Protocols for the initial treatment of moderately severe juvenile dermatomyositis: Results of a Children's Arthritis and Rheumatology Research Alliance Consensus Conference

Authors


Abstract

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 weakness, impairments in physical function and endurance, and a variety of skin rashes. Other organs may also be 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 non-medication 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 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 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 ≥75% of participants. Items above each cutoff were retained while the remainders were discarded. For the scorecards, a clear majority (≥75% 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, ≥75% of participants required).

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?
Figure 1.

Process of achieving consensus for each question considered.

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.

RESULTS

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 fourth-ranked protocol, but was not developed because of the goal of limiting the number of protocols to 2 or 3.

Table 2. Summary of medication therapy in 3 consensus protocols for the initial treatment of moderately severe juvenile dermatomyositis*
  • *

    IVMP = intravenous methylprednisolone; MTX = methotrexate; IVIG = intravenous immunoglobulin.

  • Subsequent weaning of prednisone to be determined by the treating physician.

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

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 ≥10 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 ≥75% 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 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.

Table 3. Consensus inclusion and exclusion criteria for application of initial treatment protocols for moderately severe, typical juvenile dermatomyositis*
  • *

    CMAS = Childhood Myositis Assessment Scale; MMT8 = manual muscle testing 8.

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 ≤16 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
Table 4. Consensus on minimum initial evaluation to be completed prior to starting protocol treatment and minimum data to be collected at followup evaluations*
  • *

    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.

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

Concomitant nonmedical treatments were considered required if agreed to by ≥75% of participants, with the remaining items being recommended. Dietary modifications 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 beginning 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.

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.

Acknowledgements

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.

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