49] and is a significant cause of mortality widely (3,8e19%) in several studies [7,29,30]. in PM/DM [50]. Patients with new-onset and unclear ILD may or The most common types of subsequently diagnosed CTDs are may not display signs of myositis or skin disease right from the Rheumatoid Arthritis, inflammatory myositis and undifferentiated beginning, and the lack of correlation between muscle disease and connective tissue disease (UCTD) [7,30]. As mentioned above, ILDs pulmonary symptoms often leads to delayed diagnosis and a related to SSA and t-RNA-synthetase antibodies (Sjogren€ Syn- compromised therapeutic response [49,51]. A special entity of drome, Idiopathic Inflammatory Myositis, Anti-Synthetase Syn- myositis, often lacking muscle weakness, while other systemic drome), can be diagnosed despite ANA-negativity. Therefore, features, like lung disease predominate, is the anti-synthetase myositis may be underrecognized in the ILD-population, as levels of syndrome (ASS) [52]. Anti-t-RNA synthetase autoantibodies are CK and aldolase are often not markedly elevated, ANA-negativity is the hallmarks of the ASS, which is characterized by multiple organ possible and amyopathic forms with isolated lung disease do exist involvement, primarily ILD, and is often accompanied by myositis, [30]. non-erosive arthritis, Raynaud's phenomenon, “mechanic's hands”, skin rashes, sicca syndrome and constitutional symptoms, such as fever [53,54] (see Table 2). Not all patients with anti-synthetase 2.1.1. t-RNA synthetase (ARS-) antibodies: inflammatory myopathy antibodies or even those classified as having the anti-synthetase and ASS syndrome have all manifestations of this syndrome. The preva- Cytoplasmatic fluorescence is a typical pattern for anti-t-RNA lence of interstitial lung disease in ASS is reported as 65e90% in synthetase antibodies in IIF on HEp2 cells [28]. However, due to some studies [55e57]. The existence of interstitial lung disease and the scarcity of antigen in HEp-2 cells and the fixation procedures of absence of myositis is seen more often with some anti-synthetase these cells, the associated autoantibodies are not always detected antibodies than with others [56]. This is why different pheno- [28]. Cytoplasmatic fluorescence in the ANA-test may only be types within the anti-synthetase syndrome can be assumed [58]. present in less than 50% of patients with positive t-RNA synthetase As mentioned above, anti Jo-1 is the most common autoanti- antibodies [32]. body whereas autoantibodies other than Jo-1 are found altogether The t-RNA synthetase antibodies belong to a group of anti- in 1e7% of these patients. Among non-Jo-1 ASS, anti PL-7 and anti bodies, classified as myositis-specific. Myositis-specific antibodies PL-12 autoantibodies appear to be most common [59e61], can be found in approximately 20e40% of patients with idiopathic although reliable figures are missing. The prevalence of ILD in anti- inflammatory myositis [dermatomyositis (DM), polymyositis (PM), inclusion body myositis] [33e36]. Among the t-RNA synthetase antibodies, anti-Jo-1 antibody is the most common antibody Table 2 associated with the antisynthetase syndrome, since it is found in Anti-synthetase syndrome. approximately 20e30% of patients with PM and 2e10% of those Anti-synthetase syndrome (ASS) with DM [36e39]. In patients with myositis and ILD, anti-Jo-1 an- tibodies are detected in about 30e50% [39e41]. - positive t-RNA synthetase antibodies fi Other t-RNA synthetase antibodies, namely the anti-PL-7, anti- - clinical ndings: - interstitial lung disease - myositis PL-12, anti-OJ, anti-EJ and anti-KS might be detected, all together in - symmetrical inflammatory arthritis no more than 10% of patients with myositis [34,42]. The anti EJ - fever, weight loss antibody seems to be more frequently associated with cutaneous - Raynaud Phenomenon manifestations of DM, while the anti-PL 7 and anti-PL 12 seem to be - mechanic's hands more frequently associated with the presence of pulmonary fibrosis Features of the anti-synthetase syndrome: typical clinical findings.

Table 1 ANA fluorescence pattern and related auto-antibodies.

ANA Pattern Antibody CTD

Nuclear (most frequent) - homogeneous dsDNA SLE

- speckled U1-RNP MCTD Ro/SSA, La/SSB Sjogren€ Syndrome SmD SLE Mi-2 Myositis (DM) - centromeric CENP-B SSc - nucleolar RNA-Polymerase III SSc Topoisomerase I (SCL70) SSc Th/To SSc PM-SCL 75/100 Overlap Syndrome Cytoplasmatic (less frequent) - speckled t-RNA synthetase (Jo-1, PL-7, PL-12) ASS/Myositis - mitochondrial, ribo-somal, cytoskelatal, Golgi apparatus, lysosomes Mitotic (rare) mitotic spindle (tubulin), centrosomes (enolase), NuMA, CENP-F

ANA fluorescence pattern and related specific auto-antibodies, such as underlying CTD [1,28,94]. ASS: Anti-synthetase syndrome. MCTD: Mixed Connective Tissue Disease. SLE: Systemic Lupus Erythematodes. SSc: Systemic Sclerosis. T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 83

