Academic Center for Interstitial Lung Diseases and Sarcoidosis

Last updated: 365 days ago.

Our aim is to enforce a national network to improve access to and streaming of multidisciplinary specialist care for all ILD patients, to improve diagnosis and treatment, educate colleagues and stimulate research. In clinical research, we particularly focus on identification and introduction of novel outcome measures, innovative lung function monitoring, optimizing national patient registries and bio-banking.

Next to these studies, laboratory research concentrates on effective strategies that combine studies in humans with complementary in vivo analysis in animal models. Hereby, molecular approaches are crucial to (i) unravel disease mechanisms, (ii) identify novel biomarkers, and (iii) investigate therapeutic opportunities in ILD and sarcoidosis.

Academic Center of Excellence

Research Activities

1. The differentiation program and epigenetics of T cell subsets and their role in the pathogenesis of ILD. Hereby we focus on the Th17 lineage. Longstanding collaborations, both in the Erasmus MC (within a T Cell Consortium with Rheumatology, Paediatrics and Haematology, and with the department of Cell Biology) and internationally. In particular, we have intensified our collaboration on sarcoidosis research with prof. J Grunewald, Karolinksa Institutet, Sweden.

2. The role of B-T cell interaction in the pathogenesis of ILD. - We aim to identify the positive feedback loops that are responsible for chronic inflammation and remodelling that is typically seen in ILD. We have explored B and T cell receptor signaling and have generated mouse models that mimic ILD pathology. We have recently started a collaboration with prof. J. Wienands, Goettingen, Germany.

3. Inflammation and remodelling in ILD. - This is studied in genetic mouse models, in experimentally induced ILD, and in human tissue. We benefit from a range of longstanding international collaborations, both in Europe (e.g. Institut Pasteur, Paris, France, University of Erlangen, Germany, Center for Genomic Regulation, Barcelona, Spain) and the US (University of California, San Francisco, and Yale School of Medicine, New Haven).

Main Clinical research and health science:

  1. Registry and biobank
  2. Development of better outcome measures - automated quantitative imaging (with Dept. of radiology and biotech company Promedior) - new lung function techniques (Royal Brompton Hospital, London, UK) - questionnaires (London, UK ; Catania, Italy; Lyon, France; Stockholm, Sweden, Heidelberg, Germany)
  3. Patient involvement in care and research - e-tools - care improvement (5 European ILD expert centres, European Pulmonary Fibrosis patient association, MUMC, Lung Foundation Netherlands, ZonMW project, International 7 country collaboration ).
  4. Quality of life - Lead in multicentre European study on cough in IPF, - multidisciplinary counselling (with psychology, physiotherapy, social work)
  5. Valorisation - sarcoidosis (Nieuwegein NL, Brompton UK, Cincanetti US, Leuven Be) and in systemic sclerosis

Type of

Collaborations

• ACE ‘rare immunological disease’

• ACE ‘Biomarker’

• ACE ‘IMID’

National collaborations in research with other ILD centres are present at multiple levels. The ILD department of pulmonary diseases is active in the Dutch society for physicians in pulmonary and tuberculosis (NVALT), with two board memberships and also in the research society of the NVALT as board members.

Recent research collaborations efforts exist between the ACE ILDS and multiple international centres:

• Joachim Muller-Quernheim and Gernot Zissel (Freiburg); shared biobank and Abatacept immunological analysis)

• Bob Baughman (Cincinatti), ReSAPH study pulmonary hypertension and biomarkers

• Laura Koth (University of California, San Franscisco; T cell biology

• Naftali Kaminski (Yale University); epigenetics and T-cel subsets of sarcoidosis, clinical fellowhips

• Universiteit Leuven (Stijn Verleden): Transplantation- related fibrosis

• Royal Brompton (Andrew Nicholson): childhood ILD

Our ACE collaborates with various funtamental research partners both on national and international level.

• Geert van Loo (VIB Gent, Tcel biology); Tnfaip3 flox-mice model

• Björn Clausen (University of Mainz), DC-specific Mice model

• Hamida Hammad (VIB Gent) pulmonary mucosale immunology

• Kajsa Wing (Karolinska Zweden); CTLA4 flox mice

Clinical collaborations

• “ Hypersensitivity Pneumonitis international expert panel to come to better diagnostic criteria”. J. Morisset, University of Montreal. Montreal, Canada; T. Maher Imperial College London, UK, J. Lee University of Denver Colorado, US; Brett Ley UCSF, San Francisco US, J. Myers, University of Michigan, US, D. Lynch, National Jewish Health, Colorado, US , K. Jones USCF San Francisco , US.

