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Arthritis Care & Research
Vol. 62, No. 2, February 2010, pp 219 –225
DOI 10.1002/acr.20071
© 2010, American College of Rheumatology
ORIGINAL ARTICLE
Protocols for the Initial Treatment of Moderately
Severe Juvenile Dermatomyositis: Results of a
Children’s Arthritis and Rheumatology Research
Alliance Consensus Conference
ADAM M. HUBER,1 EDWARD H. GIANNINI,2 SUZANNE L. BOWYER,3 SUSAN KIM,4 BIANCA LANG,1
CAROL B. LINDSLEY,5 LAUREN M. PACHMAN,6 CLARISSA PILKINGTON,7 ANN M. REED,8
ROBERT M. RENNEBOHM,9 LISA G. RIDER,10 CAROL A. WALLACE,11 AND BRIAN M. FELDMAN12
Objective. To use juvenile dermatomyositis (DM) survey data and expert opinion to develop a small number of consensus
treatment protocols, which reflect current initial treatment of moderately severe juvenile DM.
Methods. A consensus meeting was held in Toronto, Ontario, Canada on December 1–2, 2007. Nominal group technique
was used to achieve consensus on treatment protocols, which represented typical management of moderately severe
juvenile DM. Consensus was also reached as to which patients these protocols would be applicable (inclusion and
exclusion criteria), which initial investigations should be done prior to initiating one of these protocols, which data
should be collected to evaluate these protocols, and the concomitant interventions required or recommended.
Results. Three protocols that described the first 2 months of treatment were developed. All protocols included corticosteroids and methotrexate. One protocol also included intravenous gamma globulin. Consensus was achieved for all
issues that were addressed by conference participants, although there were some areas of controversy.
Conclusion. Despite considerable variation in clinical practice, it is possible to achieve consensus on the initial treatment
of juvenile DM. Once these protocols are extended beyond 2 months, these protocols will be available for clinical use. By
using methods that account for differences between patients (confounding by indication), the comparative effectiveness
of the protocols will be evaluated. In the future, the goal will be to identify the optimal treatment of moderately severe
juvenile DM.
INTRODUCTION
Juvenile dermatomyositis (DM) is a chronic, autoimmune,
vasculopathic illness characterized by proximal muscle
Supported by the Childhood Arthritis and Rheumatology
Research Alliance. Dr. Pachman’s work was supported by
grant R0-1-AR48289, the Cure JM Program of Excellence in
Myositis Research, and the Macy’s Miracle Foundation. Dr.
Rider’s work was supported by the intramural research
program of the National Institute of Environmental Health
Sciences, NIH. Dr. Feldman’s work was supported by a
Canada Research Chair and Friends of Childhood Arthritis
and Rheumatology Research Alliance.
1
Adam M. Huber, MSc, MD, Bianca Lang, MD, FRCP: IWK
Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada; 2Edward H. Giannini, MSc, DrPH: Cincinnati
Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio; 3Suzanne L. Bowyer, MD: Indiana
University School of Medicine, Indianapolis; 4Susan Kim,
MD: Boston Children’s Hospital, Boston, Massachusetts;
5
Carol B. Lindsley, MD: University of Kansas Medical Center and University of Kansas, Kansas City; 6Lauren M. Pachman, MD: The Children’s Memorial Hospital and Feinberg
weakness, impairments in physical function and endurance, and a variety of skin rashes. Other organs may also be
School of Medicine, Northwestern University, Chicago, Illinois; 7Clarissa Pilkington, MBBS: Great Ormond Street Hospital For Children, London, UK; 8Ann M. Reed, MD: Mayo
Clinic and Mayo College of Medicine, Rochester, Minnesota;
9
Robert M. Rennebohm, MD: Alberta Children’s Hospital
and University of Calgary, Calgary, Alberta, Canada; 10Lisa
G. Rider, MD: National Institute of Environmental Health
Sciences, NIH, Bethesda, Maryland; 11Carol A. Wallace,
MD: Seattle Children’s Hospital and University of Washington, Seattle; 12Brian M. Feldman, MD, MSc: The Dalla Lana
School of Public Health, University of Toronto, and The
Hospital for Sick Children, Toronto, Ontario, Canada.
