Lessons Learned From the 2nd American Association of Equine Practitioners Foundation's Equine Laminitis Research Workshop

In two short days, presentations and discussions of varied topics ranged from inflammation, vascular, endothelial dysfunction, insulin resistance to biomechanics and chronic pain management. What we learned is that there is much information being generated on the topic of LAMINITIS, and all the various pieces of the puzzle serve as the template for the answers to the many questions that loom surrounding this disease. The “World Café” posed a special opportunity to delve into 10 important questions that guides a plan for future funding needs and a timetable to accomplish our vision “To Conquer Laminitis by 2020!” The 2004 AAEP and 2007 Havemeyer Foundation meetings served as the initial springboard to a diversity of topics, and the 2009 workshop represents the most comprehensive coverage on laminitis research and related subjects of the equine foot. While the progress has been great, we still have a long, long way to go. Our goal to eradicate laminitis by 2020 parallels modern medicine's approach to the conquering of human ailments such as cancer and cardiovascular disease. It is indeed a complex endeavor that requires great patience as well as endless hard work over an extended period.

As I pause to summarize our current progress and what we learned during the second Laminitis Research Workshop, we continually develop and refine our vision for the future. By focusing on laminitis, many insights and developments continue to occur that improve our abilities to deal with all aspects of the equine foot and with this–improved equine care. Doing this sets precedents and methods of research, treatment, and compassionate care that serve as an example for human and veterinary medicine for all species. We nevertheless wrestle with some fundamental questions about the disease, such as is laminitis a metabolic derangement relating to insulin resistance or pars intermedia dysfunction?…an inflammatory condition?….nutritional problem?….vascular and endothelial dysfunction?….biomechanical failure of the suspensory apparatus of the distal phalanx?….a genetic flaw that predisposes some horses to be at an increased risk for the disease vs. others? It is clear that more research is essential to be able to isolate and define the precise pathophysiology of laminitis before we can conquer it. However, that does not mean research alone is the answer because research requires funding, and with funding comes the requirement for increased public awareness to stimulate the important support for research. Numerous research results and clinical protocols are providing valuable insights and new developments in our field and therefore great reason for optimism, and with this we can build on recent growth with ever increasing momentum. It just requires a tightly knit group of dedicated people working together toward our common goal. We have the ever increasing talent pool, we have the vision, and we are enlisting the support organizations to coordinate all global efforts.

There are precedents for what I am calling for here. President John F. Kennedy in the 1960's challenged our nation to land a man on the moon within a decade, and for many considered it as an impossible task; President Richard Nixon officially declared war on cancer and with this opened the floodgates for increased funding for cancer research; and finally, do not forget that polio was a deadly and incurable disease before the 1950s!

So this years Equine Laminitis Research Workshop was a jam packed series of summaries about: The Pathophysiology and Treatment of Pain by Tony Yaksh, the 2004 AAEP and 2007 Havemeyer meeting by Nat White and James Belknap, and a comprehensive plenary session on the Overview of What We Know about the Pathophysiology of Laminitis by Susan Eades. Three sets of abstract presentations on Inflammation, Vascular/Endothelial Dysfunction, Insulin Resistance, and Biomechanical/Chronic/Pain Management rounded out the scheduled presentations. All these topics accordingly enhanced our exposure to so much exciting and useful information, and galvanized the topic at hand in formulating evermore effective preventions, treatments, and understanding of the disease.

The World Cafe breakout sessions posed a series of important questions focusing on laminitis research funding and key recommendations on our next steps. The questions that were considered and addressed by the workshop attendees included:

Several other important questions that were raised and responded to by the workshop participants were as follows:

Unmistakably, we are making fine progress, but there remains much to do to reach our target goal of 2020. The next huge step is to develop a comprehensive global strategic plan for research, so there can be a balanced program that will ultimately be the most successful. This approach sets the appropriate stage for our research spirit to soar and with this come enormous progress. We should never lose site of our goal as we become immersed in our work–this should be our guiding light for every decision. And as a final point, a contagious positive attitude leads to the greatest rewards for all.

