Identification and management of connective tissue disease-associated interstitial lung disease: evidence-based Japanese consensus statements

Figures & data

Table 1. Expert consensus agreement statements on CTD-ILD.

	Statement	Consensus level, % Mean (P10, P90)
	Risk factors
1	CTD is a risk factor for developing ILD.	96.5 (90.0, 100.0)
27	Diffuse cutaneous SSc is a risk factor for developing ILD in patients with SSc.	78.7 (70.0, 90.0)
2	Male sex is a risk factor for developing ILD in patients with RA.	86.2 (70.3, 99.3)
36	Male sex may be a risk factor for progression and poor prognosis of ILD in patients with SSc.	72.0 (54.3, 88.6)
3	Advanced age (60 years or older) is a risk factor for developing ILD in patients with RA.	87.2 (80.0, 96.8)
22	Older age may be a risk factor for developing ILD in patients with SS.	70.1 (60.5, 75.9)
30	Older age is a risk factor for poor prognosis of ILD in patients with PM/DM.	82.1 (70.3, 90.0)
37	Older age may be a risk factor for progression of ILD in patients with SSc.	74.6 (60.2, 85.0)
4	Smoking history is a risk factor for developing ILD in patients with RA.	89.0 (80.0, 100.0)
23	Smoking history is a risk factor for developing ILD in patients with SSc.	78.4 (61.9, 89.9)
8	High anti-CCP antibody titers may be a risk factor for developing ILD in patients with RA.	82.2 (75.3, 93.6)
9	High RF titers may be a risk factor for developing ILD in patients with RA.	75.8 (60.0, 91.8)
10	Anti-ARS antibody is a risk factor for developing ILD in patients with PM/DM.	97.1 (90.1, 100.0)
11	Anti-MDA5 antibody is a risk factor for developing ILD in patients with DM.	96.7 (90.0, 100.0)
12	The presence of anti-TIF-1γ antibody or anti-Mi2 antibody, compared to negative cases, suggests a lower risk of developing ILD in patients with DM.	72.5 (51.0, 90.9)
14	Anti-MDA5 antibody is a risk factor for developing rapidly progressive ILD in patients with PM/DM.	94.7 (90.0, 100.0)
24	Anti-topoisomerase I antibody is a risk factor for developing ILD in patients with SSc.	87.0 (80.0, 100.0)
35	Anti-MDA5 antibody is a risk factor for poor prognosis of ILD in patients with PM/DM.	94.4 (90.0, 100.0)
15	Clinically amyopathic dermatomyositis (CADM) is a risk factor for developing rapidly progressive ILD.	88.2 (71.0, 100.0)
16	Mechanic’s hands may be a risk factor for developing ILD in patients with PM/DM.	76.2 (67.1, 90.0)
19	High serum ferritin level is a risk factor for developing rapidly progressive ILD in patients with DM.	83.6 (71.4, 96.8)
33	High serum ferritin level (≥500 ng/dL) is a risk factor for poor prognosis of ILD in patients with PM/DM.	82.2 (67.4, 90.9)
29	Usual interstitial pneumonia (UIP) pattern on HRCT is a risk factor for acute exacerbation and poor prognosis of ILD in patients with RA.	92.3 (85.1, 100.0)
43	Extent of ILD on baseline chest HRCT is a risk factor for progression and poor prognosis of ILD in patients with SSc.	91.1 (80.4, 100.0)
31	Decreased SpO2 (<95%) is a risk factor for poor prognosis of ILD in patients with PM/DM.	86.1 (80.0, 95.0)
41	Low baseline FVC is a risk factor for poor prognosis of ILD in patients with SSc.	89.8 (80.4, 100.0)
42	Low baseline DLco is a risk factor for progression and poor prognosis of ILD in patients with SSc.	84.1 (74.5, 90.0)
