REPORT FROM THE ROSS PETTY PEDIATRIC RHEUMATOLOGY SYMPOSIUM:
Old
challenges & new directions in pediatric rheumatology
C Spencer
Introduction
On
I The
History and Contributions of Canadian Pediatric Rheumatologists
Ron Laxer of
A. The early years
Pediatric rheumatology in
Meanwhile,
Ross was beginning his medical training at the
B. Contributions in the literature,
academics, center development, and training.
There have been
many contributions to pediatric rheumatology over the years by Canadian pediatric
rheumatologists with some seminal pediatric articles. The articles number over 30 and are too
numerous to enumerate here.
Canadians have made
more contributions other than published manuscripts:
1) Established Pediatric rheumatology as a
pediatric subspecialty in
2) Three training programs for fellows
certified and producing fellows regularly.
3) Trained over 20 pediatric
rheumatologists who practice outside of
4) Established the Canadian Pediatric
Rheumatology Collaborative Group,
e.g., 5,10,15 year outcome of JIA- Oen, Malleson, et al
5) Headed the ILAR Nomenclature group
-Petty et al
6) Recently published an A&R article on
use of nomenclature in JIA/JRA-Ciaran Duffy et al
7) Began and maintains the internet
pediatric rheumatology bulletin board -Peter Dent (1996)
8) Petty and Cassidy textbook-now in 4th
edition
9) Journal of Rheumatology began a
pediatric section; subsequently Arthritis & Rheumatism has
followed suit.
10) Ciaran Duffy is co-chair of Park City
VI
(Reporter’s Note: Several Canadians have
been instrumental in establishment and development of the Pediatric
Rheumatology Online Journal)
In summary,
Canadian pediatric rheumatology has been essential to the development and
leadership of pediatric rheumatology in many areas.
II
New Paradigm of Science: Discovery science, not just hypothesis driven science.
John Schrader
Genomics is now
transforming the nature of science. We have the DNA of mammals and mice and
humans as well as pathogens. We understand and utilize better genes, control
elements, maps, and markers. Humans have only a small number of genes,
approximately 27,000. This number of genes is not much more than the number of
genes of a fruit fly. The difference between the fruit fly and us is the number
of proteins we make, somewhere between 150,000-300,000 proteins! So proteomics
may be a major advance in science.
One possible goal
of proteomics is to see what protein is present in one disease or which one is
absent. It is also to see what patterns of proteins fits with what disease and
stage of disease or response to therapy. Proteomics involves first isolating a
protein, then cutting it into peptides using trypsin, and analyzing the
proteins by mass spectrometry yielding a unique protein fingerprint. The
computer will remember the fingerprint of each protein portion. This expensive
process of sample preparation, sample processing, sample analysis, and data
analysis is all done by automated robots and computers.
The discovery
science of proteomics can tackle even more complex patterns. Proteomics has the
power to digest a large mass of proteins-tens of thousands of peptides, analyze
them by mass spectrometry, and select out a target protein and then analyze
that protein by itself.
How can proteomics
be useful? First, it may be possible to associate proteins with diseases. One
example might be the recent use of proteomic patterns to identify early ovarian
cancer in 2002 in a proteomics-based work. In this study the authors
prospective evaluated 100 patients by initially digesting serum proteins of
each patient and performing proteomic computer analysis. Though controversial,
this analysis appears to have been able to identify patients totally without
ovarian cancer and patients who subsequently could be shown to have ovarian
cancer in an early disease stage.
How else can
proteomics be important? This discovery science may help us understand disease
heterogeneity and classification problems, predict outcomes, and use the right
medicine for the right patient at the right time. Current such projects
include: 1) Proteomics with synovial fluid proteins at Harvard with orthopedic
and rheumatology collaboration. The focus is initially on human proteins and
the results will then be tested in animal models, an unusual paradigm; 2)
Protein arrays for autoantibody profiling at Stanford.
The success of
proteomics will depend upon optimizing collaboration from bench to bedside with
a critical mass of excellent clinical scientists and scientific clinicians who
are catalytic, credible, and connected. Each proteomic project will require
authorities in both the clinic and bench with good communication skills in
forums and meetings with a candid exchange of ideas and hypotheses, no matter
how naïve. Cross-fertilization is critical with attitudes broadminded and
catholic.
Suggested
References
1. de Hoog CL,
Mann M. Proteomics. Annul Rev Genomics Hum Genet.
2004; 5:267-93.
