Report from the PReS
Meeting in
Clinical Presentations:
Clinical study group and PRINTO reports
Reporter: Charles H. Spencer
I PRINTO REPORT
A. Planned PRINTO prospective JDM study-Ruperto and Ravelli (
1.
5 year trial
2. Objective: Determine which
treatment regimen is associated with the lowest
occurrence of flares and toxicities.
3. Prednisone alone versus prednisone +
cyclosporine versus prednisone +
methotrexate
4.
Muscle biopsy at diagnosis will be optional.
5.
Treatment protocol:
a. 3 days pulse of methyprednisolone
at 30 mg/kg/day
b. Randomize patients to prednisone
alone versus prednisone with
cyclosporine (up to 5 mg/kg/day)
versus prednisone + weekly methotrexate.
c. Prednisone use will be formalized
and regimented with full dose for
the first month with prednisone
taper over the next 5 months at 0.2
mg/kg/day. Then in next 18 months
prednisone will be lowered
stepwise to 0.1 mg/kg/day. Each
center will use the same tapering schedule.
d. Response measures will include:
1.) Time to response of 25%, 50%,
75% improvement in first six months.
2.) Time to clinical remission or
time to flares from 6-24 months.
3.) MD global assessment
4.) Muscle strength assessment
e. Improvement criteria to be used.
f. Exclusion criteria, e.g., low
neutrophils, GI ulceration, pulmonary disease or hemorrhage
C. PRINTO cyclophosphamide study for SLE nephritis with different drug
combinations-Ruperto and Ravelli (
1. Eighty centers willing to
participate with 1-3 patients each.
2. Three 6 month therapeutic
regimens for newly diagnosed severe SLE
nephritis each beginning with a 3 day methyprednisolone
pulse at 30 mg/kg/day.
a.
1st group: oral Cytoxan daily 1-2 mg/kg/day prednisone
(cyclophosphamide exposure180
mg/kg).
b.
2nd group: oral prednisone plus cyclophosphamide with
European
style pulses every 15 days at 500
mg/m2 (exposure 108 mg/kg)
c. Prednisone + 7
monthly NIH pulses at 1000 mg/m2 (exposure 120
mg/kg).
d.
All three groups put on azathioprine plus prednisone after 6 months.
3. Inclusion criteria
a.
Newly diagnosed child with severe SLE nephritis proved by biopsy.
4. Exclusions-e.g.
a.
Previous cyclophosphamide
b.
Leukopenia, neutropenia
c.
Compliance problems
5. Use SLE PRINTO tools for
measuring outcome
a. Improvement: 2/5 measures
improved at 50% or more and with no more than 1/5 worsening by 50% or more.
6. Data collection thru website www.printo.it and final version free by
e-mail.
7. No financial support yet.
D. PRINTO prospective, randomized trial evaluating the optimal way to
utilize methotrexate
during clinical remission of JIA. Ruperto and Ravelli (
Question: How long to continue methotrexate once clinical remission
is achieved? It’s
believed that 50% of children with JIA do relapse after
methotrexate is stopped. Relapses
also appear to be independent of the duration of treatment with mtx
1. Protocol
a.
Group A methotrexate is stopped at 6 months after clinical remission
achieved.
b.
Group B methotrexate is stopped at 12 months.
c. Patients are
evaluated q 3 months for 1 year for a total of 9 visits.
2. Criteria for remission
a. No systemic features for 3 months-no abnormal exam findings,
no increased
CRP/ESR
b. No recent intraarticular
corticosteroids.
c. Low dose pred-NSAID ok
3. Blood
samples to be taken.
4 Thus
far 128 patients are entered from 70 centers (1/2 from
5. One
hundred Euro will be paid to each patient at the end of the study.
E. Ongoing report on Infliximab
study- (Other data presented last year)-Ruperto
1. Initially
would appear that fewer side effects with 3 mg/kg dose and many more SAE’s
with 6 mg/kg than 3 mg/kg by 19 to 5.