32	Elevated serum CRP (≥1.0 mg/dL) may be a risk factor for poor prognosis of ILD in patients with PM/DM.	72.1 (58.2, 90.0)
34	High serum KL-6 level (≥1,000 U/mL) is a risk factor for poor prognosis of ILD in patients with PM/DM.	77.2 (61.0, 89.5)
38	Higher modified Rodnan total skin thickness score (mRSS), compared to lower cases, is a risk factor for progression of ILD in patients with SSc.	77.0 (65.5, 90.0)
40	The SPAR model score indicates risk for progression of ILD in patients with SSc. (The SPAR model predicts progression of ILD based on ”≤94% SpO2 after 6-minute walking test” and ”presence or history of arthritis”.)	79.1 (70.0, 90.0)
46	The SADL model score indicates risk for poor prognosis of ILD in patients with SSc. (The SADL model predicts mortality risk based on “smoking history”, “age”, and “DLco” [16].)	82.0 (71.4, 90.0)
44	Pulmonary hypertension is a risk factor for poor prognosis in patients with SSc-ILD.	93.7 (89.1, 100.0)
45	High serum KL-6 level is a risk factor for progression and poor prognosis of ILD in patients with SSc.	85.4 (80.0, 90.0)
	Screening tools
47	Presence of ILD should be suspected in patients with CTD with persistent respiratory symptoms (dry cough, palpitations on exertion, and shortness of breath).	94.7 (81.7, 100.0)
49	Screening using chest auscultation is effective for ILD in patients with CTD.	85.8 (67.0, 100.0)
48	Chest X-ray is considered to be a screening tool for ILD in patients with CTD.	73.9 (60.2, 87.5)
52	Screening for ILD using chest CT is informative in patients with CTD.	90.6 (80.0, 100.0)
53	Screening for ILD using chest HRCT is informative in patients with CTD.	96.5 (90.0, 100.0)
54	Screening for ILD using chest HRCT is informative in patients with SSc with risk factors for developing ILD.	98.2 (91.4, 100.0)
55	Screening for ILD using chest HRCT is informative in patients with PM/DM with risk factors for ILD.	98.6 (95.0, 100.0)
56	Screening for ILD using chest HRCT is informative in patients with RA with risk factors for developing ILD.	97.9 (90.2, 100.0)
51	KL-6 level is considered to be a screening tool for ILD in patients with CTD.	84.5 (71.0, 91.8)
	Diagnosis assessment and severity assessments
57	HRCT is effective for diagnosis and assessment of ILD severity in patients with CTD.	97.8 (90.5, 100.0)
73	Reticulation and honeycombing scores on HRCT are informative for severity assessment of ILD in patients with RA.	87.7 (75.5, 95.9)
58	Chest X-ray is considered to be a diagnostic tool for ILD in patients with CTD.	73.6 (51.0, 99.0)
59	Serum biomarker (such as KL-6 and SP-D) measurements should be considered for detection of ILD in patients with CTD.	88.9 (80.0, 100.0)
72	Serum biomarker (such as KL-6 and SP-D) measurements should be considered for assessment of ILD severity in patients with CTD.	78.0 (55.5, 90.0)
76	KL-6 level should be considered for assessment of ILD severity in patients with anti-ARS antibody-positive PM/DM.	78.3 (60.0, 92.9)
60	Bronchoalveolar lavage (BAL) should be considered for exclusion of differential diagnosis (such as infectious diseases and alveolar hemorrhage) of ILD in patients with CTD.	77.6 (60.5, 94.6)
63	Multidisciplinary discussion (MDD) among pulmonologists, rheumatologists, radiologists, and pathologists is considered useful for diagnosis of ILD in patients with CTD.	90.6 (80.0, 100.0)
