MILES Behind Us, MILED Ahead

24 Pages·2017·5.48 MB·English

WINTER 2016 • 2017
MILES Behind Us, MILED Ahead
BY FRANK MCCORMACK, MD, LAM FOUNDATION SCIENTIFIC DIRECTOR
About 30 to 40 percent of LAM patients 3. Premenopausal menopausal status or VEGF-D of
in the United States are taking mTOR >600 pg/ml, plus
inhibitors (sirolimus or everolimus), based
• Residual volume (RV) >120 percent predicted, or
on a recent poll by The LAM Foundation.
• Diffusing capacity (DLCO) of <80 percent predicted, or
In most cases, those offered the drugs by
their physicians have met the lung function • Greater than 4 percent drop in saturation on 6-minute
enrollment criteria used in the Multicenter walk testing on room air, or
International LAM Efficacy of Sirolimus • More than 20 cysts on the carinal cut of the CT
(MILES) trial, a forced expiratory volume
The primary endpoint in the trial is the difference between placebo
Frank McCormack, MD in 1 second (FEV1) of less than 70 percent
and sirolimus groups in the change in FEV1 over time. Side effects
of predicted. However, the lung damage
will be carefully monitored and tabulated, to determine the risk and
required to produce such a reduction in lung function is substantial.
benefits of early treatment. A total of seven clinic visits are required,
Physicians have wondered if we should start mTOR inhibitor therapy
at four-month intervals. Reimbursement for the costs of travel will
earlier, to prevent progression to more advanced stages where more
be provided. Patients may exit the trial at any point, for any reason,
lung damage occurs. The potential benefits of earlier “prophylactic”
but those who experience a 10 percent or greater decline in lung
therapy must be weighed against the risks of starting the drug while
patients still have normal lung function and no symptoms, essentially function from the baseline, or who lose more than 200 cc in FEV1
extending lifetime exposure to the drug. We have very little data will be required to exit the trial and will be offered the drug. The hub
to guide treatment decisions in mild patients, primarily because for the trial is Cincinnati (University of Cincinnati), and the initial
this subgroup of individuals did not qualify for inclusion in the sites will include Boston (Brigham and Women’s Hospital), Chicago
MILES study. (Loyola University Medical Center), Palo Alto (Stanford University
Medical Center), Atlanta (Emory Healthcare), Seattle (Minor and
We are fortunate to have recently received more than $3 million
James Medical/Swedish), Denver (National Jewish Health), St.
in funding from the National Heart, Lung and Blood Institute
Louis (Washington University), Cleveland (Cleveland Clinic) and
(NHLBI) and $350,000 from The LAM Foundation to conduct
Philadelphia (University of Pennsylvania). Additional sites may be
the MILES sequel called MILED, the Multicenter Interventional
opened as required to support enrollment.
LAM Early Disease trial. This study will test the idea that early,
low-dose sirolimus will halt lung function decline in asymptomatic In my opinion, refining our approach to the use of mTOR
patients with normal lung function (FEV1>70 percent predicted). inhibitors is at the top of the priority list for our next step in LAM.
We are seeking 60 patients with mild sporadic (S-LAM) or Tuberous We need better evidence to decide who to treat, and to choose the
Sclerosis associated LAM (TSC-LAM) who are willing to be right dose and timing of intervention. The current clinical practice
randomized to receive placebo or sirolimus at a fixed dose of 1 mg of waiting until symptoms develop or lung function becomes
per day for a period of two years. We know from a recent Japanese
abnormal (and meets MILES criteria) before treatment is begun is
study and our cumulative experiences post-MILES that this low
suboptimal and inadequate. We are looking for 60 women with mild
dose is often effective at stabilizing lung function in LAM, and that
LAM who are on the fence about starting sirolimus, are comfortable
it generally produces few side effects. To qualify, patients cannot be
with a 50 percent chance of receiving placebo, and are interested in
currently taking mTOR inhibitors, and must have signs that suggest
helping to answer the question of whether LAM can be stopped in
a non-trivial burden of lung disease due to LAM including:
its tracks at a very early stage. Our launch goal is the first quarter of
1. Lung function decline of at least 60 cc per year, or 2017. Accomplishing this goal is within our reach. Please write to
2. A supplemental oxygen requirement, or [email protected] for more information.
continued on page 2...
1.877.CURE.LAM 1
continued from pg.1
On another note, we are all still basking in the glow of the Rare Lung Diseases Consortium (RLDC) 2016 conference that was
held in Cincinnati in September. The synergies that resulted from joining forces with other rare lung disease communities exceeded all
expectations, and included surprising insights, new cross-disease collaborations, and a significant increase in sponsorships. We heard
from many physicians and patients that the stories from other disease groups instilled in them a new appreciation for all that LAM has,
and a resolve to share resources for the benefit of all. We are already starting to plan for another joint meeting in 2018.
