Management of progressive pulmonary fibrosis associated with connective tissue disease

Figures & data

Table 1. Patient features and invasive and noninvasive tests useful for identifying an ILD in a CTD.

Noninvasive tests

Patient history:

Smoking

Medication use

Environmental exposures (mold, feathers, animals, metal dusts, wood dusts, plant dusts, livestock, stone polishing, and cutting)

Current or recent occupations (e.g. hairdressing) and current or recent hobbies

Family history of ILD

Pulmonary function tests:

FVC

DLCO

If possible, total lung capacity

Autoantibodies associated with an increased risk of developing ILD:

Anti-cyclic citrullinated peptide at high titers

Anti-Scl 70

Anti-Jo1, PL-7 and PL-12

Anti-Ro (SSA)

Anti-MDA 5

Anti-PM/Scl

Anti-Th/To

Imaging tests

HRCT: reticulation, bronchiectasis and traction bronchiectasis, ‘honeycombing’ pattern, ‘ground glass’.

Invasive tests

Bronchoalveolar lavage, transbronchial criobiopsy

Lung biopsy

CTD, connective tissue disease; DLCO, carbon monoxide diffusing capacity; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease.

Table 2. Radiological patterns and signs of fibrosis on chest HRCT [40].

Radiological patterns	Radiological signs
Linear-reticular pattern	Thickening of the intralobular septa: produces linear images of several centimeters in length. Intralobular interstitial thickening: presence of a fine reticular meshwork extending from the peribronchovascular structures of the center of the lobule to the interlobular septa, with a ‘spider web’ morphology.
Nodular pattern	Small nodules: > 2 mm Miliary nodules: 1–2 mm
Ground-glass pattern	Faint increase in lung density often geographically distributed, which does not obliterate adjacent vascular structures
Cystic pattern	Thin-walled rounded images (generally 1 to 3 mm thick), well-defined and with air inside them
Condensation or consolidation pattern	Increased pulmonary attenuation associated with blurring of adjacent vessel contours
Usual interstitial pneumonia (UIP)	Subpleural, basal and symmetrical localization; occasionally diffuse Apico-basal progression‘ Ground-glass’ (minimal)Reticulation, bronchiectasis and traction bronchiectasis‘ Honeycombing’ pattern
Nonspecific interstitial pneumonia (NSIP)Nonspecific interstitial pneumonia (NSIP) fibrotic*	Variable involvement (central and peripheral) Preference in inferior lobes Patchy ‘ground-glass’ opacities associated with linear, reticular and micronodular images Traction bronchiectasis/bronchilectasis* Infrequent ‘honeycombing’ pattern

*Traction bronchiectasis/bronchilectasis refers to NSIP fibrotic.

Table 3. SER-SEPAR proposed screening criteria for diffuse interstitial lung disease in patients diagnosed with rheumatoid arthritis [44].

The following 3 clinical situations are to be screened for ILD:
Patients with respiratory symptoms (cough and/or dyspnea) of more than 3 months of evolution. Patients in whom velcro-type crackles are detected in respiratory auscultation, even if they are asymptomatic. In patients without respiratory symptoms and with normal respiratory auscultation, screening will be done according to the score obtained based on the number of risk factors present for the development of this complication.
Any patient scoring ≥ 5 points will be considered eligible for screening:
Set of variables and proposed score for each of the variables for the overall score	Score
Age ≥ 60 years	2
Male sex	1
History of smoking (active smoker or former smoker) ≤ 20 packs/year: 2 points > 20 packs/year: 3 points	2 3
Duration of disease > 5 years	1
Persistently moderately-high activity: Average DAS28-VSG > 3.2 since disease diagnosis in baseline RA (time since diagnosis ≤ 12 months) or DAS28-VSG > 3.2 for a minimum of 6 months in established RA	1
Serology (only the criterion with the highest weighting is counted toward the total score) RF positive > 3 times above ULN ACPA positive ≤ 3 times the ULN ACPA positive > 3 times the ULN	1 2 3
Family history of ILD	1

ACPA: anti-cyclic citrullinated peptide antibodies; ILD: interstitial lung disease; RA: rheumatoid arthritis; RF: rheumatoid factor; SEPAR: Spanish Society of Pneumology and Thoracic Surgery; SER: Spanish Society of Rheumatology; ULN: upper limit of normal.

Table 4. Main risk factors for ILD development in SSc and RA, and prognostic factors for mortality and progression of ILD.