64	Measurement of DLco should be considered for assessment of ILD severity in patients with CTD.	82.6 (65.6, 94.6)
65	Measurement of FVC is effective for assessment of ILD severity in patients with CTD.	94.6 (90.0, 100.0)
67	Measurement of SpO2 should be considered for assessment of ILD severity in patients with CTD.	80.6 (68.1, 99.5)
68	Arterial blood gas analysis should be considered for assessment of ILD severity in patients with CTD.	76.5 (60.0, 91.8)
66	6-minute walking test should be considered for assessment of ILD severity in patients with CTD.	78.8 (62.7, 92.7)
69	Evaluations of patient reported outcomes on dyspnea (such as the modified MRC) should be considered for assessment of ILD severity in patients with CTD.	89.6 (80.0, 100.0)
70	Evaluations of patient reported outcomes on health-related QOL (such as SGRQ) should be considered for assessment of ILD severity in patients with CTD.	77.7 (60.0, 93.6)
71	The ILD-GAP model should be considered for assessment of ILD severity in patients with CTD.	76.6 (60.4, 89.5)
74	The SADL model is informative for assessment of ILD severity in patients with SSc. (The SADL model predicts mortality risk based on ”smoking history”, ”age”, and ”DLco”).	78.7 (70.2, 86.7)
75	Anti-MDA5 antibody and serum ferritin levels are informative for assessment of ILD severity in patients with anti-MDA5 antibody-positive DM.	93.1 (85.0, 100.0)
	Follow-up period
77	Chest X-ray and/or HRCT are recommended every few days to every month for patients with CTD-ILD with progression during acute/subacute course (especially for those with anti-MDA5 antibody-positive DM).	97.3 (90.0, 100.0)
78	Chest HRCT is recommended every 1 to 3 months for patients with acute/subacute CTD-ILD, and then every 6 to 12 months if there is no progression.	90.7 (80.5, 100.0)
80	Evaluations of chest HRCT, along with KL-6 and SP-D measurements, should be considered at least once a year for patients with CTD-ILD.	93.3 (85.5, 100.0)
79	Measurements of FVC (and DLco if possible) are recommended at least once a year for patients with CTD-ILD.	95.6 (90.0, 100.0)
	Initiation of treatment and drivers of treatment recommendation
81	Presence or absence of respiratory symptoms is a consideration when deciding whether to initiate treatment for patients with CTD-ILD.	88.0 (75.5, 99.5)
82	Evaluations of clinical course (disease progression) are informative when deciding whether to initiate treatment for patients with CTD-ILD.	95.9 (90.0, 100.0)
83	Evaluations of disease severity are informative when deciding whether to initiate treatment for patients with CTD-ILD.	90.5 (80.0, 100.0)
84	Evaluations of chest HRCT should be considered when deciding whether to initiate treatment for patients with CTD-ILD.	96.2 (90.0, 100.0)
85	Measurements of FVC are informative when deciding whether to initiate treatment for patients with CTD-ILD.	94.0 (90.0, 100.0)
86	Measurements of DLco should be considered when deciding whether to initiate treatment for patients with CTD-ILD.	88.4 (80.3, 95.0)
87	KL-6 measurements should be considered when deciding whether to initiate treatment for patients with CTD-ILD.	76.1 (60.1, 92.7)
88	Comprehensive evaluations of respiratory symptoms, QOL, chest HRCT, and FVC, DLco, and KL-6 levels are informative when deciding whether to initiate treatment for patients with CTD-ILD.	99.1 (95.4, 100.0)