2 Infusion
reactions much higher in 3 mg than 6 mg 9.1 to 3.0
3. Antibodies
3x more in 3 mg/kg than 6 mg/kg, antibody to infliximab-3 with high
titers
1:20480; association possible between antibody titers and infusion reactions.
4. No
TB noted in first 52 weeks.
5. Serious
infections did occur, e.g., pneumonia.
6. Efficacy profile the same between groups.
7. Side
effects overall good.
8. 3
mg/kg group had more problems with infusion side effects though drug
levels
were as good as the 6 mg/kg group and PK’s better.
9. 6
mg/kg group has more total adverse events with no added efficacy.
II PReS Working Groups
A. Lupus Working Group-Angelo Ravelli (
1. Lupus
studies at PReS in coordination with PRINTO
a. Introduction
There has been a mild decrease number of scientific work
among PReS members noted before this meeting. Several reasons may explain this
trend:
1)
There is difficulty of studying lupus in general.
2) Adult research in SLE may take
priority in funding.
3) Adult research in SLE often includes
adolescents.
4) Juvenile SLE has relatively low
prevalence.
Most studies in the past have been retrospective and
cross-sectional and few have used standardized definitions and outcome
instruments. It is time to focus on prospective studies. We would like to begin
a long term (60 months) prospective data collection via the internet as a SLE
registry that will be coordinated by PRINTO.
b. Objectives of the new
study as proposed:
1) To establish a multinational, multicenter
study
2) To assess long term outcome of juvenile SL$E
3) To describe clinical manifestations, lab,
clinical course,
treatment modalities and
complications.
4) To assess impact on prognosis of the
different treatment
modalities currently utilized for
SLE.
5) To identify early prognostic factors.
c. Inclusion criteria
1) Newly
diagnosed patients under 18 years of age
2) SLE
by ACR criteria (1992)
3) Study
approved by the IRB and ethical board
4) Appropriate
consents signed.
d. An internet based data
sheet will be utilized for ease of use.
Below is a partial list of the data
to be collected:
1) Demographic
data:
Name
or identification number, birth date, medical record number,
demographic
data, gender, date of first visit, physician’s name,
physician’s
city and country, disease onset type-acute or evolving,
sociodemographic
data
2) Presenting
clinical manifestations:
a) Organ system,
constitutional, cutaneous, msk, vascular, cardiac,
and
other organs
b) ACR criteria at time of
diagnosis-11 criteria
e. Assessment of growth and
development
1) Weight,
height
2) Tanner
Staging
f. Laboratory results to be
documented;
1) CBC, ESR, CRP
2) Creatinine,
urinalysis, 24 hour protein, creatinine clearance, C3, C4.
3) Serologies:
ANA, Anti-DNA, ENA
4) Anti-cardiolipin,
LAC
5) Other
g. Medications started at
diagnosis:
1) NSAIDs
2) Corticosteroids
(po and/or IV)
3) Hydroxychloroquine
4) Azathioprine
5) Mycophenolate
6) Methotrexate
7) Cyclophosphamide
8) Cyclosporine
A
9) Other
drugs,
h. Disease activity and
outcome measures
1) SLEDAI-2K
2) Global
assessment (VAS) by physician
3) Global
assessment (VAS) by parent/patient
4) Child
Health Questionnaire (CHQ) to be filled out by parent
for
the child
i. Additional data to be
collected every six months
1) Major
complications
2) Mortality
data including if cause of death, due to SLE
YES
NO Unclear
3) Drug
therapy in the six months since last report including the
drug,
dose, route, dates of use
j. Additional data to be
collected every 12 months
1) Growth
and Development-height, weight, Tanner
2) CHQ
parent
3) SLICC/ACR
DI
4) Global
assessment of damage by the physician
5) Global
assessment of activity by parent
2. Antiphospholipid syndrome registry-Tadej
Avcin (
A. Introduction
The International Registry for
Pediatric Patients with the Antiphospholipid
Syndrome was begun 1 ½ years ago at
the European Phospholipid Meeting in
1. Though
pediatric reports and studies have been unusual, it
is
believed that APLA problems are becoming more frequent in
2. There also are important differences
from adults with APLA, e.g.,
effects
of smoking and atherosclerosis.