Excellence Is...
BY SUSAN E. SHERMAN, MHA, EXECUTIVE DIRECTOR, THE LAM FOUNDATION
I was recently inspired by a blog
written about this quote and thought Excellence is…
that if I replaced the word “excellence” Caring more than others think is wise;
with “The LAM Community,” it would
Risking more than other this is safe;
beautifully describe my thoughts about
Dreaming more than others think is practical;
our progress and future goals. Though I
Expecting more than others think is possible.
was unable to find a definitive reference
–Anonymous
to the original author, the message in
each line is applicable to our cause.
Susan Sherman, MHA
“The LAM Community is about with LAM – and we are doing so by responding to the requests
of patients and clinicians. Watch for more information in the
caring more than others think is wise.”
early months of 2017 to learn how you can participate in these
There is a conventional wisdom that says, “best not to care
important events.
too much”. Fortunately, this brand of wisdom has not taken hold
in the LAM Community. Everyone cares deeply about each other
“The LAM Community has a habit of dreaming more than
and the Foundation, and I believe this is a key factor to why we
others think is practical.”
continue to achieve greater milestones each year. As an example,
Sue Byrnes and the first tenacious women with LAM who
in my 25 years as a healthcare executive, I have never experienced
found each other in the early 1990’s dreamed of a future filled
the consistent and sincere caring shown by LAM Clinic Directors
with answers and hope. With so few rare diseases having access to
and their staff toward their LAM patients. It is extraordinary,
money or attention from the research community, LAM seemingly
resulting in better care and confidence for those who are treating
had no better chance of a bright future than any other rare
LAM as well as those being cared for at LAM Clinics.
condition. Now we have an FDA approved treatment for LAM
and published clinical care guidelines. Looking forward, we have
“The LAM Community risks more than others think is safe.”
new dreams such as broader patient participation in research via
This statement line can be a little uncomfortable and
mobile and home monitoring devices, a seamless online repository
therefore I think it is best explained by an example. In this
of clinical and research information shared with more scientists,
edition of Journeys, you will read about the many activities and
and treatments that work for all women with LAM.
resounding success of the International Rare Lung Diseases
Research Conference & LAMposium (RLDC 2016) hosted “The LAM Foundation expects more than others think
in Cincinnati. It was a calculated risk to expand LAMposium is possible.”
to include multiple rare disease groups and to nearly double As with its approach to caring, risking and dreaming, The
attendance. We fielded many questions from patients and LAM Foundation and LAM Community have cultivated a
supporters – wondering if we might risk diluting our focus tradition of high expectations. I see it in my interactions with
on LAM. The numbers and testimonials from patients and LAM clinicians, scientists and families. Frank McCormack,
professionals describe an experience that surpassed our MD, has inspired this attitude of expecting excellence. Anything
expectations – generating new science, productive relationships less is not an option, whether it be related to scientific discovery,
and hope. FDA approval, raising critical funds or tending to the clinical
In 2017 we will expand our approach again by hosting two emotional needs of the next newly diagnosed patient.
research and educational conferences – one on each coast. We enter the new year by honoring what we know works.
We will be in Washington DC on June 22-25, 2017, to host We will pursue excellence by caring with big hearts; by taking
the International Research Conference on TSC and LAM calculated risks to expand our scientific understanding; by holding
in partnership with the Tuberous Sclerosis Alliance. From fast to our dreams of the next discovery; and by expecting that
November 9-12, 2017, we will be in Los Angeles for The Patient our work will soon be finished. LAM will be curable and LAM
Benefit Research Conference and LAMposium LA. It takes science will have informed a greater body of knowledge, lifting
courage to push outside our comfort zone. Our intention is to many closer to heath and healing. For my part, it is meaningful
reach for new discoveries that will positively affect those living beyond words to contribute to this cause.
2 WWW.THELAMFOUNDATION.ORG
Natural Killer Cells Function in LAM
SUMMARIZED BY MICHAEL BORCHERS, PHD, UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE
Our lab is new to the study of LAM, having just initiated studies serum levels of soluble NKG2D ligands are associated with a more
two years ago. Our lab primarily focuses on the function of rapid lung function decline in LAM patients.
immune cells in the lung and the effects of smoking on immune
Based on these findings, we believe that LAM cells express
responses to tissue injury and infection. We were drawn to examine
NKG2D ligands that are cleaved and released, which downregulates
immune function in LAM patients after learning of the theory
NKG2D expression and function, effectively enabling LAM cells
that the pulmonary lesions may originate from cells elsewhere in
to evade NGK2D mediated cell destruction. We believe this
the body (perhaps the uterus?) that proliferate unchecked and
dysfunction may then contribute to increased tissue destruction
spread to the lung. As an immunology lab, we questioned why
and acceleration of lung function loss. Currently, with the support
the immune system failed to detect and control the proliferation
of a generous pilot grant from The LAM Foundation, we are
and movement of these cells. Typically, abnormally proliferating
further pursuing these studies to examine the time course of these
cells are recognized by the immune system through expression of
events in the uterus and the lung of a mouse model generated
surface markers that target them for elimination, so it is important
by Stephen Hammes, MD, PhD, at the University of Rochester
to understand how LAM cells evade this immune detection.