89	Multidisciplinary discussion (MDD) among pulmonologists, rheumatologists, radiologists, and pathologists is informative when deciding whether to initiate treatment for patients with CTD-ILD.	92.2 (86.2, 100.0)
90	Individualized risk–benefit analysis is informative when deciding whether to initiate treatment for patients with CTD-ILD.	95.7 (90.0, 100.0)
91	Immediate treatment of acute/subacute onset or acute exacerbation in patients with CTD-ILD is effective.	98.1 (94.1, 100.0)
92	Presence of a usual interstitial pneumonia (UIP) pattern is a consideration when deciding whether to initiate treatment for patients with CTD-ILD.	88.3 (80.0, 99.5)
93	Treatment responses to CTD manifestations other than ILD are a consideration when selecting treatments for patients with CTD-ILD.	92.0 (82.3, 100.0)
94	Consider factors associated with poor prognosis when deciding whether to initiate treatment in patients with RA-ILD.	83.8 (78.1, 99.1)
95	Presence of anti-MDA5 antibodies is a consideration when deciding whether to initiate treatment in patients with PM/DM-ILD.	95.4 (90.0, 100.0)
97	Elevated inflammatory markers (ESR, CRP, and platelet counts) are a consideration when deciding whether to initiate treatment in patients with SSc-ILD.	72.9 (52.8, 89.6)
98	The presence or absence of early diffuse cutaneous SSc is a consideration when deciding whether to initiate treatment in patients with SSc-ILD.	85.6 (75.2, 100.0)
99	The extent of disease is informative when deciding whether to initiate treatment in patients with SSc-ILD.	89.4 (80.5, 99.6)
	Disease progression
100	Assessment of worsening respiratory symptoms should be considered when evaluating disease progression of CTD-ILD.	93.2 (85.2, 100.0)
101	Assessment of change (worsening) in the extent of fibrosis on chest HRCT should be considered when evaluating disease progression of CTD-ILD.	94.7 (90.0, 100.0)
102	Assessment of change (decline) in FVC is informative when evaluating disease progression of CTD-ILD.	95.7 (90.0, 100.0)
103	Assessment of change (decline) in DLco should be considered when evaluating disease progression of CTD-ILD.	88.6 (80.3, 99.6)
104	Combined assessment of change (decline) in FVC and DLco is informative when evaluating disease progression of CTD-ILD.	91.8 (87.3, 100.0)
105	Combined assessment of change (worsening) in the extent of fibrosis on chest HRCT and change (decline) in FVC and DLco is informative when evaluating disease progression of CTD-ILD.	97.6 (95.0, 100.0)
106	Combined assessment of worsening respiratory symptoms, change (worsening) in the extent of fibrosis on chest HRCT, and change (decline) in FVC and DLco is informative when evaluating disease progression of CTD-ILD.	98.8 (95.0, 100.0)
107	Multidisciplinary discussion (MDD) among pulmonologists, rheumatologists, radiologists, and pathologists is informative when evaluating disease progression of CTD-ILD.	90.7 (76.0, 100.0)
108	Patients requiring oxygen administration due to respiratory failure within approximately 1 month of diagnosis of ILD have rapidly progressive ILD.	75.3 (60.0, 94.8)
109	In patients with PM/DM-ILD, development of mediastinal emphysema suggests rapid disease progression.	77.4 (60.1, 92.7)