PL-7 positive patients varies from 77 to 100% [60,62]. Other 95.2% for PM/Scl-100.) In a patient with ILD of unknown origin, symptoms of ASS seem less common in patients with anti PL-7 anti- especially in the presence of a ANA test positivity with nucleolar synthetase syndrome [62]. In a study with patients having PL-12 pattern and a suspicious clinical picture, the detection of both PM/ antibodies, 90% had ILD, 90% were diagnosed for an underlying CTD Scl-75 and PM/Scl-100 suggests the diagnosis of overlap syndrome and 65% were primarily referred to a pneumologist [9]. vs. another defined major connective tissue disease [77e79].A Non-Jo-1 synthetase antibodies like anti PL-7 and anti PL-12 positive ANA-titre and distinct fluorescence pattern might give a might define a phenotype that is distinct from that of anti-Jo-1- first clue into this direction. However, as the clinical appearance positive patients and is characterized by a lower incidence of may be quite similar to t-RNA-positive ILD patients, the detection of myositis and a higher incidence of ILD [63]. These antibodies may PM/Scl also seems reasonable in case of ANA negativity. be more common among patients presenting with “idiopathic” interstitial pneumonia than formerly considered and should be 2.1.4. SSA/SSB e antibodies: Sjogren€ Syndrome checked in patients with features of antisynthetase syndrome Antibodies against Ro/SSA and La/SSB autoantigens are gener- despite a negative screen for anti-nuclear or anti-Jo-1 antibodies ally characterized by a nuclear staining pattern with speckled [60]. The response to immunosuppressive medications is generally, fluorescence in the ANA test [28]. but not universally favorable [63], underlining the therapeutic Serum containing autoantibodies directed against the Ro/SSA relevance. antigens may recognize one or both of two cellular proteins with molecular weights of approximately 52 and 60 kD (referred to as 2.1.2. Mi-2 and CADM-140 antibodies: inflammatory myopathy Ro52 and Ro60) [80,81]. Patients in whom the only autoantibodies Besides the t-RNA-synthetase antibodies, there are further an- present are anti-Ro antibodies may sometimes have a falsely tibodies described as myositis-specific, namely antibodies to signal negative ANA test using the traditional human epithelial cell line-2 recognition particle (SRP), and to the nuclear helicase Mi-2 [64]. (HEp-2) cell substrate, because Ro60 immunoreactivity may be lost The Mi-2 antibody, was first linked to dermatomyositis in 1985 [65] during denaturation [82]. The detection of Ro/SS-A by immuno- and has a diagnostic sensitivity and specificity of approximately fluorescence, on the other hand, may be missed in the presence of 4e18% and 98e100%, respectively. In a recent study by Cruellas and high titre ANAs. Furthermore, considering a detection sensitivity of colleagues, enrolling 127 patients with dermatomyositis, Mi-2 91%, a negative immunofluorescence result for Ro/SS-A does not positive patients were frequently affected by pulmonary involve- exclude the presence of this autoantibody [83]. ment [66]. Whether ILD may be the first and single sign of Mi-2 Although La/SSB has been shown to shuttle between the nucleus related dermatomyositis is not described in the currently pub- and cytoplasm, the protein is predominantly found in the nucleus lished literature. Screening for Mi-2 may be useful in suspicious of HEp-2 cells. Autoantibodies directed against La produce a patients affected by unclear ILD. speckled nuclear staining pattern and are correlated to internal There is, however, a subset of patients with idiopathic inflam- organ dysfunction (e.g. lung) [84]. matory myopathy that may have dissociated skin and skeletal Both SSA and SSB antibodies primarily identify patients with muscle involvement, and patients may have florid cutaneous Sjogrens€ Syndrome and Systemic Lupus Erythematodes (SLE). SSA manifestations of dermatomyositis for a prolonged period of time - antibodies may further be present in other autoimmune diseases, at least 2 years according to the definition [67,68] - without any including systemic sclerosis, idiopathic inflammatory myopathies evidence of underlying myositis. This condition has been termed and rheumatoid arthritis. In dermatomyositis, the presence of anti- amyopathic dermatomyositis (ADM or dermatomyositis sine Ro-52 antibody is correlated with pulmonary disorders [66].In myositis), and has been included in the clinical spectrum of idio- contrast to anti-Ro/SSA antibodies, anti-La/SSB antibodies are pathic inflammatory myopathy [69,70]. It has recently been shown relatively specific for the diagnosis of Sjogren€ Syndrome [85]. that ILD may be associated with and may antedate amyopathic Having a close look at patients with primary Sjogren€ Syndrome dermatomyositis [71]. Thus, particular attention should be paid to and interstitial lung disease, the underlying CT-pattern (UIP vs. cutaneous changes in patients with ILD, such as heliotrope rash, NSIP) seems to have no influence on disease-progression or prog- facial erythema and oedema, Gottron's papules, and periungueal nosis [86]. In general, pulmonary manifestations in Sjogren€ Syn- telangiectasia, especially if the histopathological pattern is NSIP drome have a slow progression and favorable prognosis, with the [72]. The recent identification of antibodies that may be specifically exception of primary pulmonary lymphoma and pulmonary hy- associated with amyopathic dermatomyositis (CADM-140 anti- pertension [87]. Furthermore, anti-Ro52/SSA antibodies may occur bodies, representing clinically amyopathic dermatomyositis, auto- together with antisynthetase antibodies (Jo-1, PL-7, PL-12) and this antigen of 140 kDa) might aid an earlier diagnosis of this condition combination has been associated with particularly severe ILD [73]. Patients with positive CADM-140 antibodies (also known as [88,89]. Concerning disease-onset, ILD has been shown to be the MDA-5 antibodies: melanoma differentiation-associated gene 5) first and single presentation of patients finally diagnosed with have been shown to display a rapidly progressive ILD, compared to primary Sjogren€ Syndrome. In this case minor salivary gland biopsy anti-t-RNA synthetase positive myositis patients [74]. Furthermore, may allow for a more precise diagnosis, besides serological testing, CADM-140/MDA-5 levels have been shown to indicate response to as it is possible that not only ANA and RF are negative but also SS-A treatment and disease activity in patients with DM and rapidly and SS-B [90]. For these reasons, excluding Sjogren€ Syndrome in progressive ILD [75,76]. patients with unclear ILD is not trivial and relies on a thorough medical history, proper physical examination, and comprehensive 2.1.3. PM/Scl-75/100 antibodies: overlap syndrome serological testing, including both ANA and SS-A/SS-B. Antibodies directed against PM/Scl are a heterogeneous family of molecules, the most clinically significative of which are PM/Scl- 2.1.5. Topoisomerase I (topo I/SCL-70), RNA polymerase III, Th/To 75 and PM/Scl-100. These antibodies give a nucleolar pattern of and CENP-B e antibodies: systemic sclerosis immunofluorescence at IIF. Both PM/Scl-75 and PM/Scl-100 iden- Systemic sclerosis (SSc) is a systemic autoimmune disease of tify overlap syndromes of Systemic sclerosis and Polymyositis, and unknown cause characterized by cutaneous and visceral fibrosis, give some information about clinical subsets and prognostic details. microvascular obliteration and highly specific serum autoanti- Their presence has been described as a risk factor for ILD with a bodies to nuclear autoantigens [91]. These auto-antibodies may be high level of specificity for ILD (up to 94.8% for PM/Scl-75 and up to directed against the centromere Protein B (ACA/anti-CENP-B), 84 T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 against topoisomerase I (anti-topo I/SCL-70), against RNA poly- SSc patients [108] and most of these patients have NSIP as under- merase III or against proteins of the RNase MRP and RNase P lying pattern [109]. Detecting SSc-ILD is important in any case, as ribonucleoprotein complex (Th/To) and are important diagnostic interstitial lung disease is now the most frequent cause of death in features of systemic sclerosis [91,92]. Altogether, 90% of SSc pa- systemic sclerosis, having supplanted renal crisis in that regard tients have a positive ANA-test [93] and the four just mentioned [93]. specific antibody-tests account for 75e80% of ANA positivity in In contrast to the formerly mentioned t-RNA-synthetase anti- Systemic Sclerosis [94]. The mere pattern of ANA fluorescence may bodies and SSA/SSB antibodies it is unlikely to find SSc-specific even distinguish certain specific antibodies: CENP-B antibodies auto-antibodies in the presence of a negative ANA-test. Intersti- display a distinct centromere pattern [94], whereas anti topo-I, anti tial lung disease is a complication observed relatively late in the RNA-polymerase III and anti Th/To are characterized by a nucleolar course of the disease and hardly as first or lone manifestation fluorescent pattern in the ANA test [94]. The frequency of these [110,111]. Screening for anti-topo-I, Th/To, RNA-polymearse III and antibodies is variable (ACA: 26%, anti topo-I: 28%, anti RNA- CENP-B therefore may be performed just in case of a positive ANA- polymerase III: 10%, and anti Th/To: 3%) and they are associated test and typical clinical signs and symptoms of systemic sclerosis. with distinct clinical pictures [94]. Furthermore, as SSc-specific auto-antibodies are almost invariably In clinical terms, a limited cutaneous subset (lcSSc) can be present in high titers extremely early in the disease process [112], distinguished from a diffuse cutaneous disease (dcSSc). In patients they may not necessarily be followed-up, once they have been with limited cutaneous SSc, skin sclerosis is restricted to the hands, screened. the distal forearm, such as the face and neck. These patients generally have prominent vascular manifestations, including severe 2.1.6. Sm and ds-DNA antibodies: systemic lupus erythematodes Raynaud phenomenon and cutaneous telangiectasia. Many patients In patients with Systemic Lupus Erythematodes, the ANA test is with lcSSc have manifestations of the CREST syndrome (Calcinosis virtually always positive [113]. With respect to the various clinical cutis, Raynaud phenomenon, Esophageal dysmotility, Scle- presentations, there are two autoantibodies that are disease- rodactyly, and Telangiectasia). Sclerotic skin on the chest, abdomen, specific and may therefore ease the diagnostic procedure: ds-DNA or upper arms and shoulders is indicative of diffuse cutaneous SSc and Sm-antibodies. Anti-ds DNA antibodies are specific for SLE, and patients are more likely to have significant internal organ making the presence of these antibodies very useful for dis- damage due to ischemic injury, compared to limited cutaneous SSc. tinguishing patients with SLE from patients with other systemic The prevalence of systemic sclerosis related ILD appears to be autoimmune diseases and are rarely found in patients with other higher in dcSSC than lcSSC [95]. However, autoantibody status connective tissue disorders [114]. Antibodies directed against Small seems to be a more useful predictor of organ involvement, Nuclear Ribonucleoprotein Core Proteins (anti-Sm antibodies) are including the presence of lung disease, than the pattern of skin insensitive but also highly specific markers for SLE [115]. involvement [95]. Sm-Antibodies are commonly characterized by a speckled Anti-centromere antibodies (ACA) are found in 20e30% of SSc fluorescence in the ANA-test. There is some evidence in the liter- patients and CENP-B is the major autoantigen recognized by >95% ature that ds-DNA antibodies are solely positive with high titres in of ACA-positive sera [94]. In clinical terms, CENP-B antibodies are the ANA-test (1:640) [116e118]. Antibodies against dsDNA usu- strongly associated with the CREST syndrome [96]. This CENP-B ally display a homogeneous ANA-pattern [116,119]. positive phenotype is frequently and predominantly associated Pulmonary problems are common in systemic lupus eryth- with pulmonary hypertension [97] and a low prevalence or even ematodes, and may be the presenting feature of this multi-system absence of SSc-ILD [98]. disease. The clinical spectrum ranges from mild, self-limited, Patients with positive anti-topoisomerase-I antibodies on the pleuritic chest pain to fulminant and rapidly fatal diffuse pulmo- other hand are frequently affected by lung fibrosis [99] and appear nary hemorrhage [120]. The most prevalent respiratory manifes- to be protected against isolated pulmonary arterial hypertension tations are pleuritis and pulmonary infections [121]. Interstitial [100]. Topoisomerase I antibodies (also known as SCL-70/anti- lung disease (ILD) is a minor problem and the clinical progression scleroderma-70 antibodies) are present in 20e30% of SSc patients, appears to be slow or may even stabilize with time [122]. most often with diffuse cutaneous SSc. SSc-ILD is most prevalent in Given the above mentioned facts, a patient presenting with these topoisomerase-positive patients with over 85% developing unclear ILD as first and lone manifestation of SLE and additionally a pulmonary fibrosis [101]. Interestingly, topoisomerase titres seem negative ANA test is hard to imagine. In order to avoid unnecessary to correlate with disease severity and activity, both in SSc and SSc- serological testing, it might be reasonable to explicitly search for ILD [102,103]. SLE-specific antibodies in case of (1) a (high) positive ANA-test and Like anti-topoisomerase-I-positive patients, those with positive (2) suspicious clinical signs and symptoms and a suitable medical RNA-polymerase-III antibodies also cluster with a diffuse form of history. SSc and restrictive pulmonary involvement [104,92]. However, the clinical condition more frequently influencing the course of these 2.1.7. U1-RNP antibodies: mixed connective tissue disease (MCTD) patients is renal crisis [105]. Anti-U1-RNP antibodies are characterized by a speckled nuclear Th/To antibodies only account for 3% of SSc-specific autoanti- pattern in the ANA-test [28]. Patients with positive U1-RNP and bodies. In one small study, patients, primarily diagnosed as IPF but features of more than one specific CTD are described as having with positive and nucleolar-staining ANA, were subsequently mixed connective tissue disease (MCTD), which is a specific CTD tested for Th/To-antibodies and showed positive results 50% [106]. itself [123]. MCTD was first described in 1972 as a distinct overlap The role of this rare antibody, however, remains unclear. characterized by features of SSc, SLE and PM/DM, with respiratory The general prevalence of Systemic Sclerosis ranges from 50 to involvement occurring in about 80% of patients [123]. Such patients 300/Million [107] and the spectrum of SSc-related ILD ranges from are different from those, who do not fulfill the diagnostic criteria for limited and often non-progressive lung involvement, to severe any specific CTD but display features, including serologic abnor- disease which may progress to respiratory failure and death [93]. malities and systemic extrapulmonary manifestations, that are Raynaud's phenomenon might be an important first sign of the merely reminiscent of an underlying autoimmune disease [124]. disease, as it is present in over 90% of all SSc-patients. Although The latter group of patients can be described as having undiffer- reliable figures are missing, ILD appears to be evident in 55e60% of entiated CTD (UCTD), or in case of predominant ILD: IPAF [18]. T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 85

