Test Guide - Quest Test Directory

Interstitial Lung Disease (ILD) Panel

This test is used to identify connective tissue disease (CTD) as a possible cause of interstitial lung disease (ILD).

Test Summary

Interstitial Lung Disease (ILD) Panel

Test code: 39149

Clinical use

Identify connective tissue disease (CTD) as a possible cause of interstitial lung disease (ILD)

Clinical background

ILD is characterized by scarring of the lungs, which is best identified by computerized tomography (CT).1 Dyspnea is the primary symptom, initially related to exertion, which may progress to respiratory failure at a rate dependent on the type of ILD.1 A persistent cough that impairs quality of life is common (30% to 50% of cases).1

ILD can be caused by drugs, environmental exposures, or connective tissue diseases (CTD-ILD), but it is commonly idiopathic (ie, idiopathic pulmonary fibrosis [IPF] accounts for about one-third of cases).1-3 About one-quarter of ILD cases occur among the various CTDs,1 with variable pooled prevalence: mixed connective tissue disease (MCTD, 56%), systemic sclerosis (SSc, 47%), idiopathic inflammatory myopathy (41%, which includes polymyositis [PM] and dermatomyositis [DM]), Sjögren syndrome (17%), and rheumatoid arthritis (RA, 11%).4

Determining the underlying cause of ILD can augment treatment decisions. For example, medical association guidelines recommend IPF be treated with nintedanib5 and most CTD-ILDs be treated with glucocorticoids and mycophenolate as a first-line option; however, SSc-ILD should not be treated with glucocorticoids.6

The clinical and laboratory findings that inform a diagnosis of ILD may not help identify CTD-ILD, especially when ILD is the first manifestation of the autoimmune disease.7 Fortunately, testing for specific antibodies that are associated with different CTDs can help identify an underlying CTD.7 The presence of certain antibodies may aid or satisfy, in part, classification or diagnostic criteria for CTDs (highlighted antibodies in the Table).8-24 See Autoimmune Rheumatic and Related Diseases | Clinical Focus | Quest Diagnostics for more information.

After the CTD-ILD is diagnosed, the American College of Rheumatology (ACR) recommends disease monitoring by ambulatory desaturation testing (3-12 months), high-resolution chest CT (as needed), and pulmonary function testing (with suggestions for disease-specific follow-up intervals, Table).8

Table 1. CTD-ILD Panel (test code 39149) Components: Antibodies, Prevalence, and Follow-up for Different CTDs

Antibodya	Prevalence, %		Individual test (test code)	Suggested follow-up PFT first year after diagnosis8,b
MCTD9
RNP10	100		RNP Antibody (19887)	3-12 months
Myositis11,12
EJ	<5		EJ Autoantibodies (90998)	3-6 months
Jo-113	15-30		Jo-1 Antibody (5810)
MDA5	15-20		Not available as individual test
OJ	<5		OJ Autoantibodies (90999)
PL-7	≤5		PL-7 Autoantibodies (90996)
PL-12	<5		PL-12 Autoantibodies (90997)
PM/Scl-75	<10		Not available as individual test
PM/Scl-100	<10		Anti-PM/Scl-100 Antibody, EIA (94646)
Rheumatoid arthritis14,15
	Early	All
CCP16	62	71	Cyclic Citrullinated Peptide (CCP) Antibody (IgG) (11173)	3-12 months
MCV	78	71	Mutated Citrullinated Vimentin (MCV) Antibody (13238)
RF16	72	77	Rheumatoid Factor (4418)
Sjögren syndrome9
Ro52 (SS-A)17	60-90		Sjogren’s Antibody (SS-A) (38568)	3-12 months
Systemic sclerosis9,11,18-23
CEN A or B24,c	20-40		Centromere B Antibody (16088)	3-6 months
Fibrillarin (U3-snRNP)d	3-20		Not available as individual test
Kue	3-10f		Not available as individual test
RNA Pol III24,c	5-41		RNA Polymerase III Antibody (19899)
Scl-7024,c	9-71f		Scleroderma Antibody (Scl-70) (4942)
Th/Tog	2-10f		Not available as individual test