Dr. Reed has received consultant fees, speaking fees, and/
or honoraria (less than $10,000) from Kaiser Permanente.
Address correspondence to Adam M. Huber, MSc, MD,
IWK Health Centre, 5850 University Avenue, Halifax,
Nova Scotia, Canada B3J 3G9. E-mail: adamtheresa@hfx.
eastlink.ca.
Submitted for publication April 30, 2009; accepted in
revised form September 25, 2009.
219
220
involved, including the gastrointestinal tract, heart, and
lungs. Prior to the use of corticosteroids, mortality was
observed in up to 33% of children with juvenile DM, while
another 33% were left with permanent disabilities (1).
Since then, mortality in children has decreased to ⬍2%,
although substantial numbers of children experience morbidities, including permanent changes in muscle and joint
function, chronic disfiguring skin rashes, and side effects
from prolonged courses of corticosteroids (2). These significant morbidities have led to considerable interest in
developing and evaluating optimal therapies for juvenile
DM that maximize efficacy while minimizing toxicity.
Stringer et al recently reported on the results of a large
survey of treatment in juvenile DM (3). In that study, a
survey was sent to members of the Childhood Arthritis and
Rheumatology Research Alliance (CARRA). As part of the
survey, 11 clinical case scenarios based on actual patients
were developed. Each clinical case was chosen to represent a prototypic juvenile DM presentation or disease
course. All the respondents received the case chosen to
reflect moderately severe, typical juvenile DM, as well as 3
of the remaining 10 cases. The respondents were asked to
answer 3 open-ended questions about the cases they received: 1) what investigations would you order? 2) what
medication therapy would you start? and 3) what nonmedication therapy would you start? The survey was completed by 141 CARRA members (response rate 84%).
Stringer et al found that there was considerable variation
in the treatment of all cases, including the moderately
severe, typical case. While there was general agreement on
the need to treat with corticosteroids, different doses, durations, and routes were used. Most respondents also used
second-line medications, but there was marked variation
in the choice of medication and the doses administered.
These observations are not surprising, given that there are
little data on which to base treatment decisions.
The CARRA survey characterized the range of current
treatment for juvenile DM in North America. The goal of
the present study was to use these data, supplemented by
expert opinion, to develop a small number of consensus
treatment protocols that reflect current initial treatment of
moderately severe juvenile DM, and that can be studied
and refined to improve treatment of juvenile DM.
MATERIALS AND METHODS
A consensus meeting was held in Toronto, Ontario, Canada on December 1–2, 2007. The goal of this meeting was
to develop a small number of consensus treatment protocols that reflected current initial treatment of children
with moderately severe, typical juvenile DM. Twelve pediatric rheumatologists with broad experience in the assessment and treatment of juvenile DM and 1 experienced
consensus conference facilitator attended. Prior to and at
the beginning of the meeting, data from the survey of
CARRA members regarding the case of a child with moderately severe juvenile DM were summarized and reviewed (3).
This clinical case representing moderately severe juvenile DM described a 5-year-old girl with a 5-month history
Huber et al
Table 1. Questions considered in the consensus process
to establish initial treatment protocols, inclusion and
exclusion criteria, initial investigations, followup
evaluations, and concomitant medications
1. As reflected in current practice, what are the most
important treatment combinations for which we
should develop protocols?
2. As reflected in current practice, what elements of the
initial evaluation should be standard for all
included patients?
3. What should be the criteria that allow a patient to use
these protocols (inclusion criteria)?
4. What should be the criteria that exclude a patient
from using these protocols (exclusion criteria)?
5. What dose/route/frequency should be used for each
medication in the identified protocols?
6. As reflected in current practice, what are the most
important nonmedicinal treatments that should be
used by included patients?
7. At what intervals should patients be followed for the
purposes of data collection?