• “Palliative care in ILD working group’’ Kreuter M, Heidelberg, Germany; Bendstrup E, Aarhus Denmark; Russell AM, London, UK; Bajwah S, London, UK; Lindell K, Pittsburg US; Adir Y, Haifa, Israel; Brown CE, seatle US; Calligaro G, Capetown, South Africa; Cassidy N, Corte TJ, Geissler K, Hassan AA, Johannson KA, Kairalla R, Kolb M, Kondoh Y, Quadrelli S, Swigris J, Udwadia Z, Wells A, Wijsenbeek M

• “An open label international, interventional study to evaluate the effect of diet on gastrointestinal adverse events in patients with IPF treated with pirfenidone” M. Molina-Molina, Hospital Bellvitge, Barcelona, Spain, T. Maher, Imperial College London, C. Vancheri, University Catania Italy, K. Antoniou, Crete, Greece, E. Bendstrup, Academic Hospital Aarhus, Denmark.

• “Evaluation of diurnal variation in forced vital capacity in patients with fibrotic interstitial lung diseases using home spirometry” V. Cottin, Hospices Civils de Lyon, Dept of Respiratory Medicine, National Reference Center for Rare Pulmonary Diseases, Lyon, France.

• “Torvan-study”: “The added value of comorbidities in predicting survival in idiopathic pulmonary fibrosis: a retrospective multicenter observational study”. C. Vancheri, University Catania Italy, H Collard and B Ley, UCSF, San Fransisco, USA, M. Kreuter Thorax Clinic, University Heidelberg, Germany.

• “Determining the minimal important clinical difference for the King’s Brief Interstitial Lung Disease Questionaire” . S. Birring King’s Hospital London, UK.

• “Desquamative Interstitial Pneumoniae; defining and validating diagnostic criteria” E. Bendstrup, Academic Hospital Aarhus, Denmark, W. Wuyts Universitair Ziekenhuis Leuven.

• “A multi-national registry of sarcoidosis associated PH (SAPH) patients”. B. Baughman, University of Cincinnati Medical Center, Cincinnati, USA. P. Shlobin INOVA Medical Center, Fairfax, VA, USA, A. Wells Royal Hospital Brompton, London, UK, E. Alhamad Department of Medicine, Division of Pulmonary Medicine, King Saud University, Riyadh, Saudi Arabia, D.Culver, Cleveland Clinic, Cleveland OH, USA. J. Barney University of Alabama, Birmingham, AL, USA. F. Cordova, Temple University, Philadelphia PA, USA. E. Carmona, Mayo Clinic, Rochester Minn, USA

• M. Scholand, University of Utah, Salt Lake City, UT, USA, S. Ganesh, University of Southern California, Los Angeles, CA, USA. S. Birring King's College, London, UK.

“Thuis-monitoren bij Idiopathische Long Fibrose; beter gebruik fibrose-remmers, betere kwaliteit van leven” J. Grutters UMCU, Utrecht en St Antonius Nieuwegein, C. Derksen UMCM, Maastricht, N. Chavannes LUMC, Leiden, R. Mostard Tweesteden ziekenhuis, Heerlen, P. Bresser, OLVG Leiden.

Educational

Contributions

Education is an important tool to ensure excellent patient care by training current and future generations of physicans. This ACE focusses on education on several levels, from medical students to fellow specialists:

The ACE ILDS organizes and contributes to educational activities both with the Erasmus MC as well as national and internationally. Medical students:

· Bachelor: Coordination ILD (BA1B11)

· Master: Various lectures

· Minor Programs Transplantation and Internal Medicine Opportunities: Curriculum is under revision - good to excellent. Feedback: nomination M.Wapenaar "lecturer of the year" in 2015 and 2016. Research Master students - MSc Infection and Immunity: development, core teaching, internships - MSc Molecular Medicine: development, core teaching, internships Opportunities: Curriculum is under revision (MSc Infection and Immunity)

· PhD students: - Erasmus MC Postgraduate School Molecular Medicine: education committee and core teaching (Advanced Immunology) - Organisation of T cell consortium meetings

· Opportunities: Member educational committee Feedback: nomination M. Kool 'co-promotor' of the year 2016. International visitors: Exchange program with University of Erlangen.

· AIOS: - ILD expertise rotation - chair Concilium pulmonary medicine - roles national program Opportunities: Combine with satellite centers Feedback: Well appreciated; more applications of AIOS for ILD rotations than we can handle Intenrational visotors: 3 visiting AIOS/year Medical specialists: - full week ILD-course organized by Pulmonology, Radiology, Pathology and Immunology. Since 2001 - fellowships ILD - preceptorship: 3-day hands on course for European medical specialists - multiple invited international lectures Opportunities: Member educational committee ERN rare pulmonary diseases: plans for European video lectures and expanding preceptorships in Europe Feedback: ILD course average evaluation in the past years > 8/10; preceptorships all well received and demand higher than we can offer.

