Open Access

Screening assays for primary haemophagocytic lymphohistiocytosis in children presenting with suspected macrophage activation syndrome

  • Mary Cruikshank1Email author,
  • Parameswaran Anoop2,
  • Olga Nikolajeva3,
  • Anupama Rao2,
  • Kanchan Rao3,
  • Kimberly Gilmour4,
  • Despina Eleftheriou1, 5, 6 and
  • Paul A Brogan1, 5
Pediatric Rheumatology201513:48

https://doi.org/10.1186/s12969-015-0043-7

Received: 7 May 2015

Accepted: 2 November 2015

Published: 16 November 2015

Abstract

Background

Primary haemophagocytic lymphohistiocytosis (HLH) screening assays are increasingly being performed in patients presenting with macrophage activation syndrome (MAS). The objective of this study was to describe their diagnostic and prognostic relevance in children who had presented to paediatric rheumatology and had undergone investigative work up for MAS.

Methods

Data was obtained retrospectively from an existing protein screening assay database and patient records. Assays included: intracellular expression of perforin in CD56+ Natural Killer (NK) cells; CD107a Granule Release Assay (GRA) in response to PHA in NK cells, or anti-CD3 stimulation of CD8 lymphocytes; in males Signal Lymphocyte Activating Molecule Associated Protein (SAP), and X-linked Inhibitor of Apoptosis Protein (XIAP) expression. All assays, requested by paediatric rheumatology, of children who had undergone investigative work up for MAS over a 5-year period (2007–2011) were included.

Results

Twenty-one patients (15 female), median age 6.5 years (range 0.6–16) with follow-up of 16 months (range 1–51), were retrospectively identified. At presentation, 3/21 (14 %) fulfilled HLH-2004 diagnostic criteria. At least one screening test result was available for all 21 patients; 7/21 (33 %) had at least one persistent screening test abnormality. Of this group 4/7 (57 %) died or required haematopoietic stem cell transplantation (HSCT), compared to 1/14 (7 %) with no screening test abnormality (p = 0.025). 3/21 (14 %) ultimately had a diagnosis of primary HLH (two confirmed genetically; XIAP, familial HLH type 3, and one confirmed clinically). Of the six patients with abnormal GRA 5/6 had negative routine genetic results.

Conclusions

Screening for primary HLH is warranted for children whose first rheumatological presentation is with MAS, since overall 14 % had an eventual diagnosis of primary HLH. A persistently abnormal GRA in patients presenting with MAS defines a high-risk group with poor outcome (mortality or HSCT), possibly due to as yet unidentified genetic cause.

Keywords

Haemophagocytic lymphohistiocytosis Macrophage activation syndrome Protein screening assays CD107a granule release assay Children

Background

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterised by excessive activation of T cells and macrophages and extreme uncontrolled inflammation driven by γ-interferon and other pro-inflammatory cytokines [1]. Traditionally HLH is classified into primary (genetic/familial) or secondary forms [2]. There is an increasing understanding of the genetic and molecular basis of many primary forms of HLH, summarised in Fig. 1 [310]. Secondary HLH may occur in patients with infections such as Epstein Barr Virus; haematological malignancies; metabolic conditions; and a range of autoimmune and other inflammatory conditions [2, 11]. When HLH is secondary to these latter rheumatological conditions, it is usually referred to as macrophage activation syndrome (MAS) [12]. This can be a severe and potentially fatal complication if not recognised early and treated aggressively.
Fig. 1

Proteins screened in relation to pathways involved in pathogenesis of primary haemophagocytic lymphohistiocytosis (HLH). Cytotoxic T lymphocytes and natural killer cells contain specialized secretory lysosomes - cytotoxic granules, which upon contact with a target-cell degranulate. These granules contain perforin, a membrane-disrupting protein that facilitates the delivery of granzymes (proteases) that initiate apoptotic death in target-cells. If perforin is deficient, it is suggestive of a diagnosis of Familial HLH type 2. To check the degranulation process, we can artificially activate NK and CTL cells in the laboratory and measure using flow cytometry, a cell surface protein, CD107a (Granule Release Assay (GRA). If abnormal, it is an indirect marker of a host of proteins which may be involved in the degranulation process - for example in trafficking, docking, priming for exocytosis, or membrane fusion. An abnormal GRA may be suggestive of a diagnosis of familial HLH 3–5 or Griscelli, Chediak-Higashi or Hermansky-Pudlak. In boys there are two X-Linked conditions, which result in protein deficiencies which can be screened for; SLAM – Associated Protein (SAP) which is important in the killing of EBV infected cells – if deficient – suggestive of X linked Lymphoproliferative Disease ((XLP) type 1, and X Linked Inhibitor of Apoptosis Protein (XIAP) which if deficient – suggestive of XLP type 2. XLP X linked lymphoproliferative disease type 1, XLP2 X linked lymphoproliferative disease type 2, FHLH familial haemophagocytic lymphohistiocytosis, CTL cytotoxic T lymphocyte, NK natural killer

