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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arthritis Care Res (Hoboken). Author manuscript; available in PMC May 1, 2013.
Published in final edited form as:
PMCID: PMC3336032
NIHMSID: NIHMS349088

Inactive Disease and Remission in Childhood-onset Systemic Lupus Erythematosus

Abstract

Objective

To define inactive disease (ID) and clinical remission (CR), and delineate variables that can be used to measure ID/CR in childhood-onset systemic lupus erythematosus (cSLE).

Methods

Delphi questionnaires were sent to an international group of pediatric rheumatologists. Respondents provided information about variables to be used in future algorithms to measure ID/CR. The usefulness of these variables was assessed in 35 children in ID and 31 children with minimally active lupus (MAL).

Results

While ID reflects cSLE status at a specific point in time, CR requires the presence of ID for ≥ 6 months and considers treatment. There was consensus that patients in ID/CR can have ≤ 2 mild non-limiting symptoms (i.e. fatigue, arthralgia, headaches or myalgia) but not Raynaud’s phenomenon, chest pain, or objective physical signs of cSLE; ANA positivity and ESR elevation can be present. CBC, renal function testing, and complement C3 all must be within the normal range. Based on consensus, only damage-related laboratory or clinical findings of cSLE are permissible with ID. The above parameters were suitable to differentiate children with ID/CR from those with MAL (area under the receiver operating characteristic curve > 0.85). Disease activity scores with or without the physician global assessment of disease activity and patient symptoms were well suited to differentiate children with ID from those with MAL.

Conclusions

Consensus has been reached on common definitions of ID/CR with cSLE and relevant patient characteristics with ID/CR. Further studies must assess the usefulness of the data-driven candidate criteria for ID in cSLE.

Key Terms: lupus, childhood-onset SLE, SLE, pediatric SLE, juvenile SLE, remission, inactive disease, children, cSLE

INTRODUCTION

Systemic lupus erythematosus is a complex, chronic, multi-system autoimmune inflammatory disease that primarily targets young women of non-Caucasian ancestry (1,2). Up to 20% of patients are diagnosed during childhood (cSLE) and their disease has a less favorable prognosis than those with adult onset SLE, particularly with respect to multi-organ and kidney involvement (35). The course of cSLE is characterized by episodes of disease flares, followed by periods of improvement, which are generally the result of more intensive drug therapy (6,7). As in other adult and pediatric rheumatic diseases, it is hoped that advances in the treatment of cSLE yield a state of inactive disease (ID) or even clinical remission (CR) (8,9). To permit comparability of future studies addressing ID and CR (abbreviated ID/CR), it is advisable to develop common definitions and algorithms or criteria for measuring ID/CR in cSLE.

The objectives of this project were to apply consensus formation methodology to define ID/CR in cSLE, identify variables to be considered in future criteria of ID/CR for cSLE, and derive data-driven candidate criteria for ID.

PATIENTS AND METHODS

The overall approach of the project was based on methodological strategies successfully employed by the pediatric rheumatology community in the past, following the framework developed by the Classification & Response Criteria Subcommittee of the ACR Committee on Quality Measures (10).

We performed structured consensus formation to define ID/CR and delineate variables (VAR-ID/CR) that can be used in algorithms (or criteria) to measure ID/CR (Step 1). Using data from a prospective cohort, we assessed the relevance of the VAR-ID/CR for discriminating patients with ID from patients with minimally active cSLE (abbreviated MAL) who were not in ID. We also explored data-driven candidate criteria for ID (Step 2). The study was approved by the institutional review boards of the participating pediatric rheumatology centers. Informed consent was obtained from all parents and, as appropriate, assent was given by the participants prior to the study procedures.

Step 1: Consensus methodology – International Delphi surveys

The goal of the Delphi process (11) was to define ID/CR in cSLE and create a pool of relevant variables (Var-ID/CR) to be considered in candidate criteria. Fundamental to the project was the initial review of the medical literature, addressing the constructs ID/CR, with a focus on rheumatology.

The Pediatric Rheumatology Collaborative Study Group (PRCSG), Childhood Arthritis & Rheumatology Research Alliance (CARRA), the Pediatric Rheumatology European Society (PRES) Juvenile Lupus Working Group, the Pediatric Rheumatology International Trials Organisation (PRINTO), and the Pan-American League of Arthritis & Rheumatology (PANLAR) were approached, and provided their membership. Members of these groups have prior experience in using these techniques to develop outcome measures (1214). As is commonly done, the level for consensus was set at 80% (8).

Step 2: Variable performance and data-driven candidate criteria

Patients

As part of a larger study, patients with cSLE age ≤18 years (2) were recruited during routine visits at 12 pediatric rheumatology clinics in the United States and Canada, and study visits occurred every 3 months thereafter. Some patients entered the study with active cSLE and achieved MAL rather than ID, as rated by the treating physician during follow-up. Other patients who were considered by their pediatric rheumatologist to “be in remission” were recruited, provided cSLE did not require treatment with systemic corticosteroids. Considering the scores of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI, version 2k) (6,11) and the British Isles Lupus Activity Group (BILAG) index (15), MAL was defined as the absence of BILAG A scores, 2 or fewer BILAG B scores, and a SLEDAI score of ≤ 5. These cut-offs were chosen based on the results of the Delphi survey and published literature (16). Other patients with cSLE who did not require systemic corticosteroids were also enrolled, provided their managing pediatric rheumatologist considered them to be in ID/CR. Details on the experience of these pediatrics rheumatologists in treating cSLE is described elsewhere (17). In brief, all were board-certified pediatric rheumatologist professionals who see, on average, 20 patients with cSLE weekly at their academic center and have 10 years of experience in treating childhood-onset SLE.

Outcomes

Findings on physical examination, information about prescribed medications, and standard laboratory testing were obtained, including antinuclear antibodies (ANA), erythrocyte sedimentation rate (ESR), complete blood count, liver function testing, urinalysis and microscopy, protein:creatinine ratio, complement C3 and C4 levels, anti–double-stranded DNA (anti-dsDNA) and anti-phospholipid (aPL) antibody levels. Additionally, we recorded parameters often used for assessing cSLE (12,18): physician assessment of overall disease activity as measured on a visual analog scale (PGA; 0 = inactive disease; 10 = very active disease), and the scores of several disease activity indices: Systemic Lupus Activity Measure (SLAM) (10), SLEDAI (6,11), and BILAG index (15); scores of 0 indicate inactive disease in all of these indices.

Patient symptoms

A standardized questionnaire was completed at each visit by the patient (15). This questionnaire captures symptoms often associated with cSLE, including their severity (mild – not limiting activities; moderate or severe – limiting activities). The symptoms reported on this questionnaire were reviewed by the treating pediatric rheumatologist for correctness and clinical relevance, prior to consideration of these symptoms in the subsequent analyses.

