Clinicopathological Classification of Dermatomyositis

Location: Hoofddorp, The Netherlands

Title: The 239th ENMC workshop on “The Clinicopathological Classification of Dermatomyositis”

Date: 14-16 December 2018

Organisers: Dr Y. Allenbach (France), Prof. O. Benveniste (France), Dr A. Mammen (U.S.A), Prof. W. Stenzel (Germany)

Translations of this report:
Spanish by Dr A. Selva O Callaghan
Dutch by Ms. I. de Groot and Prof. M. de Visser
Czech by Prof. J. Vencovský
Deutsch by S. Schlüter und Dr. A. v. Moers

Participants: Dr Y. Allenbach (France), Prof. O. Benveniste (France), Prof. J. de Bleecker (Belgium), Dr O. Boyer (France), Prof. L. Casciola-Rosen (U.S.A.), Dr L. Christopher-Stine (U.S.A), Dr J. Damoiseaux (The Netherlands), Prof. M. Fujimoto (Japan),  Dr C. Gitiaux (France), Ms. I. de Groot (The Netherlands),  Dr J. Lamb (United Kingdom), Dr O. Landon-Cardinal (Canada), Prof. I. Lundberg (Sweden), Dr A. Mammen (U.S.A.), Dr I. Nishino (Japan), Dr J. Radke (Germany), Dr A. Selva-O´Callaghan (Spain), Prof. W. Stenzel (Germany), Prof. J. Vencovksi (Czech Republic), Prof. M. de Visser (The Netherlands), Dr G. Wang (China), Prof. L. Wedderburn (United Kingdom) and Dr V. Werth (U.S.A.)

The 239th ENMC workshop on the “Clinicopathological Classification of Dermatomyositis” brought together experts in the field of myositis from Europe, Japan, China, Canada and the USA. Neurologists, Rheumatologists, Dermatologists, Neuropathologists and Myopathologists discussed and renewed the diagnostic criteria of dermatomyositis (DM) based on recent advances in the field. All experts agreed on the importance of mandatory testing of myositis specific autoantibodies (MSA, e.g. TIF-1γ, Mi-2, NXP2, MDA5 and SAE) in the diagnostic workup of DM patients. Furthermore, they emphasized the importance of autoantibodies to define certain subtypes of DM, which may have a characteristic clinical, pathological and even histological appearance. If the clinical presentation of a patient is classical, consisting of characteristic, DM-associated skin changes (e.g. DM-like rash), muscle weakness and detection of any MSA, the diagnosis of DM may be made, even without a muscle biopsy. Moreover, the finding of characteristic skin changes, clinically and in a skin biopsy, in combination with MSA but without muscle affection is also compatible with the diagnosis of DM. A more detailed definition of DM-like skin changes and histological criteria seen in the skin biopsy of an affected skin area in a DM patient will soon be published by an international expert team of dermatologists. It was clear to all experts that the muscle biopsy was and still is a very valuable tool and the gold standard in the diagnostic routine. Novel, specialized immunohistochemical stains further increase the certainty of a correct histological diagnosis. Especially in TIF-1γ positive DM patients, the muscle biopsy combined with the patients´ age may help to stratify patients concerning their risk of already having or developing a malignancy. It became clear, that TIF-1γ should not be misinterpreted as a bona fide tumor marker. However older patients with TIF-1γ positive DM definitely need an oncological screening in routine care since cancer risk is prominently elevated.

Additionally, the classification of the Anti-synthetase syndrome (ASS) was a matter of debate. Recent scientific data presented in the ENMC workshop clearly highlighted the differences of DM and ASS. All experts agreed on ASS being a distinct subtype, pathophysiologically clearly different from DM. Nevertheless, ASS can in very rare cases be considered as DM-related.

A full report is published in Neuromuscular Disorders (pdf).