In children, distinguishing between primary HLH and MAS can be challenging particularly when the first presentation of a rheumatological disorder is with MAS. Whilst the clinical features (including in some cases infectious triggers) may be identical for both primary HLH and MAS and in some instances rescue therapies the same, ultimately the treatments for these diseases differ significantly. For example, paediatric patients with primary HLH require rescue therapy with high-dose corticosteroids, ciclosporin, etoposide, and ultimately allogeneic haematopoietic stem cell transplantation (HSCT) [13]. Whilst these treatment approaches are required in a minority of patients with MAS, usually high-dose corticosteroids, ciclosporin and treatment of the underlying inflammatory disorder driving the MAS suffices [12]. Thus, distinguishing between primary HLH and MAS is of utmost clinical importance in order to instigate appropriate rescue therapy, provide prognostic information, plan for allogeneic HSCT where required, and to provide appropriate genetic counselling [14].

Currently the diagnosis of primary HLH is based on a set of clinical and laboratory parameters that have been developed and modified for use in therapeutic clinical trials [15]. This diagnosis requires either a molecular diagnosis (genetic confirmation), or 5/8 clinical criteria (Table 1) being met. However, the specificity of these criteria, particularly in differentiating primary from secondary HLH, is not well established. In addition, obtaining a confirmatory definitive molecular diagnosis may take several weeks or even months, and other genetic forms of HLH are yet to be described [16]. Hence genetic confirmation of primary HLH is of limited value to guide clinical management in the acute setting [13]. Diagnostic guidelines for MAS complicating sJIA and SLE exist [1720]. Although these guidelines may be helpful, they have some limitations [2123] including the fact that if MAS is the main first presenting feature, the patients’ rheumatological diagnosis may still be unclear.
Table 1

Haemophagocytic Lymphohistiocytosis (HLH) 2004 clinical trial B diagnostic (clinical) criteria from 21 patients who had investigative work up for macrophage activation syndrome at presentation and underwent protein-based and degranulation screening tests for primary HLH from a single United Kingdom Paediatric Rheumatology centre

 

Number of patients (%)

Number of patients with information available

HLH diagnosis: B Criteria

 Fever

19 (90)

21

 Splenomegaly

9 (47)

19

 Cytopenia (affected ≥2 of 3 lineages)

5 (24)

21

  Haemoglobin <9 g/dl

11 (52)

 

 (Infants <4 weeks: Haemoglobin <10 g/dl)

 

  Platelets <100 × 109/l

7 (33)

  Neutrophils <1 × 109/l

2 (1)

Hypertriglyceridaemia and/or hypofibrinogenaemia:

 Fasting triglycerides ≥3 mmol/l

8 (53)

15

 Fibrinogen ≤1.5 g/l

1 (0.1)

20

Haemophagocytosis in bone marrow or spleen or lymph nodes & no evidence of malignancy

7 (41)

17

Low or absent natural killer cell activity

Not tested

 

Ferritin ≥500 μg/l

14 (74)

19

aSoluble CD25 ≥2400 U/ml

4 (100)

4

aOnly four patients had soluble CD25 levels tested. All were ≥2400 U/ml based on the original description of raised levels. It is acknowledged that >2SD from the mean is thought to be more meaningful