So let us roll up our symbolic sleeves and get to work, to educate the general public about laminitis research, and prove to assorted funding agencies about the significance and worth in investing in our vision “To Conquer Laminitis” by 2020–it is time to seize the moment!

Second AAEP Equine Laminitis Research Workshop 

Summary Feedback from World Café Breakout Session and Laminitis Research Funding Questions, and Key Recommendations on Next Steps 

Feedback from World Café Breakout Session Questions 

Question #1A: What time is it with regard to laminitis research?

•Since the previous laminitis Workshops (2004 and 2007) there are new research tools and increased collaboration among research labs worldwide

•A tissue bank has been started

•A listserv is still needed and a shift from the old dogma to examine the results of new research and how it may change where the research should be directed in the future

•Advances in research regarding inflammation and pathology have outpaced information regarding the role of the vascular and endocrine systems

•Treatments are still lagging behind the knowledge of pathophysiology

•It is time to refocus on the disease needs in clinical cases

•Funding is improved and so has the technology with use of new molecular biological techniques

•More collaboration is needed between labs to utilize the available technology and common tissue and blood samples

Question 1B: How do we unravel the mystery of laminitis by 2020?

•Emphasis should be turned more toward the naturally occurring disease with an emphasis on disease characterization and development of biomarkers for prediction and prognostication

•A large-scale epidemiologic study of laminitis was the most frequently mentioned action plan

•This would include demographic and case information about horses with pasture-associated laminitis, metabolic disease, and other naturally occurring cases, their environment and management

•Information to be obtained must be standardized

•Grass samples should also be collected for this database

•In conjunction with epidemiologic study, an international bank of tissue from the naturally occurring disease (metabolic and sepsis/inflammation type) should be collected and maintained

•This should include laminar tissue, chestnut, coronary band, other skin, nerve, feces, and any other tissues of interest whenever possible

•Protocols for tissue collection and preservation must be standardized and information provided to participants

•The feasibility of obtaining hoof biopsy samples should be considered whenever possible

•Large-scale information campaign may improve owner compliance

•Evaluation of treatment regimens that are based on evidence accumulated during management of clinical cases

•Multicenter trials with standardized diagnostic methods and treatments are needed

•Research would be facilitated by development of new reagents, antibodies, etc.

•Collaboration and communication between the research groups must continue and should be increased

Question #2A: What is the most critical laminitis research that needs to be done and what would it cost?

•Epidemiology is needed to determine risk factors to aid in prevention

•This should be a multicentered study with sample collection for the tissue/sample bank along with collection of possible risk factors

•The results from the different studies need to be standardized for uniform interpretation of the data

•Collection by trained individuals is needed, as well as educating the horse owner and veterinarian about the data collection

•Ten thousand horses followed up over 5 years will cost at least $2.5 million

•If genetic evaluation is included, another $1.5 million minimum will be needed

•Not enough is known about the normal laminar physiology to relate to the findings with the current models

•After the normal physiology is understood, determining whether a common pathway exists among the different carbohydrate/black walnut models and the metabolic-associated laminitis is needed to reframe the problem and future research direction

•Samples from clinical cases need to be collected from postmortem and hoof biopsy technique

•A standardized method needs to be developed for collection, processing, and storage

•Development of serum biomarkers is also needed ($150,000)

•Because of the amount of research completed to date, a meta-analysis is reasonable with the current models to assess true research progress ($100,000)

Question #2B: What is the most lingering laminitis research question(s) that need to be addressed and how much would it/they cost?

•The triggers that cause the disease continue to elude us

•The quest for these should focus on naturally occurring metabolic disease and fructan models

•How do we standardize diagnostic and treatment protocols?

•What is the normal biology of the hoof (including, physiology, metabolism, morphology, immune response) from foal to adult?

•What is the predisposing phenotypic background?

•What is the predisposing genotype?

•The price tag ranged from $10 million to $80 million, and some thought that this was still too low if genetic studies were to be included

Question #3A: How do we best research mechanical/overload laminitis and what would it cost?

