research

Research in CIDP: Are we making progress?

By Jeffrey A. Allen, MD
Member, GBS|CIDP Foundation Global Medical Advisory Board


CIDP as a named disease entity is now about 4 decades old. The laboratory data that helps define the disease, nerve conduction studies and in some cases cerebral spinal fluid and nerve biopsy, is even older; and the initial description of what has now come to be known as CIDP was probably first published well over 100 years ago. CIDP evidence based treatments, corticosteroids, IVIG, and plasma exchange, have been known to be effective since the 1980’s and 1990’s.  In 2018 progress of CIDP research can seem… stagnant.

Research in CIDP: Are we making progress? By Jeffrey A. Allen, MD

And yet, despite appearances, scientific achievements within the field are unquestionable. Physicians and scientists from around the world have passionately engaged all aspects of the disease from the most fundamental immunologic derangements to better defining the clinical spectrum of CIDP to exploration of new CIDP treatment options. Thus far in 2018 over 140 CIDP papers have been published in peer reviewed medical journals1. The publication growth by decade, reflective of intellectual curiosity, has been steadfast. In 1990 a total of 31 papers were published, followed by 84 in 2000, and 107 in 2010. Just in the last several years we have learned that about 10% of those with CIDP harbor one of two autoantibodies called neurofascin 155 or contactin 1. These antibodies target a specific portion of peripheral nerve and may have important treatment implications. We’ve learned the challenges that are encountered when diagnosing CIDP, and have a better understanding on how to avoid diagnostic pitfalls. From a treatment perspective we have very recently learned that subcutaneous immunoglobulin (SCIG) is safe and effective for CIDP maintenance therapy, but that unfortunately the immunomodulating medication fingolimod does not have a role in CIDP treatment. While certainly not comprehensive of all that has been learned over the last couple years, it is examples like this that offer insight into the progress being made and what direction the field is headed. That direction is one of a greater understanding of what makes one person’s CIDP different than the next. What is the underlying immunologic problem, and what does that tell us about the diagnosis, prognosis, and treatment of any individual person.

Around the world there are currently a multitude of studies that are exploring ways to get more out of our current CIDP treatments. These studies include the ProCID and DRIP studies, largely being conducted in Europe, which will help us better understand how IVIg dose and administration frequency influence efficacy. In the Netherlands the ongoing IOC trial will help us understand how often remission occurs in CIDP. The GRIPPER study conducted in the US may shed insight on how CIDP symptoms fluctuate in between IVIg infusions. Each of these studies anticipates conclusion in 2018 or 2019.  Collectively they will inform us on how to personalize IVIg treatment: how to get more out of the treatment for those that need it, and how to get patients off treatment if it is no longer needed. Looking farther out, the OPTIC trial conducted in the Netherlands and UK will explore the roll of combining IVIG treatment with corticosteroids. This trial is expected to conclude in 2023.

Equal to better understanding how to improve our current treatment protocols is identification of new treatment options. There are many many ways to suppress or manipulate the immune system. While some of these interventions may achieve the desired result of suppressing the inflammatory attack on nerves affected by CIDP, the risk of aggressive immunosuppression can be substantial and unnecessary. The goal is to maximize efficacy while at the same time minimize risk, with escalation of risk proportional to disease severity and prior treatment history. One line of treatment that has fostered some degree of enthusiasm is that of B cell depletion therapy with rituximab. A randomized controlled trial of rituximab in CIDP is currently underway in Italian centers. US physicians have expressed similar interest in exploring this treatment pathway, and a clinical trial of B cell depletion at US centers is currently in development.  While the role of B cell depletion in the treatment of CIDP is presently unknown, the hope is that these trials will help us learn which groups of patients within the broader context of CIDP might benefit from rituximab or similar medications. The hope also is to understand how these interventions can be tailored to individual patients such that unnecessary risks can be avoided.