ARS: aminoacyl tRNA synthetase; CCP: cyclic citrullinated peptide; CRP: C-reactive protein; CT: computed tomography; CTD-ILD: connective tissue disease-associated interstitial lung disease; DLco: diffusing capacity of the lungs for carbon monoxide; ESR: erythrocyte sedimentation rate; FVC: forced vital capacity; GAP: gender, age, physiology; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; KL-6: Krebs von den Lungen 6; MDA5: melanoma differentiation-associated gene 5; MRC: Medical Research Council dyspnea scale; P: percentile; PM/DM: polymyositis/dermatomyositis; QOL: quality of life; RA: rheumatoid arthritis; RF: rheumatoid factor; SADL: smoking, age, DLco; SP-D: surfactant protein D; SPAR: SpO₂ and arthritis; SGRQ: St George’s Respiratory Questionnaire; SpO₂: peripheral oxygen saturation; SS: Sjögren’s syndrome; SSc: systemic sclerosis; TIF1γ: transcription intermediary factor 1-gamma.

Table 2. Expert consensus disagreement statements on CTD-ILD.

	Statement	Consensus level, % Mean (P10, P90)
	Risk factors
5	Obesity (BMI ≥30 kg/m^2) may be a risk factor for developing ILD in patients with RA.	46.6 (21.0, 71.8)
26	Male patients with SSc have a higher risk of developing ILD compared to female patients.	68.2 (55.2, 79.5)
6	Disease activity with DAS28-CRP ≥3.2 may be a risk factor for developing ILD in patients with RA.	67.2 (50.2, 85.0)
7	Poor functional status (HAQ-DI ≥1.0) may be a risk factor for developing ILD in patients with RA.	53.6 (40.5, 74.5)
13	Patients with PM/DM and anti-Jo-1 antibody, compared to those with non-anti-Jo-1 ARS antibodies, have a lower risk of developing ILD.	21.1 (2.1, 39.5)
25	Anticentromere antibody positivity, compared to negative cases, suggests lower risk of developing ILD in patients with SSc.	60.6 (40.0, 81.8)
28	High creatine kinase (CK) level is a risk factor for developing ILD in patients with SSc.	57.7 (36.2, 70.9)
17	Polyarthritis may be a risk factor for developing ILD in patients with PM/DM.	62.9 (45.5, 79.5)
18	Raynaud’s phenomenon may be a risk factor for developing ILD in patients with PM/DM.	60.4 (44.6, 74.5)
39	Presence of reflux esophagitis may be a risk factor for progression of ILD in patients with SSc.	65.6 (42.0, 80.0)
20	Onset during winter and spring may be a risk factor for developing rapidly progressive ILD in patients with DM.	63.4 (50.0, 79.4)
21	Environmental factor (residence close to any major waterfront) may be a risk factor for developing rapidly progressive ILD in patients with DM.	60.8 (50.0, 77.7)
	Screening tools
50	SpO2 is considered to be a screening tool for ILD in patients with CTD.	70.0* (50.7, 94.5)
	Diagnosis assessment and severity assessments
61	Transbronchial biopsy (TBLB) should be considered for diagnosis of ILD in patients with CTD.	29.0 (1.0, 49.7)
62	Transbronchial lung cryobiopsy (TBLC) should be considered for diagnosis of ILD in patients with CTD.	53.5 (30.1, 69.5)
	Initiation of treatment and drivers of treatment recommendation
96	Presence of arthritis should be considered when deciding whether to initiate treatment in patients with SSc-ILD.	54.5 (30.5, 79.2)

*Mean consensus level of 69.95% when rounded to two decimal places.

ARS: aminoacyl tRNA synthetase; BMI: body mass index; CRP: C-reactive protein; CTD-ILD: connective tissue disease-associated interstitial lung disease; DAS: disease activity score; HAQ-DI: Health Assessment Questionnaire Disability Index; ILD: interstitial lung disease; Jo-1: histidyl tRNA synthetase; P: percentile; PM/DM: polymyositis/dermatomyositis; RA: rheumatoid arthritis; SpO₂: peripheral oxygen saturation; SSc: systemic sclerosis.

Figure 1. Management algorithm for interstitial lung disease in patients with connective tissue diseases. CT: computed tomography; CTD: connective tissue disease; DLco: diffusing capacity of the lungs for carbon monoxide; DM: dermatomyositis; FVC: forced vital capacity; GAP: gender, age, physiology; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; KL-6: Krebs von den Lungen 6; MDA5: melanoma differentiation-associated gene 5; MRC: Medical Research Council dyspnea scale; QOL: quality of life; SGRQ: St George's Respiratory Questionnaire; SP-D: surfactant protein D; SpO₂: peripheral oxygen saturation.

Morisset J, Vittinghoff E, Elicker BM, et al. Mortality risk prediction in scleroderma-related interstitial lung disease: the SADL model. Chest. 2017 Nov;152(5):999–1007.

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Data availability statement

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.