Increased understanding of the cell cytotoxic pathways involved in the pathogenesis of primary HLH has led to the development of a number of assays which may be used to rapidly identify patients with primary HLH [24]. These include: flow cytometry–based protein screening assays that quantify perforin; SLAM-associated protein (SAP); X-linked inhibitor of apoptosis (XIAP) expression; and surface expression of CD107a, a surface lysosomal protein in cytotoxic granules used to quantify degranulation in the cytotoxic cellular pathway (Fig. 1). These screening tests have a quick return of results (within 48 h) and can therefore help guide acute management since it is generally assumed that abnormal results are due to underlying genetic cause and hence indicate primary forms of HLH [24]. However, given the overlapping clinical features of primary HLH and MAS, similar cytotoxic cellular pathways may also be involved in the pathogenesis of MAS [25]. For instance natural killer (NK) cell dysfunction is recognised in MAS complicating systemic Juvenile Idiopathic Arthritis (sJIA) [26, 27]. Reduced perforin expression has been observed in patients with sJIA [28] and perforin gene mutations and munc 13-4 polymorphisms have been linked to risk of MAS in sJIA [29, 30]. However, the performance of the aforementioned newer functional protein screening assays in the evaluation of patients with MAS has not yet been established.

We hypothesized that screening assays for primary HLH could be relevant to children with MAS either by: 1. identifying those with potential primary genetic HLH; and/or 2. defining a hitherto unrecognised subgroup of MAS with poor prognosis. The aims of this study were therefore to report the performance of these protein screening assays in a cohort of children referred to our tertiary paediatric rheumatology centre who underwent investigative work up for MAS due to suspected but as yet undetermined rheumatological cause. Specifically, we wished to study any potential association between the presence of any abnormal screening assay result, final diagnosis, and outcomes including mortality or HSCT.

Methods

Study population

This was a 5-year retrospective review of children referred to paediatric rheumatology at Great Ormond Street Hospital National Health Service Foundation Trust between 1st January 2007 (when the CD107a assay became routinely available at our institution) and December 31st 2011. We included all patients who underwent protein screening assays during this time period for the work up of MAS due to suspected but as yet undefined rheumatological cause. Patients were identified through a search of hospital based clinical and laboratory databases. Data collected included: sex, ethnicity, age at time of screening, disease duration, length of follow up, presenting clinical features, and the frequency of HLH 2004 clinical diagnostic criteria parameters at time of screening. Outcomes included final diagnosis, mortality or HSCT. All blood samples were collected during the acute presentation with active disease. Local research and development approval was obtained for retrospective case review (reference 12RUO1), and exemption from ethics approval, under the Governance Arrangements for Research Ethics Committee 2011, was granted.

Screening assays

Standard operating procedures for the granule release assay and detection of perforin, XIAP and SAP are included as a supplement [Additional file 1]. Cells were permeabilised and stained as per Bryceson et al. [31]. In brief whole blood samples (5–10 mL) were collected in EDTA-containing vials. One healthy control sample was processed in parallel to each patient sample.

For the granule release assay, peripheral blood mononuclear cells were separated from whole blood and stimulated overnight with IL-2. The cells were then stimulated with PHA or anti-CD3 antibody in the presence of FITC anti-CD107a antibody for 2 h, then stained with cell surface markers and analysed by flow cytometry. An abnormal GRA result is when the increase in %CD107a between stimulated and unstimulated samples was <1.5 % for cytotoxic T cells after anti CD3 stimulation and/or <15 % for NK cells after PHA stimulation [32].

Whole blood intracellular FACs for SAP, XIAP and perforin was performed by flow cytometry. Perforin is abnormal if <50 % expression and/or fails to have the brightest cells reach Mean Fluorescein Intensity of 103. SAP and XIAP are abnormal if <50 % of cells express SAP/XIAP.

Genetic analyses

Sanger sequencing of exons and exon/intron boundaries was undertaken on all patients with abnormal protein expression or degranulation. Primers and sequencing conditions are available on request.

Statistical analyses

Fisher Exact Test was used to compare the outcome between patient groups categorised based on the presence of an abnormal functional assay test. Continuous variables were presented as median and range, and categorical data as percentages and proportions. SPSS version 18 was used for statistical analysis. P values of <0.05 were considered significant.

Results

Patient demographics

Twenty-one patients (15 female) underwent screening tests. Ethnicity included white British (11), Asian/Asian British (3), black African/black British (4), Arab (1), white other (2). Median age at time of screening was 6.5 years (range 0.6–16.0) and median disease duration of 67 days (range 24 days– 6 years). One patient (an outlier) who had disease duration of 6 years was managed at another hospital prior to having been referred to the paediatric rheumatology service. Median follow-up was 16 months (range 1–51 months).