In 2019, patients with CIDP throughout the world can anticipate initiation of a CIDP study that will be known as INCbase. INCbase will not explore a specific treatment or intervention in CIDP, but rather is a registry designed to learn more about those affected by the disease. One of the challenges of finding treatments in CIDP is the realization that CIDP has many faces, and those faces may be mediated by different immunologic insults.  The objective of INCbase is to better understand what defines the faces of CIDP. What symptoms constitute the clinical boundaries of CIDP? What testing is helpful in the diagnosis? Why do some treatments help some people, but not others? How does the pathophysiology of the disease differ from patient to patient? Participants in INCbase will simply be asked a series of standardized questions and have a standardized series of metrics collected, such as grip strength. In some cases blood may be collected as well. Participants will be followed on a periodic basis over a couple years. Ultimately this information will be critical in the development of treatment protocols that are specific to any individual patient, at any given stage of their disease.

While many of us, patients and clinicians alike, yearn for an escalated pace of progress in the field of CIDP, the knowledge gathered even within just the last several years is undeniable.  We are all in debt to those affected by CIDP that participate in the research that helps advance the field forward. Patients interested in research participation are encouraged to talk to their doctor about programs that might be locally available. Physicians at GBS/CIDP Centers of Excellence can be particular helpful in this regard.  The field is trending toward personalization of therapy, whether that be by getting more out of our currently available interventions or by discovering which patients might be candidates for different treatment options that are both effective and safe. A better understanding of the clinical and laboratory boundaries that define CIDP and how individual patients under the CIDP umbrella differ will add immensely to treatment personalization. We all eagerly await the results of actively enrolling CIDP trials and look forward to initiation of new studies, such as INCbase, identification of new novel antibodies, and clinical trials of B cell depletion therapy. Collectively these studies have the capacity to change the landscape of CIDP management in ways unknown in the not too distant past. We are making progress.


  1. Pubmed search of “chronic inflammatory demyelinating polyneuropathy OR CIDP” accessed on 10/5/2018.

2018 Research Grant Finalists Announced

Research is critical to serving the cause and the community. The GBS-CIDP Foundation International believes in supporting research by funding grants for projects that contribute to the knowledge and advancement of treatment of GBS|CIDP and variants of the condition.

We are pleased to announce our 2018 Research Grant Awardees are as follows: 

1. Principal Investigator: Elisabetta Babetto, Ph.D., Research Assistant Professor

The Research Foundation for SUNY on behalf of U. at Buffalo

Project: “Targeting Wallerian-like degeneration in GBS mouse models”

Synopsis: Axon degeneration accounts for the most debilitating clinical symptoms of Guillain Barré Syndrome (GBS). Our goal is to explore the mechanisms of axon loss in this condition, by testing the hypothesis that axon degeneration in GBS is governed by a defined molecular program amenable for therapeutic intervention. Specifically we will test whether inactivation of proteins, known to dictate axon loss after experimental injury, affords axon terminal protection in murine models of GBS.


2. Principal Investigators: Luana Benedetti, MD, PhD and  Lucilla Nobbio, PhD

University of Genova, ITALY

Project: Sphingomyelin dosage in GBS/CIDP patients: biomarker validation in a multicenter, prospective study

Synopsis: The identification of a biomarker specific and sensitive to improve diagnostic accuracy, to monitor disease activity, to stage patients, and to select specific treatments is a prime goal for the GBS/CIDP Community. Due to the encouraging results we obtained by dosing SM levels in the CSF of patients affected by GBS and CIDP, we propose the present study whose major significance is to validate our results on a sizeable and carefully selected number of patients.


3. Principal Investigator: Paolo Ripellino, MD, Neurologist

Neurocenter of Southern Switzerland

Project: (IGOS) in Switzerland: a deeper look into HEV-induced GBS

Synopsis: This study will increase the amount of clinical and prognostic data of the IGOS consortium with the inclusion of patients from an important area located in the middle of Europe. The high quality of the Swiss health care system will allow researchers to obtain accurate data. The systematic collection of acute phase samples in a biobank will be fundamental for future international, cooperative studies. The subproject about the role of HEV is innovative because – although so far neglected – HEV is an increasing, preventable (by appropriate cooking and blood donors testing) disease and this infection is associated to GBS.


4. Principal Investigator: Luis Querol MD PhD

Hospital de la Santa Creu i Sant Pau, Barcelona

Project:  Disease-specific Biomarkers In Inflammatory Neuropathies

Synopsis: Inflammatory neuropathies (IN) are disorders in which disease-specific biomarkers are not required or diagnostic purposes, leading to disease heterogeneity. We discovered the association of anti-contactin-1 antibodies to a specific CIDP subset using an unbiased approach. This strategy has also proven effective in antibodies against NF155 and nodal neurofascins in CIDP, in which our group has also played a central role. The discovery of paranodal antibodies hasboosted translational research in the field, including the description of specific pathology, genetic background (DRB1*15 association with NF155 antibodies), response to treatment and animal models, supporting the idea that the classification of IN according to disease-specific biomarkers would make IN research and care more efficient.