CCP, cyclic citrullinated peptide; CEN, centromere; CTD, connective tissue disease; ILD, interstitial lung disease; MDA5, melanoma differentiation-associated protein 5; MCTD, mixed connective tissue disease; MCV, mutated citrullinated vimentin; PFT, pulmonary function testing; RF, rheumatoid factor; RNP, ribonucleoprotein; snRNP, small nucleolar ribonucleoprotein; SS-A, Sjögren syndrome-related antigen A; SSc, systemic sclerosis.
a	Highlighted antibodies are those that are included in classification or diagnostic criteria for the relevant disease per citation.
b	Spirometry, lung volumes, and diffusion capacity, then less frequently once stable.
c	The presence of scleroderma-related antibodies (centromere, Scl-70, or RNA polymerase III antibodies) is not necessary or sufficient for diagnosis but is useful for classification in the absence of diagnostic clinical findings ("clear skin thickening of the fingers extending proximal to the metacarpophalangeal joints").24
d	Strong association with African American SSc patients.19
e	Not specific for SSc but often oberved in CTD syndromes overlapping with SSc (eg, myositis).11,19
f	Markedly higher pecentage prevalence ranges have been reported in SSc-ILD (43%-57% for Ku, 67%-89% for Scl-70, and 16%-48% for Th/To).18
g	Highly specific for SSc and associated with ILD.19

Quest Diagnostics offers the Interstitial Lung Disease (ILD) Panel for simultaneous testing of biomarkers associated with CTD-ILD using one test code for ease of ordering (Table). Autoantibody panel testing may also expedite a CTD-ILD diagnosis before extrapulmonary symptoms occur.25 For testing of specific antibodies based on clinical presentation, some individual components can be ordered separately. Some tests cannot be ordered separately because certain biomarkers are not clinically meaningful when detected in isolation; these biomarkers are only tested in the multi-analyte line blot as part of a larger panel.

Individuals suitable for testing

Patients presenting with acute onset ILD of unknown cause (eg, previously healthy younger patients with dyspnea increasing over a few weeks to months)26
Patients presenting with subacute ILD of unknown cause with symptoms of CTD (eg, patients of all ages with Raynaud phenomenon, skin rash or hair loss, muscle pain or weakness, gastroesophageal reflux, and joint pain or swelling)26

Method

The following antigens are tested using a single line-blot assay: EJ, Jo-1, Ku, MDA5, OJ, PL-7, PL-12, PM/Scl-75, Ro52 (SS-A), centromere A, centromere B, fibrillarin (U3-snRNP), PM/Scl-100, Scl-70, and Th/To.
CCP and MCV tests are performed using ELISAs.
RF testing is performed using immunoturbidimetry.
RNA Pol III testing is performed using an ELISA.
RNP testing is performed using a multiplex flow immunoassay.

Interpretive information

A positive result for 1 or more of the specific biomarkers in this panel may indicate the presence of the corresponding CTD; thus, a positive result may help diagnose CTD-ILD.

A positive result for any of the myositis-specific synthetase antibodies (Jo-1, EJ, OJ, PL-7, or PL-12) is consistent with antisynthetase syndrome in myositis patients; ILD among such patients is high (70%)11 and tends to be chronic.27 Patients who test positive for myositis-specific MDA5 antibodies have been reported to be 18 times as likely to have ILD than those who test negative.28 MDA5-positive DM-ILD tends to be acute27 and is associated with high mortality (one study involving 216 patients found that 8-year mortality was almost 40%, with nearly 90% of the deaths in the first year after diagnosis29).