Euro-NMD Pathology

Location: Amsterdam Schiphol WTC, The Netherlands

Title: The 245th ENMC workshop on Euro-NMD Pathology

Date: 7 December 2018

Organisers: Prof. A. Oldfors (Sweden), Prof. W. Stenzel (Germany), Prof. B. Udd (Finland)

Participants: Dr T. Evangelista (France), Dr B. Küsters (The Netherlands), Prof. M. Lammens (Belgium), Mr. M. Marra (Italy), Prof. A. Oldfors (Sweden), Dr. N. Romero (France), Prof. C. Sewry (United Kingdom), Prof. W. Stenzel (Germany) and Prof. B. Udd (Finland)

Translations of this lay report:
German by Prof. W. Stenzel
Finnish by Prof. B. Udd
Swedish by Prof. A. Oldfors
Portugese by Dr T. Evangelista
Spanish by Dr N. Romero
Dutch by Mr. M. Lammens

All neuromuscular diseases are defined as rare diseases and many of them are very difficult to diagnose and treat. EURO-NMD is a newly established network of European Reference Centers which provides access to expert consultations on diagnostics and care for patients with undetermined neuromuscular diseases. The pathology working group of the EURO-NMD with 5 expert members, one patient representative, and 4 additional muscle pathology experts from Germany, UK, France, Finland, Sweden, Italy, Spain, Belgium and the Netherlands, took part in a one day meeting in Amsterdam on December 7th 2018 hosted by the ENMC. The purpose of the meeting was to finalize a EURO-NMD document on ’Recommended Standards’ for muscle biopsy techniques and methods to be applied in all pathology laboratories in the 61 EURO-NMD reference centers.

A survey of current practices in all centers was carried out in 2017 and based on the responses a need to harmonize muscle pathology methods in Europe was evident. The pathology working group prepared a draft for such Recommended Standards in Sept 2018 and the feedback from participating centers on the circulated draft was analyzed and discussed. The meeting resulted in a final version on the: ‘Recommended Standards for muscle pathology’, which will be published later as a meeting report in the Neuromuscular Disorders journal.

A full report will be published in Neuromuscular Disorders (pdf).

Updating management recommendations of cardiac dystrophinopathy

Location: Hoofddorp, the Netherlands

Title: The 238th ENMC International workshop on “Updating management recommendations of cardiac dystrophinopathy”

Date: 30 November – 2 December 2018

Organisers: Dr J. Bourke (UK), Prof. D. Duboc (France), Dr M. Guglieri (UK)

Translations of the lay report:
Czech by Dr S. Šedivá
German by Dr A. Florian
French by Dr K. Wahbi

Participants: Prof. A. Aartsma-Rus (The Netherlands), Dr A. Bandali (UK), Dr N. Bennet (UK), Dr J. Bourke (UK), Dr B. Cools (Belgium), Prof. L. Cripe (U.S.A), Prof. S. Dittrich (Germany), Prof. D. Duboc (France), Dr A. Florian (Germany), Prof. N. Goemans (Belgium), Dr I. de Groot (The Netherlands),  Dr M. Guglieri (UK), Dr K. Hor (U.S.A), Mr. F. van Ieperen (The Netherlands), Dr G. McGowan (UK),  Dr E. McNally (U.S.A), Prof. E. Pegoraro (Italy), Prof. L. Politano (Italy), Dr M. Sediva (Czech Republic),  Dr V. Stara (The Netherlands), Dr J. Timmermans (The Netherlands),  Drs E. Vroom (The Netherlands) and Dr K. Whabi (France),

The 238th ENMC workshop was convened between 30 November and 2 December 2018 and brought together neuromuscular and cardiology experts from Europe and United States to discuss cardiac care of patients with Duchenne and Becker muscular dystrophy. The aim was to build on the extensive International Care Considerations DMD 2010 1 and 2018 2 guidelines, adding the latest evidence and collating expert opinion on cardiac management of patients with conditions caused by mutations in the dystrophin gene.