5. Principal Investigator: Dr Laura Zambreanu, MD, MRCP

National Hospital for Neurology and Neurosurgery, UK

Project:  Intravenous immunoglobulin and intravenous methylprednisolone as optimal induction treatment in CIDP (OPTIC trial)

Synopsis:  Most CIDP patients are treated with regular intravenous immunoglobulin (IVIg) because of fast improvement and rare adverse events, but IVIg is expensive. Corticosteroid treatment is associated with longer time to improvement and more side effects, but may lead to long-term remission1,2. We intend to participate in a multicentre, randomized, double-blind, placebo-controlled superiority trial in patients with active CIDP. The primary objective is to assess whether combining IVIg and intravenous methylprednisolone (IVMP) leads to more frequent long-term remission in CIDP compared to IVIg alone. Patients will be recruited in the Netherlands and the UK.

 

Congratulations to all and thank you for your continued commitment to research in the area of GBS|CIDP and variants of the condition.

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Attention Researchers! GBS Deemed Eligible for Research Studies through Department of Defense Peer Review

In March 2018 Congress passed an omnibus bill that finalized Fiscal Year 2018 appropriations. Guillain-Barré Syndrome was again listed as a condition eligible for study! Now is the time to begin applications for available grants. Below is more detailed information regarding applications and possible awards.

The mission of the PRMRP is to encourage, identify, and select military health-related research of exceptional scientific merit. Relevance to the healthcare needs of military Service members, Veterans, and their family members is a key feature of each FY18 PRMRP award mechanism.

Award Mechanism Eligibility Key Mechanism Elements Funding
Clinical Trial Award Assistant Professor level or above (or equivalent)
  • Preproposal submission is required; application submission is by invitation only.
  • Supports the rapid implementation of clinical trials of novel interventions with the potential to have a significant impact on patient care in the topic area(s) of interest.
  • Proposed projects may range from small proof-of-concept trials through large-scale, definitive trials.
  • Investigational New Drug or Investigational Device Exemption applications, if needed, should be submitted to the Food and Drug Administration by the PRMRP application submission deadline.
  • Funding limit not defined; requested funding must be appropriate for the scope of work proposed
  • Maximum period of performance is 4 years
Discovery Award Postdoctoral fellow or clinical fellow (or equivalent) and above
  • Supports the exploration of a highly innovative new concept or untested theory.
  • Not intended to support the logical progression of an already established line of questioning.
  • Clinical trials will not be funded.
  • Reviewers will be blinded to the identity of the Principal Investigator (PI), collaborators, and their organization(s).
  • Maximum of $200,000 for direct costs (plus indirect costs)
  • Maximum period of performance is 18 months
Focused Program Award Full Professor level or above (or equivalent)
  • Preproposal submission is required; application submission is by invitation only.
  • Supports a synergistic, multidisciplinary research program of at least four distinct but complementary projects addressing an overarching goal.
  • Projects should work together to answer critical questions, resolve differing hypotheses, and translate laboratory findings to clinical applications.
  • Projects may range from exploratory/hypothesis-developing through small-scale clinical trials that together will address the overarching goal/question.
  • Research team of highly qualified, multidisciplinary project leaders should be led by a PI with demonstrated success in directing large, focused projects.
  • Maximum of $10 million for total costs (includes direct and indirect costs)
  • Maximum period of performance is 4 years
Investigator-Initiated Research Award Assistant Professor level or above (or equivalent)
  • Preproposal submission is required; application submission is by invitation only.
  • Supports research that will make an original and important contribution to the field of research or patient care in the topic area(s) of interest.
  • Partnering PI Option available.
  • Clinical trials will not be funded.
  • Maximum of $1.2 million for direct costs (plus indirect costs)
  • Maximum of $1.5 million for direct costs (plus indirect costs) for applications including a Partnering PI Option
  • Maximum period of performance is 3 years
Technology/ Therapeutic Development Award Assistant Professor level or above (or equivalent)
  • Supports the translation of promising preclinical findings into clinical applications for prevention, detection, diagnosis, treatment, or quality of life.
  • Product-oriented (e.g., device, drug, clinical guidelines). The product(s) to be developed may be a tangible item such as a pharmacologic agent (drugs or biologics) or device, or a knowledge-based product.
  • Clinical trials will not be funded.
  • Preproposal submission is required; application submission is by invitation only.
  • Maximum of $3.0 million for direct costs (plus indirect costs)
  • Maximum period of performance is 3 years