Measures of cSLE course

During follow-up visits, the managing pediatric rheumatologist rated the disease course on two separate scales: (1) In response to the sentence “Compared to the last study visit 3 months ago, the patient’s overall disease is still in ID/CR”, the physicians answered yes or no; (2) In response to the sentence stem “Compared to the last study visit three months ago, the patient’s overall disease shows”, the pediatric rheumatologist rated the disease course on a 5-point Likert scale: major flare of disease, minor flare of disease, no change in disease, minor improvement of disease, or major improvement of disease. The pediatric rheumatologists (n = 23) who provided the above ratings, were all board-certified pediatric rheumatologists and had, on average, 13 years of experience in managing cSLE.

Statistical analyses

Delphi responses were assessed for consensus at 80%. We tested whether there were systematic differences in the responses provided by Delphi respondents from different geographic regions, or with varying professional experience as measured by the duration of medical practice. Agreement among raters was assessed using Kappa (κ) statistics. A κ value can be interpreted as follows: 0– 0.20 as slight, 0.21– 0.40 as fair, 0.41– 0.60 as moderate, 0.61– 0.80 as substantial, and 0.81–1 as almost perfect agreement (19).

We compared patients with ID/CR to those with MAL for differences in the frequency or values of the Var-ID/CR, using contingency table analysis and 2-sample t-test, respectively. A patient symptom score (range 0 – 4) was calculated from the sum of the following symptoms: myalgias, arthralgias, fatigue, and headaches.

To correct for multiple comparisons between groups, only Bonferroni-corrected p-values of < 0.005 were considered statistically significant (20). Furthermore, we examined the Var-ID/CR for redundancy, using Pearson correlation coefficients (r). High (r≥ 0.6) values support redundancy or indicate that algorithms containing both predictors may cause unstable estimates, i.e. whether the patient truly has ID/CR or not. For these analyses, we used the first observation available for each patient, i.e. the enrollment visit for patients with ID/CR and the first visit when MAL was reached in the others.

Lastly, in exploratory analysis to derive data-driven criteria for ID, we performed logistic regression to predict ID (outcome variable) considering the Var-ID/CR as predictors. Given our recruitment strategy, the duration of follow-up, and the number of patients enrolled, we focused on ID and not CR in these exploratory analyses. For each model, we estimated the rescaled R2 value as a generalized measure of the model fit (21) and calculated the area under the receiver operative characteristic curve (AUC) as a measure of diagnostic accuracy for distinguishing ID from MAL. The accuracy (AUC) can be interpreted as follows: 0.9 – 1.0 as excellent, 0.81 – 0.90 as good, 0.71 – 0.80, 0.61 – 0.70 as fair, and < 0.60 as poor (22).

Open source online survey software, Limesurvey, was used for Delphi response management and as a presentation layer (see http://www.limesurvey.org/). All analyses were done using SAS 9.2 (SAS, Cary, NC) software.

RESULTS

Literature review

A detailed literature search was performed. The identified articles were screened independently by two authors (RM, HIB) and assessed for relevance to the project. All articles considered relevant for defining ID/CR by at least one were reviewed in detail by both of these authors. Relevance assessment included the provision of a definition, development of criteria, or the delineation of items considered with ID/CR. The 37 articles deemed useful for defining ID/CR, were summarized for presentation to participants in the Delphi process (see Appendix A for details on the literature search strategy and results).

Delphi survey participants

In 2009, the initial Delphi survey was sent to 137 pediatric rheumatologists who indicated their willingness to participate in this project during the consensus process for the cSLE flare criteria (15). The response rate for the first Delphi questionnaire (concerning ID/CR) was 77%.

In early 2011, the second survey was sent to 598 members of the participating organizations. There were 362 respondents to the survey (61% survey response rate), and based on the information provided, there were 240 pediatric rheumatologists among the respondents, who treated a minimum of 3 cSLE patients per month. On average, these physicians had 15.5 (range 4 – 27) years of experience treating cSLE and assessed 12 patients per month (range 3 – 80). Most of these respondents worked in the United States or Canada (46%), Europe (34%), and Central and South America (15%), followed by Asia, Africa, and Australia (5%). Responses from these 240 pediatric rheumatologists were used in the analyses while the feed-back from all other respondents was not further considered. Thus only responses of pediatric rheumatologists were included in the analysis.

Ratings from physicians in North America were comparable to those in Europe, Central and South America (all κ > 0.72) for Var-ID/CR for which consensus was achieved, and there were no parameters for which consensus was reached in only one geographic region. Likewise, there were not significant differences among respondents with different experience. This supports that there were no systematic differences in the opinion of the survey respondents from different geographic areas or different levels of experience.

Definition of the constructs

Consensus was reached in several key findings that are summarized in the following. ID and CR must be discriminated from “cure” or “minimally clinically active cSLE”. Furthermore “inactive disease” (ID) refers to a certain point in time, while “clinical remission” (CR) constitutes a time period during which a patient is considered to have ID (consensus 91%). While the use of medication was deemed irrelevant in ID, this was not the case with CR. Respondents’ consensus suggests three levels of CR, considering both the duration of ID and the medications prescribed for cSLE (Table 1).

Table 1
Definitions of inactive disease and clinical remission in cSLE

Even patients considered to have ”CR off medications” were anticipated to continue mediations to treat non-cSLE related comorbid conditions or organ damage but not medications, probiotics or nutritional supplement that are used as prophylaxis of cSLE-related disease damage or progression. These ‘preventive’ medications include (based on consensus) statins, aspirin, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, bisphosphonates, vitamin D, and omega-3-fatty acids.

Notably, there was no consensus regarding whether antimalarials or daily nonsteroidal anti-inflammatory medications (NSAIDS) should be considered a preventive medications or not.

Details on inactive disease with cSLE

Additionally, respondents achieved consensus that patients with ID/CR must have a normal physical examination but may have select laboratory abnormalities (Table 2). With ID, there may be up to 2 mild non-limiting symptoms (myalgia, arthralgia, fatigue, headaches).

Table 2
Details on permissible signs, symptoms and laboratory abnormalities of patients with inactive disease

Respondents achieved consensus that permissible laboratory abnormalities include ANA positivity, and stable levels of aPL antibodies that do not exceed twice the upper limit of normal (2xULN). The majority of the survey respondents stated that stable low levels of anti-dsDNA antibodies (73%) are permissible with ID/CR.

There was consensus that ESR elevation should be considered with ID/CR, and the majority of the raters stated that ESR levels not exceeding 2XULN (66%) were acceptable with ID/CR. Based on previous suggestions, since there are various methods for measuring the ESR (with different ULN) and clinical laboratory facilities often change assays, ESR values >50 mm/hour were considered to be > 2xULN in the subsequent analyses (15).

Based on consensus, C4 hypocomplementemia was permissible, provided that the low serum levels were due to genetic variability rather than active cSLE. In brief, there are over 40 different human polymorphic allotypes of the 2 distinct major gene product isotypes, C4A and C4B (23). Among others, serum levels of C4 are moderately correlated with the C4 gene copy numbers (24,25). Because formal genetic testing for clinical purposes of C4 gene copy numbers is unavailable, clinicians deduce that a genetic variation must be present if C4 levels do not normalize, despite apparently well controlled cSLE.