Implementation of multidisciplinary care, including steroid therapy and timely support for respiratory muscle weakness has already improved survival in Duchenne muscular dystrophy (DMD). However, it is increasingly apparent that deterioration in heart function is critical to long term survival. Silently progressive cardiomyopathy (loss of the heart pump function) affects almost all patients with DMD but only causes symptoms in later years with the onset of heart failure. Currently, there is a lack of agreement about at what age or on the basis of what test results a patient should start heart-specific medications. Some clinicians use an ultrasound test (echocardiography) to detect weakness of the heart’s main pumping chamber (left ventricular dysfunction) and others test for the presence of scars in heart muscle (myocardial fibrosis) using cardiac magnetic resonance imaging (cMRI) testing. However, the workshop concluded that the heart is affected from the beginning (even before birth) in DMD. As such, each testing method used to justify starting heart treatments simply reflects what each is capable of ‘seeing’ in the progressive process of heart involvement in DMD. The lack of sensitivity of standard echocardiography in detecting early abnormalities of heart muscle and technical issues around obtaining high quality and standardised magnetic resonance imaging of the heart across centres and in younger patients were recognized. The expert consensus was that families should be made aware around the time of diagnosis that heart care will be important throughout life. The particular heart drugs recommended – whether available now or developed in the future, and the optimum time to introduce them depend on what they are designed to do and the balance between their effectiveness and side effects.

Interesting detail was presented about the benefits of specific exercise programs for patients with DMD and the cardiovascular effects which might result. This will be the subject of ongoing research.

In a wide-ranging discussion about adults with DMD, Becker muscular dystrophy (BMD) and female- carriers of BMD/DMD, the consensus was that using devices that can correct serious, abnormal heart rhythms (implantable defibrillators) should be discussed as for patients with other forms of cardiomyopathy. Patients with less severe DMD, those with BMD and female carriers are already considered for transplantation or left ventricular assist devices (small implantable device to strengthen heart pumping) in several centres. However, it was accepted that the severity of DMD makes heart transplantation inappropriate for most patients with that condition.

The need to collect longitudinal data on the effects of different medications/interventions and the priority of reaching agreement with regulators about clinically meaningful research outcome measures for the heart in DMD was agreed.

The workshop concluded by acknowledging the many gaps that remain in our understanding of cardiac involvement in dystrophinopathies but also the promise of treatments currently under evaluation. A number of themes for collaborative research were also identified.

A full report is published in Neuromuscular Disorders (pdf).

1. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol 2010, 9(2):177-189.
2. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health and orthopaedic management. Lancet Neurol 2018, 17(4):347-361.

GNE myopathy (GNEM)

Loction: Hoofddorp, the Netherlands

Title: The 237th ENMC International Workshop on: “GNE myopathy”

Date: 14-16 September 2018

Organisers: Prof. H. Lochmüller (Germany), Dr A. Urtizberea (France), Dr Z. Argov (Israel) and Dr I. Nishino (Japan).

Translations of this lay report:
Hebrew by Dr Z. Argov
Portugese by Dr T. Evangelista
German by Dr A. Roos
Ukrainian by Dr O. Pogoryelova
Russian by Dr O. Pogoryelova
French by Dr A. Behin
Dutch by Dr M. Huizing
Japanese by Dr I. Nishino

Participants: Dr Z. Argov (Israel), Dr A. Behin (France), Dr N. Carrilo (U.S.A.), Dr M. Davidovich (Israel), Dr T. Evangelista (France), Mrs. M. Hek (The Netherlands), Dr J. Hogrel (France), Prof. R. Hortskorte (Germany), Dr M. Huizing (U.S.A.), Dr S. Krause (Germany), Dr E. Landfeldt (Sweden), Dr M. Lek (U.S.A.), Prof. H. Lochmüller (Germany), Dr H. Mansbach (U.S.A.), Dr S. Mitrani-Rosenbaum (Israel), Dr M. Mori-Yoshimura, Prof. T. Mozaffar, Dr I. Nishino (Japan), Ms. M. Patel (United Kingdom), Dr O. Pogoryelova (United Kingdom), Dr A. Roos (Germany), Dr I. Tournev (Bulgaria), Prof. B. Udd (Finland), Dr A. Urtizberea, Mrs. L. Welsh (U.S.A) and Dr A. Willems (The Netherlands)