A pre-application is required and must be submitted through the electronic Biomedical Research Application Portal (eBRAP) at https://eBRAP.org prior to the pre-application deadline. All applications must conform to the final Program Announcements and General Application Instructions that will be available for electronic downloading from the Grants.gov website. The application package containing the required forms for each award mechanism will also be found on Grants.gov. A listing of all CDMRP funding opportunities can be obtained on the Grants.gov website by performing a basic search using CFDA Number 12.420.

Applications must be submitted through the federal government’s single-entry portal, Grants.gov. Submission deadlines are not available until the Program Announcements are released.

For email notification when Program Announcements are released, subscribe to program-specific news and updates under “Email Subscriptions” on the eBRAP homepage.

For more information about the PRMRP or other CDMRP-administered programs, please visit the CDMRP website.

A Life and Legacy Dedicated to Research

On June 10, 2018 the GBS|CIDP Foundation International will be holding its 5th Annual New Jersey Walk & Roll. The event will be chaired by local resident, and Foundation volunteer, Susan Salzmann. Recently we had the pleasure of sitting down with Susan as she shared the complex story of her husband’s personal journey with CIDP.

Fiery Salzmann Image

Susan met Tom Salzmann in 1964. They were fifteen years old. “We spent our entire lives together,” said Susan as she began to explain their unexpected journey with this rare and disabling disease. Tom was a scientist and researcher with a career that began in 1975 when he joined Merck Research Laboratories in Rahway as a senior research chemist. His initial research efforts were in the area of carbapenem antibiotics, which ultimately led to a career highlight, the discovery of Primaxin. “Tom loved science and he dedicated his entire life to research,” said Susan. In 1984, he received the company’s prestigious Director’s Award, the highest award bestowed upon a Merck employee. He held positions of increasing responsibility within Merck Research Laboratories culminating with his appointment to the position of executive vice president, Worldwide Preclinical Development in 2002. Tom retired as executive vice president in 2004 after 30 years of employment with Merck. Following his retirement, he focused on consulting for the biotech industry and belonged to many scientific advisory boards of leading pharmaceutical companies.

Yet in 2009, while on a business trip to India, a sudden and frightening ailment occurred: he lost his sight entirely in one eye. “His colleagues were able to get him home and he went directly to his GP. No one really knew what was happening. Eventually he was sent to the hospital,” said Susan. “He was sent to UMass, then to a number of smaller hospitals. But his symptoms were worsening and he was beginning to lose strength in his arms and legs and he had severe back pain. Finally they transferred him to UPenn where he was diagnosed with CIDP.” Tom was treated with IVIG, which offered some short term relief. But eventually, reoccurring, severe cases of pneumonia caused his condition to worsen. After a nine month battle, including a month of rehabilitation at Kessler Institute, Tom sadly passed away on October 30, 2009.

However, Tom’s passing did not stop Susan from fighting. Only now, she is fighting for something new. She is determined to raise awareness and support for CIDP and for the global leading foundation, the GBS|CIDP Foundation International.

“In 2013 I got more involved with the GBS|CIDP Foundation and read all about the condition. I received their newsletters, booklets, and learned about their programs and fundraising walks. Then, I got invited to the Walk & Roll in Pennsylvania. I went to it and I thought to myself, I can put a walk together in New Jersey! I have a big family and a very supportive community, I knew they would want to get involved.” Susan was encouraged by meeting other GBS and CIDP patients and grew more determined to help other families who were going through the same hardship of coping with a rare disease. “There was always such confusion in the ICU, and Tom couldn’t speak for himself. I am determined to educate and help others in that situation.”