· (international) Visitors: ~50 specialist/year; 1 fellow yearly Dutch or Belgian; 4x4 European pulmonologists/year Nurses: - Preceptorship, hands-on for visiting specialist nurses Opportunities: educational symposium for specialist nurses in ILDS -

· international) Visitors: - 3-5 /year Dutch, Belgian, German and UK Patients: - Patient and partner empowerment program pulmonary fibrosis (PEP) - yearly patient day ILD - two yearly multidisciplinary patient day sarcoidosis Opportunities: Implementing PEP program nationally together with Longfonds Feedback: - high patient satisfaction and measurable improvement in HROL.

· Visitors: ~16 people twice per year; - 120 patient ILD; -200 patients saroidosis all: - "Bridgemeeting" for basic, translational and clinical researchers, clinicians and patients twice per year Feedback: not officially evaluated Visitors: 30-40 people

· Transdisciplinary education on ILD and sarcoidosis in Erasmus Medical center, e.g. ophthalmology, rheumatology, immunology, internal medicine.

· National education of pulmonary physicians and rheumatologists: Congress on systemic sclerosis

· National ILD specialist meeting of NVALT (Dutch society of pulmonology)

· International course on ILD for Pulmonary physicians, radiologists, immunologists, pathologists and rheumatologists (ILD winter course, Davos, Switzerland)

· Patient education: annual patient meetings with education on fibrosis and sarcoidosis (120 visitors)

Patient

Care Activities

Care is organized in clinical pathways around weekly multidisciplinary meetings (MDTs) and parallel outpatient consultations, which are closely linked to different lines of research. The ILD-MDTs are already taking place since start (Pulmonary Medicine, Radiology, Pathology, Immunology) and since 2017 a weekly MDT for sarcoidosis (with also ophthalmology, dermatology, cardiology, neurology).

The ILD-centre is one of the two National expert centres, as appointed by the NFU and TRF. The centre plays a national role with weekly video conferencing MDT meetings with 17 different centres (e.g. Leiden, The Hague, Zwolle, Nijmegen, Breda, Dordrecht, Rotterdam, Aruba and Cape town in development) and is appointed by the "Zorg Institute" as a centre for the prescription of orphan drugs for idiopathic pulmonary fibrosis. According to Robijn 81% of care was labelled as academic in 2014 and this number is expected to be higher now due to centralisation of care for pulmonary fibrosis from 2014 onward.

The ACE-ILDS participates in an international project on value base health care for sarcoidosis. For IPF outcome parameters are defined and collected. The ACE is participating in the ErasmusMC "value based health care" program as well. Clinical auditshave been performed and only minor comments were raised. A plan was written, executed and evaluated in response to these comments, with good outcome.

Recent initiatives on ACE care activities:

  • Value based healthcare track with systemic sclerosis clinical pathway (collaboration Pulmonology, rheumatology, immunology nd cardiology dept. )
  • Home monitoring project (pulmonary function at home with digitalization of data
  • Collaboration with pathology department; new techniques with cryobiopsy to minimize impact of pulmonary biopsy for patients
  • Doubled MDT meetings on sarcoidosis from twice monthly to weekly meetings

Societal Relevance to Research, Education and Patient Care

There is an urgent need for better treatment and follow up that increases survival while maintaining or increasing quality of life. The ACE ILDS is determined to continuously improve current- and develop new treatment, in order to maintain the highest standard of care for patients. Our main focus is on quality of life, increasing survival and minimising side effects. As a tertiary referral centre, we facilitate peripheral centres in providing the best standard of care by organising and participating in MDTs. The members of the ACE have contributed significantly to the ILD field for all stake holders, examples of achievements the past years were:

  • Co-chair of the international guideline on the treatment of IPF
  • Secretary of the European Respiratory Society Idiopathic Interstitial Pneumonia group.
  • Writing committee of the national position paper on IPF and lympangioleiomyomatisis
  • Chair of the Concilium of pulmonary medicine - Secretary of the Dutch national ILD section
  • Rewarder the "Longfonds publieksprijs 2016 ", award chosen by all pulmonary patients in the Netherlands from 72 submitted projects, indicating societal relevance.
  • Rewarded the Longfonds Dirkje Postma Price for sarcoidosis research 2018
  • Rewarded the patient participation price 2018
  • Negotiating access of anti-fibrotic drugs with VWS and ZIN on behalf of Dutch pulmonologists
  • Done presentations at the European Parliament to call for action in the care for rare pulmonary diseases (IPF-Charter 2014 and 2016) - Advisory board member of patient's associations
  • Development of a questionnaire to evaluate patient experience and satisfaction for expensive medication, also for "low literacy" , to give more patients a voice in reimbursement decisions.
  • Acknowledged as TRF and NFU expert centres

Viability of Research, Education and Patient Care

    • Weekly multidisciplinary meetings and parallel outpatient consultations, which are closely linked to different lines of research. Regular 'bridge meetings' which include both clinicians and (basic) scientists within the Ace. - The ACE believes that its viability, creativity and experiences are ensured by the diversity of its members, which is reflected not only in age, but also in gender, cultural background and medical background.
    • Talent identification and stimulation is actively pursued, 2 members have done the female career development program, several members have followed leadership programs, PhD students are doing part of their research abroad (currently one in Yale and one in Hull). PhD students are strongly encouraged to actively participate in international conferences and training programs (oral and poster presentations).
    • Research is done in close collaboration with other international centres (see also item 9).