Clinical features and laboratory tests

Of the results available, only 3/21 (14 %) fulfilled a minimum of 5/8 of the HLH -2004 (B) diagnostic clinical criteria (Table 1). At presentation 19/21 (90 %) had fever; 12/20 (60 %) had hepatomegaly; 11/21 (52 %) had arthritis; 9/19 (47 %) had splenomegaly; and 6/20 (30 %) had evidence of central nervous system involvement (defined as irritability, disorientation, headache, seizure or coma). The median ferritin was 2531 (range 38–22076) μg/l; median ESR 23 (range 3–160) mm/h; and median CRP 39 (range <5–187) mg/l. Table 2 summarises the clinical and laboratory features for the patients with abnormal screening results. Summary data set for each patient is available [Additional file 2].
Table 2

Clinical and laboratory features of 7 patients referred with suspected macrophage activation syndrome who had abnormal screening results (GRA and XIAP)

Patient

3

4

5

6

7

8

18

Sex

f

f

f

m

f

f

m

HLH 2004 B clinical criteria

 Fever

yes

yes

yes

yes

no

yes

yes

 Splenomegaly

yes

/

yes

no

no

no

yes

 Cytopenia at least 2/3

yes

no

yes

yes

yes

no

yes

  Hb <90

yes

yes

yes

yes

yes

yes

no

  Plt <100

no

no

yes

yes

yes

no

yes

  Neut <1

yes

no

no

no

no

no

yes

 Hypertriglyceridemia &/or hypofibrinogen

yes

yes

/

no

/

yes

/

  Triglycerides >265

yes

yes

/

no

/

yes

/

  Fibrinogen <1.5

no

no

no

no

no

no

no

 Haemophagocytosis in bone marrow, spleen or lymph nodes

no

no

/

no

yes

yes

/

 Low or absent NK cell activity

/

/

/

/

/

/

/

 Ferritin >500 ng/ml

yes

yes

yes

yes

yes

yes

no

 Soluble CD25 >2400units/ml

yes

/

/

/

/

/

/

 Number of HLH B clinical (2004)

6

3

4

3

3

4

3

 Ferritin ng/ml

21065

1679

523

6759

2801

22076

38

 ALT IU/L

17

17

12

453

6

354

102

 Arthritis

yes

no

no

yes

yes

yes

yes

 ESR mm/h

100

10

78

20

18

120

6

 CRP mg/L

48

74

60

/

51

87

6

Screening tests

 GRA

abnormal

abnormal

abnormal

abnormal

abnormal

abnormal

normal

 SAP

/

/

/

normal

/

/

normal

 XIAP

/

/

/

normal

/

/

absent

 PERFORIN

normal

normal

normal

normal

/

normal

normal

 Genetics sent

yes

yes

yes

yes

yes

yes

yes

 Genetics

no mutation found

c.2335G>A/wt and possible deletion/splicing defect

no mutation found

no mutation found

no mutation found

no mutation found

c.1082C>G (p.Ser361X)

 Diagnosis

sJIA

primary HLH (FHLH type 3)

primary HLH

overlap syndrome (JDM//SLE/sJIA)

SJIA

SJIA

primary HLH (XLP2)

 HSCT

no

no

no

no

yes

no

yes

 Survival

alive

deceased

deceased

alive

alive

alive

alive

/= not done/no data available

HLH haemophagocytic lymphohistiocytosis, Hb haemoglobin, Plt platelets, Neut neutrophils, NK natural killer, AST aspartate aminotransferase, WCC white cell count, CNS central nervous system, SoJIA systemic onset juvenile idiopathic arthritis, ALT alanine transaminase, ESR erythrocyte sedimentation rate, CRP C reactive protein, GRA granule release assay, SAP SLAM associated protein, XIAP X linked inhibitor of apoptosis protein, HSCT haematopoietic stem cell transplantation, JDM juvenile dermatomyositis, SLE systemic lupus erythematosus, XLP2 X linked lymphoproliferative syndrome type 2

Protein and degranulation assay results

At least one screening test result was available for all 21 patients. Nineteen patients had the CD107a GRA performed; for two patients the assays were technically inadequate to interpret. A total of 6/17 (35 %) had a persistently abnormal GRA. A persistently abnormal GRA was defined as a minimum of two abnormal GRA, as per routine clinical practice). The median time between first and second abnormal GRA was 27.5 days (range 4 – 276 days). One boy had absent XIAP expression. Nineteen patients had perforin screened, and five male patients were screened for SAP expression; all had normal perforin and SAP results respectively.