•Questions still remain about how weight bearing or excessive weight bearing causes or is associated with laminitis

•Research should be completed to see if laminitis can be created in a non–weight-bearing limb and is a constant in all types of laminitis

•Use of computer models may help to determine the load with estimates of compromise of the blood supply or tissue structure within the foot during loading.

•Use of microdialysis technique may help to elucidate the mechanism during overload laminitis

•This will need to be adapted to clinical cases

•Use of cell culture to mimic physical loads may be viable

Question #3B: How do we best approach chronic laminitis research and what would it cost?

•We first need to standardize the assessment of horses with chronic laminitis for consistent case definition, using history, pain scale, clinical progress, radiography, force plate, MRI, metabolic/blood markers, venogram, and biopsy specimens evaluated over time

•Categorize severity based on degree of structural damage and severity of pain and whether there is an acute exacerbation

•After case assessments are standardized and categories of disease are accepted, we should generate a prospective study of different treatment options, including: tenotomy, hoof wall resection, shoeing options, botulinum toxin, barefoot trimming, pain management, stem cells, drugs to modify extracellular matrix, etc.

•Cost estimated to be at least $5,000 per horse

•Studies should be performed to evaluate alteration of the extracellular matrix and inflammation that are reported in the acute models of laminitis, the regenerative process, pathogenesis of ongoing lamellar damage (e.g., autoimmune disease, infection, etc.), changes in nerves, and the mechanical alterations present with structural damage

•Cost estimated to $30 million over next 10 years

•Laminar biopsy technique should be validated for use in assessment of chronic laminitis

•More attention should be diverted to assessment of the equine metabolic syndrome as detailed in questions 1B and 2B

Question #4A: How do we optimize the use of The Laminitis Discovery Database?

•A secure website needs to be established for specific users to see what tissues/samples are available

•Instructions for reagent use and sample collection are needed

•Someone will need to be responsible for the sample storage and distribution of samples for use by numerous laboratories

•Maintaining this database and collection of samples will require ongoing funding

•A system for veterinary collection of case material should be developed so practitioners can participate

•This will require a quick and efficient way to biopsy the hoof from a recently euthanatized horse and to process, store, and/or ship the samples

•Collection at university hospitals and practices is best completed by trained technicians who are paid to collect and manage the sampling and transfer of information and samples to the database

•A granting agency should be sought to provide ongoing funding for database support

•Granting agencies should require that all laminitis research studies involving collection of tissue/blood or other samples from horses with naturally acquired or experimental laminitis submit samples to The Laminitis Database

•A system will need to be developed whereby there is an objective and fair method for investigators to request samples, and it be determined whether or not the proposed study meets the criteria for use of the samples, etc.

Question #4B: What experimental laminitis therapies should receive priority for evaluation and how should these studies be approached?

•Therapies need to be optimized experimentally, and then a large multicenter placebo-controlled trial with strict entrance and rejection criteria should be designed to objectively evaluate chosen therapies

•Treatments named most often included

•Cryotherapy

•Pentoxifylline

•Anti-inflammatory drugs

•Biomechanical interventions

•Barefoot with trimming

•Tenotomy

•Induced recumbency

•Hoof wall resection

•Hoof casts

•Corrective shoeing

•Frog supports

•Other treatments mentioned included

•Chronic preventatives

•Virginiamycin

•Dietary management

•Exercise

•Acute preventatives

•MMP inhibitors

•Rheologic agents

•Vasoactive agents

•Pain management

•These treatments should be applied to specific groups, such as horse-at-risk, acute and chronic laminitis

•Many of these treatments or preventatives will require more background experimental research before they can be implemented in a clinical trial

•Other considerations

•Biomarkers to assess treatment outcome and effectiveness

•Novel administration methods such as regional perfusion and intraosseous therapy.

•Determine what is acceptable quality of life for horse with chronic laminitis?

Question #5A: What strategy and approach should be used to develop a productive multi-year collaborative multidisciplinary laminitis research project?