While a large number of patients with MCTD have pulmonary ascertain whether the combination of anti-CCP and rheumatoid involvement, most have relatively mild disease, and many are factor provides additional benefit over anti-CCP alone in diagnosing asymptomatic [125]. Severe lung fibrosis is associated with rheumatoid arthritis [137]. increased mortality [126]. The most severe clinical manifestation, The prevalence of rheumatoid arthritis associated ILD (RA-ILD) however, is pulmonary hypertension which contributes to prema- varies from 1 to 40%, depending on the definition for ILD [138].A ture death in patients who have MCTD [127]. population-based study estimated a prevalence of about 1 in 10 ANA-testing appears to be positive in virtually all patients with patients with RA [139]. While RA occurs more commonly in females positive U1-RNP antibodies [128]. Therefore it might be eligible to (female to male ratio 3:1), RA-ILD is more frequent in males. The assess U1-RNP antibodies in a patient, presenting with ILD of un- presence of ILD is associated with a significantly shortened survival clear origin and no signs or symptoms of an underlying CTD just in in patients with rheumatoid arthritis, compared to those patients case of a positive ANA-test. without ILD, as lung disease is the second most common cause of death for RA patients [138,140]. The manifestation of an ILD can 2.2. ANCA: ANCA-associated vasculitis precede the RA diagnosis in some cases [140]. Taking into account that rheumatoid arthritis is the most common of all CTDs, it is Antibodies directed against neutrophil cytoplasmic antigens reasonable to search for CCP antibodies and RF in patients pre- (ANCA) are associated with different forms of vasculitis. Two types senting with an ILD of unknown origin, mainly if the patients of ANCA assays are currently in wide use: Indirect immunofluo- presents articular symptoms. However, seronegative rheumatoid rescence assay, using alcohol fixed buffy coat leukocytes and arthritis is also possible and a negative result of RF and CCP does not Enzyme-linked immunosorbent assay (ELISA), using purified spe- exclude an underlying RA. Rechecking RF and CCP in the clinical cific antigens. Of these two techniques, the immunofluorescence course of an unclear ILD might be reasonable as the serotype might assay is more sensitive and the ELISA more specific. The optimal change over time. approach to clinical testing for ANCA is therefore to screen with immunofluorescence assays, if available, and to confirm all positive results with ELISAs directed against the vasculitis-specific target 3. Connective tissue disease-related ILD: the pulmonologists antigens [129,130]. point of view The two main patterns of ANCA staining, recognised by indirect immunofluorescence microscopy, are cytoplamatic (c-ANCA) and 3.1. Epidemiology perinuclear (p-ANCA). Both target antigens are associated with different clinical syndromes [131]. Perinuclear p-ANCA is most To precisely estimate the incidence and prevalence rates of ILD is often and almost uniquely associated with syndromes character- for several reasons quite difficult. On one hand, before the ized by small vessel vasculitis, such as microscopic poliangiitis Consensus Guidelines were enacted in 2002, there was a lack of (MPA) [132]. international standard that has resulted in variable and confusing ILD is known to be an early lesion of MPA in some cases [133] criteria and nomenclature. On the other hand, despite the guide- and positive ANCA-titres in patients presenting with an ILD of lines, IIP remains a diagnosis of exclusion requiring extensive unknown origin might be the first sign of ANCA-associated vascu- investigation, which is seldom possible [141]. Furthermore, many of litis [134]. In a number of case reports, retrospective and case- the available data are taken from registries or hospital clinics and control studies it is reported, that the initial diagnosis of an idio- therefore suffer from selection bias [142]. On a population-based pathic interstitial pneumonia had to be revised during the clinical approach, there are two important studies. course on behalf of a newly diagnosed MPA [133e135]. The studies The most important registry study was undertaken in Bernalillo by Nishkantha (2011) and Foulon (2008) contain two important County, New Mexico, USA. All diffuse interstitial lung diseases messages. First, virtually all patients displaying a positive ANCA test together were found to have a prevalence of 60-80/100.000 and an in the clinical course show a perinuclear pattern (p-ANCA) in IIF, incidence rate around 30/100.000. Sarcoidosis and idiopathic pul- with specifity to MPO in EIA, finally leading to a diagnosis of monary fibrosis were the two most frequent diseases, accounting microscopic polyangiitis. Second, ANCA assessment in many cases together for more than 50% of all cases, followed by ILD related to was not available at the first manifestation of ILD, which led to a connective tissue disease and to immunologic lung disease [143]. delayed diagnosis. The prevalence of ILD in males (80.9/100,000) was in general 20% As clinical, radiologic and bronchoalveolar lavage data are higher, than in females (67.2/100,000), and the prevalence of pre- similar between ANCA-positive and ANCA-negative patients at clinical or undiagnosed ILD among all deaths in the New Mexico time of diagnosis [135], a systemical screening for ANCA in patients cohort was found to be 1.8%. with unclear interstitial lung disease appears reasonable. Screening In a Danish nationwide population-based study the overall for p-ANCA may be the first step because of the high sensitivity of incidence rate of ILD was around 31 per 100.000 person-years in IIF. However, p-ANCA can also be positive in other medical condi- the time period of 2001e2005 [144]. In general, these results from tions and a positive result might be confirmed by screening for Kornum et al. in Denmark accord with those from Coultas et al. in MPO-specifity, indicating an underlying microscopic polyangiitis. New Mexico, despite the use of different case ascertainment Nontheless, about 25% of patients diagnosed as having MPA are methods and patients' exposure to different environmental factors ANCA-negative and ANCA status may change over time [136].A [144]. negative ANCA assay at initial screening therefore might be Very little data from population-based registries are available rechecked in the clinical course. from other countries. The few published reports suggest interna- tional differences, concerning the prevalence of ILD [141]. The 2.3. RF and CCP-antibodies: rheumatoid arthritis inconsistency of estimated incidence rates may stem from differ- ences in sampling procedures and diagnostic criteria and mea- CCP-antibodies have a sensitivity of 57% and a specifity of 96% in surement bias arising from variation in coding practices and case detecting patients with rheumatoid arthritis (RA). Compared to ascertainment [144]. The overall prevalence of connective tissue rheumatoid factor, CCP-antibodies have greater specifity (96% vs. disease-related ILD among all patients with ILD is estimated to be 86%), with similar sensitivity. There is only insufficient evidence to 7.1%/11,6% (male/female) [145]. 86 T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92

3.2. Histopathology Table 3 Connective tissue disease: clinical signs and symptoms.

Connective tissue diseases are systemic disorders characterized Important clinical signs and symptoms by autoimmunity and autoimmune-mediated organ damage. The Specific clinical features lungs are frequently involved and diffuse parenchymal lung injury - Distal digital fissuring (i.e. “mechanic hands”) patterns, characterized by varying degrees of inflammation and - Distal digital tip ulceration fibrosis, are common manifestations of CTD [8]. -Imflammatory arthritis or polyarthicular morning stiffness In patients with connective tissue disease, NSIP is the most - Palmar and face teleangiectasia - Raynaud's phenomenon common histological pattern of CTD-ILD [147]. Especially in pa- - Unexplained digital oedema tients diagnosed as idiopathic NSIP (iNSIP), the development of - Unexplained fixed rash on the digital extensor surfaces (Gottron's sign) connective tissue disease, as well as the development of autoim- Non-specific clinical features mune thyroiditis has to be considered within the clinical course and - arthralgia/multiple joint swelling - unintentional weight loss might occur in almost 50% of the patients primarily diagnosed iNSIP - recurrent unexplained fever (11% connective tissue disease, 22% undifferentiated connective - dry mouth or dry eyes (sicca features) tissue disease, 26% autoimmune thyroiditis) [148]. Lung injury - dysphagia often arises within the first two years after disease onset [148] or - oral ulceration fl may be the first manifestation [8], even several months before - gastroesophageal re ux - photosensitivity development of a typical CTD [149]. Therefore, a link between the - non androgenic alopecia clinical entity of NSIP and autoimmune disorders is suspected and - proximal muscle weakness idiopathic NSIP might represent an early lung manifestation of an Important clinical signs and symptoms, indicative of an underlying CTD in patients, autoimmune disease [15,148]. primarily presenting to the pulmonologist for the evaluation of an unclear ILD [18,148,150]. 3.3. Prognosis

As mentioned above, NSIP is the histological pattern, seen most Furthermore, basic laboratory data should be obtained, fl often in CTDs - except for RA, characterized by a higher frequency of including at least complete blood count, indices of in ammation, UIP. Compared to the idiopathic variety of UIP in IPF, UIP pattern in liver and kidney function, creatine kinase (CK), lactate dehydroge- CTD-related ILD is associated with a significantly better survival nase (LDH), myoglobin, aldolase, C3 and C4 complement factors, [150]. Patients not meeting the criteria for a connective tissue such as serum protein electrophoresis and urine analysis. disease but having clinical signs and symptoms suggestive of a CTD, As listed in the recent ERS/ATS statement [18], a huge number of suitable serologic tests and/or a suitable morphological pattern serologic auto-antobodies represents the serologic domain of fi (HRCT, Histopathology, multicompartment involvement) may be classi cation criteria for IPAF, namely ANA, RF, anti-CCP, anti-ds supposed to have IPAF [18]. The recent consensus definition of this DNA, anti-Ro (SSA), anti-La (SSB), anti-ribonucleoprotein, anti- entity surely will raise the awareness within the medical commu- Smith, anti-topoisomerase (SCL-70), anti-tRNA synthetase, anti nity, but conclusions with respect to prognosis cannot be drawn yet PM-Scl and anti-MDA. Some of these serologic tests are also listed [17]. in the ERS/ATS/JRS/ALAT statement on the diagnosis of IPF [19], Rheumatoid Arthritis is by far the most common CTD and although recommendations beyond ANA, RF and anti-CCP are clinically significant RA-ILD occurs in about 10% of the Rheumatoid vague and irrespective of cost. The predictive value of positive auto- Arthritis population. It has been clearly shown that the presence of antibody results in the diagnostic approach of unclear ILD remains fi e RA-ILD is associated with shortened survival and more severe un- a matter of scienti c debate and somehow elusive. Positive fi derlying disease [139,151]. Whereas overall mortality rates for RA serologic results may be unspeci c laboratory abnormalities, fl have fallen, those associated with RA-ILD have increased signifi- markers of a distinct underlying auto-immune disease, or re ect an cantly in older age groups [139]. Better strategies for the treatment ongoing immunologic process that can be described phenomeno- fi of ILD are supposed to lower mortality among individuals with logically - without the chance of proper etiologic classi cation, Rheumatoid Arthritis [140]. according to current knowledge. Given these considerations and Concerning the field of t-RNA synthetase antibodies and bearing in mind that auto-antibody testing is rather expensive and myositis, variable clinical courses can be observed. Resolution of not easily available all around the globe, this review focuses on two pulmonary disorders can be detected, as well as deterioration. major goals: Mortality rates differ considerably among patients with ILD dete- rioration and those without (47.1% vs. 3.3%) [152]. Whether more 1. Evaluating the predictive value of single auto-antibody tests in aggressive therapy in PM/DM patients presenting with ILD really the context of ILD. leads to a better outcome is still an open question. 2. Reaching interdisciplinary consensus on a stepwise approach for autoantibody testing in ILD, based on the currently available fi 3.4. Diagnostic algorithm for serologic autoimmune testing e why? scienti c knowledge, the clinical expertise of dedicated pul- monologists and rheumatologists and also on economic The main challenge for pulmonologists approaching a patient considerations. with HRCT scan evidence of an ILD is to discriminate whether the ILD is idiopathic or secondary to a known cause. As mentioned So - when to perform serology for autoimmunity? And which above, since CTD represents a possible cause of ILD, and ILD may be serology should be tested in which order? The answer to these the first manifestation of some systemic autoimmune disease questions depends on the clinical presentation, such as the HRCT- which can manifest later, an accurate clinical history together with pattern and histopathology (if available). According to our serology must be evaluated. opinion, the basic set of laboratory tests for excluding an underlying The main clinical systemic signs and symptoms which should be CTD in the patient presenting without any signs or symptoms asked and detected in every patient presenting with an ILD are reminiscent of an underlying CTD but with a highly probable listed in Table 3. diagnosis of an idiopathic interstitial pneumonia should meet T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 87 the following criteria: with high ANA titres. Nonetheless, the ANA-test has its limitations, Given the ANA-test as generally accepted screening test, a more as some specific autoantibodies (tRNA-synthetase, Ro/SSA) are not comprehensive basic laboratory testing set should include those readily detected. Concerning age-related differences in the ANA- antibody tests that might produce positive results even in case of titres, data of elderly control subjects are sparse. Different cut- ANA-negativity. Furthermore, basic laboratory testing in these pa- offs for ANA-positivity are not recommended, but results should tients should also include those antibody tests that identify CTDs, be interpreted with caution. frequently accompanied and preceded by ILD as their first and lone The emerging field of anti-synthetase antibodies and anti- manifestation. The chosen set of laboratory tests should be able to synthetase syndrome is challenging. As there are frequent detect frequent errors in the diagnostic work-up. The exclusion of screening failures in the ANA-test, we recommend including the underlying CTD in order to diagnose an idiopathic interstitial most common one for myositis e anti Jo-1 e in routine screening. pneumonia firstly is the job of a pulmonologist e any positive re- However, if there is reasonable suspicion for myositis, anti- sults in serological evaluation, such as any clinical signs and synthetase syndrome or overlap syndrome, further serological symptoms indicative of an underlying CTD should, however, lead to testing can be useful, even in case of a negative ANA-test. By current a multidisciplinary approach, together with an experienced knowledge PL-7 and PL-12 appear to be those antigens, most rheumatologist. frequently associated with ILD, and should be part of an advanced Given the case that medical history, clinical symptoms, HRCT laboratory work-up. The assessment of other antibodies like OJ, EJ, pattern, such as histopathology and the overall impression don't KS, Mi-2 and PM/SCL-75/100 depend on the individual circum- connect to a conclusive picture e and might now be called IPAF stances. Idiopathic inflammatory myopathy with ILD as organ according to 2015 ATS/ERS research statement [18] e a more so- complication might be an underrecognised condition and checking phisticated serological testing might be necessary. Especially in especially for the most frequent t-RNA synthetase antibodies might middle-aged women with a new diagnosis of ILD and NSIP pattern, be rewarding. a more comprehensive serological testing might be reasonable, Ro/SSA and La/SSB antibodies should be included in the routine since symptoms might be sometimes underestimated, or might be testing in our opinion, because of relatively frequent screening not clear enough for a specific diagnosis. The aim of this advanced failures in the ANA test, especially concerning SSA antibodies. laboratory testing is to search for rare cases, rather than excluding Positive results might point to an underlying Sjogren€ Syndrome, the most probable options. which can be an attendant phenomenon of other CTDs, especially Another important question is, whether an autoimmune SLE, or can exist as a single specific entity of a connective tissue assessment should be performed during the follow-up of patients disease. with an existing diagnosis of an idiopathic ILD or IPAF. In our Rheumatoid Arthritis is the most common CTD, often associated opinion, the answer is positive, especially in patients with NSIP, with ILD. The occurrence of an ILD can precede definite diagnosis of since evidence demonstrates a later manifestation of a CTD/UCTD rheumatoid arthritis. Therefore RF and anti-CCP antibody screening in a relevant percentage of cases [148,153]. We suggest the same should be included in routine screening laboratory testing. In serologic testing both at baseline and at follow up (e.g. once a year) microscopic polyangiitis (MPA), ILD also can be the first apparent or whenever the clinical status seems to change. symptom, which makes a routine screening for ANCA, especially p- Although autoimmune thyroiditis does not represent a systemic ANCA reasonable and recommendable. autoimmune disease, but an organ-specific autoimmune disease, it In case of a positive ANA-test and in accordance with the clinical represents a late autoimmune manifestation in patients with picture, medical history and other diagnostic results, advanced idiopathic NSIP [148], and specific serology might be reasonable as laboratory testing for specific autoantibodies should be considered. well [TSH, anti-thyroglobulin (anti-Tg), and anti-thyroid peroxidase Systemic Sclerosis and CREST-Syndrome, Systemic Lupus Eryth- (anti-TPO) antibodies]. ematodes and Mixed connective tissue disease are often accom- panied by clinical, radiologic or other features that might call the 4. Suggestion for a diagnostic algorithm: serological physicians attention into a certain direction. For this reason, evaluation in patients with ILD screening for Scl-70, Th/To, RNA-Polymerase III and CENP-B (SSc/ CREST), as well as Sm and dsDNA (SLE) and for U1-RNP (MCTD) A pragmatic and clinically useful diagnostic algorithm must might be part of a more sophisticated serological approach in order be able to take several requirements into account: it should be to search for rare and neglected cases. evidence-based, it should be doable in every-day clinical routine Apart from the above mentioned recommendations for sero- and it should be economical. By focusing on a rational set of tests, logical testing, the importance of medical history and physical ex- unnecessary laboratory testing can be avoided and health care amination, such as careful performance and interpretation of costs can be reduced. According to the presented data in the text radiological images cannot be stressed enough. Even a compre- and after careful reviewing the available literature, we suggest a hensive routine laboratory data set might provide first important diagnostic algorithm for pulmonologists dealing with ILD- insights. Screening for viral hepatitis and HIV might also be useful patients. Fig. 1 depicts the consensus for antibody testing that in some cases and should be considered. was reached amongst authors. We recommend that the basic The current algorithm aims to combine simplicity and practi- laboratory screening should include tests for autoantibodies cality for the work up of pulmonary involvement in ILD. Obviously against Ro/SSA, La/SSB, Jo-1 and CCP, such as an ANA, ANCA and this consensus approach leaves room for local adaption of the RF test. diagnostic strategy depending on the availability of diagnostic ca- Screening for antinuclear antibodies is generally accepted and a pacity and cost. It is our hope, however, that the rational and basic diagnostic tool for screening connective tissue diseases with stepwise approach of serological testing for ILD will ultimately save high sensitivity and poor specifity. The pattern of immunofluores- unnecessary expenses associated with general laboratory cence can provide a first clue which specific antibody-test might screening. Finally a broader consensus on the strategy for laboratory give further insight into the exact diagnosis. The probability to testing in ILD in general might also improve the detection level of detect an underlying connective tissue disease is higher in patients these relatively rare diseases and this will ultimately improve 88 T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92

