Report from
the PReS Meeting in
Clinical Presentations
Reporter: Charles H. Spencer
I Clinical study: IVIG
therapy for pediatric polyarteritis nodosa-P Quartier (
A. Working Group is presently devising
diagnostic criteria
B. These will include some combination of fever, weight
loss, skin lesion (often transient),
arthralgias,
arthritis, myalgia, abdominal pain, hypertension
C. In this study 27 patients were
evaluated (16 girls, 11 boys)
D. Biological markers utilized included: Signs of marked
systemic inflammation with
increased
WBC and ESR, no eosinophilia, no elevated ANCA titers.
E. Biopsy best means
of diagnosis often skin with typical fibrinoid changes in
the
blood vessel wall.
F. Treatment
1. An NSAID was begun at diagnosis
in 20/27 patients.
2. In 7 patients corticosteroids
-effective in 6
3. IVIG
a.
Six female, 4 male patients
b.
Each had more severe skin and systemic involvement that did not
respond
to previous treatment (9 NSAID’s,1 cyclophosphamide)
c. Protocol: monthly IVIG for six months.
d. An excellent clinical response was seen in
9/10.
1) Five did not require steroids again.
2) Nine did well compared to
previous treatment regimen
4. Conclusions
a.
Consider IVIG early with NSAID’s
for milder forms
b. Steroid
sparing effect is useful in relapsing or more severe
PAN
disease.
c. PAN in childhood is a rare disease
so we may need an
international
trial.
II Clinical Study:
Rituximab in SLE-Willem (
A. Twenty-four adult patients have been
reported that have been treated successfully for
autoimmune hemolytic anemia with
rituximab; One child with SLE with ITP has been
similarly treated
B.
This
was a multicenter (12 hospitals in
juvenile SLE that included
11 patients with severe SLE diagnosed before age 16
years by the ACR SLE
criteria.
1. Eight with nephritis (6 with WHO Class IV
previously treated with
cyclophosphamide)
2.
One
each with autoimmune anemia, autoimmune thrombocytopenia, or
antiprothrombin antibody
C.
The
mean age at onset of rituximab treatment was 13.9 years old.
D. The
patients received from 2-7 infusions at standard dose of 375-450 mg/m2.
Premedications
with an antihistamine and acetaminophen were given in 9/12. Two
patients
received cyclophosphamide as well. Two patients were taking cyclosporine
or
methotrexate.
E. Results:
Remission was achieved in 5 patients with lupus nephritis and two with
cytopenia
(mean follow-up 13 months). Anti-DNA antibodies decreased in 6/11
and
anticardiolipin antibodies in 3/6 patients. C3 and C4 levels normalized in 5/8.
Depletion
of peripheral B cells was observed in 7/8 patients tested with poor
responders
having only a transient lowering of the peripheral B cells.. Two patients
definitely
failed rituximab therapy and in two patients it was inconclusive. Three
patients
developed adverse events (neutropenia, infection-sepsis).
F. Conclusion:
Rituximab was effective in 7/11 children with severe SLE in achieving
short-term
improvement with some side effects.
III CLINICAL STUDIES
A. Adverse
events in JIA taking etanercept and methotrexate.
1. British
Collaborative Group-12 British centers
2. Post-marketing
experience over 4 months in 2005 in patients with JIA.
3. 122
JIA patients on Enbrel, 30 patients on methotexate.
4. Enbrel
patients’ mean age was 11 years, methotrexate group 8 years.
5. Enbrel
JIA patients had more severe disease.
6. 62
patients suffered at least one adverse event.
7. 145
patient years of exposure.
8. The
patients on etanercept experienced 72 total adverse events for Enbrel
while patients on methotexate had 70.
9. Gastrointestinal
problems were greater in methotrexate patients while both
groups
had infections to a relatively equal extent.
10. Enbrel
patients had 8 serious adverse events including 4 disease flares,
hypertension,
sepsis, and skin rash.
11. Methotexate-nausea,
abnormal liver function tests, menstrual problems, panic
attacks,
mood changes, increased anxieties.