The PGA and the scores of disease activity indices were deemed important for determining ID/CR. Consensus was also reached that, irrespective of the measure considered (SLAM, SLEDAI, BILAG), the scores of a disease activity index alone were insufficient to identify ID/CR, and that ID/CR could be present even if the disease activity scores were > 0.

VAR-ID/CR in patients considered to be in ID/CR by the managing pediatric rheumatologists

There were 35 patients with ID/CR and 31 patients with MAL, as rated by their pediatric rheumatologist (Table 3). The groups differed significantly in the frequency of abnormal findings on physical examination. Leukopenia, lymphopenia, neutropenia, anemia, and C3 hypocomplementemia were less common with ID/CR than with MAL. Of note, the groups were comparable for values of low levels of C4, ESR values exceeding 2xULN, and positivity of anti-dsDNA antibodies (Table 4).

Table 3
Patients with inactive disease by the treating pediatric rheumatologist
Table 4
Differences between patient with inactive disease and minimally active stable disease activity

With the exception of the WBC and the absolute neutrophil count (r = 0.92), none of the other Var-ID/CR were more than moderately correlated with each other. Details of the results of laboratory testing are provided in Table 5. We did not have access to aPL antibody levels. Therefore, we excluded aPL antibodies from the pool of VAR-ID/CR in the subsequent analyses.

Table 5
Differences in variables considered important for assessing inactive disease in cSLE

Construct validity of the definition of ID/CR

The ability of all Var-ID/CR to discriminate patients with ID (n=35) from those with MAL (n=31) was explored. These analyses focused only on the patient phenotype with ID (or CR) and not on the concomitant use of medications. Assuming that, as is shown in Table 2, all Var-ID/CR deemed permissible but none of those considered unacceptable, can be present with ID/CR, we tested the agreement between the treating pediatric rheumatologists and the consensus achieved via Delphi surveys (Table 6).

Table 6
Performance of disease activity indices as measured by the area under the ROC curve

The agreement between treating physician and the consensus definition of ID/CR was slight when C4 hypocomplementemia was considered to reflect active cSLE (κ= 0.16). When considering all Var-ID/CR but assuming that C4 hypocomplementemia was due to genetic variability (rather than active cSLE), then the agreement was moderate (κ= 0.44), and agreement further increased (κ= 0.48) when ESR elevation was no longer considered for characterizing patients with ID/CR.

Data-driven candidate criteria for ID

To increase the feasibility of future criteria of ID/CR, it is highly desirable to minimize the number of variables to be included in future criteria of ID/CR. All of the Var-ID/CR (except aPL antibody levels) are items of disease activity indices that are commonly used in cSLE (SLAM, SLEDAI, BILAG). Therefore, in exploratory analyses using logistic models, we considered the scores of the disease indices as predictors of ID, under consideration of ESR levels exceeding 2XULN (here: > 50 mm/ hour) and C4 hypocomplementemia (Table 6).

When all Var-ID/CR (except aPL antibody levels) were included in the model, the outcome ID could be predicted very well, irrespective of C4 and ESR status. In conjunction with laboratory testing suggesting inactive lupus nephritis and a normal physical examination, the SLAM and the BILAG (domain scores or total summary score) were similar in their ability to predict ID. Only when the PGA and patient symptom score were added to the SLEDAI as predictors, did the resulting logistic model of ID perform as well (AUC, R2) as the models that included the BILAG or the SLAM. Conversely, adding the PGA and the patient symptom score to models that contained the SLAM or the BILAG as predictors of ID did not importantly improve model performance (AUC) or fit (R2).

Thirty-two of the 35 patients in ID/CR at baseline continued to be in ID/CR at the 6 month follow-up visit. Repetition of the above analyses using the follow-up data of these 32 patients yielded similar results.

DISCUSSION

Using consensus formation methodology, we developed a taxonomy for generally accepted future criteria of ID and CR in cSLE. Additionally, variables deemed central for the measurement of these constructs were delineated, and data-driven candidate criteria for ID derived.

Clinical remission in other conditions such as malignancies (26), infections (27) and rheumatoid arthritis is defined as a time point when the disease is very well controlled (9,28). Conversely, there was consensus among pediatric rheumatologists that CR in cSLE constitutes a time period. Hence, the construct of CR in cSLE embraces a concept that is already in use for juvenile idiopathic arthritis (8). Implicit to this concept is the need for an ID construct to define the disease state (or patient phenotype) that is present throughout the CR period.

Different from CR, medication use is not part of the definition of ID in cSLE. This is sensible when considering the proposed use of ID/CR criteria in future clinical trials, where medication adjustments are closely regulated to help delineate the safety and efficacy of the study drug. Concomitant medication usage is only relevant for disease modifying medications in long-term follow-up, and this will be captured by the different levels of CR proposed.

There was no consensus regarding whether antimalarials and NSAIDS should be allowed nor was there consensus to prohibit NSAIDS or antimalarials in patients who are in ”CR on preventive medications“. NSAIDS are widely used in the general population ’as needed‘, while regular intake likely suggests the presence of clinically relevant joint inflammation or damage. Antimalarials are anti-inflammatory and widely used in cSLE for the prevention of damage (29), and often continued, irrespective of the patients‘ disease control. The prospective data collected for this study were not suited to explore medication usage during CR, and additional studies are needed to determine antimalarial and NSAID usage in the context of CR.

Disease activity indices and the PGA have a long history of use to delineate the course of cSLE and SLE. (18,30, 31). The same is true for ID/CR. Both the PGA and disease activity index scores were deemed central to, but not sufficient for identifying ID/CR in cSLE. There was consensus that any objective abnormalities on physical examination were incompatible with ID/CR. Likewise, several symptoms (arthralgia, myalgia, headaches, fatigue) that are associated with cSLE activity were considered relevant when classifying a patient to be in ID/CR.

Similar to the cSLE flare criteria, patient well-being and health-related quality of life are not among the candidate variables to be considered for future criteria of ID/CR (8,18). Instead, there was consensus to consider specific symptoms that are known to have detrimental impact on health-realted quality of life and well-being with cSLE in such criteria.

The presence of aPL antibodies was deemed permissible with ID/CR, by consensus, provided aPL antibody levels are ≤ 2xULN. However, aPL testing is not standardized, both in terms of assays and the units used to reporte levels, making the uniform interpretation of the degree of aPL antibody elevation impossible (3234). The remaining Var-ID/CR (without aPL antibodies) were able to accurately discriminate patients with ID from those with MAL, raising the possibility that aPL antibody levels may not be required to identify patients with ID/CR. This will need confirmation in future studies.

Consensus was reached that complement C4 levels should be normal with ID/CR, unless due to genetic variability. However, clinical testing for the gene copy numbers of C4 is not readily available at present. Based on our exploratory analyses, it is very likely that the elimination of C4 hypocomplementemia from the pool of Var-ID/CR will not significantly change the measurement properties of future criteria of ID/CR. In contrast to C4 not being a critical determnant of the VAR-ID/CR, eliminating of the ESR from the pool of VAR-ID/CR considerably decreased the accuracy with which ID was predicted in our data sets. The agreement between the treating rheumatologist and the consensus phenotype with ID was fair to moderate but well in line with what was observed in previous studies (8,18).