We collaborate on a specific fellowship for ILD, to ensure broader education and training of future colleagues. The ACE is always investigating new innovative care programs and research projects to ensure optimal care and research.

Key and relevant publications of the last five years

  • An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, Cunningham W, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A, Wells AU, Hoogsteden H, Schünemann HJ; American Thoracic Society; European Respiratory society; Japanese Respiratory Society; Latin American Thoracic Association. Am J Respir Crit Care Med. 2015 Jul 15;192(2):e3-19.
  • Decreased Cytotoxic T-Lymphocyte Antigen 4 Expression on Regulatory T Cells and Th17 Cells in Sarcoidosis: Double Trouble? Broos CE, van Nimwegen M, In 't Veen JC, Hoogsteden HC, Hendriks RW, van den Blink B, Kool M. Am J Respir Crit Care Med. 2015 Sep 15;192(6):763-5
  • GATA-3 function in innate and adaptive immunity.Tindemans I, Serafini N, Di Santo JP and Hendriks RW (2014). Immunity 41:191-206.
  • The unfolded-protein-response sensor IRE-1α regulates the function of CD8α+ dendritic cells.Osorio F, Tavernier SJ, Hoffmann E, Saeys Y, Martens L, Vetters J, Delrue I, De Rycke R, Parthoens E, Pouliot P, Iwawaki T, Janssens S, Lambrecht BN Nat Immunol. 2014 Mar;15(3):248-57..
  • Perigranuloma localization and abnormal maturation of B cells: emerging key players in sarcoidosis? Kamphuis LS, van Zelm MC, Lam KH, Rimmelzwaan GF, Baarsma GS, Dik WA, Thio HB, van Daele PL, van Velthoven ME, Batstra MR, van Hagen PM, van Laar JA. Am J Respir Crit Care Med. 2013 187:406-16.
  • Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis.Bardou O, Menou A, François C, Duitman JW, von der Thüsen JH, Borie R, Sales KU, Mutze K, Castier Y, Sage E, Liu L, Bugge TH, Fairlie DP, Königshoff M, Crestani B, Borensztajn K S.Am J Respir Crit Care Med. 2016 Apr 15;193(8):847-60.
  • IFN-γ-Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells.Ramstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, Woodruff PG, Bhakta NR, Christian L, Nguyen CP, Antalek BJ, Benn BS, Hendriks RW, van den Blink B, Kool M, Koth LLAm J Respir Crit Care Med. 2016 Jun 1;193(11):1281-91.
  • European IPF Patient Charter: unmet needs and a call to action for healthcare policymakers. Bonella F, Wijsenbeek M, Molina-Molina M, Duck A, Mele R, Geissler K, Wuyts W. Eur Respir J. 2016 Feb;47(2):597-606.
  • Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: safety, pharmacokinetics and exploratory efficacy. Van den Blink B, Dillingh MR, Ginns LC, Morrison LD, Moerland M, Wijsenbeek M, Trehu EG, Bartholmai BJ, Burggraaf J. Eur Respir J. 2016 Mar;47(3):889-97.
  • Efficacy of adalimumab in chronically active and symptomatic patients with sarcoidosis. Kamphuis LS, Lam-Tse WK, Dik WA, van Daele PL, van Biezen P, Kwekkeboom DJ, Kuijpers RW, Hooijkaas H, van Laar JA, Bastiaans J, Baarsma GS, van Hagen PM. Am J Respir Crit Care Med. 2011 184:1214-6.

PhD theses of the last five years

  • Btk in autoimmunity and leukemia: too much of a good thing? Laurens Kil, 2013
  • Clinical Outcomes in Interstitial lung diseases, M. van Maanen, 2017
  • It takes two to tangle, Caroline Broos 2017
  • Th17 cytokines in autoimmunity. Odilia Corneth, 2013
  • The Many Faces of Sarcoidosis. Novel insights into pathogenesis, diagnostics and therapy. Lieke Kamphuis, 2016
  • The T helper 17 lineage in pulmonary diseases. Cytokine analysis in local and systemic inflammation. Marthe Paats, 2012
  • Translational Aspects of Behçet’s Disease , JH Kappen, 2015

Non-scientific publications related to the ACE

Principal coordinator(s)