Medical Center. Our hope is that the results of these studies will
Activation of the NKG2D receptor on lymphocytes called provide a much more complete picture of immune evasion in LAM
Natural Killer (NK) cells by NKG2D attachment points (ligands) and identify new therapeutic targets.
on the surface of target cells induces cell death. NKG2D ligand
expression is generally absent on healthy cells, but is abundant on
the surface of tumor cells. Recent studies demonstrate that the
release of soluble NKG2D ligands into the bloodstream suppresses
tumor immunity by acting as a ‘sink’ and downregulating NKG2D
expression and function. Based on interactions with the UC Rare
S
Lung Disease group, we investigated the potential function of
C
NKG2D in LAM in a large cohort of LAM patients. Our studies I
E
revealed that NKG2D ligand expression is abundant on smooth N
muscle cells comprising cystic LAM lesions and that soluble C
NKG2D ligands are present at high levels in the serum of LAM E

patients but not controls. Furthermore, we found that NKG2D A
N
expression is reduced on NK cells of LAM patients possibly
Left to Right: Michael Borchers, PhD, Jennifer Flury, BS,
D
rendering them less functional. Finally, we showed that elevated Andrew Osterburg, PhD, Rebecca Nelson, BS, Huan Liu, MD
R
E
S
E
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Cincinnati Children’s Hospital’s MRI Research Study Includes LAM R
C
BY JASON WOODS, PHD, DIRECTOR, CENTER FOR PULMONARY IMAGING RESEARCH, CINCINNATI CHILDREN’S HOSPITAL MEDICAL CENTER H
Researchers in the Center for Pulmonary Imaging Research from this study will be submitted to the American Thoracic Society
(CPIR) at Cincinnati Children’s Hospital Medical Center for presentation at its annual meeting in the spring.
are developing new magnetic resonance imaging (MRI) methods
The CPIR would like to thank all of the volunteers for their
to visualize and quantify lung diseases, including LAM. Under
time and participation and The LAM Foundation for their
the direction of Dr. Jason Woods, the CPIR has developed new
support. If you are interested in participating in a future imaging
MRI methods which provide images of the lung tissue similar in
study, please contact Erin Watters at 513.803.7024 and visit
quality to computed tomography (CT) but without exposure to
cpir.cchmc.org for more information.
ionizing radiation. The group also developed novel hyperpolarized
129Xe MRI techniques which, in a single breath-hold, can depict
regional ventilation deficits or airspace size. Both are potentially
important to characterize structural and functional abnormalities
in the lungs of LAM patients. The CPIR is one of only a few sites
in the world to have hyperpolarized 129Xe MRI capabilities.
During LAMposium 2016, the CPIR imaged 12 LAM patients
using this combined structural and functional MRI. The goal of
this project was to characterize the regional pathology of LAM and
its heterogeneity across different patients. A preliminary analysis
of the imaging data revealed a wide range of regional structural
and functional pathologies across individual LAM patients.
Additional analysis to relate the imaging findings to pulmonary Front row, left to right: Zack Cleveland, PhD, Leslie Korbee, Laurie
function testing and clinical characteristics is ongoing. However, Vanderah, RN, Matt Freeman, PhD, Jason Woods, PhD
early results indicate that these novel MRI techniques are very Back row, left to right: David Roach, PhD, Robert Thomen, PhD,
Nara Higano, MS
sensitive to the early regional lung pathology of LAM. The results
1.877.CURE.LAM 3
LAM Pearls: 10 Things I Want Every LAM Patient To Know
BY FRANK MCCORMACK, MD, LAM FOUNDATION SCIENTIFIC DIRECTOR; ADAPTED FROM MY PATIENT SESSION AT LAMPOSIUM 2016
1. LAM is rich compared to other rare diseases science is rewriting biochemistry textbooks and reshaping our
LAM is blessed with abundant clues from nature that have thinking about approaches to cancer. The FDA approval of
yielded a rich understanding of the molecular basis of LAM in sirolimus for LAM, based on the MILES trial alone, has resulted
record time. The LAM community has assembled a solid network in approvals in several other countries.