8. What elements of the followup evaluation should be
considered standard for all included patients?
of progressive weakness and classic heliotrope and Gottron’s rashes. She had difficulty walking up hills or stairs,
and needed help to get dressed and brush her hair. She
found it somewhat difficult to swallow, but there was no
choking. Strength of the shoulder and hip girdle muscles
was assessed as grade 3/5. She was unable to lift her head
off the bed, and had a marked head lag when assisted to
the seated position. She had a positive Gower’s sign and
when walking had a Trendelenburg’s gait with exaggerated
lumbar lordosis. Results of her blood work showed elevations in all muscle enzymes. Findings from her muscle
magnetic resonance imaging and electromyography were
both abnormal and consistent with myositis. She had a
Childhood Health Assessment Questionnaire score of
2.125 (potential range 0 –3, where higher scores denote
worse physical function) and a Childhood Myositis Assessment Scale score of 21 (potential score 0 –52, where
higher scores denote better strength and function).
The questions that were considered at this consensus
meeting are listed in Table 1. Nominal group technique
was used to reach consensus (4). The process followed for
each question is shown in Figure 1. First, there was an
item generation phase. After 5 to 10 minutes of individual
contemplation, a list of items was created without discussion. There was no limit on how many items could be
contributed by an individual. Next, each participant had 1
to 2 uninterrupted minutes to speak to the group about the
items they felt were most relevant to the question. Then
there was a vote. Voting was done using either stickers
(questions 1, 3– 6) or scorecards (questions 2, 7, 8) (Table
1). In the sticker voting, each conference participant was
given 7 colored stickers. The items for the question were
written on flip-charts. Participants then physically placed
their stickers on the flip-charts to indicate their support for
an item. Stickers could be distributed in any manner the
participant desired (including putting multiple stickers on
1 item). The total number of stickers associated with each
Consensus Protocols for Initial Treatment of Juvenile DM
221
RESULTS
Figure 1. Process of achieving consensus for each question considered.
item was then counted. In the score card voting, participants voted to support or reject each item individually.
This meant that an individual could vote in support of
multiple items (for example, investigations to be done as
part of initial evaluation). There was no limit to how many
items an individual could support. After this vote, each
participant once again had 1 to 2 minutes to speak to the
group and present their viewpoint on the issue; this was
followed by a short, general discussion. There followed a
second round of sticker voting or scorecard voting. For the
sticker voting, natural cutoffs became apparent for all
questions (a relatively small number of items had most of
the stickers/votes), and agreed to by ⱖ75% of participants.
Items above each cutoff were retained while the remainders were discarded. For the scorecards, a clear majority
(ⱖ75% of participants) was required to reflect consensus
on each item. Where additional clarification was required,
consensus was reached using either additional rounds of
sticker voting as described above or through a show of
hands (clear majority, ⱖ75% of participants required).
Three treatment protocols were developed that reflected
typical treatment practices, extending for the first 2
months of treatment. Participants also reached consensus
on inclusion and exclusion criteria to identify patients
with moderately severe juvenile DM and initial investigations, which should be done prior to initiating one of these
protocols. On the assumption that these protocols would
be evaluated in the future, conference participants also
reached consensus regarding data collection, both measures to be administered and frequency of assessments,
and on concomitant medications that would be required or
recommended.
Medication therapy in each of the consensus protocols is
summarized in Table 2. All protocols include corticosteroid and methotrexate, although the route of corticosteroid
varies. Protocol B differs from Protocol A in the additional
use of intravenous immunoglobulin (IVIG). Protocol C differs from Protocol A in that oral corticosteroid is used
instead of pulse intravenous methylprednisolone (IVMP).
It was agreed that similar doses of medications would be
used across protocols in order to facilitate comparisons in
the future. A protocol including IVMP, methotrexate,
prednisone, and hydroxychloroquine was the fourthranked protocol, but was not developed because of the goal
of limiting the number of protocols to 2 or 3.