B. Juvenile dermatomyositis and
muscle disease.-Alexii Grom
1. What is reason for vasculopathy in JDM? CXC
chemokines may provide
explanation
of persistent angiostatic problems, e.g., IP-10.
2. Study
of 7 pretreatment JDM muscle biopsies compared to 9 muscle biopsies done
for neurological disease and 7 JIA
biopsies
3. Results:
a. All
dermatomyositis specimens had positive results, e.g., Ip-10 was
found
in areas of muscle with perifascular atrophy;
b. MIG mRNA
expressed in large amounts in JDM compared to normal
and
JIA muscle samples.
c. These
findings correlated well with the loss of capillary bed and
myofibrosis
findings typical of vasculospathy.
d. IP-10 was
found in blood vessel walls and CXCR3 expressed in
endothelium.by
immunohistochemistry.
e. ELR-CXC chemokines is a feature of JDM that
correlates with
vasculopathy.
The vaculopathy may be correlated with IFN-alpha
induction.
This brings up the question: Is JDM a
disease of blood vessels more
than
a muscle disease?
C. Juvenile systemic
sclerosis-Francisco Zulian
1 .At
the first juvenile scleroderma consensus conference, the preliminary
juvenile scleroderma classification
criteria were chosen-One major criterion and
one
minor criterion or 2 major criteria.
2 The challenges were how to detail
better the clinical and immunological
information
and also how to describe organ involvement.
3. The conference met again in June
2004. The group had developed a large data bank of patient data.
4. A pre-conference survey was done
assessing organ involvement and possible
criteria,
major and minor with rankings.
5. The survey also considered
prevalence of JSS signs and symptoms at diagnosis e.g., Raynaud’s at 76%.
6. Top three criteria
selected were Raynaud’s, sclerosis/induration, sclerodactly; 18 minor criteria
identified.
7. Tested criteria with the data of 181
patients in the group’s data bank with awareness of confounding factors such as
overlap syndrome.
8. Evaluated 160: 73160 all agreed
had scleroderma; 57 all agreed did not have
scleroderma;
21 no consensus as to whether scleroderma was the right diagnosis or not.
9. Next all criteria tested as well
from many other sources with statistical analysis –
Then
ranked top 10 prelim criteria-using this approach
10. Thus far the diagnosis requires the
presence of sclerosis/ induration plus 2/19
minor
criteria.
IV Example of “Meet the Professor”- Uveitis- Bodaghi
(
A. Uveitis characteristics in JIA with systemic,
polyarticular, and oligoarticular onset.
1. Bilateral in 75%
2. Onset usually
asymptomatic
3. Non-granulomatous
4. Spill over vitriitis
5. Moderate level of corneal
deposits
6. Long-term visual prognosis may be
poor
B. Uveitis in spondyloarthropathy in children
1. Very different disease in
juvenile spondyloarthropathy
2. Often unilateral
3. Acute onset with symptoms
frequently present
4. Usually responsive to steroids
drops
C. Complications of chronic uveitis band
1. Band keratopathy
2. Synechiae
3. Glaucoma
4. Cataract,
5. Posterior segment disease
D. Laser Flare Photometry
Laser Flare Photometry (LFP) can quantitate the degree of flare
much more than 1+ to 4+ flare scoring used in conventional slit lamp exams.
This technique is non-invasive, but does require some cooperation from the
child. It is a major help in monitoring uveitis. It is used extensively in
Here is an illustrative
study utilizing LFP in uveitis of JIA.
The study attempted to distinguish the more severe, poor
prognosis uveitis patients from the milder course, better prognosis JIA uveitis
patients.
Group A-severe Group B-milder; mean follow-up 3 years
Results:
Group A-10 patients with a mean
flare ranging from 237 at onset of treatment to
125 after aggressive therapy.
Group B-14 pts with a mean flare
72.8 initially to 26.5 after aggressive therapy.
Five patients in Group A developed glaucoma compared to 3
patients in group B.
Five patients in Group A required cataract removal surgery
and none in Group B.
This study appeared to demonstrate that LFP could help
separate the children with a more difficult prognosis with their uveitis from
those with a better prognosis. LFP appears to be particularly useful in guiding
therapy when the uveitis is at a low level of inflammation.