The SLAM and the BILAG scores include subjective symptoms as well as objective abnormal findings, while the SLEDAI only scores the latter. In regression models that considered a disease activity index as predictor, only the SLAM or the BILAG index identified patients with ID at good to excellent accuracy. Conversely, only the combination of the SLEDAI, PGA, plus patient symptoms score was comparable in distinguishing patients with ID from those with MAL.

If confirmed in a larger prospective data set, disease activity index scores alone, or in combination with the PGA and the patient symptom score, appear to accurately identify patients in ID, provided there is a normal physical examination and laboratory testing suggests inactive lupus nephritis.

The OMERACT filter is used to evaluates the usefulness of criteria for rheumatic diseases (35). The OMERACT filter encompasses three components of clinimetrics: truth, discrimination, and feasibility. Truth captures four aspects of validity: face, content, criterion, and construct. Discrimination is the second component of the OMERACT filter and asks if the criteria are able to distinguish between states of interest. Feasibility, the third component of the filter and refers to how practical it is for the measurement of the outcome to be carried out quickly, easily, using a simple scoring method, and at a minimal cost in a physician’s office. The international consensus process that led to the definition of ID/CR and delineated a pool of VAR-ID-CR are in support of the first component, the ability of data-driven candidate criteria to distriminate between ID and MAL supports the second component, while the limited number and type of the parameters considered the candidate criteria are in support of the third component of the OMERACT filter.

A limitation of our study is the limited number of patients studied. However, ID/CR is an exceedingly rare disease state in adults with lupus and occurs even less frequently in children (3,36). Hence, the results of the logistic regression models were considered exploratory in nature only.

In summary, a framework for defining and measuring ID and CR in cSLE has been developed. Despite the complexity of cSLE, our research suggests that in patients with a normal physical examination and clinically inactive lupus nephritis, simple algorithms are sufficient to identify patients with ID. The presented data-driven algorithms to measure ID based on the score of a disease activity index, PGA and ESR, will need to be verified in future studies. Specifically, we expect that a consensus conference for additional consensus formation will yield further specification of the ID/CR criteria, preferably using data from clinical trials aimed at achieving ID/CR in cSLE. Next steps in the development of criteria to measure ID/CR will also include further consensus formation around medication usage with CR.

Significance & Innovation

  • The study newly defines internationally accepted constructs of inactive disease and clinical remission in cSLE.
  • Inactive disease and clinical remission in cSLE requires the absence of laboratory evidence compatible with active lupus nephritis and objective physical findings of cSLE activity.
  • Candidate variables to be considered in future criteria are delineated and their validity is confirmed using prospective data.

Acknowledgments

Grant Support:

The study is supported by NIH grants U01-AR51868 and U01-AR055054, P30-AR AR47363, P60-AR047884 and UL1RR026314.

Dr. Mina was supported by a NIAMS training grant T32100291.

Acknowledgments – Other:

CCHMC: Joshua Pendl and Jamie Meyers-Eaton (site coordination and database management); Lukasz Itert – survey management; CCHMC Biomedical Informatics (Web-based data management application development); Jill Segerman (editoral support with the manuscript preparation).

Texas Scottish Rite Hospital: Marilynn Punaro (data collection), Shirley Henry (site coordination).

University of Chicago Comer Children's Hospital: Becky Pupluva (site coordination).

Children’s Memorial Hospital: Dina Blair (site coordination).

British Columbia Children’s Hospital: Lori Tucker Tucker (data collection), America Uribe (site coordination)

Morgan Stanley Children’s Hospital: Deborah Levy and Any Eichenfield (data collection).

MetroHealth Medical Center and Case Western Reserve University: Elizabeth Brooks, Kabita Nanda and Nellie Coughlin (data collection).

University of Oklahoma Health Sciences Center: Lauren Kickingbird Walters, Kimberly Benjamin (site coordination).

Duke Medical Center: Janet Wooton (site coordination)

Acknowledgement – External Scientific Advisory Committee:

We are indebted to the members of the External Scientific Advisory Committee of this study for their advice in the study implementation, conduction and its statistical analysis: Drs. Carol Wallace, Suzanne Bowyer, Vern Farewell, Rosalind Ramsey-Goldman, Nicola Ruperto, Carlos Rose, and James Witter.

Appendix A. PubMed Search Strategy for Remission of Childhood-onset Systemic Lupus Erythematosus

The following limits* were placed on all searches: English, Human

PubMed Search Strategy for SLE

The entry term “Rheumatology” and X were entered with X being one of search term or search term combinations noted below:

  • Search Remission AND Systemic Lupus Erythematosus with limits*
  • Search Inactive Disease AND Systemic Lupus Erythematosus with limits*
  • Search Minimal Disease Activity AND Systemic Lupus Erythematosus with limits*

PubMed Search Strategy for Other Rheumatologic Diseases

The entry term “Rheumatology” and X were entered with X being one of search term or search term combinations noted below:

  • Search Remission AND Rheumatology with limits*
  • Search Inactive Disease AND Rheumatology with limits*
  • Search Minimal Disease Activity AND Rheumatology with limits*