A positive result and high level of RNP antibody usually suggests MCTD but may also indicate an SSc overlap syndrome. ILD is common (>50%) in patients with MCTD.4 In the context of an SSs overlap syndrome, a positive RNP result may indicate that the patient is more likely to develop progressive fibrosis.30

A positive result for RF suggests a diagnosis of rheumatoid arthritis, which is confirmed by additional positive results for CCP and/or MCV antibodies. The lifetime risk of developing ILD in patients with rheumatoid arthritis is 10%.31

A positive result for Ro52 (SS-A) antibodies may indicate the presence of Sjögren syndrome. ILD is among the most common respiratory manifestations of Sjögren syndrome and develops in up to 20% of patients within 5 years of diagnosis.32

A positive result for centromere A or B, Scl-70, RNA Pol III, fibrillarin, or Th/To antibodies may help inform a diagnosis of SSc. Among patients with SSc, >40% develop clinically significant ILD.4 In the context of SSc, positive results for Ku or Pm/Scl antibodies suggest the presence of an overlap syndrome.

Negative results may help exclude CTDs as a potential cause of ILD but do not always rule out a CTD; some individual markers are not diagnostic and have variable sensitivity and specificity for individual CTDs.

References

Maher TM. Interstitial lung disease: a review. JAMA. 2024;331(19):1655-1665. doi:10.1001/jama.2024.3669
Jee AS, Adelstein S, Bleasel J, et al. Role of autoantibodies in the diagnosis of connective-tissue disease ILD (CTD-ILD) and interstitial pneumonia with autoimmune features (IPAF). J Clin Med. 2017;6(5):51. doi:10.3390/jcm6050051
Bahmer T, Romagnoli M, Girelli F, et al. The use of auto-antibody testing in the evaluation of interstitial lung disease (ILD)—a practical approach for the pulmonologist. Respir Med. 2016;113:80-92. doi:10.1016/j.rmed.2016.01.019
Joy GM, Arbiv OA, Wong CK, et al. Prevalence, imaging patterns and risk factors of interstitial lung disease in connective tissue disease: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(167)doi:10.1183/16000617.0210-2022
Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47. doi:10.1164/rccm.202202-0399ST
2023 American College of Rheumatology (ACR) guideline for the treatment of interstitial lung disease in people with systemic autoimmune rheumatic disease: guideline summary. American College of Rheumatology. Updated August 12, 2023. Accessed May 20, 2024. https://rheumatology.org/api/asset/bltaedebda97a351d47
Raghu G, Remy-Jardin M, Myers J. Diagnosis of idiopathic pulmonary fibrosis. An official American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68. doi:10.1164/rccm.201807-1255ST
2023 American College of Rheumatology (ACR) guideline for the screening and monitoring of interstitial lung disease in people with systemic autoimmune rheumatic disease: guideline summary. American College of Rheumatology. Updated August 12, 2023. Accessed May 20, 2024. https://rheumatology.org/api/asset/blt7e2cadfc7bc986fb
Mahler M, Meroni PL, Bossuyt X, et al. Current concepts and future directions for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. J Immunol Res. 2014;2014:315179. doi:10.1155/2014/315179
John KJ, Sadiq M, George T, et al. Clinical and immunological profile of mixed connective tissue disease and a comparison of four diagnostic criteria. Int J Rheumatol. 2020;2020:9692030. doi:10.1155/2020/9692030
Lega JC, Fabien N, Reynaud Q, et al. The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome. Autoimmun Rev. 2014;13(9):883-891. doi:10.1016/j.autrev.2014.03.004
Satoh M, Tanaka S, Ceribelli A, et al. A comprehensive overview on myositis-specific antibodies: new and old biomarkers in idiopathic inflammatory myopathy. Clin Rev Allergy Immunol. 2017;52(1):1-19. doi:10.1007/s12016-015-8510-y