Conference participants agreed on the initial dosage of
IVMP (30 mg/kg/day for 3 days). The majority of participants also recommended the continued weekly use of
single dosages of IVMP, but this was not unanimous. This
recommendation was retained as an option in Protocols A
and B. Participants also agreed on the dose and frequency
of methotrexate (the lesser of 15 mg/m2 or 1 mg/kg, maximum 40 mg). Although all participants agreed that the
subcutaneous route for methotrexate was preferable, the
option of oral methotrexate was left for circumstances
where the subcutaneous route was not considered possible. The participants agreed on a starting dose of oral
prednisone of 2 mg/kg, but there was also discussion of
lower dosages (0.5–1.5 mg/kg/day). There was considerable variation in suggested initial tapering of prednisone,
but a consensus was reached that prednisone would continue at 2 mg/kg/day for 4 weeks, and then would be
reduced by 20% if the patient was stable and doing well.
There was some disagreement regarding the recommended
dosage of IVIG (2 gm/kg/month [maximum 100 –120 gm]
versus 2 gm/kg/2 weeks for 3 doses and then monthly
[maximum 70 gm]). A third round of voting resulted in a
decision for the latter approach (8 votes to 4).
Inclusion and exclusion criteria (Table 3), baseline investigations and data collection (Table 4), and concomitant medications were common to all protocols. There was
clear agreement on inclusion criteria, with all retained
criteria having ⱖ10 votes and no rejected criteria having
⬎3 votes. It was agreed that all items receiving any votes as
exclusion criteria would be kept (unanimous decision).
For baseline investigations, all items that received votes
from ⱖ75% of participants as “definitely indicated” were
retained. There was considerable discussion about the inclusion of muscle biopsy. However, in the end, it received
only 4 of 12 votes as being “definitely indicated,” due to
concerns about muscle biopsy not being performed routinely in many centers. There was general agreement (11 of
12 votes) on frequency of clinical and research assessments for children being treated with these protocols, as
well as for which assessments should be included as part
of a research evaluation. However, there was disagreement
about the inclusion of the Paediatric Rheumatology International Trials Organisation (5) and/or the International
Myositis Assessment Collaborative Study Group (6) core
sets. These received the largest number of votes in the first
round. However, through the discussion concerns were
222
Huber et al
Table 2. Summary of medication therapy in 3 consensus protocols for the initial
treatment of moderately severe juvenile dermatomyositis*
Protocol A
IVMP
30 mg/kg/day (maximum 1 gm) for 3 days
Continue once/week, optional
MTX
Subcutaneous unless only oral possible
Lesser of 15 mg/m2 or 1 mg/kg (maximum 40 mg) once/week
Prednisone
2 mg/kg/day (maximum 60 mg) once/day for 4 weeks, then decrease by 20%†
Protocol B
IVMP
30 mg/kg/day (maximum 1 gm) for 3 days
Continue once/week, optional
MTX
Subcutaneous unless only oral possible
Lesser of 15 mg/m2 or 1 mg/kg (maximum 40 mg) once/week
Prednisone
2 mg/kg/day (maximum 60 mg) once/day for 4 weeks, then decrease by 20%†
IVIG
2 gm/kg (maximum 70 gm) every 2 weeks for 3 weeks, then monthly
IVMP once with each dose, optional
Protocol C
MTX
Subcutaneous unless only oral possible
Lesser of 15 mg/m2 or 1 mg/kg (maximum 40 mg) once/week
Prednisone
2 mg/kg/day (maximum 60 mg) divided twice/day for 4 weeks, then consolidate to
once/day†
* IVMP ⫽ intravenous methylprednisolone; MTX ⫽ methotrexate; IVIG ⫽ intravenous immunoglobulin.
† Subsequent weaning of prednisone to be determined by the treating physician.
raised that completion of the core sets would be burdensome to treating physicians. In the end, the complete core
sets were included as optional assessments.