GNE myopathy is a rare muscle-wasting disorder caused by mutations in the GNE gene, which contains the instructions to make an enzyme that has a key role in the production of sialic acid in the body. A deficiency of the enzyme in the muscle cells leads to increasing disability from a young adult age in most individuals affected by it. The condition was described first in Israel and in Japan under different names – ‘Hereditary Inclusion Body Myopathy’ (HIBM) and ‘Nonaka Distal Myopathy’, nevertheless, it has a worldwide distribution.

There is currently no approved treatment or medication available that would cure the disease or slow the disease progression. A recent, well-controlled clinical trial led by Ultragenyx, did not show significant efficacy for the medication (sialic acid slow release) under investigation.

The workshop participants reviewed the current medical and scientific knowledge relevant to GNE myopathy to achieve a better understanding of GNE myopathy epidemiology, phenotype and genetics. They agreed on a standard of care (SOC) for GNE myopathy patients, discussed the strength and weakness of the currently available animal models, and attempted to improve their understanding of the biochemical consequences of the GNE defect on muscle tissue leading to muscle damage and weakness. Additionally, participants deliberated other potential treatments for the condition such as gene therapy ManAc therapy and stem cell therapy.

The participants committed to provide patient-friendly inclusive information and collect standardized clinical information for further research in accessible formats, which would help to build a robust cohort. They undertook to work collaboratively towards treatments for patients, and to share data and biomaterials. They will make genetic information on rare GNE gene variants available for genetic diagnosis and propose standards of care for GNE myopathy patients.

They concluded that further preclinical and clinical research is required to develop suitable models of the disease in laboratory animals, to identify molecules in blood and muscle of patients to monitor disease progression and response to treatment (biomarker) and to validate clinical endpoints, outcome measures and study designs for future clinical trials. Ideas and actions as to achieving each of these topics were assigned for future research.

A full report is published in Neuromuscular Disorders.

Bone Protective Therapy in Duchenne MD

Location: Hoofddorp, The Netherlands

Title: The 236th ENMC International Workshop on: “Bone protective therapy in DMD”

Date: 1-3 June 2018

Organisers: Dr R. Quinlivan (United Kingdom), Prof. V. Straub (United Kingdom), Prof. L. Ward (Canada), Dr J. Wong (United Kingdom)

Translations of this report:

Dutch translation by Dr E. Niks
Italian translation by Dr F. Broggi
Arabic translation by Dr. F. Aljuraibah
Greek translation by A. Kyriakou

Participants: Dr J. Adachi (Canada), Prof. F. Ahmed (United Kingdom), Dr M. Anderton (United Kingdom), Dr F. Broggi (Italy), Dr N. Crabtree (United Kingdom), Ms. P. Furlong (U.S.A.), Dr I. de Groot (The Netherlands), Dr M. Guglieri (United Kingdom), Mr. F. van Ieperen (The Netherlands), Dr S. Joseph (United Kingdom), Dr R. Keen (United Kingdom), Prof. A.  Klein (Switzerland), Mr. J. Kuijer (The Netherlands), Prof. Z. Mughal (United Kingdom), Dr E. Niks (The Netherlands), Dr S. Novotny (U.S.A.), Dr R. Quinlivan (United Kingdom), Dr S. Roberts (United Kingdom), Prof. L. Sävendahl (Sweden), Prof. U. Schara (Germany), Prof. V. Straub (United Kingdom), Mrs. A. Stringer (United Kingdom), Drs E. Vroom (The Netherlands), Dr L. Ward (Canada), Dr D. Weber (U.S.A.), Dr J. Wong (United Kingdom) and Dr M. Zacharin (Australia)

Muscle and bone strength are closely related, the ‘mechanostat theory’ describes how muscle strength, which normally increases throughout childhood, promotes bone development. In Duchenne muscular dystrophy (DMD) muscle weakness, corticosteroid treatment and delayed puberty lead to an increased risk of bone fractures (limb and vertebral). Fractures have serious consequences including pain, loss of ambulation and fat embolus syndrome. Bone health, to assess risk of fractures can be assessed by different imaging methods.