of expert centers for both clinical care and translational research,
as well as registries, a tissue bank and a data center. LAM 4. The most immediate next research steps in LAM are clear
researchers and healthcare providers have also formed invaluable One of the highest priorities for LAM research is determining
partnerships with the Tuberous Sclerosis Complex community, exactly how to use mTOR inhibitors, such as sirolimus and
the National Heart, Lung and Blood Institute and several everolimus. Guidelines for the use of sirolimus have recently
rare lung disease communities. Most importantly, we have an been published based on data that has been gathered from
organized, motivated patient community. During the past decade, MILES and other studies, but there is much more to do. We
the LAM Foundation has raised $21.2 million; $12.5 million of need to know the best dose, who to treat, when to start and
which has been committed to research and has funded more than when, if ever, we can stop (such as after menopause?). Two key
119 projects and 77 unique investigators. The data generated studies that aim to tackle these issues are the MIDAS Registry
with funds from The LAM Foundation have formed the basis for (Multicenter International Durability of Sirolimus Study) to
clinical trials that identified an effective treatment, and a useful examine durability of sirolimus effectiveness and side-effects
diagnostic biomarker. Research is the key to further progress. over time, and the MILED Trial (Multicenter Interventional
LAM Early Disease Trial), funded by the NIH. MILED is
S 2. The future is bright for patients with LAM designed to determine whether early, low dose treatment with
C There is a pervasive optimism throughout the LAM scientific sirolimus is sufficient to suppress LAM progression.
I
E and patient community that this problem is scientifically tractable
N
C and potentially solvable in our lifetimes. Today’s patients have every 5. Healthcare professionals are developing methods
E reason to be optimistic. We already have an effective suppressant to predict how LAM will likely behave in

A therapy in sirolimus. Because LAM is the simplest, most individual patients
N decipherable neoplasm in creation, some of the best scientists in
In any given patient, the best indicator for predicting how LAM
D the world are interested in LAM as a model for studying more
will behave in the future is studying the way LAM has behaved
R complex cancers. In addition, LAM research is adding to our
E for them in the past. We know now that menopausal status has a
S fundamental knowledge regarding cellular metabolism, diabetes,
big effect, resulting in considerable slowing in LAM progression.
E
obesity and aging. Researchers have dozens of promising ideas
A VEGF-D testing also appears to have value in predicting if LAM
R for trials with repurposed drugs, many of which are already FDA-
C will progress and respond to therapy, and many other biomarkers
approved and ready for testing. Best of all, LAM patients and their
H are being tested. Using data from the National Disease Research
families are focused on finding solutions and living full lives, and
Interchange (NDRI), Center for Disease Control and Prevention
the joie de vivre and courage that radiates from you is empowering
(CDC), and the United Network for Organ Sharing (UNOS),
to all of us who work in LAM.
researchers are working to develop a LAM Risk Score Calculator
that may be useful for predicting the disease course and making
decisions of whether to start therapy.
There is a pervasive optimism throughout the
LAM scientific and patient community that
6. Every patient should know her FEV1 trajectory
‘‘
this problem is scientifically tractable and
Lung function measures, imperfect as they may be, are still
potentially solvable in our lifetimes.
our best biomarkers for LAM. In my opinion, every patient
should know her FEV1 percent predicted and should plot her
FEV1 (in milliliters or liters) over time. Whenever possible,
3. The profile of LAM has never been higher post-bronchodilator FEV1 values should be used. Periods of
LAM is the fastest moving science in pulmonary medicine. sirolimus use should be plotted on the same graph, to determine
LAM advances have been highlighted out of more than 7,000 if the drug is having the intended effect of slowing lung function
rare diseases – in recent high profile addresses, such as by Dr. decline. The graph should be reviewed at every clinic visit.
Chris Austin, Director of the National Center for Advancing The Foundation is hoping to launch an app to make this task
Translational Services (NCATS) to the NIH Advisory Council, easier. Patients being faced with treatment decisions or who are
and Dr. Francis Collins, Director of the NIH at the 2016 NIH being monitored for treatment response should have spirometry
Rare Disease Day. In addition, the recent publication of LAM frequently, such as every three months. Someday we hope to
science in the most prestigious of journals, such as Science, Cell be able to monitor lung function with home spirometry, as
and Proceedings of the National Academy of Sciences (PNAS), frequently as daily, with direct uploads through the web into a
attests to the rigor and impact of our scientist’s work. LAM database housed on LAM360.