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Articles Included in Final Table Presented to Delphi Respondents
TermDiseaseDefinitionSourceTime point or period
Inactive DiseaseJIAChildren without synovitis and extra-articular JIA features(37)Time point
Clinical remission on medicationsJIAChildren with inactive disease for 6 months while receiving medication for JIA(37)Time period
Clinical remission off medicationsJIAChildren with inactive disease for 12 months while not receiving medication(37)Time period
Minimal active diseaseRACDAI* ≤10 or SDAI** ≤ 11
* TJC28, SJC28, VAS-patient, VAS-MD
** SDAI, CRP
(38)Time point
Minimal disease activityRAOMERACT: no tender joints, no swollen joints, ESR ≤ 10
EULAR: DAS28 < 2.85 or 5/7
ILAR (meet 5 out of 7): pain ≤2, swollen joints ≤ 1, VAS-MD ≤ 1.5, VAS-patients≤ 2, ESR ≤ 20, HAC ≤ 0.5
(39)Time point
Clinical remissionRAACR: Opposite of active disease as measured by swollen joints, tender joints, ESR,CRP, VAS MD-activity, HAQ(38)Time point
Clinical remissionRAEULAR: Opposite of active disease as measured by DAS or DAS28, SDAI, or CDAI(38)Time point
Clinical remissionRAARA Criteria: no fatigue, no joint pain (by history), no SJC, no TJC, ESR < 30 (females) or 20 (males)(40)Time point
Clinical remissionRAFDA Criteria: ACR clinical remission and absence of radiological progression over a continuous 6 month period in the absence of a DMARD(41)Time period
Complete clinical remissionRARemission (see above) while treated with DMARD(41)Time period
Sustained remissionRADAS < 1.6 for 2 years on or off medications ; concludes that current definition is dissatisfactory because of damage accrual over 2 year(42)Time period
Long-term sustained remission on/off medicationRARemission needs consideration of damage increase over time for patient in remission whether achieved off or on medication(43)Time period
Major clinical responseRAACR 70 for at least 6 months(41)Time period
Clinical remissionPsATime period of at least 3 consecutive months with active joint count =0 (no stress pain, no joint line tenderness no effusion)(44)Time period
Complete remissionJDMComplete clinical response (= normal strength, normal enzymes, normal von Willebrand factor, normal MRI of upper thighs) for 6 months on medications(45)Time period
Sustained remissionJDMComplete clinical response for 6 months off medications(45)Time period
Clinical RemissionIIM6 mo continuous period of no evidence of disease activity (normal enzymes, stable muscle strength and damage; no active muscular or extramuscular disease) while not receiving any myositis therapy(46)Time period
Complete clinical responseIIM6 mo continuous period of no evidence of disease activity while still receiving myositis therapy(46)Time period
RemissionSLESLEDAI = 0(47)Time point
RemissionSLEResolution of clinical symptoms, normalization of laboratory findings on a minimal maintenance therapy (low dose prednisone, hydroxychloroquine, immunosuppressive, ANA positivity and anti-dsDNA permissible(48)Time point
RemissionSLELack of clinical disease activity and off all SLE medication; laboratory abnormalities are acceptable as long as they do not require medications(49)Time point
RemissionSLEEULAR clinical trial endpoint = major clinical response, which may be defined as
  • low levels of disease activity measured by specific indices
  • no disease activity on < 10 mg of prednisone and/or hydroxychloroquine and/or stable immunosuppressant
(50)Time point
Complete remissionSLEEULAR Taskforce for randomized control trials (RCT):
  • ‘Major clinical response’ or ‘complete clinical response’ are preferable terms to ‘complete remission’
  • There may be low level of disease activity that are not sufficient to sufficient to increase therapy: SLEDAI ≤ 2, BILAG C scores
  • Independent of therapy
(51)Time point
Complete remissionSLETrial: Absence of BILAG A, B or C scores(52)Time point
Complete remissionSLEAbsence of clinical sign plus no laboratory abnormalities except ANA(53)Time point
Treatment-free clinical remissionSLEAbsence of clinical sign plus no laboratory abnormalities–hydroxychloroquine permissible but not prednisone(54)Time point
Serologically active clinically inactive SLESLEAsymptomatic and untreated for at least 2 years but with persistently positive laboratory abnormalities(55)Time period
RemissionSLELack of clinical disease activity for ≥ 1 year off all SLE medication; laboratory abnormalities are acceptable as long as they do not require medications(56)Time period
RemissionSLELack of clinical disease activity for ≥ 1 year off all SLE medication; laboratory abnormalities are acceptable as long as they do not require medications Clinical disease activity: all SLEDAI organ systems plus fatigue, LN, arthralgia and myalgia, chorea(57)Time period
Clinical remissionSLEMed-SLEDAI = 0 off medication for at least 1 year(58)Time period
Disease remissionSLEChange from a BILAG A or B score to a score of C or D in every organ system(59)
RemissionSLENo clinical signs of SLE off therapy for SLE for at least 1 year. Laboratory abnormalities not requiring therapy are allowed(49)Time period
Prolonged complete remissionSLEAbsence of clinical sign plus no laboratory abnormalities except ANA for > 5 years(53)Time point
Clinical remissionSLE/hemeResolution of signs on therapy (including normalization of laboratory testing) on medication(60)Time point
RemissionSLE/hemeAbsence of clinical sign plus no laboratory abnormalities except ANA(61)Time point
RemissionSLE/hemeAbsence of clinical sign plus no laboratory abnormalities(62)Time point
RemissionSLE/hemeAbsence of clinical sign plus no laboratory abnormalities(63)Time period
Long-term remissionSLE/hemeAbsence of clinical sign plus no laboratory abnormalities > 15 mo(62)Time period
RemissionLNAll of the following: inactive urine sediment, <500 mg of protein /day,nl BUN and creatinine and GFR, no immunosuppressive; while treated with prednisone < 10 mg/day and/or hydroxychloroquine(64)Time point
Complete remissionLNSerum creatinine < 1.4 plus proteinuria < 333 mg/ day(65)Time point
Complete remissionLNRCT: All renal parameters on testing with 1 month in between: normal serum creatinine and albumin, inactive sediment, 24hr-proteinuria < 500 mg(66)Time point
Complete remissionLNPlasma creatinine normal, C3 and C4 normal, negative anti-dsDNA antibodies, no proteinuria (24hr) and inactive urinary sediment(67)Time point
Partial remissionLN< 25% increase of serum creatinine from baseline and ≥ 50% reduction of daily proteinuria to 0.34 – 1.49 grams/day(65)Time point
Partial remissionLNRCT: All items on testing with 1 month in between: > 50% improvement of abnormal renal parameters.(66)Time point
Complete renal remissionLNNormal serum creatinine, serum BUN and GFR for at least 6 months, proteinuria < 0.5 gram/day urinary RBC < 5/HPF(68)Time period
Partial renal remissionLN30% improvement of serum creatinine from baseline (after a nephritis flare) but persistent active urinary sediment; 50% improvement of proteinuria (after a nephritic flare)(68)Time period
Sustained remissionLNRemission (see above) for at least 3 years(64)Time period
Long-term remissionLNNo proteinuria, on < 5 mg of prednisone every other day for 3 years(69)Time period
RemissionNPSLEComplete resolution of clinical and imaging abnormalities; no information on therapy at the time of remission(70)Time point
RemissionNPSLEAbsence of clinical sign plus no laboratory abnormalities(71)Time point

Attachment - Investigators – Consensus formation (to be mentioned in PubMed)

Adam Huber, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada;

Alan Rosenberg, Royal University Hosp., Saskatoon, Saskatchewan, Canada;

Alberto Martini, University of Genoa, Genoa, Italy;

Alejandra Pringe, Hosp. Pedro de Elizalde, Buenos Aires, Argentina;

Ali Yalcindag, Rhode Island Hosp., Providence, RI, USA;

Amita Aggarwal, SGPGI, Lucknow, India;

Anders Fasth, Göteborg University, Göteborg, Sweden;

Andrew Lasky, Children’s Mercy Hosp., Kansas City, KS, USA;

Andrew Zeft, University of Utah, Salt Lake City, UT, USA;

Ann Reed, Mayo Clinic, Rochester, MN, USA;

Anne Stevens, Seattle Children's Hosp., Seattle, WA, USA;

AnneMarie Brescia, DuPont Hosp. for Children, Wilmington, DE, USA;

Annet Van Royen, Wilhelmina Children’s Hosp., Utrecht, Netherlands;

Basil Fathalla, Detroit Medical Center, Detroit, MI, USA;

Berit Flatø, RiksHosp.et University Hosp., Oslo, Norway;

Blanca Elena Rios Gomes Bica, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;

Brigitte Bader-Meunier, Hôpital Robert Debré, Paris, France;

Carmen Laura De Cunto, Hosp. Italiano, Buenos Aires, Argentina;

Carol Wallace, Childrens Hosp. & Regional Medical Ctr, Seattle, WA, USA;

Carolina Duarte Salazar, Instituto Nacional de Rehabilitación, Mexico City, Mexico;

Cassia M. P L. Barbosa, UNIFESP, Sao Paulo, Brazil; Cecilia Coto Hermosilla, Hosp.