3. There appear to be unique factors in children
to evaluate,
e.g.,
a. prevalence of specific disease
manifestations
b. increased incidence of infection.
c. effects of long-term APLA therapy in
kids
B. Objectives
1. Organize an international and European
registry.
2. Study long term outcomes.
C. Organization
1. Collaboration
of PRINTO and European Forum on
antiphospholipid
antibodies.
2.
It will be an online, internet-based registry.
3. Confidentiality
issues will be addressed.
D. Inclusion. Criteria
1. Diagnosis of APS before 18th year
2. Preliminary
clinical criteria-vascular thrombosis; Lab criteria;
anticardiolipin antibody of IgG
and/or IgM (IgG and
IgM
medium to high positive) or positive lupus anticoagulant.
E. Study data sheet on internet
The data sheet included demographic
data, disease related data
(arterial, venous, small vessel
thromboses, neurological diseases,
hematological disorders, skin
disorders, and other disorders). It
also will include the APLA lab
findings with the detection methods
used as well as the SLE diagnostic
assays utilized. The treatment
and outcome data will also be
collected.
Please e-mail Dr. Avcin if you are interested in
participating in this study.
III JUVENILE
DERMATOMYOSITIS (JDM) STUDY GROUP-C. Pikington (
Discussion topics
A. IVIG study
B. Muscle biopsy scoring project
C. Allied health professionals report
D. IMACS project + Rituximab study
E. Criteria for DM diagnosis
F. Classification of myopathies
Survey
of 50 studies-most centers start with steroids. IVIG only occasionally
used.
In discussions with members, it was agreed that an IVIG study appears to
be
too expensive. Plus there does not seem to be sufficient interest in what may
be
a difficult study. A study comparing cyclosporin A and methotrexate may be
more
pertinent. A pilot trial has been begun and contact Dr. Pilkington if you are
interested.
There are few if any pediatric
rheumatologists who are experts in interpreting
muscle biopsies. So muscle
histopathologists were needed. The pathologists
were recruited from
was to develop a muscle biopsy
scoring system which has never been done
for JDM. To develop this scoring, it
was necessary to convene a muscle
biopsy consensus meeting. For this meeting, a cooperative
retrospective,
multicenter study of juvenile dermatomyositis
patients who have had muscle
biopsies was needed.
The initial Biopsy Consensus
Conference was held in March 2005 in
took one day to agree upon a scoring
system. The second day the scoring
system was tried out on muscle
biopsies. The pathologists were introduced to
the VAS tool which they adjusted to.
It turned out to be easy to agree upon
whether a biopsy was technically
acceptable but there was less agreement on
the findings of each biopsy. The 2nd
meeting of histopathologists is planned in
March 2006. The study remains a work
in progress. Funding is being provided
by several
C. Allied
Health Professional report
A survey was performed on physical therapy (PT)
interventions in early JDM-PT’s in 19 countriesreplied-50% had no PT
intervention in active phase of JDMS-It is tentatively planned to repeat the
study with more centers.
A new survey will look at another part of PT intervention,
the need for a fatigue assessment/measurement.
This tool should be easy, practical, and quick. Eventually complementary core outcome
measures for PT are needed that might fit well with the PRINTO JDM outcome
measures
1. JDM outcome measure is being
tested that includes among others:
a.
Physician global activity: 10 cm VAS
b.
Patient or parent VAS
c.
Manual muscle testing
d
Physical function-outcome
e.
Laboratory tests
Definition of improvement
is: 3/6 criteria improved by >20%
No more than 2 worse by >20% (not
including the manual muscle testing)
2. Rituximab study at NIH
This is an international study
involving both adult and childhood JDM. This study is limited to
refractory patients with JDM. The dose will be 750 mg/m2 at weeks
1 and 2. It includes two treatment
groups.