Fig. 1. Suggested diagnostic algorithm for the serological approach to the patient presenting with unclear ILD. In the presence of any suspicious clinical signs or symptoms, reflective of an underlying CTD, early consultation of an experienced rheumatologist is recommended, even in the absence of any positive laboratory results. ASS: Anti-synthetase syndrome. CREST (syndrome): Calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and teleangiectasia. MCTD: Mixed Connective Tissue Disease. MPA: Microscopic Polyangiitis. RA: Rheumatoid Arthritis. SLE: Systemic Lupus Erythematodes. management and care of patients suffering from these complex CREST (syndrome) Calcinosis, Raynaud's phenomenon, disorders. Esophageal dysmotility, Sclerodactyly, and Teleangiectasia Acknowledgment DPLD Diffuse Parenchymal Lung Disease ELISA Enzyme Linked Immuno Assay TB, MR, FG, MC and KFR performed the literature search, EIA Enzyme Immune Assay designed the figures, contributed to the manuscript, and approved ENA Extractable Nuclear Antigens its final version. ILD Interstitial Lung Disease IIF Indirect Immunofluorescence LDH Lactate Dehydrogenase Glossary LIA Line Immunoassay MCTD Mixed Connective Tissue Disease MPA Microscopic Polyangiitis Abbreviations and eponyms SLE Systemic Lupus Erythematodes AAV ANCA-Associated Vasculitis SSc Systemic Sclerosis ASS Anti-Synthetase Syndrome dcSSc diffuse cutaneous Systemic Sclerosis C3/C4 Complement protein 3/4 lcSSc limited cutaneous Systemic Sclerosis CK Creatine Kinase UCTD Undifferentiated Connective Tissue Disease CTD Connective Tissue Disease T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 89