Susan and her family are now planning their 5th annual Walk & Roll event. “Each year it grows. We see new teams and meet new people. Honestly, I was going to pass the torch to another Walk chairperson this year but when I told my grandkids they were very, very disappointed,” said Susan. “But we have to do this! It’s for grandpa!” they all said. “I quickly realized that this had become a lot more than a fundraising walk for my family. It was a way to stay connected to their grandfather too.”

When Susan learned that funds raised during the 2018 Walk & Roll program would be donated to GBS, CIDP research she said, “Tom spent his whole life in research. And now it is just so ironic that we can still, as a family, be so involved in research, even after his passing. Only this time its research for CIDP.”

Walk & Roll is the Foundation’s signature community event designed to create awareness of GBS, CIDP and Multifocal Motor Neuropathy (MMN.).  Walk & Roll is held in cities all across the US and brings together patients, family members and caregivers. As of 2018, the Foundation announced that funds raised through Walk & Roll will support research for treatments, diagnostic efficiency and genetic inheritance for GBS, CIDP and its variants. If you are interested in attending the June 10th, 2018 Walk & Roll in Basking Ridge, New Jersey, you can sign up HERE or would like to plan a Walk & Roll of your own, please contact Jessica McManus, at GBS|CIDP Foundation International at 610-667-0131 x 21 or  jessica.mcmanus@gbs-cidp.org.

2017 GBS|CIDP Foundation Grant Awardees

(#1) Title of the project: Enhance Peripheral Nerve Repair by Modulating Macrophage Subsets

Investigator:

Gang Zhang, M.D; Ph.D
Assistant Professor of Neurology
University of Texas, Health Sciences Center at Houston

Synopsis:

Intravenous immunoglobulin (IVIg) is now the first-line therapy for Guillain-Barré syndrome (GBS). However, there are many disadvantages including high cost, supply shortages, and multiple side effects that are usually associated with high dose and long infusion time of IVIg. Therefore, new therapeutic strategies that can limit the nerve injury during the acute phase of the disease and enhance repair during recovery period are highly desirable. It is in this context we propose a novel strategy of modulating macrophage polarization (promote M2 polarization) for treating GBS.


(#2) Title of the project: Probing the role of skin biopsy in CIDP nodo-paranodopathies

Investigator:

Raffaella Lombardi, B.S., Fondazione IRCCS Instituto Neurologico C. Besta, Milan, Italy

Co-Investigators:

Jerome Devaux, Ph.D,

Diego Franciotta, M.D., Ph.D,

Giuseppe Lauria, M.D.1

Synopsis:

IgG4 antibodies against some proteins at the node of Ranvier, anti-neurofascin 155 (Nfasc155) or anti-contactin 1 (CNTN1) have recently been identified in the serum of a subset of CIDP patients. Identification of specific changes in myelinated dermal skin nerves and correlation with clinical course and serological data are unknown. We aim addressing these issues to provide new biomarkers of disease activity and patient stratification. 


(#3) The Ernest Hayden Award
Title of the project: Flavivirus and Arbovirus associated Guillain-Barré syndrome in South and South-East Asia.

Investigator:

Dr. Thirugnanam Umapathi

Department of Neurology, National Neuroscience Institute (NNI), Singapore,

Co-Investigators:

Dr Say Saysavath, Mittaphab Hospital; Dr Somchit Vorachit, Setthathirath Hospital,Vientiane,

Laos. Dr Hoang Nghia, Vietnam 175 Hospital, Ho Chi Minh City, Vietnam,Dr Surat Tanprawate, Chiangmai University, Thailand, Dr Mohammad Wasay; Dr Sara Khan, Aga Khan University, Karachi, Pakistan, Dr Terrence Thomas, KKH Children’s Hospital, Singapore,Dr Hugh Willison, Glasgow University, UK Dr Bart Jacobs, Erasmus University, Rotterdam, Netherlands

Dr Ooi, Eng Eong, Duke-NUS, Singapore, Dr Lisa F.P. Ng, A*Star Singapore.

Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit’s (LOMWRU), Vientiane, Laos

Synopsis:

This is a prospective, observational multi-center study of GBS in six S SEA countries. GBS patients and hospital, community controls will be tested for evidence of recent infection and serological response to previous/coinfections with flavi/arbovirus.

For information regarding Grants please contact Lori.Basiege@gbs-cidp.org.