2. Yarmush ML, Jayaraman A. Advances in
proteomics technologies. Annu Rev
Biomed
3. Tilleman K, Deforce D, Elewaut D.
Rheumatology: A close encounter with
proteomics. Rheumatology (
III
Innate Immunity and rheumatology
Stuart Turvey
Dr. Turvey began
with a case presentation of a two year old with recurrent cervical adenitis
whose brother had died of pneumococcal meningitis at age 5 years. All initial
immunological tests were negative.
Dr. Turvey
discussed that innate immunity is phylogenetically ancient and targeted mostly
against most multicellular organisms. It is the quick responder with an immune
response within hours. It involves neutrophils, macrophages, monocytes, NK
cells, complement, and antimicrobial peptides. In contrast, the adaptive immune
system is sexier but slower, taking days to have its full effect.
Toll mutations are
a new focus. The Toll system is an ancient immune alarm system that empowers
the adaptive response against most all bacteria. Toll mutations in fruit flies
makes them susceptible to fungal infections. There are 10 Toll-like receptors
in humans. Toll-like receptor 4 recognizes lipopolysaccharide. Toll-like
receptor 5 recognizes flagella. Toll-like receptor 9 recognizes the
unmethylated CpG motifs in bacteria. The Toll-like receptors activate
cytokines, activate antigen presenting cells, induce maturation of dendritic
cells, and have other functions. These receptors are critical for NFK-B
signaling. Toll-like receptors serve as bridge from the innate to the adaptive
immune system.
The two year old patient was found to be having a diminished Toll-cell
response with a gene mutation of TLR4 that blunts Toll-like receptor signaling
and affects PAMP activity. A TLR5 that recognizes flagella is associated with
an increased susceptibility to Legionnaire disease. Toll-like receptors may be
important in rheumatic disease, e.g., in molecular mimicry models-cross
recognition of microbial and self epitopes. In
In
Suggested
References
1. Staros EB Innate immunity: New
approaches to understanding its clinical significance. Am J
Clin Path. 2005 Feb;123(2):305-312.
2. Brentano F, Kyburz D, Schorr O, Gay R,
Gay S. The role of Toll-like receptor signaling in the
pathogenesis of arthritis. Cell Immunol. 2005 Jun 14
3. Pasare C, Medzhitiv R. Toll-like
receptors: Linking innate and adaptive immunity. Adv Exp Med
Biol. 2005;560:1-8
IV
Maternal microchimerism in rheumatic disease
Anne Stevens
Maternal
microchimerism is a process where cells from the mother pass into her fetus
during pregnancy. These cells are usually tolerated well by the child’s immune
system and the cells may last for decades. The cells can be protective or
damaging. This microchimerism has been detected in patients post-transplant and
with rheumatic diseases.
The detection of male fetal progenitor cells in a mother with a
rheumatic disease was first reported in 1996. These fetal cells were in the
skin, kidney, spleen, and thyroid in multiple rheumatic diseases, especially
scleroderma, lupus, primary bilary cirrhosis, thyroid, and Sjogrens syndrome.
How common is maternal microchimerism? All cord blood has some maternal
cells and it appears that everybody has maternal cells for 40-50 years.
Microchimerism has been found in half of systemic scleroderma patients compared
to 20% of controls, noted in muscles in juvenile dermatomyositis, and in the
heart tissue of neonates with neonatal lupus. Ann Reed has reported that 85% of
juvenile dermatomyositis patients have microchimerism with CD4 and CD8 positive
maternal cells (5-10% in controls). Could these cells be attacking the muscle
in this illness?
Dr. Stevens noted that her research has shown that five percent of
neonates with the SS-A/SS-B antibodies develop neonatal lupus. In these
neonatal lupus newborns, maternal cells have been found in heart tissue of the
AV node. These maternal cells in muscle cells express the sacrophage antigen.
Also maternal cells can differentiate in renal, liver, and pancreas tissue and
in the pancreas these cells can express insulin.
In SLE, the
maternal microchimerism suggests a loss of tolerance of the host to these
cells. In one study, microchimerism is only 19% in SLE patients while 40% in
controls. Are SLE patients eliminating these cells from their blood and other
tissues? A recent report of an increase of interferon-gamma and IL-4 produced
by maternal cells in patients with SLE does suggest some loss of tolerance. Yet
male microchimerism is increased in female patients who have SLE.
Dr. Stevens
summarized by saying that maternal microchimerism is common in humans and these
cells persist for decades both in blood and tissue. Maternal cells appear to be
well tolerated by a child’s immune system except in SLE. Male microchimerism in
females with SLE is interesting and may turn out to have a role in the
etiopathogenesis of SLE.