Antibodies and Antibody-Tests disease: a focused review, J. Intensive Care Med. 30 (7) (2015 Oct) 392e400. ANA Anti-Nuclear Antibodies [9] M. Kalluri, S.A. Sahn, C.V. Oddis, S.L. Gharib, L. Christopher-Stine, S.K. Danoff, L. Casciola-Rosen, G. Hong, P.F. Dellaripa, K.B. Highland, Clinical profile of ANCA Anti-Neutrophil Cytoplasmic Antibodies anti-PL-12 autoantibody Cohort study and review of the literature, Chest 135 MPO-ANCA Myeloperoxidase Anti-Neutrophil (6) (2009 Jun) 1550e1556. Cytoplasmic Antibodies [10] G.E. Tzelepis, S.P. Toya, H.M. Moutsopoulos, Occult connective tissue diseases mimicking idiopathic interstitial pneumonias, Eur. Respir. J. 31 (2008) CADM-140 Anti - Clinically Amyopathic DM polypeptide 11e20. Antibody (140 kd) aka. MDA-5 [11] T. Suda, M. Kono, Y. Nakamura, N. Enomoto, Y. Kaida, T. Fujisawa, CENP-B/-F Centromere Protein B/F antibody S. Imokawa, K. Yasuda, H. Hashizume, K. Yokomura, M. Toyoshima, N. Koshimizu, H. Suganuma, T. Shirai, D. Hashimoto, N. Inui, T.V. Colby, CCP Cyclic Citrullinated Peptide antibody K. Chida, Distinct prognosis of idiopathic nonspecific interstitial pneumonia dsDNA double strand Deoxyribonucleopreotein (NSIP) fulfilling criteria for undifferentiated connective tissue disease antibody (UCTD), Respir. Med. 104 (10) (2010 Oct) 1527e1534. [12] C.J. Ryerson, E. Vittinghoff, B. Ley, J.S. Lee, J.J. Mooney, K.D. Jones, B.M. Elicker, EJ Glycyl antibody P.J. Wolters, L.L. Koth, T.E. King Jr., H.R. Collard, Predicting survival across Jo-1 Histidyl antibody chronic interstitial lung disease: the ILD-GAP model, Chest 145 (4) (2014 KS Asparaginyl antibody Apr) 723e728. Mi-2 Nuclesome remodeling-deacetylase (NuRD) [13] J.H. Park, D.S. Kim, I.N. Park, S.J. Jang, M. Kitaichi, A.G. Nicholson, T.V. Colby, Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen complex e antibody vascular disease-related subtypes, Am. J. Respir. Crit. Care Med. 175 (7) (2007 NuMA Nuclear matrix protein Apr 1) 705e711. OJ Isoleucyl antibody [14] T.J. Corte, S.J. Copley, S.R. Desai, C.J. Zappala, D.M. Hansell, A.G. Nicholson, T.V. Colby, E. Renzoni, T.M. Maher, A.U. Wells, Significance of connective PL-7 Threonyl antibody tissue disease features in idiopathic interstitial pneumonia, Eur. Respir. J. 39 PL-12 Alanyl antibody (3) (2012 Mar) 661e668. PM/Scl-75/100 Polymyositis-scleroderma overlap [15] B.W. Kinder, H.R. Collard, L. Koth, D.I. Daikh, P.J. Wolters, B. Elicker, K.D. Jones, T.E. King Jr., Idiopathic nonspecific interstitial pneumonia: lung syndrome-related antibody (75/100 kDa), manifestation of undifferentiated connective tissue disease? Am. J. Respir. human exosome complex Crit. Care Med. 176 (7) (2007 Oct 1) 691e697. RF Rheumatoid Factor [16] A. Fischer, S.G. West, J.J. Swigris, K.K. Brown, R.M. du Bois, Connective tissue disease-associated interstitial lung disease: a call for clarification, Chest 138 RNA-Polymerase III n/a (2) (2010 Aug) 251e256. SSA Sjogren Syndrome-A antibody (Ro [17] R. Vij, I. Noth, M.E. Strek, Autoimmune-featured interstitial lung disease: a ribonucleoprotein: Ro52/Ro60) distinct entity, Chest 140 (5) (2011 Nov) 1292e1299. [18] A. Fischer, K.M. Antoniou, K.K. Brown, J. Cadranel, T.J. Corte, R.M. du Bois, SSB Sjogren Syndrome-B antibody (La J.S. Lee, K.O. Leslie, D.A. Lynch, E.L. Matteson, M. Mosca, I. Noth, L. Richeldi, ribonucleoprotein domain family) M.E. Strek, J.J. Swigris, A.U. Wells, S.G. West, H.R. Collard, V. Cottin, “ERS/ATS Sm Smith antibody (Small Nuclear task force on undifferentiated forms of CTD-ILD”.Anofficial European res- Ribonucleoprotein Core Proteins) piratory society/American thoracic society research statement: interstitial pneumonia with autoimmune features, Eur. Respir. J. 46 (4) (2015 Oct) Th/To Proteins of the RNase MRP and RNase P 976e987. Ribonucleoprotein Complex [19] G. Raghu, H.R. Collard, J.J. Egan, F.J. Martinez, J. Behr, K.K. Brown, T.V. Colby, Topo-I Topoisomerase I (aka. SCL-70: scleroderma J.F. Cordier, K.R. Flaherty, J.A. Lasky, D.A. Lynch, J.H. Ryu, J.J. Swigris, A.U. Wells, J. Ancochea, D. Bouros, C. Carvalho, U. Costabel, M. Ebina, 70 antibody) D.M. Hansell, T. Johkoh, D.S. Kim, T.E. King Jr., Y. Kondoh, J. Myers, U1 RNP U1-Ribonucleoprotein antibody N.L. Müller, A.G. Nicholson, L. Richeldi, M. Selman, R.F. Dudden, B.S. Griss, S.L. Protzko, H.J. Schünemann, ATS/ERS/JRS/ALAT committee on idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pul- Conflict of interest monary fibrosis: evidence-based guidelines for diagnosis and management, Am. J. Respir. Crit. Care Med. 183 (6) (2011 Mar 15) 788e824. [20] C. Bonaguri, A. Melegari, A. Ballabio, M. Parmeggiani, A. Russo, L. Battistelli, The authors declare that they have no competing interests. R. Aloe, T. Trenti, G. Lippi, Italian multicentre study for application of a diagnostic algorithm in autoantibody testing for autoimmune rheumatic disease: conclusive results, Autoimmun. Rev. 11 (1) (2011 Nov) 1e5. References [21] A. Man, K. Shojania, C. Phoon, J. Pal, M.H. de Badyn, D. Pi, D. Lacaille, An evaluation of autoimmune antibody testing patterns in a Canadian health [1] J.H. Ryu, E.J. Olson, D.E. Midthun, S.J. Swensen, Diagnostic approach to the region and an evaluation of a laboratory algorithm aimed at reducing un- patient with diffuse lung disease, Mayo Clin. Proc. 77 (2002) 1221. necessary testing, Clin. Rheumatol. 32 (5) (2013 May) 601e608. [2] H.R. Collard, T.E. King Jr., Demystifying idiopathic interstitial pneumonia, [22] J.J. Solomon, S. Chartrand, A. Fischer, Current approach to connective tissue Arch. Intern Med. 163 (2003) 17. disease-associated interstitial lung disease, Curr. Opin. Pulm. Med. 20 (5) [3] T.E. King Jr., Clinical advances in the diagnosis and therapy of the interstitial (2014 Sep) 449e456. € lung diseases, Am. J. Respir. Crit. Care Med. 172 (2005) 268. [23] J. Voigt, C. Krause, E. Rohwader, S. Saschenbrecker, M. Hahn, M. Danckwardt, [4] T. Bryson, B. Sundaram, D. Khanna, E.A. Kazerooni, Connective tissue disease- C. Feirer, K. Ens, K. Fechner, E. Barth, T. Martinetz, W. Stocker,€ Automated associated interstitial pneumonia and idiopathic interstitial pneumonia: indirect immunofluorescence evaluation of antinuclear autoantibodies on similarity and difference, Semin. Ultrasound CT MR 35 (1) (2014 Feb) 29e38. HEp-2 cells, Clin. Dev. Immunol. 2012 (2012) 651058. [5] W.D. Travis, U. Costabel, D.M. Hansell, T.E. King Jr., D.A. Lynch, A.G. Nicholson, [24] D.A. Gonzalez, A.C. Leon, A.R. Varela, M.G. García, S. Rahola Mde, C. Perez C.J. Ryerson, J.H. Ryu, M. Selman, A.U. Wells, J. Behr, D. Bouros, K.K. Brown, Mdel, A.G. Hernandez, M.J. Falcon, B.B. Díaz, Autoantibody detection with T.V. Colby, H.R. Collard, C.R. Cordeiro, V. Cottin, B. Crestani, M. Drent, indirect immunofluorescence on HEp-2 cells: starting serum dilutions for R.F. Dudden, J. Egan, K. Flaherty, C. Hogaboam, Y. Inoue, T. Johkoh, D.S. Kim, systemic rheumatic diseases, Immunol. Lett. 140 (1e2) (2011 Oct 30) 30e35. M. Kitaichi, J. Loyd, F.J. Martinez, J. Myers, S. Protzko, G. Raghu, L. Richeldi, [25] E.M. Tan, T.E. Feltkamp, J.S. Smolen, B. Butcher, R. Dawkins, M.J. Fritzler, N. Sverzellati, J. Swigris, D. Valeyre, ATS/ERS committee on idiopathic T. Gordon, J.A. Hardin, J.R. Kalden, R.G. Lahita, R.N. Maini, J.S. McDougal, interstitial pneumonias. An official American thoracic society/European N.F. Rothfield, R.J. Smeenk, Y. Takasaki, A. Wiik, M.R. Wilson, J.A. Koziol, respiratory society statement: Update of the international multidisciplinary Range of antinuclear antibodies in “healthy” individuals, Arthritis Rheum. 40 classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. (9) (1997 Sep) 1601e1611. Care Med. 188 (6) (2013 Sep 15) 733e748. [26] D.H. Solomon, A.J. Kavanaugh, P.H. Schur, American college of rheumatology [6] N. Arulkumaran, N. Periselneris, G. Gaskin, N. Strickland, P.W. Ind, C.D. Pusey, Ad Hoc committee on immunologic testing guidelines. Evidence-based A.D. Salama, Interstitial lung disease and ANCA-associated vasculitis: a guidelines for the use of immunologic tests: antinuclear antibody testing, retrospective observational cohort study, Rheumatol. Oxf. 50 (11) (2011 Nov) Arthritis Rheum. 47 (4) (2002 Aug) 434e444. 2035e2043. [27] H. Nossent, O.P. Rekvig, Antinuclear antibody screening in this new millen- [7] Y. Homma, Y. Ohtsuka, K. Tanimura, H. Kusaka, M. Munakata, Y. Kawakami, nium: farewell to the microscope? Scand. J. Rheumatol. 30 (3) (2001) H. Ogasawara, Can interstitial pneumonia as the sole presentation of collagen 123e126 discussion 127e8. vascular diseases be differentiated from idiopathic interstitial pneumonia? [28] R. Tozzoli, et al., Italian society of laboratory medicine study group on the Respiration 62 (5) (1995) 248e251. diagnosis of autoimmune diseases. Guidelines for the laboratory use of [8] J.J. Solomon, A. Fischer, Connective tissue disease-associated interstitial lung autoantibody tests in the diagnosis and monitoring of autoimmune 90 T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92