4 WWW.THELAMFOUNDATION.ORG
7. Trials (and other studies) are the key to more and effective treatments and, ultimately, a cure for LAM through:
effective treatments
• Developing mechanisms for rapid trials within The LAM
The progress that we have achieved to date was made Foundation Clinic Network
possible by LAM patients who enrolled in clinical trials and
• Refining the approach to suppressive therapy with
other research studies. Participation in research can take many
mTOR inhibitors
forms. This may include enrolling in interventional trials (such
as MILED, SLAM or SOS), observational trials (such MIDAS), • Developing clinically impactful biomarkers and remission-
donating samples, releasing medical information for research, inducing therapies
participating in surveys from the Foundation, attending regional
meetings and LAMposiums or enrolling in the Rare Lung Diseases 10. How grateful I am to have such meaningful work
Contact Registry. Working for patients and families with LAM has been a
source of great joy for me. I want to thank Sue Byrnes for roping
8. Who benefits from sirolimus use and how we me in some 22 years ago.
administer it safely
Sirolimus is used to treat LAM patients with abnormal lung
function as well as asymptomatic patients who are declining
rapidly and approaching the abnormal range. In small studies,
sirolimus has been quite effective for problematic effusions and
S
lymphangioleiomyomas. Because sirolimus can have side effects
C
and is often taken for long periods, physicians strive to determine I
E
the lowest effective dose. The ATS/JRS LAM Guidelines that N
were just published provide a roadmap for sirolimus use that will C
E
be useful for clinicians. The Foundation has produced a white
A
paper for monitoring sirolimus therapy that is now included on
N
the website. D

R
E
9. The top priorities for The LAM Foundation
Frank McCormack, MD, presenting at LAMposium 2016 S
scientific community E
A
The LAM Foundation’s first priority is the discovery of safe R
C
H
Helen Green Research Travel Fund
Women with LAM understand the importance of participating in LAM research. One of the most
comprehensive and longest running LAM research studies is at the National Institutes of Health
(NIH). For years, the NIH has generously provided travel reimbursement for women with LAM to travel
to the NIH to take part in the LAM protocol. Last year, patients new to the protocol had to cover their
own travel expenses. When LAM patient Becky Hobgood found out about this change, she decided to
do something about it.
After discussing the idea with her family, Becky and her siblings established the Helen Green Research
Travel Fund, named in honor of their mother. This fund will be used specifically to help women with LAM
cover travel costs associated with traveling to the NIH in Bethesda, MD, for their first visit. Subsequent
visits may be covered by the NIH.
If you are a newly diagnosed woman with LAM and are interested in finding out more about the
Helen Green Research Travel Fund, or how you can participate in research, contact our Patient Services
& Education Manager, Anne McKenna, at [email protected] or 513.777.6889.
Helen Green
1.877.CURE.LAM 5
Make Sure You Are Part of the Conversation
BY ANNE MCKENNA, PATIENT SERVICES AND EDUCATION MANAGER
Twelve years ago when my sister, Katie, was first diagnosed there are different ways to participate. The Questions and
with LAM, the information that was known about the Answers forum is the place to get questions answered. Whether
disease was limited. The genetic pathway that causes the disease you’re getting an answer from others living with the disease, The
hadn’t been found yet. There was no treatment. There were no LAM Foundation staff or a LAM expert, you’ll be sure to get
doctors in her hometown that understood the disease and they the answers you’re looking for. This forum is also searchable so
couldn’t answer her questions. But there was one important way you will be able to look for other related questions. While you’re
that Katie was able to get information about the disease – from getting the answers you need, clinicians and researchers will also
other women living with LAM. Unfortunately, I know there are be able to see what questions and issues are most important to
too many others out there that share Katie’s story. you. This could lead to the further study of those issues. The
LAM360 Blog is another great new feature. Articles will be
Today, we know a lot more about LAM but we still have a
informational and provide the latest news and updates in a timely
long way to go. There are still many questions that need to be
way. Blog posts are interactive, and we expect some lively debates
answered. But one thing remains the same – the best way to get
in the comments section.
this information is directly from women living with the disease.
LAM360 will continue to grow and evolve. We plan to use this
Recently, there have been many articles published about the
platform as a one-stop place where patients and families can
importance of the “Patient Voice”. Lots of important organizations
share their experiences through surveys, by using interactive
are talking about it these days; The National Health Council,
devices such as home spirometers and by ultimately using all of
The New England Journal of Medicine, the FDA, the NIH.
this information to create a patient registry. A patient registry is
S But here at The LAM Foundation, we’ve known for a long time
C an important step to finding further treatments and ultimately, a
I that the patient voice is invaluable and the fastest way to get the cure for LAM. We have a lot of work to do to get there and we
E
N best results. need your help.
C
E That’s why I’m proud to announce our newest project, Getting signed up with LAM360 is easy. Go to
LAM360. This interactive portal that is integrated with our www.thelamfoundation.org and click on the Register link in
A
N website is a place where women with LAM, their families and the upper right corner of the page. Everything you need to get
D friends can come to together with researchers and clinicians started can be found under the LAM360 menu on the home
R to make sure that their voice is heard. Does this remind you page of the site. If you have questions, call the Foundation and
E of anything? Think LAM360 as a virtual LAMposium where we’ll be happy to help.