Group A: Rituximab in week 1 and 2
Group B: Placebo infusions at weeks
1 and 2.
This group will receive Rituximab at 9 weeks.
Study Investigators had a meeting in
Sept 2005, beginning patient recruitment in autumn 2005.
E. Criteria for diagnosis of JDM
Initial survey on diagnostic
criteria was sent out to 110 centers. So far only 42
replies have been received, a 38 %
response rate. Three criteria had wide
agreement: muscle weakness, rash,
and muscle enzyme elevation. There was
little agreement after that, though
the EMG and MRI tests were close to
obtaining the necessary number of
responses to be a criterion. There
was interest in a formal study on
criteria in the 41/42 centers that responded.
Thirteen centers could provide all
categories of cases-paper cases that are
retrospective. Both JDM and overlap
JDM diagnostic criteria would be
analyzed. Brian Feldman in
to collate and analyze the data. An
internet data form will be used. No funding is
available yet. Expect that an e-mail
from Dr. Pilkington will sent out soon.
F. Classification
study of JDM/overlap syndromes
There has been no past consensus on
the meaning of JDM overlap syndromes. Now there
is a huge and complicated effort on classification for JDM
and other muscle diseases in adults and children that will address overlap as
well as all myopathy categories. It will be a multispecialty consensus study
including adult and pediatric neurologists as well as adult and
pediatric rheumatologists. Classification will include
inflammatory myositis, limb girdle dystrophies, fasculoscapular dystrophy, drug
toxin myopathy, infectious myopathy, and others. Funding is from the ACR and
EULAR The next meeting will be in November 2005.
IV. RATIO registry organization
A. French collaborative group includes
internist and pediatric organization of rheumatologists, gastroenterologists,
pulmonologists, infectious disease specialists, and general internists.
B. The collaborative group surveys for side
effects of TNF therapy in
TB, Listeria, aspergillus, pneumocytis, and others.
C. The group is particularly alert for lymphoma.
D. Methods
1. Prospective registry since February 2004
2.
Surveying for severe bacterial infections, opportunistic infections, and
lymphoma.
3.
Participants included 474 centers in
4.
Mail was sent out with 4 reminders per yea.
5.
Reports made obligatory to govt
6.
Confirmed infection or lymphoma was checked thoroughly.
7.
When medicine was given is important, e.g., if medicine was given > 2
years ago, the infection
is not counted. (Not so lymphoma)
8.
Three committees set up to review and verify validity of reports.
E. Present
results
1.
137 cases of infection or malignancy
2.
Sixty infections were severe bacterial infections.
3.
Sixty-three infections were opportunistic.
4.
Thirteen lymphomas were noted.
5. Only 2 children in the 137 cases
6. The majority were adults with rheumatoid
arthritis or spondyloarthropathy
7.
Nineteen were on infliximab, 25 etancecept, 9 Humira
9.
Opportunistic Infections (20 TB, 15 viral, 13 legionnaires, 4
aspergillosis, 3 pneumocytis)
F. Tuberculosis
1.
Tuberculosis: in first 12 months, 13 cases noted (8 RA, 5AS)-on
infliximab 7,
Humira 6, etanercept 1.
2.
This data suggests that despite guidelines on anti-TNF medications, TB
is still
a major problem. Guidelines should be revisited and perhaps
not disregarding the 5 mm positive PPD.
G. Lymphoma
1.
Thirteen patients developed lymphoma during the year (4 Hodgkins, 1
diffuse B cell, 1 Mast B cell
lymphoma with Sjogrens (10 RA, 2 AS, 1 Sjogrens)
H. Conclusions
1.
Surveys must be national
2.
Participation must be made mandatory and keep pushing them
3.
Good example btw cooperation of gov and medicine and pharmo
4.
Led to change in length of treatment for prophylaxis to make it longer
and reduction of
PPD
positivity back to 5 mm