Lundberg IE, Tjärnlund A, Bottai M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017;76(12):1955-1964. doi:10.1136/annrheumdis-2017-211468
Liu X, Jia R, Zhao J, et al. The role of anti-mutated citrullinated vimentin antibodies in the diagnosis of early rheumatoid arthritis. J Rheumatol. 2009;36(6):1136-1142. doi:10.3899/jrheum.080796
Zhu JN, Nie LY, Lu XY, et al. Meta-analysis: compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the rheumatoid arthritis classification criteria? Clin Chem Lab Med. 2019;57(11):1668-1679. doi:10.1515/cclm-2019-0167
Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. doi:10.1002/art.27584
Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017;76(1):9-16. doi:10.1136/annrheumdis-2016-210571
Hamaguchi Y, Takehara K. Anti-nuclear autoantibodies in systemic sclerosis: news and perspectives. J Scleroderma Relat Disord. 2018;3(3):201-213. doi:10.1177/2397198318783930
Mahler M, Hudson M, Bentow C, et al. Autoantibodies to stratify systemic sclerosis patients into clinically actionable subsets. Autoimmun Rev. 2020;19(8):102583. doi:10.1016/j.autrev.2020.102583
Stochmal A, Czuwara J, Trojanowska M, et al. Antinuclear antibodies in systemic sclerosis: an update. Clin Rev Allergy Immunol. 2020;58(1):40-51. doi:10.1007/s12016-018-8718-8
Shah AA, Hummers LK, Casciola-Rosen L, et al. Examination of autoantibody status and clinical features associated with cancer risk and cancer-associated scleroderma. Arthritis Rheumatol. 2015;67(4):1053-1061. doi:10.1002/art.39022
Sobanski V, Dauchet L, Lefevre G, et al. Prevalence of anti-RNA polymerase III antibodies in systemic sclerosis: new data from a French cohort and a systematic review and meta-analysis. Arthritis Rheumatol. 2014;66(2):407-417. doi:10.1002/art.38219
Pokeerbux MR, Giovannelli J, Dauchet L, et al. Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis Res Ther. 2019;21(1):86. doi:10.1186/s13075-019-1867-1
van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737-2747. doi:10.1002/art.38098
Stevenson BR, Thompson GA, Watson MC, et al. Autoantibodies in interstitial lung diseases. Pathology. 2019;51(5):518-523. doi:10.1016/j.pathol.2019.03.007
Mathai SC, Danoff SK. Management of interstitial lung disease associated with connective tissue disease. BMJ. 2016;352:h6819. doi:10.1136/bmj.h6819
Nakashima R. Clinical significance of myositis-specific autoantibodies. Immunol Med. 2018;41(3):103-112. doi:10.1080/25785826.2018.1531188
Zhang L, Wu G, Gao D, et al. Factors associated with interstitial lung disease in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis. PLoS One. 2016;11(5):e0155381. doi:10.1371/journal.pone.0155381
Lian X, Ye Y, Zou J, et al. Longitudinal study of patients with antimelanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease. Rheumatology (Oxford). 2023;62(5):1910-1919. doi:10.1093/rheumatology/keac525
Chevalier K, Chassagnon G, Leonard-Louis S, et al. Anti-U1RNP antibodies are associated with a distinct clinical phenotype and a worse survival in patients with systemic sclerosis. J Autoimmun. 2024;146:103220. doi:10.1016/j.jaut.2024.103220
Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010;62(6):1583-1591. doi:10.1002/art.27405
Flament T, Bigot A, Chaigne B, et al. Pulmonary manifestations of Sjögren's syndrome. Eur Respir Rev. 2016;25(140):110. doi:10.1183/16000617.0011-2016

Content reviewed 06/2024

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Related tests (10)

5810 - Jo-1 Antibody

Jo-1 Antibody occurs most frequently (31%) in patients with polymyositis, but has also been found in patients with dermatomyositis, and the polymyositis/scleroderma "overlap syndrome" (PM/SCL) or polymyositis/systemic lupus erythematosis "overlap syndrome" (PM/SLE).

4942 - Scleroderma Antibody (Scl-70)

Scl-70 antibody is present in approximately 40% of patients with progressive systemic sclerosis (PSS).