This assessment of low level of uveitis inflammation can be
very hard with the slit lamp
E. Treatment:
1. Steroid drops/injections
2.
NSAID
3.
Mydriatics
4.
Prednisone (more in
5.
Cyclosporine A is not used much in
6.
Methotrexate
7.
Azathioprine
8.
Etanercept
9.
Infliximab
10.
Humira
Comments: Dr. Bodaghi and his group have not used
mycophenolate yet but it may turn out to be useful. In the
The anti-TNF alpha
medication etanercept has been studied recently for uveitis
and no benefit was shown by slit lamp exam. But there may be a benefit in introocular
lens implantation (IOL)Requires aggressive immunosuppression steroids and
mtx-no eye glasses allowable, usually < 5 years Vitreous inflammation=pars
planis-if no uveitis, watch- if uveitis very active,
must go to immunosuppressive and treatment is often very
long for macular edema Optic Coherence
Tomography needed for posterior uveitis complications that produces macular
edema.
F. High risk JIA
uveitis patients:
1.
Boys more than girls
2.
Short duration from diagnosis of JIA to uveitis onset
3.
No change in the prognosis of this group in the last decade.
4. Suggest q 6 month visits for high risk kids x
2 years, then q year
G. Notes about other diseases:
1.
Behcet’s syndrome eye disease requires aggressive approach with
immunosuppressives;
papilledema or papillitis vitriitis not uncommon.
2. Tips:
a.
If note granulomatous keratin infiltrates-check retina as you may see
new and old lesions secondary to toxoplasmosis.
b. Papillilitis-cat scratch disease
c. Peripheral retinal
necrosis, red infiltrates, ant uveitis seen, think of herpes
H. Conclusions:
1.
Multidisciplinary approach needed.
2.
Aggressive surveillance and early treatment
3.
Don’t under-treat and don’t allow smoldering inflammation.
4.
LFM seems to be a helpful tool for the monitoring anterior uveitis
5. 75% reduction after initial anti-inflammatory
eye drops is a good prognostic
sign.
6.
Surgery may be needed for selective problems.
Uveitis case presentation #1:
4 cases of optic neuritis with treatment with etanercept.
3 females, 1 male all
at a dose 25 mg subcutaneously 2x/week
a. Case 1-12 yr old
oligo JIA at age 3 years developing
to extended oligoarticular.
Treatment included intravenous methotrexate and
intraarticular steroids. Etanercept
added and the drug helped the joint problems. But at age 8 uveitis developed; the
uveitis was treated conventionally but a cataract was noted.
Optic neuritis started 2 ½
months after the cataract was noted. The optic neuritis was
confirmed by
ultrasonography and the etanercept was stopped.
b. Case 2
Etanercept started for arthritis and
8 months later the child developed
optic neuritis.
c. Case 3
20 yr old with JIA due to psoriasis;
etanercept helped with severe arthritis but 1 ½
years later she developed optic
neuritis.
d. Case 4
18 year old with spondyloarthropathy
whose arthritis was not nearly as bad as his
uveitis, especially in the right eye. At first cyclosporine
A was begun and he developed hearing loss and cyclosporine was stopped. Then he
was switched to etanercept His eyes then went into remission for first time.
But 9 months later he developed optic neuritis. Due to the benefits, the
patient chose to continue the etanercept and his eyes stabilized.
Uveitis case presentation
#2-preliminary results
Evaluation
of etanercept versus infliximab for uveitis secondary to JIA.
108 total patients with uveitis evaluated.
a. 46/108 with severe uveitis treated had been treated with
mtx-all but 4 had been on
methotrexate
before uveitis was diagnosed.
b. 20 on infliximab-all 20 had been on infliximab prior to
uveitis.
c. 24 on etanercept-20 begun on the drug prior to uveitis
noted.
d. Results
Etanercept-3 better by their outcome
measures
Infliximab-9 better
Etanercept flare-ups:1.35 per year
Infliximab flare-ups were 0.71 per
year (p=0.025)
V Clinical Heuristics and Diagnostic
Problem Solving: A talk for rheumatologists in
training. Balu
Athreya (
A. Basics
The definition of heuristics: Relating to or constituting an
educational method in which learning takes place through discoveries made by
the students from investigations of the students. This can also mean making
your mind work in a way that is transferable to a machine such as a computer
with its organizational logic and problem-solving techniques. You ask what is
in a patient’s case that I am able to understand and what is in the case that I
do not understand it and how does it add up to knowing what to do.