Final diagnoses

All seven patients with abnormal screening assays (six with abnormal GRA, and one with absent expression of XIAP) went on to have genetic testing for known mutations associated with primary HLH. One patient with absent expression of XIAP had subsequent genetic confirmation of XLP type 2 (c.1082C>G (p.Ser361X)). Only 1/6 patients with an abnormal GRA had positive genetics (heterozygous UNC13 mutation as well as a second heterozygous sequence variant, suggesting the diagnosis of Familial HLH type 3); the remaining 5/6 patients with abnormal GRA had no identifiable mutations in munc or syntaxin genes. Their final diagnoses were: sJIA with MAS (n = 3); primary HLH but without genetic confirmation (n = 1); and overlap syndrome with features of juvenile dermatomyositis, systemic lupus erythematosus and sJIA (n = 1). The final diagnoses of the 11/17 patients with normal GRA screening test abnormality are provided in Table 3.
Table 3

Outcome - mortality or haematopoietic stem cell transplantation (HSCT) in relation to presence of protein based and degranulation screening abnormalities in 21 patients with referred with suspected macrophage activation syndrome

 

Mortality or HSCT

Alive and no HSCT

Total

P value

Abnormal screening test

4

3

7

 

 CD107a GRA (persistently abnormal)

Primary HLH n = 2 (1 UNC13D variant)

sJIA n = 2

sJIA n = 1

Overlap syndrome (JDM/SLE/sJIA) n = 1

 Absent XIAP

Primary HLH (XLP2) n = 1

n = 0

Normal screening test

1

13

14

0.0253

 Normal:

 

sJIA n = 4

  

 CD107a GRA

sJIA n = 1

SLE n = 1

 Perforin

Streptococcal infection n = 1

 XIAP

Pancreatitis and SIRS n = 1

 SAP

Unclassified immunodeficiency n = 1

Langerhans Cell Histiocytosis n = 1

No clear diagnosis n = 4

Final diagnoses listed. Children with abnormal screening test results were more likely to die or undergo HSCT. p <0.05 by Fisher Exact Test was considered significant

HLH haemophagocytic lymphohistiocytosis, GRA granule release assay, sJIA systemic juvenile idiopathic arthritis, JDM juvenile dermatomyositis, SLE systemic lupus erythematosus, XIAP X linked inhibitor of apoptosis protein, XLP2 X linked lymphoproliferative syndrome type 2, SAP SLAM associated protein, SIRS systemic inflammatory response syndrome

Outcomes

Of the group of children with any persistent screening test (GRA and XIAP) abnormality, 4/7 (57 %) either died (2/7), or required HSCT (2/7), compared to 7 % with no screening abnormality (none died, and 1/14 underwent HSCT); p = 0.025; Table 3. When data was analysed specifically comparing outcome between abnormal and normal GRA it was not found to be statistically significant.

Discussion

In this study we report the use of protein-based and degranulation screening assays for primary HLH in a cohort of children referred to our tertiary paediatric rheumatology centre with MAS due to suspected but as yet undetermined rheumatological cause. We established that these functional tests can direct genetic analyses and may allow a rapid and reliable classification of patients, and are important prognostically. The presence of persistently abnormal screening tests, defined a high risk group with poor outcome (mortality or HSCT in 4/7 cases, 57 %). Although our data did not show a statistical difference in outcome for patients when the data was specifically analysed comparing those who had abnormal and normal GRA tests, our numbers are small and it is important still to highlight that 3/6 patients (50 %) who had an abnormal GRA either died or required HSCT. Overall 3/21 (14 %) of our patients who had protein-based and degranulation screening tests were diagnosed with primary HLH (two confirmed genetically, one clinical diagnosis); novel molecular defects may be implicated in the pathogenesis of HLH in the remaining cases with abnormal GRA but negative routine genetic results. To date, stratification of the mortality risk and/or the need for urgent consideration of HSCT in patients presenting with MAS has not been possible. Our findings, albeit preliminary and retrospective, suggest for the first time that a persistently abnormal CD107a degranulation screening assay may identify patients presenting with MAS with poorer outcomes. Further prospective multicentre studies are now needed to validate this observation.