Suggested
References
1. Stevens AM, Hermes HM, Rutledge JC,
Buyon JP, Nelson JL. Myocardial-tissue-specific
phenotype of maternal microchimerism in neonatal lupus congenital heart
block. Lancet 2003
Nov 15:362(9396):1596-7
2. Reed AM, McNallum K, Wettstein P, Vehe
R, Ober C. Does HLA-dependent chimerism unlie?
the pathogenesis of juvenile dermatomyositis. J Immunol. 2004 Apr
15;172(8):501-6
3. Sarkar K, Miller FW. Possible roles and
determinants of microchimerism in autoimmune and
other disorders. Autoimmun Rev. 2004 Aug:3(6):454-63
4. Stevens AM, Hermes HM,
sibling microchimerism in twins and triplets discordant for neonatal
lupus syndrome-congenital
heart block. Rheumatology (
V Views form the bench-Kawasaki Disease
Rai
Yeung
Dr. Yeung described
her rheumatology unit’s interest in the Lactobacillus casei cell wall mouse
model as a murine model for KD. In this model, the cell walls are injected
intraperitoneally into the mouse at day 0 and a vasculitis develops with
maximal disease at day 28. The arteritis (LCA) is most prominent in the
coronary arteries and the aorta. Disruption of elastin is noted by day 42. This
arteritis responds to immunoglobulin treatment just like KD.
This unit has
demonstrated that a superantigen appears to be crucial to the development of
LCA. If there is an absence of a superantigen, no disease occurs. If a
superantigen is present, the LCA is expressed. The superantigen appears to
cooperate with the Toll-like receptor in some models. Dr. Yeung noted that, in
her opinion, it is unclear yet whether the TLR are crucial to LCA.
T
cells and T-cell receptors may have an important role in LCA as the arteritis
does not occur in C3h-Hej mice which have a T-cell receptor VB
14 defect. Interferon-gamma (IF-g) mRNA has been
shown to be produced as early as day 3 in these LCA mice and as late as day 28
in the LCA coronary vessel wall. Yet IF-g appears
not to be essential to the development of LCA as the IF-g
knock-out
mouse can still develop LCA.
What about TNF-a?
KD kids have increased TNF-a levels and
anti-TNF-a
therapies
such as infliximab have been used to treat KD with some success. TNF-a knockout mouse did not develop the
LCA with no elastin breakdown.
TNF-a dependent
upregulation of migration molecules has been noted in this model as well.
Apoptosis does not
appear to be increased in this model. Caspace-3 is not increased in LCA with no
increased apotosis at vessel walls. Elastin breakdown was investigated by
looking at extracellular matrix regulation. MMP-9, a metalloproteinase, was
found to be increased in the cardiac tissue level but not in serum. The MMP-9
knock-out mice injected with L casei cell wall extract did have LCA
inflammation but exhibited no elastin breakdown. Neutrophil elastin factor is
currently being looked at. Interesting, high dose ASA, a staple of KD treatment
since the 1970’s, does have an effect on elastin. It also inhibits NF-kB
nuclear translocation, TNF-a cytokine pathways,
and MMF-2 and MMF-9 metalloproteinases.
VI Barriers to care in pediatric
rheumatology
A. The UK view-Helen Foster
The key questions are:
How common is delay of diagnosis in pediatric rheumatology? Does it really
matter? What are the barriers? What can be done to overcome barriers to
treatment for patients with juvenile rheumatic disease.
It is essential to
start with the fact that studies have shown that JIA is not a benign disease.
Children do suffer. Joint damage and disability can occur and still often does.
Children do not grow out of JIA and need early and aggressive treatment. In the
2001 article of
A prospective study
of JIA in
There did not
appear to be a single referral pattern problem. Patients tended to go through a
morass of a referral tunnel of orthopedics, adult rheumatology, and other
physicians before getting to a pediatric rheumatologist. Does this delay
matter? Yes, it does. Most of these 120 children had prolonged active disease,
missed school (mean of 14 days), and had a significant delay in starting
aggressive treatment such as methotrexate. This delay has many fathers which
involves organizational obstacles, social patterning issues, hospital and
hospital contract barriers, and limitations of medicines and services.
One major barrier
is the musculoskeletal exam skills of many physicians. Multiple studies have
documented this deficit. Dr. Foster mentioned her recent study that showed that
only 4% of pediatric inpatients in one hospital had a documented
musculoskeletal exam. Even if the child was being evaluated for a limp, the
documentation of this musculoskeletal exam was poor. In children being worked
up for JIA, the documentation of the musculoskeletal exam was improved, but the
laboratory workup and initial treatment was lacking. Much remains to be done to
improve education of medical students and residents in the musculoskeletal
exam. Dr. Foster has worked with a group in the
In summary, Dr.