•This will require a common focus and purpose

•To be successful, barriers need to be removed at universities and methods, policies, or practices need to be adapted for collaborative research, including overhead or indirect cost arrangements, distribution of effort, and recognition for CO-PI's at each university

•The process needs to start by identification of the problem and priorities and then developing workable solutions

•Increased bureaucracy of a central administration system should be avoided

•Frequent communication between small groups that complete work independently is likely the most productive way to achieve success

•A method of communication is needed, including development and implementation of a listserv

•Some duplication of the work is needed and appropriate without unnecessary redundancy

•This process helps decrease the number of horses needed for research

•Use of a central database and tissue or sample bank should be a required part of these collaborative studies

Question #5B: How do we facilitate large-scale, collaborative, multi-institutional epidemiologic or clinical trials of horses with naturally acquired laminitis?

•Plan and develop a central organizing committee that is unaffiliated with any research group to organize and oversee. The name “LCTN”—laminitis clinical trial network, was coined. The AAEP was one suggested group to oversee this process

•Responsibilities would include

•Recruit and contract with collaborators

•Train participants

•Distribution of money

•Disseminate information about data collected, protocols, and meta-analysis to all participants

•Need a plan for funding

•Need novel ways to recruit private funds (e.g., donation attached to product purchases)

•Need participation by veterinarians, epidemiologists, forage scientists, nutritionists, and experts in biomechanics

•Should focus on pasture-associated, supporting limb, and disease-associated laminitis

•Should include focused (get best information without being too cumbersome for participants) surveys to clients and equine practitioners

•Need standardized protocols for gathering information and collecting, processing, storing, and shipping samples for tissue or sample bank

•Need incentives for client, RDVM participation

Feedback from Laminitis Research Funding Questions 

All ELRW attendees were asked these two questions, and they each independently wrote down their answers to these questions on index cards. The composite data presented include number of responses along with the median and range values for these questions.

Question #1: How much money is it going to take to conqueror laminitis by 2020?

•Median, $15–$20 million

•Range, $200,000–Billions

•Number of responses

•$200,000 (2)

•$2,000,000–$7,000,000 (4)

•$10,000,000 (7)

•$15,000,000 (4)

•$20,000,000 (2)

•$30,000,000 (2)

•$40,000,000–$50,000,000 (6)

•$50,000,000–$100,000,000 (3)

•Billions (2)

•Other responses

•Too much! (1)

•A lot more! (1)

•More than we'll ever get! (1)

•Unrealistic question! (1)

•Who knows? (1)

Question #2: How much money is needed annually to promote effective laminitis research collaboration?

•Median, $1–2 million

•Range, $100,000–$10 million

•Number of responses

•$100,000–$500,000 (13)

•$1,000,000–$2,000,000 (10)

•$2,000,000–$3,000,000 (7)

•$4,000,000–$5,000,000 (4)

•$10,000,000 (3)

•Other responses

•No amount of money (1)

Key Recommendations on Next Steps 

1.Collaboration

a.We have come a long way in a short period of time, especially since the 2004 AAEP Equine Laminitis Research Panel and Meeting in Louisville, and especially considering the dollars spent and horses used

i.Collaboration has really be unequalled in veterinary research

b.We must maintain a “full court press” with regard to laminitis research collaboration

i.Equine Laminitis Research Listserv is a must

ii.Secure website with logins for data submission and tissue bank needed

1.Maintain list of samples and data available for use

2.List of available resources, reagents, antibodies, etc.