These problem-solving skills can be
learned. You need to develop more creative,
constructive techniques. They should
not be reflexive, a knee-jerk response, but
rather reflective, choosing a
diagnostic plan or treatment regimen after some
reflection. So heuristics involves
learning from each experience and learning how
mind works in solving problems.
This is important in this age of
mega-workups and of information overload. It
involves learning from contemplative
learning. You need to be aware of mental
process, need to think, and need
time to think. In busy schedules these days
having time to think can be a
challenge. Don’t expect the kids to read the book
and fit neatly into diagnostic
categories. As Sidney Gellis of
you are someone who likes every
piece to fall in place, you should be in
carpentry”.
How does your mind work?
So as a physician you start with your patient—You ask a
question-You analyze your own mental process based on the questions you ask and
see how you problem-solve.
You should start with a system of history, physical exam,
laboratory, and assessment in detail. Yet it is OK to jump around some and to
hound-dog and go out on a trail, but come back when the scent disappears. Words
can get in the way-flexion contractures versus flexion deformities. Is it
arthritis versus an arthropathy? Is there inflammation?
Don’t swallow the diagnosis of someone else? Look at it
afresh. Why it is necessary for us to rethink medical problems and not accept
others assessments? One reason is that we are trained to compete-We also often
have limited data; children’s diseases often evolve gradually and the
information you have now may be different than the data another physician had
to evaluate.
B. Some history of the heuristic approach in medicine:
1. Voltaire-“Those who make
you believe absurdities can make you commit
atrocities”
2. Voltaire: the Method of Zidig with retrospective prophesy-reconstructing
the
broken glass.
3. Giovelli Morelli-systematic
attention to detail leading to logical conclusions.
4. Thomas Henry Huxley-get
to the point, don’t let the patient free associate and
go on and on.
5. A manuscript: The Art of Diagnosis: David Eddy and
Charles Clanton NEJM
1982
6. Aggregate element findings
You start with any
single piece of information and then build up to an
aggregate of
information by combining 3 or 4 pieces of information. This is
crucial as your
mind tends to aggregate information, using high abstraction to
achieve an
aggregate with fewer information pieces to remember. Remember
that the human
mind can only hold up to 7 facts at a time and your mind cuts
it off there.
7. Arrange findings in a creative
way.
a.
Selection of a pivot-move from a list of findings to a list of causes-
choose one pivot, a single item or an aggregate with a decision to
ignore other findings. Generate a list of causes that does not try to
explain everything.
b.
Move from textbook to patients to design the list of causes.
c.
Prune the list and compare one by one the patient’s findings and
symptoms of disease-seek out the pattern in the list-If you are
fortunate you will end up with only one!!
d. Seek comparisons and not equalities.
8. Then select the diagnosis. To do
so, take diseases 2 or 3 at a time-then also
bring in the lab
or other data and make your assessment and choose one
disease. Then
validate this conclusion-Can this disease explain all the
findings?-if not,
realign the aggregate, choose a different pivot and start all
over.
C. Major areas of deficiency/errors
1. Very early hypothesis generation is
problematic-making an early decision and
staying with it, regardless of later
signs, symptoms, lab, and course.
2.
Patient already has a diagnosis and you accept it on face value.
So
when you hear the patient’s symptoms and signs and the previous
diagnosis,
then define: What is the patient’s problem? Exclude-What is the
diagnosis
now-Confirm-How can you know for sure?
D. Concept of a critical question:
There is always one critical question and you must look for it. That
critical
question can make all the difference.
It could be that the fit is
excellent or not perfect. It could be that the patient’s
features that don’t fit the best
diagnosis may not been described yet but may
be in the future. Accept the
diagnosis for now but keep your mind
open. So for now go with the
diagnosis but be alert for future changes and
possible other diagnoses.