Possible Value of Antifibrotic Drugs in Patients With Progressive Fibrosing Non-IPF Interstitial Lung Diseases

Sebastiano Emanuele Torrisi; Nicolas Kahn; Julia Wälscher; Nilab Sarmand; Markus Polke; Kehler Lars; Monika Eichinger; Claus Peter Heussel; Stefano Palmucci; Francesca Maria Sambataro; Gianluca Sambataro; Domenico Sambataro; Carlo Vancheri; Michael Kreuter

Disclosures

BMC Pulm Med. 2019;19(213)

Conclusions

Antifibrotic treatment after multidisciplinary team discussion and with patient consent may be a valuable treatment option in patients with progressive fibrosing non-IPF ILDs that do not benefit from corticosteroids and immunosuppressive treatments if no other treatment options exist. However, prospective, randomized clinical trials are urgently needed to assess the real impact of antifibrotic therapy in these patients.

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Abbreviations
BAL: Bronchoalveolar lavage; DLCO: Diffusing capacity of the lung for carbon monoxide; FVC: Forced vital capacity; HRCT: High resolution computed tomography; IPAF: Interstitial pneumonia with autoimmune features; IPF: Idiopathic Pulmonary Fibrosis; MDT: Multidisciplinary team; PFILDs: Progressive fibrosing non-IPF interstitial lung diseases; PPFE: Pleuroparenchymal fibroelastosis; SSc-ILD: Systemic sclerosis associated-ILD

Acknowledgements
Not applicable

Funding
None.

Availability of data and materials
The data analyzed in the current study are not publicly available but may be made available from the corresponding authors on reasonable request.

Ethics approval and consent to participate
The ethics committee of the University of Heidelberg approved this retrospective study. Due to the retrospective nature of this analysis and according to the vote of the ethics committee, written informed consent could not be obtained by the patients but patient records/information were anonymized and de-identified prior to analysis.

Consent for publication
Not applicable

Table 1. Baseline characteristics of patients
	Mean ± SD orn (%)	Median (range interquartile)
Age at diagnosis (years)	62.09 ± 12.80	63 (50, 76)
Age at initiation of antifibrotic therapy	63.72 ± 12.72
Male	8 (72.72)
Former smoker	5 (45.45)
Never smoker	6 (54.54)
Cryobiopsy	9 (81.81)
Follow-up time (days) since diagnosis		903 (381, 1489)
Follow-up time (days) since antifibrotic initiation		333 (156, 421)
FVC% pred at baseline	62.82 ± 22.30	52.7 (49, 77)
DLCO% pred at baseline	35.55 ± 10.74	34 (29, 37.1)
TORVAN index (points)	17.18 ± 5.13	19 (13, 21)
HRCT features
Reticulations	7 (63.6)
Traction bronchiectasis	8 (72.7)
Honeycombing	2 (27.2)
Ground-glass	7 (63.6)
Consolidations	3 (27.2)
Mosaic attenuation	2 (27.2)
Upper-mid lung predominance	3 (27.2)
Lower lung predominance	4 (36.3)
Prednisone	11 (100)
Daily dosage (mg)	16.81 ± 11.18
Azathioprin	5 (45.04)
Daily dosage (mg)	150
Methotrexate	1 (9,09)
Weekly dosage (mg)	7.5
Cyclophosphamide	1 (9.09)
Dosage i.v. per cycle (mg)	1000