Pedro Borras Astorga, Habana, Cuba;

Christian Hümer, Abteilung fur Pädiatrie, Vorarlberg, Austria;

Christina Boros, University of Adelaide, Adelaide, Australia;

Claire LeBlanc, University of Alberta, Alberta, Canada;

Claudio A. Len, UNIFESP, Sao Paulo, Brazil;

Consuelo Modesto, Hosp. Vall d'Hebron, Barcelona, Spain;

Deborah McCurdy, Mattel Children, Los Angeles, CA, USA;

Daniel Kingsbury, Legacy Emanuel Children's Hosp., Portland, OR, USA;

Daniel Lovell, Children's Hosp. of Cincinnati, Cincinnati, OH, USA;

David Cabral, BC Children's Hosp., Vancouver, BC, Canada;

David Sherry, Children's Hosp. of Philadelphia, Philadelphia, PA, USA;

Deborah Rothman, Shriner’s Hosp. for Children, Springfield, MA, USA;

Delfor Alberto Giacomone, Hosp. de Niños Sor María Ludovica, La Plata, Argentina;

Diana Milojevic, The University of California, San Francisco, CA, USA;

Dorothee Stichweh, Children's Medical Center, Dallas, Texas, USA;

Dowain Wright, Children's Hosp. Central California, Madera, CA, USA;

Dolores Teresa Cantera Oceguera, Hosp.

Pedro Borras Astorga, Habana, Cuba;

Edsel Arce, Children's Hosp. Central California, Madera, CA, USA;

Elizabeth Chalom, Saint Barnabas Medical Center, Livingston, NJ, USA;

Emilia Spangenberg, Sociedad Uruguaya de Reumatología, Montevideo, Uruguay;

Esi Morgan DeWitt, Children's Hosp. of Cincinnati, Cincinnati, OH, USA;

Eyal Muscal, Baylor College of Medicine, Houston, TX, USA;

Frank Dressler, Medizinische Hochschule Hannover, Hannover, Germany;

Gaelle Chedeville, Montreal Children's Hosp., Quebec, Canada;

Gail Faller, Chris Hani Baragwanath Hosp., Johannesburg, South Africa;

Gary Sterba, Hosp. J. M. de los Rios, Caracas, Venezuela;

Gerd Horneff, Asklepios Klinik für Kinder, Sankt Augustin, Germany;

Giovany Beltrán Avendaño, Bogotá, Columbia;

Harry L Gewanter, Pediatric & Adolescent Health Cntr, Midlothian, VA, USA;

Hartmut Michels, Mengel E. Rheumatic Children's Hosp., Garmisch-Partenkirchen, Germany;

Hermann Girschick, University of Würzburg, Würzburg, Germany;

Irama Maldonado, Centro Nacional de Enfermedades Reumáticas, Caracas, Venezuela;

Ivan Foeldvari, Kinder- & Jugendrheumatologie, Hamburg, Germany;

Jaime de Inocencio, Centro de Salud Jazmín, Madrid, Spain;

Janis Dionne, BC Children's Hosp., Vancouver, BC, Canada;

Jelena Vojinovic, University of Niš, Niš, Serbia;

Jennifer Huggins, Children's Hosp. of Cincinnati, Cincinnati, OH, USA;

Jennifer Weiss, Joseph M. Sanzari Children's Hosp., Hackensack, NJ, USA;

Jenny Soep, The Children's Hosp., Aurora, CO, USA;

James N. Jarvis, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA;

Jing-Long Huang, Chang Gung Children's Hosp., Taoyuang Hsien, Taiwan;

Johannes Roth, University Hosp. Münster, Münster, Germany;

Jordi Antón, Hosp. Sant. Joan de Déu, Barcelona, Spain;

Jose Goldenberg, Hosp. Israelita, Sao Paulo, Brazil;

Joyce Hsu, Lucile Packard Children's Hosp., Palo Alto, CA, USA;

Judy Olson, Medical College of Wisconsin, Milwaukee, WI, USA;

Juliana Sato, Istituto G. Gaslini, Genoa, Italy;

Kathleen A. Haines, New York University, New York, NY, USA;

Kelly Rouster Stevens, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA;

Ken Schikler, University of Louisville, Louisville, KY, USA;

Isabelle Kone-Paut, Hôpital de Bicêtre, Le Kremlin Bicêtre, France;

L. Nandini Moorthy, Robert Wood Johnson Medical School, New Brunswick, NJ, USA;

Lawrence Jung, National Children’s Hospital, Washinton, DC, USA;

Lenore Buckley, Virginia Commonwealth University School of Medicine, Richmond, VA, USA;

Leonard H Sigal, Robert Wood Johnson Medical Grp, New Brunswick, NJ, USA;

Leslie Abramson, Vermont Children's Hosp., Burlington, VT, USA;

Linda Wagner-Weiner, University of Chicago, Chicago, IL, USA;

Liora Harel, Schneider Children's Medical Center, Petah Tikva, Israel;

Lisa Rider, National Institutes of Health, Bethesda, MD, USA;

Manuel Ferrandiz, Instituto de Salud del Niño, Lima, Peru;

Mara Becker, The Children's Mercy Hosp., Kansas City, MO, USA;

Lori Tucker, British Columbia Children’s Hospital ;

María Martha Katsicas, Hosp. de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina;

Maria Odete Esteves Hilario, Universidade Federal de São Paulo, São Paulo, Brazil;

Maria Teresa Apaz, Universidad Católica Clinica Reina Fabiola, Cordoba, Argentina;

Maria Teresa Terreri, Universidade Federal de São Paulo, São Paulo, Brazil;

Mario J. Moreno, Hurtado 202 y Machala Edificio Crespo 1er, Ceunca, Ecuador;

Mathew Adams, Children's Hosp. of Michigan, Detroit, MI, USA;

Matthew Stoll, Children's Medical Center - Dallas, Dallas, TX, USA;

Marilynn Punaro Texas Scottish Rite Hospital, Dallas, TX, USA;

Mauricio Alegria Mendoza, Colonia Médica, San Salvadore, El Salvadore;

Melissa Elder, University of Florida, Gainesville, FL, USA;

Michael Henrickson, Children's Hosp. of Cincinnati, Cincinnati, OH, USA;

Michael S. Borzy, Ohio State University, Columbus, OH, USA;

Monica Patricia Velasquez Mendez, Universidad Nacional De Colombia, Bogotá, Columbia;

Nico Wulffraat, UMC Utrecht, Utrecht, Netherlands;

Nicola Ruperto, University of Genoa, Genoa, Italy;

Norm Ilowite, Children's Hosp. at Montefiore, New York City, NY, USA;