13238 - Mutated Citrullinated Vimentin (MCV) Antibody

Anti-mutated citrullinated vimentin (MCV) antibody is one of several specific anti-citrullinated protein antibodies which may be used as a second-line marker of rheumatoid arthritis (RA), in addition to rheumatoid factor and anti-cyclic citrullinated peptide (CCP). MCV antibody is less specific than CCP but has a slightly higher sensitivity and the addition of MCV to CCP adds 5-10% sensitivity for the diagnosis of RA. MCV antibody positivity is also associated with more severe disease and greater radiologic progression.

19899 - RNA Polymerase III Antibody

Autoantibodies to RNA Polymerase III antigen are found in 11% to 23% of patients with systemic sclerosis. Patients who are positive for RNA Polymerase III antibodies do not have any of the other antibodies typically found in systemic sclerosis patients such as anti-centromere, anti-Scl-70, or anti-Pm/Scl antibodies. Thus, they are a separate serologic group. Numerous studies have shown that these patients have an increased risk of the diffuse cutaneous form of scleroderma, with high likelihood of skin involvement and hypertensive renal disease.

Antibodies to several different types of RNA Polymerases are found in patients with systemic sclerosis. The immunodominant epitope or RNA Pol III was identified and cloned. The recombinant immunodominant epitope of RNA Pol III can be used in ELISA with high specificity to detect anti-RNA Pol III antibodies in patients with the diffuse cutaneous form of systemic sclerosis, with a high incidence of skin involvement.

19887 - RNP Antibody

RNP Antibodies have been associated with Mixed Connective Tissue disease.

39149 - Interstitial Lung Disease Panel

A subset of interstitial lung disease (ILD) patients have underlying connective tissue diseases (CTDs). This panel serves as an aid for the diagnosis of CTDs, including rheumatoid arthritis, inflammatory myositis, systemic sclerosis, and Sjogren’s syndrome, that are associated with the development of ILD. If left untreated, these CTD patients may develop lung fibrosis and inflammation. ILD is a direct consequence of these pathological changes. When severe, ILD leads to restrictive lung disease, pulmonary arterial hypertension, and cardiac disease (cor pulmonale).

4418 - Rheumatoid Factor

Elevated RF is found in collagen vascular diseases such as SLE, rheumatoid arthritis, scleroderma, Sjogren's syndrome, and in other conditions such as leprosy, tuberculosis, syphilis, malignancy, thyroid disease and in a significant percentage of otherwise normal elderly patients.

11173 - Cyclic Citrullinated Peptide (CCP) Antibody (IgG)

A synthetic circular peptide containing citrulline called CCP IgG (cyclic citrullinated peptide) has been found to be better at discriminating Rheumatoid Arthritis patients from patients with other diseases such as hepatitis C infection. Rheumatoid Arthritis Classification Criteria include CCP IgG Antibody, rheumatoid factor, C-reactive protein and erythrocyte sedimentation rate (ESR). Approximately 70% of patients with Rheumatoid Arthritis are positive for Anti-CCP IgG, while only about 2% of random blood donors and disease controls subjects are positive.

16088 - Centromere B Antibody

Centromere B Antibody is diagnostic for the form of scleroderma known as CREST (calcinosis, Raynaud's phenomenon, esophageal immotility, sclerodactyly, and telangiectasia).

38568 - Sjogren's Antibody (SS-A)

Sjögren's Antibodies (SS-B) is detected in approximately 15% of patients with Sjögren's Syndrome. Sjögren's Antibody (SS-B) is present only if Sjögren's Antibody (SS-A) is also detected. The presence of both antibodies (SS-A and SS-B) strengthen the diagnosis of Sjögren's Syndrome and conveys prognostic information.

Related guides (1)

Idiopathic Inflammatory Myopathies: Laboratory Support for Diagnosis

This Clinical Focus provides an overview of the use of laboratory testing to diagnose myositis caused by the idiopathic inflammatory myopathies.

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Reference ranges are provided as general guidance only. To interpret test results use the reference range in the laboratory report.

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