Bone protective therapy involves prevention of fractures, detection of vertebral fractures, which can be asymptomatic, treatment of fractures to reduce pain and enable ‘reshaping’ of fractured vertebrae during childhood. Most boys with DMD have delayed puberty management of this is important for bone health. It was felt that oral bisphosphonates, a class of drugs that prevent the loss of bone density, are not as effective as intravenously administered bisphosphonates, furthermore compliance with oral treatment is poor. Intravenous bisphosphonates reduce pain and promote vertebral fracture healing but there is a risk of important side effects, usually with first dose. Newer bone drugs are increasingly available and could be studied in DMD.

Clinician and patient education on bone health is essential to advance the field of bone health in DMD. Combining data that may already exist could help to answer questions about bone health. A small placebo controlled trial for prevention of first fractures is necessary together with trials comparing bisphosphonates with new treatments to treat fractures ultimately optimize care of patients with DMD. Future steps include dissemination of knowledge across all stakeholders, establishing a working group and exploring funding possibilities.

A full report is published in Neuromuscular Disorders (pdf).

The position of neuromuscular patients in Shared-Decision-Making (SDM)

Location: Milan, Italy

Title: The 235th ENMC Workshop on: “The position of the neuromuscular patient in Shared Decision Making”

Date: 19-20 January 2019

Organizers: Prof. H. Lochmüller (UK), Prof. A. Tibben (Netherlands), the ENMC Executive Committee and the ENMC office.

Translations of this report:
German by Prof. U. Schara
Danish by Ms. A. Mahony
French by Dr A. Méjat
Italian by Dr F. Bertinotti
Spanish by Ms. M. de Lemus
Dutch by Dr A. Breukel
Polish by Mr. M. Rataj
Greek by Ms. E. Oikonomidou

Participants: Dr A. Ambrosini (Italy), Dr D. Dimitrios (Greece), Mrs. N. Bere (United Kingdom), Dr F. Bertinotti (Italy), Dr A. Breukel (The Netherlands), Mr. F. Buccella (Italy), Dr N. Bungay (United Kingdom), Mrs. C. Daly (Switzerland), Prof. B. van Engelen (The Netherlands), Mr. E. Galluccio (Italy), Dr C. Gamroth (Germany), Prof. N. Goemans (Belgium), Mr. G. Gömöri (Hungary), Prof. M. Hansson (Sweden), Mr. F. Lamy (France),  Dr E. Landfeldt (Sweden), Dr M. de Lemus (Spain), Mrs. A. Lennox (United Kingdom), Prof. H. Lochmüller (Germany), Dr E. Mazzone (Italy), Dr I. Meijer (The Netherlands), Dr A. Méjat (France), Mrs. A. Mels (The Netherlands), Dr A. von Moers (Germany), Dr L. Monaco (Italy), Prof. G. Padberg (The Netherlands), Dr H. Peay (U.S.A.), Dr R. Quinlivan (United Kingdom), Dr J. Rahbek (Denmark), Dr M. Rasconi (Italy), Mr. M. Rataj (Poland), Dr S. Rico (U.S.A.), Dr F. Salama (France), Dr V. Sansone (Italy), Prof. U. Schara (Germany), Prof. G. Schrijvers (The Netherlands), Dr M. Snape (United Kingdom), Dr E. Sterrenburg (The Netherlands), Prof. A. Tibben (The Netherlands), Mrs. K. Trant (U.S.A.), Drs E. Vroom (The Netherlands), Dr R. Willmann (Switzerland), Dr M. de Wit (The Netherlands) and Mrs. A. Zittersteijn (The Netherlands)

The workshop was organised to celebrate the 25th Anniversary of the ENMC. It was held in Milan, Italy on 19-20 January in 2018 and attended by 45 participants from 15 different countries: Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Italy, The Netherlands, Poland, Spain, Sweden, Switzerland, UK and the USA. This group represented a wide range of experts: patients and parents, representatives from neuromuscular diseases organisations, clinicians, health care professionals, researchers, societal and policy researchers, psychologists, ethicists, representatives from regulatory authorities and pharmaceutical companies.