3.List of what has and has not worked with regard to methods

4.Tissue or sample wish list

c.Continued interdisciplinary and multi-institutional collaboration is needed to optimize resources and to capitalize on synergies

2.Need to turn our focus toward investigation of naturally-acquired clinical cases

a.We now have some research tools, and are developing more, with which to study status of inflammatory events and extracellular matrix that we can and should apply to clinical cases

b.Still need to further characterize equine metabolic syndrome and chronic laminitis to bring our knowledge base of these to the level we know about acute laminitis and other models

3.Need for large-scale inclusive epidemiological study on naturally acquired laminitis cases

a.Pasture-associated, metabolic syndrome, Cushing's disease, disease (sepsis/inflammation)-related acute laminitis, chronic laminitis, etc.

b.Designed by epidemiologists with input from clinicians, researchers, forage specialists, nutritionists, etc.

c.Goals

i.Identify risk factors and causes

ii.Characterize different forms of disease and provide basis for categorizing clinical diseases for experimental study

d.Collect data, tissue, and other specimens (through biopsy technique, etc.) for submission and storage at The Laminitis Database

i.Data collected should include signalment, history, treatments, preventives, use of horse, environment, management, etc.

ii.Samples collected could/should include laminar, liver, skin, pituitary, chestnut, forage, etc.

iii.Standardization of the nomenclature of acute and chronic laminitis

iv.Define minimum database (standard tests or imaging modalities) for diagnosis of laminitis

v.Need for prospective analysis of Chronic Laminitis

1.History

2.Pain scale

3.Progress

4.Imaging (radiography, MRI, CT, venography, etc.)

5.Force plate

6.Diet

7.Exercise

8.Endocrinologic and metabolic testing

9.Laminar biopsies

10.Other

vi.Need for prospective analysis of Equine Metabolic Syndrome

1.Forage testing

2.Tracking environmental and management conditions

3.Quantify body fat (and different fat depots)

4.Quantify body condition

5.Measure metabolic markers

a.Insulin, leptin, adiponectin, etc.

6.Laminar biopsies

vii.Promotional campaign aimed at owners or caretakers and veterinarians to inform or educate them on the importance of their involvement in data or sample collection

viii.Establishment of a committee to oversee setting protocols, tissue use, brainstorm ways to facilitate this for busy (practitioners) and emotional (owners) people

ix.Perhaps consider developing some sort of incentive program for veterinarians and clients to encourage timely and appropriate collection and submission of data and samples

e.Funding needed for collection, processing, storage, shipment, and maintenance of data and specimens

4.Multicentered project(s) are needed

a.More communications among laboratories required

b.Need appropriate funding to effectively facilitate

c.Central organizing committee to focus research efforts among laboratories

d.More collaboration with different laboratories completing parts of a project

e.Funding for a multilaboratory project(s) needed

5.Define the physiology of the normal lamina

a.Vascular

b.Load effect

c.Insulin effect

6.Determine role of the extracellular matrix

7.Develop and apply new techniques to laminitis research

a.Develop biomarkers for laminitis (prediction and prognosis)

b.Biomechanical testing

c.Laminar biopsies

i.Validate and gain acceptance of this technique

d.Incorporate study of nerves into laminitis research

8.Develop new treatments

a.Some treatments are perhaps close to clinical application and testing

i.Clinical trials to assess current therapies

1.Must evaluate on a prospective basis

b.Other potential treatments need to be further studied or optimized in experimental studies and/or using in vitro methods

c.Further study intraosseous and/or regional perfusion treatment regimens

d.Relief of pain

e.Assess mechanical treatments

i.Tenotomy, shoeing, botulinum toxin, trimming, etc.

9.Increase public awareness to increase funding

a.Educate horse-owning public about this devastating and complex disease, and thus the need for large-scale funding to unravel the mysteries and “conquer” it

i.Funding agency marketing

ii.Owner educational programs

iii.Disseminate research results to stimulate interest and funding

10.Need for the Equine Laminitis Research Community to develop a 5- to 10-year strategic plan that provides a framework or roadmap to help guide our collective efforts and to optimize limited resources

a.It was suggested that we try to gather a core group of laminitis researchers and others familiar with the status and future needs (perhaps 10–15 total) within the next 4–6 months and have this strategic planning session facilitated by a professional facilitator

11.On the basis of feedback gathered through an forma evaluation of the workshop, there was overwhelming consensus that the group preferred to have the next Equine Laminitis Research Workshop or other similar gathering within 2 years