rheumatic diseases, Am. J. Clin. Pathol. 117 (2) (2002 Feb) 316e324. M.J. Walport, Polymyositis, pulmonary fibrosis and autoantibodies to [29] B.H. Kang, J.K. Park, J.H. Roh, J.W. Song, C.K. Lee, M. Kim, S.J. Jang, T.V. Colby, aminoacyl-tRNA synthetase enzymes, Q. J. Med. 77 (282) (1990 Oct) D.S. Kim, Clinical significance of serum autoantibodies in idiopathic inter- 1019e1038. stitial pneumonia, J. Korean Med. Sci. 28 (5) (2013 May) 731e737. [55] M. Fathi, M. Dastmalchi, E. Rasmussen, I.E. Lundberg, G. Tornling, Interstitial [30] S. Mittoo, A.C. Gelber, L. Christopher-Stine, M.R. Horton, N. Lechtzin, lung disease, a common manifestation of newly diagnosed polymyositis and S.K. Danoff, Ascertainment of collagen vascular disease in patients presenting dermatomyositis, Ann. Rheum. Dis. 63 (3) (2004 Mar) 297e301. with interstitial lung disease, Respir. Med. 103 (8) (2009 Aug) 1152e1158. [56] B. Hervier, H. Devilliers, R. Stanciu, A. Meyer, Y. Uzunhan, A. Masseau, [31] A. Kavanaugh, R. Tomar, J. Reveille, D.H. Solomon, H.A. Homburger, Guide- S. Dubucquoi, P.Y. Hatron, L. Musset, B. Wallaert, H. Nunes, T. Maisonobe, lines for clinical use of the antinuclear antibody test and tests for specific N.O. Olsson, D. Adoue, P. Arlet, J. Sibilia, M. Guiguet, D. Lauque, Z. Amoura, autoantibodies to nuclear antigens American college of pathologists, Arch. E. Hachulla, M. Hamidou, O. Benveniste, Hierarchical cluster and survival Pathol. Lab. Med. 124 (1) (2000 Jan) 71e81. analyses of antisynthetase syndrome: phenotype and outcome are corre- [32] B. Hervier, Y. Uzunhan, E. Hachulla, O. Benveniste, H. Nunes, P. Delaval, lated with anti-tRNA synthetase antibody specificity, Autoimmun. Rev. 12 (2) L. Musset, S. Dubucquoi, B. Wallaert, M. Hamidou, Antisynthetase syndrome (2012 Dec) 210e217. positive for anti-threonyl-tRNA synthetase (anti-PL7) antibodies, Eur. Respir. [57] M. Kalluri, S.A. Sahn, C.V. Oddis, S.L. Gharib, L. Christopher-Stine, S.K. Danoff, J. 37 (3) (2011 Mar) 714e717. L. Casciola-Rosen, G. Hong, P.F. Dellaripa, K.B. Highland, Clinical profile of [33] L.A. Love, R.L. Leff, D.D. Fraser, I.N. Targoff, M. Dalakas, P.H. Plotz, F.W. Miller, anti-PL-12 autoantibody Cohort study and review of the literature, Chest 135 A new approach to the classification of idiopathic inflammatory myopathy: (6) (2009 Jun) 1550e1556. myositis-specific autoantibodies define useful homogeneous patient groups, [58] I. Marie, S. Josse, O. Decaux, S. Dominique, E. Diot, C. Landron, P. Roblot, Med. Baltim. 70 (6) (1991 Nov) 360e374. S. Jouneau, P.Y. Hatron, K.P. Tiev, O. Vittecoq, D. Noel, L. Mouthon, [34] R. Brouwer, G.J. Hengstman, W. Vree Egberts, H. Ehrfeld, B. Bozic, J.F. Menard, F. Jouen, Comparison of long-term outcome between anti-Jo1- A. Ghirardello, G. Grøndal, M. Hietarinta, D. Isenberg, J.R. Kalden, I. Lundberg, and anti-PL7/PL12 positive patients with antisynthetase syndrome, Auto- H. Moutsopoulos, P. Roux-Lombard, J. Vencovsky, A. Wikman, H.P. Seelig, immun. Rev. 11 (10) (2012 Aug) 739e745. B.G. van Engelen, W.J. van Venrooij, Autoantibody profiles in the sera of [59] Y. Yamasaki, H. Yamada, T. Nozaki, J. Akaogi, C. Nichols, R. Lyons, A.C. Loy, European patients with myositis, Ann. Rheum. Dis. 60 (2) (2001 Feb) E.K. Chan, W.H. Reeves, M. Satoh, Unusually high frequency of autoanti- 116e123. bodies to PL-7 associated with milder muscle disease in Japanese patients [35] A. Selva-O’Callaghan, M. Labrador-Horrillo, X. Munoz-Gall,~ X. Martínez- with polymyositis/dermatomyositis, Arthritis Rheum. 54 (6) (2006 Jun) Gomez, J. Majo-Masferrer, R. Solans-Laque, et al., Polymyositis/dermatomy- 2004e2009. ositis associated lung disease: analysis of a series of 81 patients, Lupus 14 [60] A. Fischer, J.J. Swigris, R.M. du Bois, D.A. Lynch, G.P. Downey, G.P. Cosgrove, (2005) 534e542. S.K. Frankel, E.R. Fernandez-Perez, J.Z. Gillis, K.K. Brown, Anti-synthetase [36] M. Dalakas, R. Hohlfeld, Polymyositis and dermatomyositis, Lancet 362 syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic (2003) 971e982. interstitial pneumonia, Respir. Med. 103 (11) (2009 Nov) 1719e1724. [37] M.G. Cruellas, S. Viana Vdos, M. Levy-Neto, F.H. Souza, S.K. Shinjo, Myositis- [61] S. Sato, M. Hirakata, M. Kuwana, K. Nakamura, A. Suwa, S. Inada, T. Mimori, specific and myositis-associated autoantibody profiles and their clinical as- Y. Ikeda, Clinical characteristics of Japanese patients with anti-PL-7 (anti- sociations in a large series of patients with polymyositis and dermatomyo- threonyl-tRNA synthetase) autoantibodies, Clin. Exp. Rheumatol. 23 (5) sitis, Clin. (Sao Paulo) 68 (7) (2013 Jul) 909e914. (2005 Sep-Oct) 609e615. [38] I.N. Targoff, Humoral immunity in polymyositis/dermatomyositis, J. Invest [62] A. Labirua-Iturburu, A. Selva-O'Callaghan, M. Vincze, K. Danko, J. Vencovsky, Dermatol 100 (1993) 116Se123S. B. Fisher, P. Charles, M. Dastmalchi, I.E. Lundberg, Anti-PL-7 (anti-threonyl- [39] M.C. Hochberg, D. Feldman, M.B. Stevens, F.C. Arnett, M. Reichlin, Antibody tRNA synthetase) antisynthetase syndrome: clinical manifestations in a se- to Jo-1 in polymyositis/dermatomyositis: association with interstitial pul- ries of patients from a European multicenter study (EUMYONET) and review monary disease, J. Rheumatol. 11 (5) (1984 Oct) 663e665. of the literature, Med. Baltim. 91 (4) (2012 Jul) 206e211. [40] W.W. Douglas, H.D. Tazelaar, T.E. Hartman, R.P. Hartman, P.A. Decker, [63] J. Solomon, J.J. Swigris, K.K. Brown, Myositis-related interstitial lung disease D.R. Schroeder, J.H. Ryu, Polymyositis-dermatomyositis-associated intersti- and antisynthetase syndrome, J. Bras. Pneumol. 37 (1) (2011 Jan-Feb) tial lung disease, Am. J. Respir. Crit. Care Med. 164 (7) (2001 Oct 1) 100e109. 1182e1185. [64] I.N. Targoff, Myositis specific autoantibodies, Curr. Rheumatol. Rep. 8 (3) [41] I. Marie, E. Hachulla, P. Cherin, S. Dominique, P. Hatron, M. Hellot, et al., (2006 Jun) 196e203. Interstitial lung disease in polymyositis and dermatomyositis, Arthritis [65] I.N. Targoff, M. Reichlin, The association between Mi-2 antibodies and der- Rheum. 47 (2002) 614e622. matomyositis, Arthritis Rheum. 28 (7) (1985 Jul) 796e803. [42] M.G. Cruellas, S. Viana Vdos, M. Levy-Neto, F.H. Souza, S.K. Shinjo, Myositis- [66] M.G. Cruellas, S. Viana Vdos, M. Levy-Neto, F.H. Souza, S.K. Shinjo, Myositis- specific and myositis-associated autoantibody profiles and their clinical as- specific and myositis-associated autoantibody profiles and their clinical as- sociations in a large series of patients with polymyositis and dermatomyo- sociations in a large series of patients with polymyositis and dermatomyo- sitis, Clin. (Sao Paulo) 68 (7) (2013 Jul) 909e914. sitis, Clin. (Sao Paulo) 68 (7) (2013 Jul) 909e914. [43] M. Mahler, F.W. Miller, M.J. Fritzler, Idiopathic inflammatory myopathies and [67] R.L. Euwer, R.D. Sontheimer, Amyopathic dermatomyositis (dermatomyositis the anti-synthetase syndrome: a comprehensive review, Autoimmun. Rev. sine myositis) presentation of six new cases and review of the literature, 13 (4e5) (2014 Apr-May) 367e371. J. Am. Acad. Dermatol 24 (6 Pt 1) (1991 Jun) 959e966. [44] A.R. Frazier, R.D. Miller, Interstitial pneumonitis in association with poly- [68] R.D. Sontheimer, Would a new name hasten the acceptance of amyopathic myositis and dermatomyositis, Chest 65 (4) (1974 Apr) 403e407. dermatomyositis (dermatomyositis sine myositis) as a distinctive subset [45] S.Y. Ji, F.Q. Zeng, Q. Guo, G.Z. Tan, H.F. Tang, Y.J. Luo, Z.Q. Tang, Y.F. Han, within the idiopathic inflammatory dermatomyopathies spectrum of clinical Predictive factors and unfavourable prognostic factors of interstitial lung illness? J. Am. Acad. Dermatol 46 (2002) 626e636. disease in patients with polymyositis or dermatomyositis: a retrospective [69] R.L. Euwer, R.D. Sontheimer, Amyopathic dermatomyositis: a review, study, Chin. Med. J. Engl. 123 (5) (2010 Mar 5) 517e522. J. Invest Dermatol 100 (1993) 124Se127S. [46] M. Hirakata, S. Nagai, Interstitial lung disease in polymyositis and derma- [70] L.A. Saketkoo, D.P. Ascherman, V. Cottin, L. Christopher-Stine, S.K. Danoff, tomyositis, Curr. Opin. Rheumatol. 12 (6) (2000 Nov) 501e508. C.V. Oddis, Interstitial lung disease in idiopathic inflammatory myopathy, [47] M. Fathi, J. Vikgren, M. Boijsen, et al., Interstitial lung disease in polymyositis Curr. Rheumatol. Rev. 6 (2) (2010 May) 108e119. and dermatomyositis: longitudinal evaluation by pulmonary function and [71] V. Cottin, F. Thivolet-Bejui, M. Reynaud-Gaubert, J. Cadranel, P. Delaval, radiology, Arthritis Rheum. 59 (5) (2008) 677e685. P.J. Ternamian, J.F. Cordier, Groupe d'Etudes et de Recherche sur les Maladies [48] K.W. Grathwohl, J.W. Thompson, K.K. Riordan, B.J. Roth, T.A. Dillard, Digital ”Orphelines“ Pulmonaires. Interstitial lung disease in amyopathic dermato- clubbing associated with polymyositis and interstitial lung disease, Chest myositis, dermatomyositis and polymyositis, Eur. Respir. J. 22 (2) (2003 Aug) 108 (6) (1995 Dec) 1751e1752. 245e250. [49] E.H. Kang, E.B. Lee, K.C. Shin, C.H. Im, D.H. Chung, S.K. Han, Y.W. Song, [72] V. Cottin, A.V. Donsbeck, D. Revel, R. Loire, J.F. Cordier, Nonspecific interstitial Interstitial lung disease in patients with polymyositis, dermatomyositis and pneumonia. Individualization of a clinicopathologic entity in a series of 12 amyopathic dermatomyositis, Rheumatol. Oxf. 44 (10) (2005 Oct) patients, Am. J. Respir. Crit. Care Med. 158 (1998) 1286e1293. 1282e1286. [73] S. Sato, M. Hirakata, M. Kuwana, et al., Autoantibodies to a 140-kd poly- [50] M. Fathi, I.E. Lundberg, G. Tornling, Pulmonary complications of polymyositis peptide, CADM-140, in Japanese patients with clinically amyopathic der- and dermatomyositis, Semin. Respir. Crit. Care Med. 28 (2007) 451e458. matomyositis, Arthritis Rheum. 52 (2005) 1571e1576. [51] I. Tillie-Leblond, M. Wislez, D. Valeyre, B. Crestani, A. Rabbat, D. Israel-Biet, [74] N. Ikeda, K. Takahashi, Y. Yamaguchi, M. Inasaka, M. Kuwana, Z. Ikezawa, M. Humbert, L.J. Couderc, B. Wallaert, J. Cadranel, Interstitial lung disease and Analysis of dermatomyositis-specific autoantibodies and clinical character- anti-Jo-1 antibodies: difference between acute and gradual onset, Thorax 63 istics in Japanese patients, J. Dermatol. 38 (10) (2011 Oct) 973e979. (1) (2008 Jan) 53e59. [75] T. Gono, S. Sato, Y. Kawaguchi, M. Kuwana, M. Hanaoka, et al., Anti-MDA5 [52] A.W. Friedman, I.N. Targoff, F.C. Arnett, Interstitial lung disease with auto- antibody, ferritin and IL-18 are useful for the evaluation of response to antibodies against aminoacyl-tRNA synthetases in the absence of clinically treatment in interstitial lung disease with anti-MDA5 antibody-positive apparent myositis, Semin. Arthritis Rheum. 26 (1) (1996 Aug) 459e467. dermatomyositis, Rheumatol. Oxf. 51 (9) (2012 Sep) 1563e1570. [53] M. Mahler, F.W. Miller, M.J. Fritzler, Idiopathic inflammatory myopathies and [76] S. Sato, M. Kuwana, T. Fujita, Y. Suzuki, Anti-CADM-140/MDA5 autoantibody the anti-synthetase syndrome: A comprehensive review, Autoimmun. Rev. titer correlates with disease activity and predicts disease outcome in patients 13 (4e5) (2014 Apr-May) 367e371. with dermatomyositis and rapidly progressive interstitial lung disease, Mod. [54] C. Marguerie, C.C. Bunn, H.L. Beynon, R.M. Bernstein, J.M. Hughes, A.K. So, Rheumatol. 23 (3) (2013 May) 496e502. T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92 91