Foster emphasized that a delay in referral of JIA patients appears to be very
common and a significant problem. The problem and solutions may be multifaceted
but the lack of physician musculoskeletal skills is critical. Better education
is the key.
Suggested
reference
1. Myers, McDonagh JE, Gupta K,
joints’: assessment of the musculoskeletal system is poorly documented
in routine paediatric
clerking. Rheumatology (
B. Access to
Care-The
There are problems
and obstacles. For example, the Arthritis Foundations appears to underestimate
the juvenile arthritis/rheumatic diseases at only 300,000 children.
Approximately one-third of US medical schools are without a pediatric
rheumatologist to teach residents and medical students as well as care for
children with these illnesses in their affiliated medical system. There are 202
board certified pediatric rheumatologists in the
Obstacles to care include a lack of public
awareness, the belief that there is not much to do for arthritis, the cost of
care for children with a chronic illness, and a long waiting list to be seen at
many pediatric rheumatology centers.
Rheumatic disease
in children and adults is one of the leading causes leading cause of disability
in US. We recently began a study of lack of access to care for children with
rheumatic disease at 4 pediatric rheumatology centers at
What can be done to
get these kids into sooner? First of all, we need to Increase medical teaching
skills. We should utilize tools such as the pediatric GALS screen (gait, arms,
leg, and spine) in development. The observer evaluates a child walking, her
hands and arm movement, and checks her legs and spine. This is a very simple
and quick musculoskeletal screen which was developed for the education of
medical students
Another approach is a yearly 4 hour seminars for local pediatric
generalists. This can include a case-based diagnostic discussion, a show and
tell, hands-on physical exam lab with patients, and a treatment discussion. The
To conclude, a
delay in diagnosis is still too common and often appears universal. The biggest
obstacle is a low awareness of both the public and physicians. We should work
to educate all levels-medical students, residents, pediatricians, other
professionals, and the general public.
We do need more rheumatology fellows and faculty-The needed funding for
these positions is another challenge and a subject for another talk.
VII Amplified musculoskeletal pain
syndromes in children (AMPS)
David Sherry
You may often feel:
Why me? But questions persist: Who are these kids-How to establish diagnosis?
How to explain it to others? How do you treat these kids? First, you have to
start with the fact that the pain is real and you must believe these kids-There
are many different scenarios you can describe for these kids but in all of
them, the kids suffer. In this process, though, it is important to keep an eye
out for other diagnoses: JIA, tumor, lupus, and celiac disease .
We use the term
reflex sympathetic dystrophy or pain amplication to describe these patients.
They have RSD with and without overt autonomic dysfunction. The problems are
quite variable and intermittent, with mixes of symptoms and signs. The
disorders are seen more in females. They
have increasing pain over time they may have started with a minor trauma. They
develop allodynea/hyperaesthesia that worsens with rest, casting, and
splinting. They have clearcut autonomic nerve dysfunction.
These patients are
often accomplished athletes, dancers, and performers. Sometimes they have
suffered multiple injuries. They usually appear mature but are pseudomature.
They are achievers, people-pleaser, and perfectionists. They strive to meet
other people needs, not their own needs. They often have la belle indifference,
incongruent affects, even smiling with pain, and not unhappy to be in the
situation they’re in. Major life events often have occurred recently. These
adolescents usually have a role model for pain in the family or among neighbors
or friends.
You may sometimes
think that you can negotiate with terrorists more easily than with some of the
mothers of these children. The mother often speaks for the child. The mother
and teen may exhibit enmeshment extraordinaire, each often finishing sentences
for each other. The teen may even dress like the mother!
Physical findings
often include severe swelling and edema in the involved extremity, particularly
in the hand or foot. Color changes such as erythema and temperature changes may
be present. There are often variable levels of pain, tenderness, and
hyperaesthesia. Labs are usually normal and a bone scan usually reveals
decreased uptake, if anything. Our working model for the pathophysiology of
this pain amplification is a persistent reflex arc.
Our treatment
program is simple. We discontinue all meds and discuss pain amplification. The critical treatment is 5 hours of physical
or occupational therapy per day every day. A psychological evaluation is
essential. Rarely behavioral modification is needed. In 103 patients with who
have completed this exercise program, 69% have recovered without a problem, 31%
had relapses. Of the 31% who relapsed, about half could treat themselves with
the exercise program. 10% of the 103 patients had a chronic pain problem. These
adolescents often had associated symptoms such as eating disorders, conversion
disorder, depression and suicide attempts. The program should attempt to
identify stress factors in the teen’s life and help them start to develop
individualization away from their family. Family counseling is crucial.