Patricia Woo, Great Ormond Street Children Hosp., London, England;

Pavla Dolezalova, Charles University in Prague, Prague, Czech Republic;

Peter Blier, Baystate Children's Hospital, Springfield, MA, USA;

Peter Chira, Stanford University, Stanford, CN, USA;

Pilar Guarnizo, Universidad del Rosario Bogotá, Bogotá, Columbia;

Polly Ferguson, University of Iowa, Iowa City, IA, USA;

Prieur Anne-Marie, Hôpital Necker-Enfants-Malades, Paris, France;

Hans-Iko Huppertz, Hess-Kinderklinik, Bremen, Germany;

Pierre Quartier, Hôpital Necker-Enfants Malades, Paris, France;

Raju Khubchandani, Jaslok Hosp. & Research Center, Mumbai, India;

Randy Cron, University of Alabama, Birmingham, AL, USA;

Raphael Hirsch, Children’s Hosp. Pittsburgh, Pittsburgh, PA, USA;

Raúl Gutiérrez Suárez Hosp. General de México, Mexico City, Mexico;

Ricardo Russo, Hosp. de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina;

Richard Vehe, University of Minnesota, Minneapolis-Saint Paul, MN, USA;

Richard Vesely, Detska Fakultna Nemocnica, Košice, Slovakia;

Rik Joos, Jan Palfijn Ziekenhuis, Merksem, Belgium;

Rita Jerath, Medical College of Georgia, Augusta, GA, USA;

Riva Brik, Rambam Medical Center, Haifa, Israel;

Rob Nickeson, University of South Florida, Tampa, FL, USA;

Robert Sundel, Boston Children's Hosp., Boston, MA, USA;

Roberto Carreño Manjarrez, Hosp. Infantil De Mexico, Mexico City, Mexico;

Rolando Cimaz, AOU Meyer and University of Florence, Florence, Italy;

Rosario Jurado, Sanitorio Americano, Montevideo, Uruguay;

Rotraud K. Saurenmann, University Children's Hosp., Zurich, Switzerland;

Ruben Burgos-Vargas, Hosp. General de México, Mexico City, Mexico;

Ruben Cuttica, Hosp. General de Ninos Pedro de Elizalde, Buenos Aires, Argentina;

Ruth Eraso, Universidad De Antioquia, Medellín, Colombia;

Sheila Knupp Feitosa de Oliveira, Instituto de Puericultura e Pediatria Martagão Gesteira, Rio de Janeiro, Brazil;

Shirley Tse, The Hosp. for Sick Children, Toronto, Ontario, Canada;

Silvia Magni-Manzoni, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;

Silvia Meiorin, Hosp. de Niños Ricardo Gutierrez, Buenos Aires, Argentina;

Stacy Ardoin, Ohio State University, Columbus, OH, USA;

Stefan Hagelberg, Karolinska University Hosp., Stockholm, Sweden;

Stella M. Garay, Hosp. Sor Maria Ludovica, La Plata, Argentina;

Susa Benseler, The Hosp. for Sick Children, Toronto, Ontario, Canada;

Susan Nielsen, Juliane Marie Centret, RigsHosp.et, Copenhagen, Denmark;

Terry L. Moore, Saint Louis University School of Medicine, Saint Louis, MO, USA;

Thomas Griffin, Children's Hosp. of Cincinnati, Cincinnati, OH, USA;

Tim Beukelman, University of Alabama - Birmingham, Birmingham, AL, USA;

Tracy Ting, Children's Hosp. of Cincinnati, Cincinnati, OH, USA;

Witske Kuis, Wilhelmina Children’s Hosp., Utrecht, Netherlands;

Wineke Armbrust, University Medical Center Groningen, Groningen, Netherlands;

Yosef Uziel, Sapir Medical Center, Kfar Saba, Israel;

Yuki Kimura, Hackensack University Medical Center, Hackensack, NJ, USA

Footnotes

Disclosure

None

LITERATURE

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2. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. [PubMed]
3. Brunner HI, Gladman DD, Ibanez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2008;58(2):556–562. [PubMed]
4. Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr. 2008;152(4):550–556. [PubMed]
5. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore) 2006;85(3):147–156. [PubMed]
6. Ruperto N, Martini A. International research networks in pediatric rheumatology: the PRINTO perspective. Curr Opin Rheumatol. 2004;16(5):566–570. [PubMed]
7. Brunner HI, Mina R, Pilkington C, Beresford MW, Reiff A, Levy DM, et al. Preliminary criteria for global flares in childhood-onset systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2011 [PMC free article] [PubMed]
8. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63(7):929–936. [PubMed]
9. Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573–586. [PMC free article] [PubMed]
10. Singh JA, Solomon DH, Dougados M, Felson D, Hawker G, Katz P, et al. Development of classification and response criteria for rheumatic diseases. Arthritis Rheum. 2006;55(3):348–352. [PubMed]
11. Delbecq AL, Van de Ven AH, Gustafson DH. Group techniques for program planning : a guide to nominal group and Delphi processes. Glenview, Ill: Scott, Foresman; 1975.
12. Brunner HI, Mina R, Pilkington C, Beresford MW, Reiff A, Levy DM, et al. Preliminary criteria for global flares in childhood-onset systemic lupus erythematosus. Arthritis Care & Research. 2011:n/a-n/a. [PMC free article] [PubMed]
13. Lovell DJ, Passo MH, Beukelman T, Bowyer SL, Gottlieb BS, Henrickson M, et al. Measuring process of arthritis care: a proposed set of quality measures for the process of care in juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63(1):10–16. [PMC free article] [PubMed]
14. Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004;31(11):2290–2294. [PubMed]
15. Brunner HI, Feldman BM, Bombardier C, Silverman ED. Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 1999;42(7):1354–1360. [PubMed]
16. Ruperto N, Ravelli A, Oliveira S, Alessio M, Mihaylova D, Pasic S, et al. The Pediatric Rheumatology International Trials Organization/American College of Rheumatology provisional criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: prospective validation of the definition of improvement. Arthritis Rheum. 2006;55(3):355–363. [PubMed]
17. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33(1):159–174. [PubMed]
18. Galambos J, Simonelli I. Bonferroni-type inequalities with applications. New York: Springer; 1996.
19. Shtatland ES, Barton MB. SUGI’98 Proceedings; 1998; Cary: SAS Institute Inc.; 1998. An information-gain measure of fit in PROC LOGISTIC; pp. 1194–1199.
20. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36. [PubMed]
21. Brunner HI, Feldman BM, Bombardier C, Silverman ED. Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 1999;42(7):1354–1360. [PubMed]
22. Yang Y, Chung EK, Zhou B, Lhotta K, Hebert LA, Birmingham DJ, et al. The intricate role of complement component C4 in human systemic lupus erythematosus. Curr Dir Autoimmun. 2004;7:98–132. [PubMed]
23. Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet. 2007;80(6):1037–1054. [PMC free article] [PubMed]
24. Chung EK, Yang Y, Rennebohm RM, Lokki ML, Higgins GC, Jones KN, et al. Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. Am J Hum Genet. 2002;71(4):823–837. [PMC free article] [PubMed]
25. Cheung KL, Robertson FR. Objective measurement of remission and progression in metastatic breast cancer by the use of serum tumour markers. Minerva Chir. 2003;58(3):297–303. [PubMed]
26. Eyer-Silva WA, Couto-Fernandez JC, Caetano MR, Chequer-Fernandez SL, Pinto JF, Morais-De-Sa CA, et al. Remission of HIV-associated myelopathy after initiation of lopinavir in a patient with extensive previous exposure to highly active antiretroviral therapy. AIDS. 2002;16(17):2367–2369. [PubMed]
27. Boers M, Felson DT, Wells G, van Tuyl LH, Zhang B, Funovits J, et al. Progress toward the development of a new definition of remission in rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2010;68(2):140–142. [PubMed]
28. Brunner HI, Klein-Gitelman MS, Higgins GC, Lapidus SK, Levy DM, Eberhard A, et al. Toward the development of criteria for global flares in juvenile systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2010;62(6):811–820. [PMC free article] [PubMed]
29. Bruce IN. Re-evaluation of biologic therapies in systemic lupus erythematosus. Curr Opin Rheumatol. 2010;22(3):273–277. [PubMed]
30. Bertolaccini ML, Amengual O, Atsumi T, Binder WL, de Laat B, Forastiero R, et al. 'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus. 2011;20(2):191–205. [PubMed]
31. Pierangeli SS, de Groot PG, Dlott J, Favaloro E, Harris EN, Lakos G, et al. 'Criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. Lupus. 2011;20(2):182–190. [PubMed]
32. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69(1):20–28. [PubMed]
33. Urowitz MB, Feletar M, Bruce IN, Ibanez D, Gladman DD. Prolonged remission in systemic lupus erythematosus. J Rheumatol. 2005;32(8):1467–1472. [PubMed]
34. Boers M, Brooks P, Strand CV, Tugwell P. The OMERACT filter for Outcome Measures in Rheumatology. J Rheumatol. 1998;25(2):198–199. [PubMed]