[77] K. Hanke, C.S. Brückner, C. Dahnrich,€ D. Huscher, L. Komorowski, W. Meyer, anti-topoisomerase I a serum marker of pulmonary involvement in systemic A. Janssen, M. Backhaus, M. Becker, A. Kill, K. Egerer, G.R. Burmester, F. Hiepe, sclerosis? Chest 116 (3) (1999 Sep) 715e720. W. Schlumberger, G. Riemekasten, Antibodies against PM/Scl-75 and PM/Scl- [100] V. Steen, T.A. Medsger Jr., Predictors of isolated pulmonary hypertension in 100 are independent markers for different subsets of systemic sclerosis pa- patients with systemic sclerosis and limited cutaneous involvement, tients, Arthritis Res. Ther. 11 (1) (2009) R22. Arthritis Rheum. 48 (2) (2003 Feb) 516e522. [78] M. Mahler, R. Raijmakers, Novel aspects of autoantibodies to the PM/Scl [101] D.C. Briggs, R.W. Vaughan, K.I. Welsh, A. Myers, R.M. duBois, C.M. Black, complex: clinical, genetic and diagnostic insights, Autoimmun. Rev. 6 (7) Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis, Lan- (2007 Aug) 432e437. cet 338 (8768) (1991 Sep 14) 661e662. [79] R. Raijmakers, W.V. Egberts, W.J. van Venrooij, G.J. Pruijn, The association of [102] M. Kuwana, Y. Okano, J.P. Pandey, R.M. Silver, N. Fertig, T.A. Medsger Jr., the human PM/Scl-75 autoantigen with the exosome is dependent on a Enzyme-linked immunosorbent assay for detection of anti-RNA polymerase newly identified N terminus, J. Biol. Chem. 278 (33) (2003 Aug 15) III antibody: analytical accuracy and clinical associations in systemic scle- 30698e30704. rosis, Arthritis Rheum. 52 (8) (2005 Aug) 2425e2432. [80] E. Ben-Chetrit, B.J. Gandy, E.M. Tan, K.F. Sullivan, Isolation and character- [103] P.Q. Hu, N. Fertig, T.A. Medsger Jr., T.M. Wright, Correlation of serum anti- ization of a cDNA clone encoding the 60-kD component of the human SS-A/ DNA topoisomerase I antibody levels with disease severity and activity in Ro ribonucleoprotein autoantigen, J. Clin. Invest. 83 (4) (1989 Apr) systemic sclerosis, Arthritis Rheum. 48 (5) (2003 May) 1363e1373. 1284e1292. [104] Y. Okano, V.D. Steen, T.A. Medsger Jr., Autoantibody reactive with RNA po- [81] E.K. Chan, J.C. Hamel, J.P. Buyon, E.M. Tan, Molecular definition and sequence lymerase III in systemic sclerosis, Ann. Intern Med. 119 (10) (1993 Nov 15) motifs of the 52-kD component of human SS-A/Ro autoantigen, J. Clin. Invest. 1005e1013. 87 (1) (1991 Jan) 68e76. [105] O. Meyer, L. De Chaisemartin, P. Nicaise-Roland, J. Cabane, F. Tubach, [82] Y. Itoh, M. Reichlin, Autoantibodies to the Ro/SSA antigen are conformation P. Dieude, G. Hayem, E. Palazzo, S. Chollet-Martin, A. Kahan, Y. Allanore, Anti- dependent I: Anti-60 kD antibodies are mainly directed to the native pro- RNA polymerase III antibody prevalence and associated clinical manifesta- tein; anti-52 kD antibodies are mainly directed to the denatured protein, tions in a large series of French patients with systemic sclerosis: a cross- Autoimmunity 14 (1) (1992) 57e65. sectional study, J. Rheumatol. 37 (1) (2010 Jan) 125e130. [83] W. Pollock, B.H. Toh, Routine immunofluorescence detection of Ro/SS-A [106] A. Fischer, F.J. Pfalzgraf, C.A. Feghali-Bostwick, et al., Anti- Th/To-Positivity in autoantibody using HEp-2 cells transfected with human 60 kDa Ro/SS-A, a cohort of patients with idiopathic pulmonary fibrosis, J. Rheumatol. 33 J. Clin. Pathol. 52 (9) (1999 Sep) 684e687. (2006) 1600e1605. [84] H. Locht, R. Pelck, R. Manthorpe, Clinical manifestations correlated to the [107] H. Chifflot, B. Fautrel, C. Sordet, E. Chatelus, J. Sibilia, Incidence and preva- prevalence of autoantibodies in a large (n¼321) cohort of patients with lence of systemic sclerosis: a systematic literature review, Semin. Arthritis primary Sjogren's€ syndrome: a comparison of patients initially diagnosed Rheum. 37 (4) (2008 Feb) 223e235. according to the Copenhagen classification criteria with the American- [108] D. Launay, M. Remy-Jardin, U. Michon-Pasturel, I. Mastora, E. Hachulla, European consensus criteria, Autoimmun. Rev. 4 (5) (2005 Jun) 276e281. M. Lambert, V. Delannoy, V. Queyrel, A. Duhamel, R. Matran, P. De Groote, [85] F. Franceschini, I. Cavazzana, Anti-Ro/SSA and La/SSB antibodies, Autoim- P.Y. Hatron, High resolution computed tomography in fibrosing alveolitis munity 38 (1) (2005 Feb) 55e63. associated with systemic sclerosis, J. Rheumatol. 33 (9) (2006 Sep) [86] Y. Enomoto, T. Takemura, E. Hagiwara, T. Iwasawa, Y. Fukuda, N. Yanagawa, 1789e1801. F. Sakai, T. Baba, S. Nagaoka, T. Ogura, Prognostic factors in interstitial lung [109] D. Bouros, A.U. Wells, A.G. Nicholson, T.V. Colby, V. Polychronopoulos, disease associated with primary Sjogren's€ syndrome: a retrospective analysis P. Pantelidis, P.L. Haslam, D.A. Vassilakis, C.M. Black, R.M. du Bois, Histo- of 33 pathologically-proven cases, PLoS One 8 (9) (2013) e73774. pathologic subsets of fibrosing alveolitis in patients with systemic sclerosis [87] M. Kokosi, E.C. Riemer, K.B. Highland, Pulmonary involvement in Sjogren€ and their relationship to outcome, Am. J. Respir. Crit. Care Med. 165 (12) syndrome, Clin. Chest Med. 31 (3) (2010 Sep) 489e500. (2002 Jun 15) 1581e1586. [88] R. La Corte, A. Lo Mo Naco, A. Locaputo, F. Dolzani, F. Trotta, In patients with [110] R.M. Lomeo, R.J. Cornella, S.I. Schabel, R.M. Silver, Progressive systemic antisynthetase syndrome the occurrence of anti-Ro/SSA antibodies causes a sclerosis sine scleroderma presenting as pulmonary interstitial fibrosis, Am. more severe interstitial lung disease, Autoimmunity 39 (3) (2006 May) J. Med. 87 (5) (1989 Nov) 525e527. 249e253. [111] P.R. Bauer, D.N. Schiavo, T.G. Osborn, D.L. Levin, J. St Sauver, A.C. Hanson, [89] A. Vancsa, I. Csípo, J. Nemeth, K. Dev enyi, L. Gergely, K. Danko, Characteristics D.R. Schroeder, J.H. Ryu, Influence of interstitial lung disease on outcome in of interstitial lung disease in SS-A positive/Jo-1 positive inflammatory systemic sclerosis: a population-based historical cohort study, Chest 144 (2) myopathy patients, Rheumatol. Int. 29 (9) (2009 Jul) 989e994. (2013 Aug) 571e577. [90] A. Fischer, J.J. Swigris, R.M. du Bois, S.D. Groshong, C.D. Cool, H. Sahin, [112] H.D. Tramposch, C.D. Smith, J.L. Senecal, N. Rothfield, A long-term longitu- D.A. Lynch, J.Z. Gillis, M.D. Cohen, R.T. Meehan, K.K. Brown, Minor salivary dinal study of anticentromere antibodies, Arthritis Rheum. 27 (2) (1984 Feb) gland biopsy to detect primary Sjogren syndrome in patients with interstitial 121e124. lung disease, Chest 136 (4) (2009 Oct) 1072e1078. [113] A. Ippolito, D.J. Wallace, D. Gladman, P.R. Fortin, M. Urowitz, V. Werth, [91] F. van den Hoogen, D. Khanna, J. Fransen, S.R. Johnson, M. Baron, A. Tyndall, M. Costner, C. Gordon, G.S. Alarcon, R. Ramsey-Goldman, P. Maddison, M. Matucci-Cerinic, R.P. Naden, T.A. Medsger Jr., P.E. Carreira, A. Clarke, S. Bernatsky, S. Manzi, S.C. Bae, J.T. Merrill, E. Ginzler, J.G. Hanly, G. Riemekasten, P.J. Clements, C.P. Denton, O. Distler, Y. Allanore, D.E. Furst, O. Nived, G. Sturfelt, J. Sanchez-Guerrero, I. Bruce, C. Aranow, D. Isenberg, A. Gabrielli, M.D. Mayes, J.M. van Laar, J.R. Seibold, L. Czirjak, V.D. Steen, A. Zoma, L.S. Magder, J. Buyon, K. Kalunian, M.A. Dooley, K. Steinsson, R.F. van M. Inanc, O. Kowal-Bielecka, U. Müller-Ladner, G. Valentini, D.J. Veale, Vollenhoven, T. Stoll, M. Weisman, M. Petri, Autoantibodies in systemic M.C. Vonk, U.A. Walker, L. Chung, D.H. Collier, M. Ellen Csuka, B.J. Fessler, lupus erythematosus: comparison of historical and current assessment of S. Guiducci, A. Herrick, V.M. Hsu, S. Jimenez, B. Kahaleh, P.A. Merkel, seropositivity, Lupus 20 (3) (2011 Mar) 250e255. S. Sierakowski, R.M. Silver, R.W. Simms, J. Varga, J.E. Pope, 2013 classification [114] A. Kavanaugh, R. Tomar, J. Reveille, D.H. Solomon, H.A. Homburger, Guide- criteria for systemic sclerosis: an American college of rheumatology/Euro- lines for clinical use of the antinuclear antibody test and tests for specific pean league against rheumatism collaborative initiative, Ann. Rheum. Dis. 72 autoantibodies to nuclear antigens American college of pathologists, Arch. (11) (2013 Nov) 1747e1755. Pathol. Lab. Med. 124 (1) (2000 Jan) 71e81. [92] J.D. Reveille, D.H. Solomon, Evidence-based guidelines for the use of [115] F.A. Barada Jr., B.S. Andrews, J.S. Davis 4th, R.P. Taylor, Antibodies to Sm in immunologic tests: anticentromere, Scl-70, and nucleolar antibodies, patients with systemic lupus erythematosus correlation of Sm antibody ti- Arthritis Rheum. 49 (2003) 399e412. ters with disease activity and other laboratory parameters, Arthritis Rheum. [93] A.U. Wells, Interstitial lung disease in systemic sclerosis, Presse Med. 43 (10 24 (10) (1981 Oct) 1236e1244. Pt 2) (2014 Oct) e329ee343. [116] M. Frodlund, O. Dahlstrom,€ A. Kastbom, T. Skogh, C. Sjowall,€ Associations [94] M. Koenig, M. Dieude, J.L. Senecal, Predictive value of antinuclear autoanti- between antinuclear antibody staining patterns and clinical features of bodies: the lessons of the systemic sclerosis autoantibodies, Autoimmun. systemic lupus erythematosus: analysis of a regional Swedish register, BMJ Rev. 7 (8) (2008 Sep) 588e593. Open 3 (10) (2013 Oct 25) e003608. [95] U.A. Walker, A. Tyndall, L. Czirjak, C. Denton, D. Farge-Bancel, O. Kowal- [117] A. Almogren, Anti-double stranded antibody Association with titers and Bielecka, U. Müller-Ladner, C. Bocelli-Tyndall, M. Matucci-Cerinic, Clinical fluorescence patterns of anti-nuclear antibody in systemic lupus erythe- risk assessment of organ manifestations in systemic sclerosis: a report from matosus, Saudi Med. J. 31 (1) (2010 Jan) 32e36. the EULAR Scleroderma trials and research group database, Ann. Rheum. Dis. [118] T.C. Mohan, M. Nadarajah, E.H. Sng, Relation of antinuclear fluorescence 66 (6) (2007 Jun) 754e763. patterns and titres to autoantibody prevalence, Ann. Acad. Med. Singap. 18 [96] M.J. Fritzler, T.D. Kinsella, The CREST syndrome: a distinct serologic entity (4) (1989 Jul) 339e344. with anticentromere antibodies, Am. J. Med. 69 (4) (1980 Oct) 520e526. [119] G. Verstegen, M.C. Duyck, P. Meeus, I. Ravelingien, K. De Vlam, Detection and [97] G.M. Mitri, M. Lucas, N. Fertig, V.D. Steen, T.A. Medsger Jr., A comparison identification of antinuclear antibodies (ANA) in a large community hospital, between anti-Th/To- and anticentromere antibody-positive systemic scle- Acta Clin. Belg. 64 (4) (2009 Jul-Aug) 317e323. rosis patients with limited cutaneous involvement, Arthritis Rheum. 48 (1) [120] R.D. Brasington, D.E. Furst, Pulmonary disease in systemic lupus erythema- (2003 Jan) 203e209. tosus, Clin. Exp. Rheumatol. 3 (3) (1985 Jul-Sep) 269e276. [98] G.C. Kane, J. Varga, E.F. Conant, P.W. Spirn, S. Jimenez, J.E. Fish, Lung [121] J.M. Pego-Reigosa, D.A. Medeiros, D.A. Isenberg, Respiratory manifestations involvement in systemic sclerosis (scleroderma): relation to classification of systemic lupus erythematosus: old and new concepts, Best. Pract. Res. based on extent of skin involvement or autoantibody status, Respir. Med. 90 Clin. Rheumatol. 23 (4) (2009 Aug) 469e480. (4) (1996 Apr) 223e230. [122] L. Weinrib, O.P. Sharma, F.P. Quismorio Jr., A long-term study of interstitial [99] E. Diot, B. Giraudeau, P. Diot, D. Degenne, L. Ritz, J.L. Guilmot, E. Lemarie, Is lung disease in systemic lupus erythematosus, Semin. Arthritis Rheum. 20 92 T. Bahmer et al. / Respiratory Medicine 113 (2016) 80e92