The team approach
is essential to achieve these goals including nurses, social workers,
psychologists, educator, and particularly
physical and occupational therapists. Everyone has to like these kids and
believe their pain to work well in this program. It takes patience. These are good
kids in real need and their pain is a red flag for significant problems.
The rheumatologist
and the team are doing a real service in reducing pain and suffering,
decreasing disability, decreasing the cost to health insurance and the medical
system. Excellent cure rates are possible in the range of 90-95%. Much research
remains to be done to delineate the pathophysiology of this syndrome and better
treatment.
Suggested
References
1. Sherry DD, Wallace CA, Kelley C, Kidder
M, Sapp L. Short- and long-term outcomes
of
children with complex regional pain syndrome type I treated with
exercise program.
2. Sherry D, Malleson PN. The idiopathic
musculoskeletal pain syndromes in childhood. Rheum
Dis North Am. 2002 Aug;28(3):669-85
VIII Beware of data from clinical trials
Alice Klinghoff
It is very
important to be aware of the dangers and conflicts of clinical trials. For
example, 70% of trials are commercial. In 25% there are financial relationships
between the investigator and the commercial interest, and 60% of trials involve
startup companies originating in a university with a very real financial
interest.
There is also a
tendency to highlight benefits and minimize risks in these trials. Especially
worrisome are confidentiality agreements that prevent investigators from
speaking out about certain side effects. One example might be that
investigators and the drug companies emphasized that the major adverse
reactions in anti-TNF-a medications were limited only to
injection site reactions and minimized serious infections Yet the FDA website
noted early on problems with multiple infections with tuberculosis,
histoplasmosis, atypical TB, and other infections.
Another clinical
trial issue is a delay in publication of negative side effects, e.g., 1
positive trial and 5 negative trials on anti-depressants for teenagers and the
positive trial was published first. Another example might be the usefulness of
mycophenylate for arthritis.
One way of
summarizing clinical trial pitfalls is BIA$. “B” is Beta error. This is the
risk of missing a treatment benefit because the sample size is not large
enough, e.g., methotrexate in scleroderma. “I” is for Integrity and for conflict of interest, e.g., the
suppression of negative results or adverse side effects (Vioxx). “A” is for
fraud and external validity, e.g., does this study apply to my patients? “S” is
for statistics that lie and for $ bias. Are the side effects systemically and
completely reported? Consider the bias-is it the truth, the whole truth, and
nothing but the truth?
IX The Future of Pediatric Rheumatology
(PR)
Alan Rosenberg
“The future as it used to be needs new
directions
The future is not as good as it used to be”
There has not been
as much progress as Alan had hoped there would have been in PR. Causes are
still not known. There has been some progress with more pediatric
rheumatologists, much better treatment, and better programs. But there remains
of much to be done with new progress into cause of diseases and prevention-Like
Winnie the Pooh, we can love the anticipation of eating honey.
We need better
clinical Care and education. Is our care cost-effective? Are all the treatment
steps needed? Do we have underutilization or overutilization? Do our
medications really work? Are we using the wrong members on our team for tasks.
We should reappraise our treatments all the time and develop practice
guidelines-debate, discuss, and improve them. We should go beyond biology by
looking into psychosocial, family, environmental influences on disease. We must
be always intolerant of an “idiopathic” status and go for real causes that make
the idiopathic term anachronistic.
We have clearly
established our niche but maybe have separated or isolate ourselves from adult
rheumatologists too much. We need to work together and investigate how adult
disease may start in childhood, teen years, even in utero. In our training and
mentoring, we should examine carefully who we train. We should choose
candidates that fit our needs and our ambitious agenda. We must anticipate
scientific questioning and increase our collaboration with scientists in other
disciplines-basic science colleagues, clinical researchers, rheumatologists,
pediatricians, allied health professionals, and patients and families.
We should continue advocacy-Make it special
but broad in scope by developing pediatric rheumatology that in turn helps and
cross-pollinates adult rheumatology, genetics and other specialties in
collaboration with many disciplines.
Our research
priorities should be determined by our patients and not by the outside agendas
of others.-We can secure funding by an aggressive solicitation of funding for
areas of genetics and biotechnology. We should continue our state-of-the art
treatment regimens and outcome measures as tools to help children now, but
strive for the causes of our diseases and how the cause changes the treatment
and how psychosocial and environmental factors affect the cause and treatment.
We can achieve
dramatic progress in the near future with these steps-much sooner than anyone
imagines. We can survive without a Ross Petty in part because of the foundation
that he has helped establish.
Reporter’s note: The conference thus ended
and was a great success and a fine tribute to an extraordinary leader of
pediatric rheumatology.