Concomitant nonmedical treatments were considered
required if agreed to by ⱖ75% of participants, with the
remaining items being recommended. Dietary modifica-
Table 3. Consensus inclusion and exclusion criteria for application of initial treatment
protocols for moderately severe, typical juvenile dermatomyositis*
Inclusion, all criteria must be present
Rash (Gottron’s rash, heliotrope rash, or extensor surface rash)
Muscle weakness
Evidence of myositis (by biopsy, magnetic resonance imaging, or electromyography)
Age ⱕ16 years at onset
Physician global assessment of moderate (on a 3-category scale of mild, moderate, or
severe)
Exclusion, all criteria must be absent
Severe disability as defined by “can’t get out of bed,” CMAS score ⬍15, or MMT8
score ⬍30
Parenchymal lung disease
Gastrointestinal vasculitis (as determined by imaging or presence of bloody stools)
Other autoimmune or mimicking disease (as determined by the treating physician)
Requires intensive care unit management
Presence of aspiration or dysphagia to the point of inability to swallow
Central nervous system disease (defined as decreased level of consciousness or seizures)
Skin ulceration
Medication contraindication
Myocarditis
Pregnancy
Significant calcinosis (as determined by the treating physician)
Age ⬍1 year
* CMAS ⫽ Childhood Myositis Assessment Scale; MMT8 ⫽ manual muscle testing 8.
Consensus Protocols for Initial Treatment of Juvenile DM
223
Table 4. Consensus on minimum initial evaluation to be completed prior to starting
protocol treatment and minimum data to be collected at followup evaluations*
Initial evaluations
Physician global assessment of disease activity (10-cm VAS)
Parent global assessment of disease impact (10-cm VAS)
CMAS
C-HAQ
Manual muscle testing
Documentation of muscle involvement (biopsy, electromyography, or magnetic
resonance imaging)
Nailfold capillaroscopy (using hand-held magnifier, ophthalmoscope, or microscope)
Chest radiograph
Complete blood count
Basic biochemistry
Erythrocyte sedimentation rate
Muscle enzymes (preferably several of AST, CK, LDH, ALT, aldolase)
Quantitative immunoglobulins (IgG, IgA, IgM)
Antinuclear antibody
Other autoantibodies
Extractable nuclear antigens plus other myositis-specific/associated antibodies as
indicated
Extramuscular disease activity (10-cm VAS)
Followup evaluations
Physician global assessment of disease activity (10-cm VAS)
Parent global assessment of disease impact (10-cm VAS)
CMAS
C-HAQ
Complete blood count
Muscle enzymes (choice of AST, CK, LDH, ALT, aldolase)
Extramuscular disease activity (10-cm VAS)
Full PRINTO 5 or IMACS 6 core sets at initial and followup evaluations, optional
* Recommended data collections are at 1, 2, 6, 12, and 18 months. Clinical followup will likely be more
often. VAS ⫽ visual analog scale; CMAS ⫽ Childhood Myositis Assessment Scale; C-HAQ ⫽ Childhood
Health Assessment Questionnaire; AST ⫽ aspartate aminotransferase; CK ⫽ creatine kinase; LDH ⫽
lactate dehydrogenase; ALT ⫽ alanine aminotransferase; PRINTO ⫽ Paediatric Rheumatology International Trials Organisation; IMACS ⫽ International Myositis Assessment Collaborative Study Group.
tions and dietary consultation if possible (to minimize
prednisone toxicity), sunscreen counseling, and folic acid
supplementation (if taking methotrexate) were considered
required, while calcium/vitamin D supplementation and
referral to physiotherapy and/or occupational therapy was
recommended. There was some disagreement on whether
supplementation with calcium and vitamin D should be
required or recommended. After an additional round of
discussion and voting, it was agreed that it should be
recommended (11 in favor). The detailed protocols will be
available to members of CARRA online at http://www.
carragroup.org/.
DISCUSSION
We have shown that it is possible to achieve consensus on
the treatment of juvenile DM, despite considerable variation in clinical practice. We have developed 3 consensus
protocols, which are intended to reflect current standard
initial care of patients with moderately severe typical juvenile DM. We have also established consensus on inclusion and exclusion criteria, initial investigation, followup
data collection, and concomitant medications, thereby facilitating future evaluation of these protocols.