S
E everyone across the LAM community can come together, learn
The LAM Foundation started with Sue Byrnes making phone
A from each other and help improve the lives of women living
R calls to connect women with LAM. Today, we’re lucky to have
C with LAM.
this high tech platform for connecting those affected by the
H
Our intent is for LAM360 Community to become the hub disease and making sure their voices get heard. Sign up today
where all of these interactions take place. Within the Community, to make sure that you are a part of the future.
6 WWW.THELAMFOUNDATION.ORG
Vaccinations for Patients with LAM
BY FRANK MCCORMACK, MD AND SENU APEWOKIN, MD
3. Shingles (H. Zoster) vaccination should NOT be given
while on mTOR inhibitors:
• Patients over age 50 who are about to begin mTOR
inhibitor therapy should be vaccinated, optimally at least
4 weeks prior to starting.
• Patients could be vaccinated during a hiatus in therapy
with mTOR inhibitors, such as when they are held for
upcoming surgery.
• A new zoster subunit vaccine that would be appropriate
for use in patients on mTOR inhibitors is under
Frank McCormack, MD, Senu Apewokin, MD,
The LAM Foundation University of Cincinnati development (Cunningham, A.L. NEJM 2016) and may
Scientific Director Medical Center be available soon.
4. Hepatitis (A and B) vaccines: recommended for all patients.
Patients with LAM should maintain appropriate
5. Tetanus vaccine: recommended for all patients.
vaccinations. Live vaccines should be avoided in
patients taking immunosuppressive agents, so vaccination 6. Avoid other live virus vaccines:
recommendations below differ between LAM patients who are • Measles, mumps, rubella
on mTOR inhibitors and those who are not. • Oral polio
• Smallpox
For LAM patients who are NOT taking mTOR inhibitors, • Rotavirus
we recommend: • Yellow fever
1. Annual influenza vaccination with the inactivated • Rabies
vaccine. Flumist (live attenuated influenza vaccine) is
General comments C
not recommended in LAM patients, because diffuse lung
disease is a relative contraindication. Inactivated or recombinant flu vaccines (i.e. the injectable LI
N
types of flu vaccine that your physician will offer to you)
2. Vaccination against pneumococcus: should not be used in anyone with prior severe allergy without IC
• All patients should receive Prevnar, one dose in lifetime; consulting an allergist, and should be used with caution in: A
L
ideally given before Pneumovax, but at least 1 year after patients with moderate or severe acute illness with or without
Pneumovax. fever, a history of Guillain-Barré syndrome within 6 weeks of
• All patients should receive Pneumovax, one dose every 5 previous influenza vaccination, or people with egg allergy (hives
years; given at least 2 months after Prevnar. only allergy can be mitigated with additional safety measures).
3. Shingles (H. Zoster) vaccination: Minor illnesses (such as diarrhea, mild upper respiratory
• For those over age 60. infection with or without low-grade fever, other low-grade
• For those over age 50 who are about to begin mTOR febrile illness) are not contraindications to vaccination. Adults
inhibitor therapy, optimally at least 4 weeks prior with egg allergy of any severity can receive inactivated vaccines
to starting. with the same indications as those without egg allergy, since
• Since immunity only lasts 5 years, revaccination may be the new preparations contain much smaller quantities of
necessary (although not if on mTOR inhibitor therapy by egg products.
that time).
Contraindications to Pneumovax and Prevnar include severe
4. Hepatitis (A and B) vaccines: recommended for all patients.
prior allergic reaction, and moderate or severe acute illness.
5. Tetanus vaccine: recommended for all patients. Patients with a documented true allergic reaction (rather than a
history of egg allergy) to Prevnar or Pneumovax should seek the
advice of an allergist.
For LAM patients who ARE taking mTOR inhibitors,
we recommend: Although inactivated and recombinant flu and pneumococcal
1. Annual influenza vaccination with the inactivated vaccinations can result in soreness and low-grade fever and
vaccine. Flumist (live attenuated influenza vaccine) is not muscle aches, they cannot produce flu or pneumonia.
recommended in patients with LAM. There is a growing literature suggesting that patients on low
2. Vaccination against pneumococcus: dose immunosuppression (such as low dose sirolimus) can take
• All patients should receive Prevnar, one dose in lifetime; shingles vaccine safely, but further studies are needed before
ideally given before Pneumovax, but at least 1 year this recommendation can be made.
after Pneumovax.
• All patients should receive Pneumovax, one dose every 5
years; given at least 2 months after Prevnar.