Our study focused on children in whom MAS was the presenting feature and the remaining clinical manifestations were initially atypical for an established underlying inflammatory disease. As primary HLH and MAS overlap clinically, we suggest that rapid screening for primary HLH in these patients is warranted; however, clinicians could consider these investigations for children with MAS even with an established underlying rheumatological disorder, particularly for those cases not responding to high-dose corticosteroids and ciclosporin. Abnormal screening test findings could also define a high risk group in that context, and this remains an area worthy of future study.

Notably, three patients with sJIA and one patient with overlap syndrome (with features of juvenile dermatomyositis, systemic lupus erythematosus and sJIA) had a persistently abnormal CD107a test with negative genetic tests (Table 3), suggesting that this assay is not entirely specific for primary forms of HLH, and that this pathway could be involved in the pathogenesis of MAS in some patients. A recent study using whole-exome sequencing in patients with systemic JIA and MAS identified rare protein-altering variants in known HLH-associated genes as well as in new candidate genes [33]. This may be of relevance for our cohort. Importantly, we have not yet examined the effect of immunosuppressive treatment on this assay on this cohort of patients. However, in patients with primary HLH treated with HLH-94 and HLH-2004 treatment protocols, immunosuppressive therapy does not significantly affect the degranulation assay result [31]. Previous studies have suggested temporary defects of NK cell perforin expression in children with active sJIA that normalises with successful treatment [16]. However, in our cohort of patients, perforin expression was normal.

Our study is limited by all the confounding factors associated with any retrospective case series, and we acknowledge the small size and heterogeneity of this cohort. In addition, there is a possibility that referral bias resulted in us receiving the most severe cases of secondary HLH/MAS. It is noted that perforin and SAP assays were all normal in this cohort. Given the small cohort size and rarity of primary HLH conditions it would be incorrect to conclude from these findings that they are not clinically helpful. As previously mentioned, the longitudinal effect of immunosuppressive treatment was not assessed, and requires further investigation.

Conclusions

This study provides support that screening for primary HLH is warranted for children whose first rheumatological presentation is with MAS, since overall 14 % had an eventual diagnosis of primary HLH. A persistently abnormal GRA in patients presenting with MAS defines a high-risk group with poor outcome (mortality or HSCT), possibly due to as yet unidentified genetic cause. Protein-based and degranulation screening assays may therefore facilitate rapid identification of high risk groups of patients referred to paediatric rheumatology with MAS; we suggest these tests may be able to help the clinician in those first few days to reach a diagnosis of either primary HLH or MAS, and therefore may be able to guide treatment decisions and improve prognosis for this potentially fatal complication.

Abbreviations

GRA: 

granule release assay

HLH: 

haemophagocytic lymphohistiocytosis

HSCT: 

haematopoietic stem cell transplantation

JIA: 

juvenile idiopathic arthritis

MAS: 

macrophage activation syndrome

NK: 

natural killer

SAP: 

signal lymphocyte activating molecule associated protein

sJIA: 

systemic juvenile idiopathic arthritis

XIAP: 

X-linked inhibitor of apoptosis protein

Declarations

Acknowledgments

We acknowledge the assistance of the Great Ormond Street Hospital Immunology Laboratory, North East Thames regional genetics service and particularly Maurizio Aricò, Coordinatore Rete Regionale Oncoematologia Pediatrica Istituto Toscano Tumori, Pieraccini, Firenz, Italy, for their help in undertaking the protein and genetic analysis in these patients.

This research has been supported by the National Institute for Health Research, Great Ormond Street Hospital University College London Biomedical Research Centre award.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Departments of Rheumatology, Great Ormond Street Hospital NHS Foundation Trust
(2)
Departments of Haematology, Great Ormond Street Hospital NHS Foundation Trust
(3)
Departments of Bone Marrow Transplantation, Great Ormond Street Hospital NHS Foundation Trust
(4)
Departments of Immunology, Great Ormond Street Hospital NHS Foundation Trust
(5)
Institute of Child Health, University College London
(6)
Arthritis Research UK Centre for Adolescent Rheumatology

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© Cruikshank et al. 2015

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