Despite its acknowledged value and ubiquitous use, the
administration of corticosteroids in the treatment of juvenile DM has never been studied in a randomized controlled trial (RCT). In fact, there have been almost no RCTs
of any medications in juvenile DM. The explanation for
this is largely related to the rarity of juvenile DM (incidence of 2– 4 cases per million per year) (7), but also to the
difficulties in studying this complex disease and the lack
of tools with which to measure outcome. Recent efforts
have largely eliminated the latter issue. There are now a
variety of tools that have been shown to be valid assessments of muscle function (8 –10), skin disease activity
(11,12), extramuscular disease activity (13), and overall
disease activity (13–16). Unfortunately, researchers are
still left with the challenges presented when studying a
rare illness.
In order to improve outcomes in juvenile DM and minimize both morbidity and mortality, it is necessary to
optimize currently available therapeutic regimens and to
evaluate new medications that may become available. It
will be difficult for traditional RCTs to achieve these goals
because of the small number of patients available for study
and the costs associated with conducting clinical trials
that must include large numbers of centers and encompass
vast geographic areas.
Development of these protocols is a first step in be-
224
ginning to study treatments in juvenile DM using a new
approach. We envision a study where treating physicians could choose the protocol that most closely reflected their typical treatment of patients with moderately severe juvenile DM. By collecting data in a
standardized fashion, data could be pooled from multiple physicians, who are all engaging in routine care
decisions. These data could then be analyzed using statistical methods that account for variations in illness
severity and other factors measured at baseline that may
influence outcomes (confounding by indication) (17,18).
In this way, these protocols could be compared without
the expense and complexity of infrastructure that would
be required for an RCT. However, this study scenario
assumes that it is possible to ensure that similar patients
are being compared, and that differences between patients are accounted for. All important disease and patient characteristics would need to be measured. Advances in statistical methods (such as propensity
scoring and other techniques) and development of a
variety of validated measurement tools in juvenile DM
make this less problematic. However, it remains to be
seen whether this type of analysis will ultimately be
successful.
Our study should be interpreted in the light of potential
limitations. Although these protocols should be similar to
treatment decisions made by most pediatric rheumatologists, they cannot represent all possible options. For example, the initial use of hydroxychloroquine or cyclosporine is not addressed, as these medications were not as
widely used in the CARRA survey. Also, data and expert
opinion used in this project were primarily derived from
North American pediatric rheumatologists. This may
mean that not all pediatric rheumatologists will be able to
identify a protocol that is similar to their usual practice.
However, the protocols should have wide enough applicability to allow their evaluation. Finally, new data are
emerging to show that there may be more sensitive, immunologic-based indicators of continued disease. These were
not included in our consensus discussions, but may one
day play a role in determining therapy.
It should be emphasized that these treatment protocols
are not intended as treatment recommendations. They
have been chosen to reflect care provided by clinicians.
Given the near complete lack of clinical trial data, it is not
clear if one of these protocols is the optimal treatment for
children with moderately severe juvenile DM. Future research will need to investigate this question.
In conclusion, we have developed 3 protocols that reflect current treatment of children with moderately severe
juvenile DM. These protocols are the first step to allow
comparison of different approaches to the treatment of
juvenile DM. In order to achieve this goal, future work will
need to extend the treatment protocols beyond the initial
period, develop a plan for data collection, and develop
methods to account for differences between patients in
whom these protocols are used. Subsequently, the protocols will need to be further updated as new medications or
treatment approaches become available.
Huber et al
ACKNOWLEDGMENTS
The authors would like to thank the following for their
assistance with technical, administrative, and organizational matters for this project: Sylvia Ota, Stephanie
Gomer, and Haddas Grosbein. We would also like to thank
Drs. Kathleen Coyle, Olcay Jones, and Frederick Miller for
critical review of the manuscript.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Huber
had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data
analysis.
Study conception and design. Huber, Giannini, Bowyer, Lang,
Lindsley, Pachman, Pilkington, Reed, Wallace, Feldman.
Acquisition of data. Huber, Giannini, Kim, Lang, Lindsley, Pachman, Pilkington, Reed, Rennebohm, Rider, Wallace, Feldman.
Analysis and interpretation of data. Huber, Giannini, Bowyer,
Pachman, Pilkington, Reed, Wallace, Feldman.
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