(1) (1990 Aug) 48e56. citrullinated Peptide antibodies for diagnosing rheumatoid arthritis, Ann. [123] G.C. Sharp, W.S. Irvin, E.M. Tan, R.G. Gould, H.R. Holman, Mixed connective Intern Med. 152 (7) (2010 Apr 6) 456e464. W155-66. tissue diseaseean apparently distinct rheumatic disease syndrome associ- [138] M.R. Horton, Rheumatoid arthritis associated interstitial lung disease, Crit. ated with a specific antibody to an extractable nuclear antigen (ENA), Am. J. Rev. Comput. Tomogr. 45 (5e6) (2004) 429e440. Med. 52 (2) (1972 Feb) 148e159. [139] A.L. Olson, J.J. Swigris, D.B. Sprunger, A. Fischer, E.R. Fernandez-Perez, [124] R. Cervera, M.A. Khamashta, G.R. Hughes, 'Overlap' syndromes, Ann. Rheum. J. Solomon, J. Murphy, M. Cohen, G. Raghu, K.K. Brown, Rheumatoid arthritis- Dis. 49 (11) (1990 Nov) 947e948. interstitial lung disease-associated mortality, Am. J. Respir. Crit. Care Med. [125] E. Bodolay, Z. Szekanecz, K. Dev enyi, L. Galuska, I. Csípo, J. Vegh, I. Garai, 183 (3) (2011 Feb 1) 372e378. G. Szegedi, Evaluation of interstitial lung disease in mixed connective tissue [140] T. Bongartz, C. Nannini, Y.F. Medina-Velasquez, S.J. Achenbach, C.S. Crowson, disease (MCTD), Rheumatol. Oxf. 44 (5) (2005 May) 656e661. J.H. Ryu, R. Vassallo, S.E. Gabriel, E.L. Matteson, Incidence and mortality of [126] R. Gunnarsson, T.M. Aaløkken, Ø. Molberg, M.B. Lund, G.K. Mynarek, interstitial lung disease in rheumatoid arthritis: a population-based study, A.S. Lexberg, K. Time, A.S. Dhainaut, L.T. Bertelsen, O. Palm, K. Irgens, Arthritis Rheum. 62 (6) (2010 Jun) 1583e1591. A. Becker-Merok, J.L. Nordeide, V. Johnsen, S. Pedersen, A. Prøven, [141] G. Raghu, F. Nyberg, G. Morgan, The epidemiology of interstitial lung disease L.S. Garabet, J.T. Gran, Prevalence and severity of interstitial lung disease in and its association with lung cancer, Br. J. Cancer 91 (Suppl 2) (2004 Aug) mixed connective tissue disease: a nationwide, cross-sectional study, Ann. S3eS10. Rheum. Dis. 71 (12) (2012 Dec) 1966e1972. [142] D.W. Mapel, W.C. Hunt, R. Utton, K.B. Baumgartner, J.M. Samet, D.B. Coultas, [127] I.E. Lundberg, The prognosis of mixed connective tissue disease, Rheum. Dis. Idiopathic pulmonary fibrosis: survival in population based and hospital Clin. North Am. 31 (3) (2005 Aug) 535e547 vii-viii. based cohorts, Thorax 53 (6) (1998 Jun) 469e476. [128] G. Reimer, U. Huschka, J. Keller, R. Kammerer, O.P. Hornstein, Immunofluo- [143] D. Valeyre, O. Freynet, G. Dion, D. Bouvry, I. Annesi-Maesano, H. Nunes, rescence studies in progressive systemic sclerosis (scleroderma) and mixed Epidemiology of interstitial lung diseases, Presse Med. 39 (1) (2010 Jan) connective tissue disease, Br. J. Dermatol. 109 (1) (1983 Jul) 27e36. 53e59. [129] E.C. Hagen, K. Andrassy, E. Csernok, M.R. Daha, G. Gaskin, W.L. Gross, [144] J.B. Kornum, S. Christensen, M. Grijota, L. Pedersen, P. Wogelius, B. Hansen, Z. Heigl, J. Hermans, D. Jayne, C.G. Kallenberg, P. Lesavre, A. Beiderbeck, H.T. Sørensen, The incidence of interstitial lung disease 1995- C.M. Lockwood, J. Lüdemann, F. Mascart-Lemone, E. Mirapeix, C.D. Pusey, 2005: a Danish nationwide population-based study, BMC Pulm. Med. 8 (2008 N. Rasmussen, R.A. Sinico, A. Tzioufas, J. Wieslander, A. Wiik, F.J. Van der Nov 4) 24. Woude, Development and standardization of solid phase assays for the [145] M. Demedts, A.U. Wells, J.M. Anto, U. Costabel, R. Hubbard, P. Cullinan, detection of anti-neutrophil cytoplasmic antibodies (ANCA) A report on the H. Slabbynck, G. Rizzato, V. Poletti, E.K. Verbeken, M.J. Thomeer, second phase of an international cooperative study on the standardization of J. Kokkarinen, J.C. Dalphin, A.N. Taylor, Interstitial lung diseases: an epide- ANCA assays, J. Immunol. Methods 196 (1) (1996 Sep 13) 1e15. miological overview, Eur. Respir. J. Suppl. 32 (2001 Sep) 2se16s. [130] E.C. Hagen, M.R. Daha, J. Hermans, K. Andrassy, E. Csernok, G. Gaskin, [147] D. Tansey, A.U. Wells, T.V. Colby, S. Ip, A. Nikolakoupolou, R.M. du Bois, P. Lesavre, J. Lüdemann, N. Rasmussen, R.A. Sinico, A. Wiik, F.J. van der D.M. Hansell, A.G. Nicholson, Variations in histological patterns of interstitial Woude, Diagnostic value of standardized assays for anti-neutrophil cyto- pneumonia between connective tissue disorders and their relationship to plasmic antibodies in idiopathic systemic vasculitis EC/BCR Project for ANCA prognosis, Histopathology 44 (6) (2004 Jun) 585e596. Assay Standardization, Kidney Int. 53 (3) (1998 Mar) 743e753. [148] M. Romagnoli, C. Nannini, S. Piciucchi, F. Girelli, C. Gurioli, G. Casoni, [131] S. Lionaki, E.R. Blyth, S.L. Hogan, Y. Hu, B.A. Senior, C.E. Jennette, C. Ravaglia, S. Tomassetti, Gurioli Ch, G. Gavelli, A. Carloni, A. Dubini, P.H. Nachman, J.C. Jennette, R.J. Falk, Classification of antineutrophil cyto- F. Cantini, M. Chilosi, V. Poletti, Idiopathic nonspecific interstitial pneu- plasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic monia: an interstitial lung disease associated with autoimmune disorders? autoantibody specificity for myeloperoxidase or proteinase 3 in disease Eur. Respir. J. 38 (2) (2011 Aug) 384e391. recognition and prognosis, Arthritis Rheum. 64 (10) (2012 Oct) 3452e3462. [149] T. Sato, J. Fujita, I. Yamadori, Y. Ohtsuki, T. Yoshinouchi, S. Bandoh, [132] J.W. Tervaert, R. Goldschmeding, J.D. Elema, P.C. Limburg, M. van der Giessen, M. Tokuda, T. Ishida, Non-specific interstitial pneumonia; as the first clinical M.G. Huitema, M.I. Koolen, R.J. Hene, T.H. The, G.K. van der Hem, Association presentation of various collagen vascular disorders, Rheumatol. Int. 26 (6) of autoantibodies to myeloperoxidase with different forms of vasculitis, (2006 Apr) 551e555. Arthritis Rheum. 33 (8) (1990 Aug) 1264e1272. [150] A. de Lauretis, S. Veeraraghavan, E. Renzoni, Review series: Aspects of [133] G.M. Eschun, S.N. Mink, S. Sharma, Pulmonary interstitial fibrosis as a pre- interstitial lung disease: connective tissue disease-associated interstitial lung senting manifestation in perinuclear antineutrophilic cytoplasmic antibody disease: how does it differ from IPF? How should the clinical approach microscopic polyangiitis, Chest 123 (1) (2003 Jan) 297e301. differ? Chron. Respir. Dis. 8 (1) (2011) 53e82. [134] T. Nozu, M. Kondo, K. Suzuki, J. Tamaoki, A. Nagai, A comparison of the [151] G. Koduri, S. Norton, A. Young, N. Cox, P. Davies, J. Devlin, J. Dixey, A. Gough, clinical features of ANCA-positive and ANCA-negative idiopathic pulmonary P. Prouse, J. Winfield, P. Williams, ERAS (Early Rheumatoid Arthritis Study). fibrosis patients, Respiration 77 (4) (2009) 407e415. Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results [135] G. Foulon, P. Delaval, D. Valeyre, B. Wallaert, M.P. Debray, M. Brauner, from an inception cohort, Rheumatol. Oxf. 49 (8) (2010 Aug) 1483e1489. P. Nicaise, J. Cadranel, V. Cottin, A. Tazi, M. Aubier, B. Crestani, ANCA-asso- [152] I. Marie, P.Y. Hatron, S. Dominique, P. Cherin, L. Mouthon, J.F. Menard, Short- ciated lung fibrosis: analysis of 17 patients, Respir. Med. 102 (10) (2008 Oct) term and long-term outcomes of interstitial lung disease in polymyositis and 1392e1398. dermatomyositis: a series of 107 patients, Arthritis Rheum. 63 (11) (2011 [136] L. Guillevin, B. Durand-Gasselin, R. Cevallos, M. Gayraud, F. Lhote, P. Callard, Nov) 3439e3447. J. Amouroux, P. Casassus, B. Jarrousse, Microscopic polyangiitis: clinical and [153] I.N. Park, Y. Jegal, D.S. Kim, K.H. Do, B. Yoo, T.S. Shim, C.M. Lim, S.D. Lee, laboratory findings in eighty-five patients, Arthritis Rheum. 42 (3) (1999 Y. Koh, W.S. Kim, W.D. Kim, S.J. Jang, M. Kitaichi, A.G. Nicholson, T.V. Colby, Mar) 421e430. Clinical course and lung function change of idiopathic nonspecific interstitial [137] P.F. Whiting, N. Smidt, J.A. Sterne, R. Harbord, A. Burton, M. Burke, R. Beynon, pneumonia, Eur. Respir. J. 33 (1) (2009 Jan) 68e76. Y. Ben-Shlomo, J. Axford, P. Dieppe, Systematic review: accuracy of anti-