Table 2. Detailed characteristics of patients
Characteristics	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8	Case 9	Case 10	Case 11
BMI	24	37	23	19	30	23	21	31	25	21	31
Smoking history (pack years)	Former (12 py)	Former (70 py)	Never	Never	Never	Never	Former (20 py)	Former (15 py)	Former (25 py)	Never	Never
ILD relevant exposure	no	no	no	Powders, detergents	no	no	no	Cement powders	powders	no	no
Autoantibodies	ANA 1:80; ENA negative	ANA 1:320; ENA negative	ANA 1:640; ENA negative	negative	ANA 1:80; ENA negative	ANA 1:1280; ENA negative	ANA 1:160; ANCA 1:32; ENA negative	ANA 1:320; ENA negative	ANA 1:320; ENA negative	ANA 1:160; ENA negative	ANA 1:160; ENA negative
FVC L (%) at baseline	1.9 (63)	1.82 (48)	2.74 (77)	1.26 (52.7)	2.1 (49)	2.31 (52.7)	4.28 (101)	3.37 (97.7)	3 (73)	0.93 (26.5)	1.47 (51.5)
DLCO % at baseline	38	35	unable	27.4	27	30	64	29	37.1	33	35
TORVAN index	19	21	19	22	14	24	13	17	7	12	21
BAL findings at initial diagnosis	Macrophages 65%, Lymphocytes 13%, Neutrophils 22%	Macrophages 85%, Lymphocytes 12%, Neutrophils 3%, Eosinophils 0%	Macrophage 76%, Lymphocytes 10%, Neutrophils 9%, Eosinophils 3%, Mastcells 2%	/	Macrophage 89%, Lymphocytes 9%, Eosinophils1%	Macrophages 89%, Lymphocytes 14%, Neutrophils 2%	Macrophage 96%, Lymphocytes 2%, Neutrophils 2%	Macrophage 91%, Lymphocytes 9%, Neutrophils 10%	Macrophages 77%, Lymphocytes 5%, Neutrophils 8%, Eosinophils 10%	/	/
Histological pattern	NSIP	/	Indeterminate	Compatible with PPFE	Indeterminate	Indeterminate	Indeterminate	UIP-like	Indeterminate	/	Indeterminate
LTOT at initiation of antifibrotic therapy	Yes	Yes	No	No	No	No	No	Yes	Yes	No	Yes
Distance at 6MWT (meters)	425	/	578	363	313	402	540	323	480	418	/
MDT diagnosis	iNSIP	uILD (IPAF)	uILD (IPAF)	PPFE	uILD	uILD (IPAF)	uILD	Asbestos-associated fibrosis	ILD in Hermansky-Pudlak syndrome	PPFE	uILD
Treatment before antifibrotics	Pred. 30 mg; AZT 125 mg; NAC 1800 mg	Pred. 15 mg; AZT 150 mg; MTX 7,5 mg	Pred. 30 mg; AZT 150 mg	Pred. 10 mg;	Pred. 10 mg;	Pred. 7,5 mg; AZT 150 mg; NAC 1800 mg	Pred. 7,5 mg; Cycl. (6 cycles)	Pred. 15 mg; AZT 150 mg	Pred. 10 mg;	Pred. 10 mg;	Pred. 40 mg;
Antifibrotic treatment	Pirf 2403 mg	Nint. 300 mg	Pirf 2403 mg	Pirf 1602 mg	Pirf 2403 mg	Pirf 2403 mg	Pirf 2403 mg	Pirf 2403 mg	Pirf 1602 mg	Pirf 2403 mg	Pirf 2403 mg

Footnotes: BMI Body mass index, FVC Forced Vital capacity, DLCO Diffusing Capacity for carbon monoxide, BAL Bronchial alveolar lavage, LTOT long term oxygen therapy, MDT multidisciplinary discussion, iNSIP idiopathic-Non specific interstitial Pneumonia, uILD unclassifiable Interstitial lung disease, PPFE pleuroparenchymal fibroelastosis, Pred. prednisone, AZT Azathioprin, MTX Methotrexate, Cycl. cyclophosphamide, Pirf. Pirfenidone, Nint. Nintedanib

Authors and Disclosures

Sebastiano Emanuele Torrisi^1,2, Nicolas Kahn¹, Julia Wälscher¹, Nilab Sarmand¹, Markus Polke¹, Kehler Lars¹, Monika Eichinger³, Claus Peter Heussel³, Stefano Palmucci⁴, Francesca Maria Sambataro^3,5,6, Gianluca Sambataro^2,6, Domenico Sambataro⁷, Carlo Vancheri² and Michael Kreuter¹*

¹Center for interstitial and rare lung diseases, Pneumology, Thoraxklinik, University of Heidelberg, Germany and German Center for Lung Research, Heidelberg, Germany. ²Department of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung Diseases, A.O.U. Policlinico-Vittorio Emanuele, University of Catania, Catania, Italy. ³Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik, University of Heidelberg and Translational Lung Research Center Heidelberg, member of the German Center for Lung Research, Heidelberg, Germany. ⁴Radiology I Unit, Department of Medical Surgical Sciences and Advanced Technologies, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy. ⁵Department of Imaging, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, CTO Hospital, Via Zuretti 29, 10126 Turin, Italy. ⁶Artroreuma s.r.l. Outpatient of Rheumatology accredited with the National Health System, c.so S. Vito 53, 95030 Mascalucia, CT, Italy. ⁷Department of Clinical and Experimental Medicine, Internal Medicine Unit, Cannizzaro Hospital, University of Catania, Via Messina 829, 95100 Catania, Italy.

*Correspondence
kreuter@uni-heidelberg.de

Authors' contributions
SET, NK, SP, FMS, GS, DS contributed to the conception and design of the work, to data analysis and interpretation, and to the drafting and substantial revision of the work. JW, NS, MP, KL, ME have made contribution to acquisition of data. CPH, CV and MK revised the manuscript. All authors read and approved the final manuscript.

Competing interests
S.E. Torrisi reports grants from Boehringer Ingelheim and F Hoffman La-Roche, outside the submitted work. J. Wälscher reports fees for consulting from Boehringer Ingelheim and Roche/InterMune, outside the submitted work. C. Vancheri reports grants and speaker's fees from Boehringer Ingelheim and Intermune/F Hoffman La-Roche, outside the submitted work. M. Kreuter reports grants and fees for consulting from Boehringer Ingelheim and Roche/InterMune, outside the submitted work. The other authors report no conflicts of interest.

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Possible Value of Antifibrotic Drugs in Patients With Progressive Fibrosing Non-IPF Interstitial Lung Diseases

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