1.877.CURE.LAM 7
American Thoracic Society and Japanese
Respiratory Society Publish LAM Guidelines
The American Thoracic Society (ATS) and the Japanese Respiratory Society (JRS), in
conjunction with an ad hoc guideline development committee of LAM experts, prepared
guidelines for the treatment of lymphangioleiomyomatosis. These guidelines were approved by
the ATS Board of Directors and the JRS, and endorsed by The LAM Foundation in May 2016.
This past September, the ATS’s American Journal of Respiratory and Critical Care Medicine
published the guidelines.
The intent of the guidelines is to empower clinicians to apply the recommendations
to their individual patients and tailor their decisions to the clinical situation at hand.
These guidelines answer the first four questions regarding the treatment and diagnosis
of LAM:
1. Sirolimus is the recommended treatment for patients
with LAM with abnormal/declining lung function.
2. Hormonal therapy is not recommended.
3. Doxycycline is not recommended.
4. VEGF-D is useful for diagnosis.
The next phase of the guidelines is set to be published in 2017. These guidelines will
answer another set of questions pertaining to the management of LAM, such as issues
regarding pregnancy, safety of air travel, pleural interventions and the use of bronchodilators.
You can print and review the guidelines from The LAM Foundation website under the
Healthcare Providers tab, titled Treatment Guidelines.
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BY LAURA BOWERS, DIAGNOSED 2013
This time last year, I discovered an opportunity to apply for a grant through my pharmacy school
program at the UNC Eshelman School of Pharmacy. I knew that I wanted to find a way to use
the grant to help educate physicians about LAM, but I was not sure exactly what or how to go about
it. I called Sue Sherman and told her about the opportunity and we brainstormed. Sue informed
me the new LAM Guidelines would be published in 2016 by the American Thoracic Society. In
healthcare, promoting guidelines can be a challenge. It is both expensive and time consuming, so
I pitched the idea to Sue that I write a grant to help spread the news about the new guidelines.
The competition for the Eshelman Institute for Innovation grants was stiff, but after a one-
minute live pitch followed by a three-minute question and answer session; the committee funded
the Air We Breathe Campaign. This exciting campaign will educate emergency room physicians,
obstetricians and gynecologists on the new LAM guidelines. This will be accomplished in three
main ways:
Laura Bowers
First, there will be several pages on The LAM Foundation’s website dedicated to the
campaign. Physicians, healthcare educators and patients can visit the website to find a link to the new guidelines and to download
educational materials.
Second, a continuing medical education (CME) video is being developed for physicians highlighting the new guidelines.
Finally, in the spring of 2017 I will attend professional conferences for emergency room physicians and obstetricians and gynecologists,
presenting information from the guidelines pertinent to each specialty.
At LAMposium and the Rare Lung Diseases Research Conference, other rare disease organizations thanked The LAM Foundation
for blazing the trail and setting the gold standard for raising awareness. The Air We Breathe Campaign will expand upon these incredible
efforts and continue to broaden the circle of healthcare providers who know how to properly diagnose and treat LAM. You can read the
new guidelines and find more information on the Air We Breathe Campaign by visiting The LAM Foundation website.
8 WWW.THELAMFOUNDATION.ORG
The LAM Foundation and Rare Lung Diseases Consortium
welcomed rare lung disease organizations and thought
leaders to attend the International Rare Lung Diseases
Research Conference in September 2016. Researchers,
clinicians, patients and families gathered for a purpose driven
event where LAM and rare lung disease research were
discussed in detail, trials were planned for pediatric ILD, PAP
CINCINNATI, OHIO
and PLCH, and patient participation put a human face on rare
lung diseases.