Systemic sclerosis
Risk factors for ILD development
Male gender African-American or Asian ethnicity Diffuse skin involvement Cardiac involvement Anti-Scl 70 or topoisomerase I and anti-Th/To positivity
Variables associated with an increased risk of ILD progression
Demographic	Male sex Older age African-American ethnicity Smoking
Clinical	Diffuse skin involvement with elevated Rodnan index scores at diagnosis of ILD Poorly controlled gastroesophageal reflux disease Presence of arthritis Time of disease evolution (first 3 years)
Laboratory	Elevated C-reactive protein Anti-Scl 70 antibody positivity Anti-RNA polymerase III antibody positivity Elevated KL-6 levels
Pulmonary function tests	Low basal FVC (< 70%) Low basal DLCO not due to other causes (mainly pulmonary arterial hypertension) Deterioration of FVC ≥ 10% during follow-up or fall in its values between 5% and 9% with a deterioration of DLCO ≥ 15%
HRCT	Extent of fibrotic changes > 20%
Rheumatoid arthritis
Risk factors for ILD development
Male sex Advanced age Late onset of the disease Duration of RA Smoking Moderate or high sustained RA activity according to DAS28 scores RF positive ACPA positive Antibodies directed against carbamylated proteins (anti-CarP) MUC5B gene mutations Mutations of telomerase genes leading to accelerated telomere shortening
Prognostic factors
Variables associated with ILD progression	Radiologic pattern of UIP Elevated ACPA titers Degree of baseline DLCO deterioration (having been demonstrated with two cutoff points: DLCO < 45% and, in those patients with a progressive fibrosing phenotype, DLCO < 54%), decrease ≥ 10% in FVC during follow-up Extensive pulmonary involvement on HRCT of the chest Elevated serum levels of IL-6 and KL-6
Prognostic factors for mortality	Advanced age at the time of diagnosis of ILD (> 60-65 years) Male sex Duration of RA (the longer the duration of disease at the time of ILD diagnosis, the higher the mortality) Moderate or high disease activity as assessed by the DAS28-VSG index UIP pattern* FVC and/or low baseline DLCO Decrease in FVC >10% or DLCO >15% during follow-up Extensive lung involvement on HRCT of the chest (>20-30%) Elevated serum levels of KL-6

ACPA, anti-cyclic citrullinated peptide antibodies; DLCO, carbon monoxide diffusion capacity; FVC, forced vital capacity; HRCT, high-resolution computed tomography; IL-6, interleukin-6; ILD, interstitial lung disease; KL-6, Krebs von den Lugen glycoprotein; RA, rheumatoid arthritis; RF, rheumatoid factor; SSc, systemic sclerosis; UIP, usual interstitial pneumonia.

*In some studies, the radiological pattern is no longer a predictor of mortality after adjustment for confounding variables in the different multivariate analysis models. The main prognostic factors are the degree of baseline deterioration in the pulmonary functional tests (FVC and DLCO) and the magnitude of its worsening during follow-up.

Table 5. Panel of antibodies to be requested in the evaluation of an ILD to assess its possible association with a CTD.

In the initial evaluation of all patients
Antinuclear antibodies (detection by indirect immunofluorescence)
Rheumatoid factor and anti-cyclic citrullinated peptide antibodies (ACPA)
If rheumatoid arthritis is suspected
Anti-citrullinated peptide antibody (ACPA)
Rheumatoid factor
If systemic sclerosis is suspected
Anti-Scl70/topoisomerase I	Anti-U3RNP (anti-fibrillarin)
Anti-centromere	Anti-Th/To
Anti-RNA polymerase III	Anti-PM/Scl
Anti-U1RNP	Anti-Ku
Anti-NOR 90
If inflammatory myopathy is suspected
Anti-synthetase (Jo-1, PL-7, PL-12, EJ, OJ and KS)	Anti-HMG-CoA reductase
Anti-MDA5	Anti-SAE
Anti-Mi-2	Anti-U1RNP
Anti-NXP2	Anti-PM/Scl75
Anti-TIF1-γ	Anti-PM/Scl100
Anti-SRP	Anti-Ku
If primary Sjögren’s syndrome is suspected
Anti-SSA/Ro60	Anti-SSB/La
Anti-TRIM21/Ro52	Rheumatoid factor
If ANCA vasculitis is suspected*
Anti-neutrophil cytoplasm antibody (ANCA)

HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; MDA5: melanoma differentiation-associated protein 5; NXP2: nuclear matrix protein 2; PM/Scl: polymyositis/scleroderma; RNP: ribonucleoprotein; SAE: small ubiquitin-related modifier-activating enzyme; SRP: signal recognition particle; SSA/Ro: Sjögren-specific antibody A; SSB/La: Sjögrens-specific antibody B; TRIM: Tripartite Motif Containing 21;TIF1-: transcriptional intermediary factor 1 gamma.

*10-11% of patients with idiopathic pulmonary fibrosis develop ANCA (anti-myeloperoxidase or anti-proteinase 3), in most cases in the absence of symptoms of systemic vasculitis [50,51].

Figure 1. Proposed algorithms to stratify the prognosis of patients with interstitial lung disease associated with systemic sclerosis (SSc-ILD). (a). Algorithm proposed by Goh et al. [58] (b). SPAR model [59] FVC, forced vital capacity; HRCT, high-resolution computed tomography.

Giménez Palleiro A, Franquet T. Radiological patterns in interstitial lung disease. Semin Fund Esp Reumatol. 2013;14(4):97–105.

 Google Scholar

Narváez J, Aburto M, Seoane-Mato D, et al. Criterios de cribado de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide: propuesta de expertos basada en metodología Delphi. Reumatol Clin. 2022. [en prensa].

 Google Scholar

Ando M, Miyazaki E, Ishii T, et al. Incidence of myeloperoxidase anti-neutrophil cytoplasmic antibody positivity and microscopic polyangitis in the course of idiopathic pulmonary fibrosis. Respir Med. 2013 Apr;107(4):608–615.

 PubMed Web of Science ®Google Scholar

Kagiyama N, Takayanagi N, Kanauchi T, et al. Antineutrophil cytoplasmic antibody-positive conversion and microscopic polyangiitis development in patients with idiopathic pulmonary fibrosis. BMJ Open Respir Res. 2015;2(1):e000058.

 PubMedGoogle Scholar

Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008 Jun 1;177(11):1248–1254.

 PubMed Web of Science ®Google Scholar

Wu W, Jordan S, Becker MO, et al. Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model. Ann Rheum Dis. 2018 Sep;77(9):1326–1332.

 PubMed Web of Science ®Google Scholar