References for Appendix Table

1. Smolen JS, Strand V, Cardiel M, et al. Randomized clinical trials and longitudinal observational studies in systemic lupus erythematosus: consensus on a preliminary core set of outcome domains. J Rheumatol. 1999 Feb;26(2):504–507. [PubMed]
2. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725. [PubMed]
3. Brunner HI, Gladman DD, Ibanez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2008 Feb;58(2):556–562. [PubMed]
4. Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr. 2008 Apr;152(4):550–556. [PubMed]
5. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore) 2006 May;85(3):147–156. [PubMed]
6. Ruperto N, Martini A. International research networks in pediatric rheumatology: the PRINTO perspective. Curr Opin Rheumatol. 2004 Sep;16(5):566–570. [PubMed]
7. Brunner HI, Mina R, Pilkington C, et al. Preliminary criteria for global flares in childhood-onset systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2011 May 25; [PMC free article] [PubMed]
8. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011 Jul;63(7):929–936. [PubMed]
9. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011 Mar;63(3):573–586. [PMC free article] [PubMed]
10. Singh JA, Solomon DH, Dougados M, et al. Development of classification and response criteria for rheumatic diseases. Arthritis Rheum. 2006 Jun 15;55(3):348–352. [PubMed]
11. Delbecq AL, Van de Ven AH, Gustafson DH. Group techniques for program planning : a guide to nominal group and Delphi processes. Glenview, Ill: Scott, Foresman; 1975.
12. Brunner HI, Mina R, Pilkington C, et al. Preliminary criteria for global flares in childhood-onset systemic lupus erythematosus. Arthritis Care & Research. 2011 n/a-n/a. [PMC free article] [PubMed]
13. Lovell DJ, Passo MH, Beukelman T, et al. Measuring process of arthritis care: a proposed set of quality measures for the process of care in juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011 Jan;63(1):10–16. [PMC free article] [PubMed]
14. Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004 Nov;31(11):2290–2294. [PubMed]
15. Brunner HI, Feldman BM, Bombardier C, Silverman ED. Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 1999 Jul;42(7):1354–1360. [PubMed]
16. Wais T, Fierz W, Stoll T, Villiger PM. Subclinical disease activity in systemic lupus erythematosus: immunoinflammatory markers do not normalize in clinical remission. J Rheumatol. 2003 Oct;30(10):2133–2139. [PubMed]
17. Brunner HI, Higgins GC, Wiers K, et al. Prospective validation of the provisional criteria for the evaluation of response to therapy in childhood-onset systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2010 Mar;62(3):335–344. [PMC free article] [PubMed]
18. Ruperto N, Ravelli A, Oliveira S, et al. The Pediatric Rheumatology International Trials Organization/American College of Rheumatology provisional criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: prospective validation of the definition of improvement. Arthritis Rheum. 2006 Jun 15;55(3):355–363. [PubMed]
19. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977 Mar;33(1):159–174. [PubMed]
20. Galambos J, Simonelli I. Bonferroni-type inequalities with applications. New York: Springer; 1996.
21. Shtatland ES, Barton MB. An information-gain measure of fit in PROC LOGISTIC. Paper presented at: SUGI’98 Proceedings 1998; Cary. 1998.
22. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36. [PubMed]
23. Yang Y, Chung EK, Zhou B, et al. The intricate role of complement component C4 in human systemic lupus erythematosus. Curr Dir Autoimmun. 2004;7:98–132. [PubMed]
24. Yang Y, Chung EK, Wu YL, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet. 2007 Jun;80(6):1037–1054. [PMC free article] [PubMed]
25. Chung EK, Yang Y, Rennebohm RM, et al. Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. Am J Hum Genet. 2002 Oct;71(4):823–837. [PMC free article] [PubMed]
26. Cheung KL, Robertson FR. Objective measurement of remission and progression in metastatic breast cancer by the use of serum tumour markers. Minerva Chir. 2003 Jun;58(3):297–303. [PubMed]
27. Eyer-Silva WA, Couto-Fernandez JC, Caetano MR, et al. Remission of HIV-associated myelopathy after initiation of lopinavir in a patient with extensive previous exposure to highly active antiretroviral therapy. AIDS. 2002 Nov 22;16(17):2367–2369. [PubMed]
28. Boers M, Felson DT, Wells G, et al. Progress toward the development of a new definition of remission in rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2010;68(2):140–142. [PubMed]
29. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010 Jan;69(1):20–28. [PubMed]
30. Brunner HI, Klein-Gitelman MS, Higgins GC, et al. Toward the development of criteria for global flares in juvenile systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2010 Jun;62(6):811–820. [PMC free article] [PubMed]
31. Bruce IN. Re-evaluation of biologic therapies in systemic lupus erythematosus. Curr Opin Rheumatol. 2010 May;22(3):273–277. [PubMed]
32. Bertolaccini ML, Amengual O, Atsumi T, et al. 'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus. 2011 Feb;20(2):191–205. [PubMed]
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