SEPTEMBER 22-25
470 PARTICIPANTS
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2
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1
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9 RARE LUNG DISEASE PATIENT ADVOCACY GROUPS
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233 RESEARCHERS AND CLINICIANS L
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17 RARE LUNG DISEASE INTENSIVE SESSIONS P
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60,334,427 TOTAL MEDIA
IMPRESSIONS
4 RARE LUNG DISEASE WORKSHOPS
35 GLOBAL LAM CLINICS REPRESENTED
FOCUSED ON LAM AND DEVELOPING
AT THE FIRST RARE LUNG DISEASE CLINIC
TRIALS IN PLCH, PAP AND SURFACTANT
DIRECTOR’S CONGRESS
MUTATION DISORDERS
$ NEARLY $400,000 RAISED FROM 30 GENEROUS SPONSORS AND ATTENDEES
$260,000 DONATED TO SUPPORT THE LAM FOUNDATION AT THE BREATH OF HOPE GALA
1.877.CURE.LAM 9
The International LAM Research Conference: Basic Science Overview
BY ROBERT KOTLOFF, MD, PROFESSOR AND CHAIR OF PULMONARY MEDICINE, CLEVELAND CLINIC,
AND WILLIAM C. PARKS, PHD, PROFESSOR OF MEDICINE AND BIOMEDICAL SCIENCES, CEDARS-SINAI MEDICAL CENTER
1. The Extracellular Matrix (ECM) in LAM
Speakers
• William Parks, PhD, Professor Of Medicine And Biomedical Sciences, Cedars-Sinai Medical
Center; Overview of the ECM in Lung and Destructive Lung Diseases
• Robert Mecham, PhD, Alumni Endowed Professor of Cell Biology and Physiology, Washington
University; Extracellular Matrix Regulation of Cell Function
• Enid Neptune, MD, Associate Professor of Medicine, Johns Hopkins University; The Active
Matrix in Genetic Emphysema
Robert Kotloff, MD
• Merv Merrilees, PhD, Associate Professor of Anatomy and Radiology, University of Auckland;
Matrix Proteoglycans in LAM: Variants of Versican as Targets for Interventions
Dr. Parks provided an overview of extracellular matrix (ECM) and how it is organized in the lung
(and most tissues). In simple terms, the ECM is all the stuff outside of cells. More precisely, the ECM
is composed of a wide range of structural proteins, which are deposited in the spaces between cells,
and numerous related proteins, such the enzymes that form fibers, proteinases that remodel ECM (see
below), cytokines and growth factors that are stored within ECM, and more. Dr. Parks then focused on
R alveolar destruction (or expansion) and indicated that destruction of alveolar ECM was a critical causative
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C William C. Parks, PhD ECM components in the alveolar wall are collagen (largely Type I and III collagens – the most abundant

• proteins in our body) and elastin fibers. Both are large, tough, insoluble, and very long-lived polymers.

2 Collagen fibers provide tensile strength, whereas elastin provide passive recoil during breathing. Destruction of either or both of these
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critical ECM components will lead to alveolar expansion.
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As is summarized in Section 2, various proteinases have been implicated in causing alveolar destruction by degrading critical
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ECM components. But a flip side to this is repair. That is, even though proteinases – which likely come from inflammatory cells
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A – are degrading ECM, why don’t the alveolar cells deposit new ECM to repair this damage? Dr. Mecham’s presentation addressed
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this issue. He discussed that the assembly of any single ECM component is a complex process involving numerous cofactors and
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O chaperons and the sequential production of other proteins and their associated cofactors. For example, elastin fiber assembly requires
S that a scaffold of fibrillins (and other) proteins be deposited before elastin synthesis begins. Once the fibrillin scaffold is complete,
IU then elastin expression turns on, and the precursor protein – tropoelastin – is secreted, deposited, and covalently cross-linked on the
M scaffold. Indeed, the difficulty of regenerating degraded elastic fibers in emphysema illustrates this principle.
Dr. Neptune expanded on these concepts, suggesting that by examining genetic diseases with similar pathologic outcomes, such
as Marfan Syndrome (MFS), would shed light on critical mechanisms. Indeed, in MFS, the mutated protein is fibrillin-1, which, as
discussed, is necessary for elastic fiber formation. Furthermore, Dr. Neptune indicated that associated processes could be identified
and targeted for therapy. In her collaborative studies with MFS, they discovered that TGF-β signaling – which is controlled in part by
interactions with fibrillin – is excessive and likely contributes to many of the disease ECM manifestations. Thus, they began clinical trials
to blocked TGF-β signaling with Losartan, and their findings to date have been quite promising, with MFS patients showing marked
improvement.
Dr. Merrilees presented a potential and novel way to promote repair of elastic fibers. In collaborative studies with Dr. Thomas
Wight in Seattle, they discovered that a fragment of versican, an abundant ECM component in most tissues, potently induces
renewed elastin synthesis and elastic fiber formation. Versican is a proteoglycan, a class of ECM components in which numerous long
sugar chains (specifically glycosaminoglycans) abundantly decorate the protein core. To be called a proteoglycan, the mass of the sugar
chains must exceed the mass the protein (if the protein component is larger, then it is called a glycoprotein). In studying the basic
biochemistry of versican, they created a mutant – called V3 – that lacks glycan chains, and they discovered that this truncated protein
markedly stimulated (more than 20-fold in some settings) formation of new elastic fibers both in cell culture and in mice. Hence,
these exciting findings may point the way to overcome the inherent difficulties in repairing damaged alveolar ECM.
2. Destruction of ECM in LAM
Speakers
• Simon Johnson, PhD, Professor of Respiratory Medicine, University of Nottingham; Proteases in Destructive Lung Disease
• Victoria Stepanova, PhD, Assistant Professor, University of Pennsylvania; Urokinase-Type Plasminogen Activator Contributes
to Progression of TSC2-negative Tumors
10 WWW.THELAMFOUNDATION.ORG