In the field of neuromuscular disorders, engaging patients is since long recognized as key issue. The ENMC anticipated that for patients and patient organizations this anniversary is the time to discuss how and when they want to be engaged in research and how patients want co-creation to further develop. The ENMC has been encouraging patient participation to each of its workshops in the past years. With this anniversary workshop, ENMC aims to further strengthen patient participation for a set of important domains that are, in many European countries, still predominantly in the hands of researchers and clinicians:

  1. psycho-social support of families going through the processes of screening and diagnosis
  2. transition from child, to adolescent to adult patient
  3. research that has major impact on daily life (nutrition, pain, fatigue)
  4. registries and biobanks
  5. clinical trial design
  6. regulatory and consenting processes

Shared Decision Making is a model of bilateral interaction between the patient and the clinician, normally applied to find consensus on treatment options. It consists of three phases; option talk, choice talk and decision talk. This practical aspect was used in the workshop to drive the interactive discussion between patient representatives and clinicians/researchers and discuss the level of patient participation and patient involvement in the six fields mentioned above. Note that shared decision making intended mainly to structure the interactions between stakeholders and was used as a tool to operationalize participation. After introducing the concept of Shared Decision Making and the six topics, participants were divided into six discussion groups, with a careful attention to a fair representation of interests, countries and competences.

Overall, there were common points in each discussion. It became clear that education about the involvement of patients up to the level of decision-making requires training and coaching of all stakeholders, including the physicians, health care professionals, pharmaceutical industry, regulatory bodies, people with a neuromuscular condition, the families and patient associations. The roles and preferences of all stakeholders should be made more explicit. With regards to all these stakeholders, it is important to ensure proficient communication about the wishes and challenges we face in implementing patients’ participation at the co-creation level in the various topics addressed. This effort requires changing attitudes, and therefore, ambassadors are needed who inspire and empower others about the benefits of patients’ participation and perhaps at the local level it may need individual coaching. In some of the discussion groups it was concluded that a follow-up meeting or working group is required to delve deeper on how and what to implement to ensure optimal patient participation in that specific topic. Furthermore, it was emphasized that exchange at the European level is also needed. More specific actions and goals for each of the six topics will be described in the white paper (see below).

The aims of the workshop are:

1. To create a white paper that positions the patient and patient organizations in neuromuscular disorders as co-creator and co-responsible partner. This document can be then used in discussions with local, regional, national and international stakeholders as well as with fellow patient organizations to achieve endorsement and support for change. In this effort, the role of participants as ambassadors of this change at the local levels and at international organizations, through their networks, will be key.

2. To improve awareness, by disseminating and presenting in the neuromuscular community the outcomes of this workshop and the white paper. ENMC will publish the full workshop report in adequate scientific journals and have the lay report translated in several languages. Here, the role of patient organizations and clinical centers will be key to set the stage for change and transformation in the relation of patients with all stakeholders (researchers, regulatory agencies and industry).

Quotations by some participants:

“I am currently writing a grant application, and after the 235th ENMC workshop, I think I will change it by including patient representatives and/or advocacy groups participation throughout the whole design of the trial, including this concept both in the structure of the Methods section and in the composition of the trial budget, considering a percentage of the grant budget is for the patient association and support groups.” ….. Said Dr. Valeria Sansone, Director of the NEMO Clinical Centre, Milan, Italy

Participants of the 235th ENMC workshop, taking place at the ATA hotel, Expo Fiera in Milan, Italy

We would like to thank the following patient organisations for their help in local management of this meeting in Milan:

Three papers resulting from this meeting can be downloaded here: Papers on Patient Participation – ENMC

A full report is published in Neuromuscular Disorders (pdf)