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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

The UK Juvenile-Onset Systemic Lupus Erythematosus (JSLE) Cohort Study is a multicenter collaborative network established with the aim of improving the understanding of juvenile SLE. The present study was undertaken to describe the clinical manifestations and disease course in patients with juvenile SLE from this large, national inception cohort.

Methods

Detailed data on clinical phenotype were collected at baseline and at regular clinic reviews and annual followup assessments in 232 patients from 14 centers across the UK over 4.5 years. Patients with SLE were identified according to the American College of Rheumatology (ACR) SLE classification criteria. The present cohort comprised children with juvenile SLE (n = 198) whose diagnosis fulfilled ≥4 of the ACR criteria for SLE.

Results

Among patients with juvenile SLE, the female:male sex distribution was 5.6:1 and the median age at diagnosis was 12.6 years (interquartile range 10.4–14.5 years). Male patients were younger than female patients (P < 0.01). Standardized ethnicity data demonstrated a greater risk of juvenile SLE in non-Caucasian UK patients (P < 0.05). Scores on the pediatric adaptation of the 2004 British Isles Lupus Assessment Group disease activity index demonstrated significantly increased frequencies of musculoskeletal (82%), renal (80%), hematologic (91%), immunologic (54%), and neurologic (26%) involvement among the patients over time. A large proportion of the patients (93%) were taking steroids and 24% of the patients required treatment with cyclophosphamide. Disease damage was common, with 28% of the patients having a Systemic Lupus International Collaborating Clinics/ACR damage score of ≥1.

Conclusion

The data on these patients from the UK JSLE Cohort Study, comprising one of the largest national inception cohorts of patients with juvenile SLE to date, indicate that severe organ involvement and significant disease activity are primary characteristics in children with juvenile SLE. In addition, accumulation of disease-associated damage could be seen.

Juvenile-onset systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease characterized by autoantibodies directed against nuclear antigens. Up to 20% of all patients with SLE experience disease onset prior to adulthood (1). The annual incidence of juvenile SLE is estimated to be 0.36–0.9 per 100,000 children per year, and is generally higher in non-Caucasian children, especially black, Hispanic, and Asian populations (2–9).

Over recent decades, survival of patients with juvenile SLE has improved considerably, with 10-year survival rates now being ∼90% (10, 11). Despite these advances, patients with juvenile SLE have a significantly lower life expectancy than the general population, with a 4-fold greater risk of death. Moreover, mortality rates are higher in patients with juvenile SLE than in patients with adult-onset SLE, and the mortality risk increases with longer disease duration (12, 13).

The American College of Rheumatology (ACR) has provided a revised set of 11 criteria for classification of the symptoms and signs of adult-onset SLE. Of these criteria, at least 4 are required to be present for diagnosis, although not necessarily simultaneously (14, 15). These same criteria are generally used for diagnostic purposes in both adult-onset and juvenile-onset SLE (16). However, significant differences in the disease onset and course have been described between adult-onset SLE and juvenile-onset SLE (1, 17–19).

The UK Juvenile-Onset SLE (JSLE) Study Group (for details, see http://www.liv.ac.uk/ukjsle) is a multidisciplinary, multicenter collaborative network established in 2006 with the primary aim of determining the clinical characteristics of patients with juvenile SLE in the UK, as well as supporting a program of clinical translational research. Through the data repository of the UK JSLE Cohort Study, the Study Group collects detailed clinical data on a regular basis, using a biobank containing linked blood samples from children and young people with lupus across the UK. It includes detailed data on demographics, ACR criteria for the classification of SLE, disease activity, medication use, and disease damage indices. The JSLE Cohort Study is run from a national coordinating center in Liverpool, and participating institutions include all pediatric rheumatology and nephrology centers in the UK.

The aim of the present study was to describe, for the first time, the clinical manifestations and disease course of juvenile SLE in patients from the UK JSLE Cohort Study, using detailed data collected over 5 years from across the UK.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All pediatric rheumatology and nephrology centers across the UK were invited to participate in the UK JSLE Cohort Study. Parental consent/patient consent or assent to take part in the study was obtained from all families. The JSLE Cohort Study received appropriate ethics approval, and was supported through its adoption onto the UK Clinical Research Network Study Portfolio (for details, see http://public.ukcrn.org.uk/search/).

All patients with onset of symptoms prior to the age of 17 years and who had received a clinician's diagnosis of juvenile SLE were eligible to be recruited to the JSLE Cohort Study. In addition to compiling data on disease activity, severity, and damage, the aim of the JSLE Cohort Study was to capture the potential development/evolution of lupus over time. For the purposes of the present study, only those patients fulfilling ≥4 of the ACR classification criteria for SLE at the time of data analysis were included (14, 15).

A priori data reviews were used to collect comprehensive data on the clinical phenotype of each patient. At baseline (time of diagnosis), detailed demographic data, including sex and date of birth, as well as the date of symptom onset, date of diagnosis of lupus, family history of lupus and/or other autoimmune disorder, and ethnicity were collected. Patient's ethnicity was defined according to the UK National Census categorizations (20). In addition, features meeting the ACR SLE classification criteria (as well as duration of each feature) were recorded. The British Isles Lupus Assessment Group (BILAG) disease activity index, previously validated in a UK pediatric cohort (21), was adapted to include parameters relevant to childhood; for example, hypertension was interpreted using the 95th percentile of blood pressure according to age, sex, and height of the child. We used the pediatric adaptation of the 2004 update of the BILAG index, hereafter referred to as the pBILAG-2004 (22). Details on use of medications, parent's and physician's global assessments of disease activity, and standard biomarkers of disease activity were also collected. For the purposes of this report, use of medications was defined as a patient ever having received such therapy during the study period.

At every clinic review (i.e., every 3 months or as appropriate, such as at the time of a flare), information on disease activity according to the organ-based domains of the pBILAG-2004 index was collected. At the annual assessment (i.e., the clinic visit nearest to the patient's birthday), all patients were reviewed for the presence of the ACR criteria for SLE, and the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (23) was determined using patient-reported data on annual assessment forms. Prospective data collection took place at 66% of the visits, while retrospective case record review was undertaken to complete missing data sets. All data were submitted anonymously to the coordinating center and stored electronically.

The database was programmed to calculate pBILAG-2004 disease activity scores. For each encounter, a 5-tiered alphabetical score (A–E) was assigned within each organ-based BILAG domain, in accordance with the definitions of lupus disease activity previously described in the BILAG-2004 index for patients with adult-onset SLE (24). Briefly, scores were assigned as follows: A = severe disease activity (i.e., requiring urgent change in corticosteroid and/or disease-modifying immunosuppressant therapy); B = moderate disease activity (i.e., demanding close attention, often with symptomatic therapy, such as low-dose corticosteroids or hydroxychloroquine); C = stable disease activity present in the organ, but not requiring treatment alterations; D = inactive disease, but previous organ involvement; and E = no organ involvement ever. Numerical scoring was then applied to each domain (score A = 9, score B = 3, score C = 1, score D/E = 0) (25) to produce an overall pBILAG-2004 score according to the original BILAG scoring system (based on previous use in the pediatric age group [21,26]). The database was also programmed to calculate SLE Disease Activity Index (SLEDAI) scores (27).

Data are expressed as the median with interquartile range (IQR). For statistical analyses, we utilized the Mann-Whitney U test of significance, unless otherwise stated. Results were analyzed using SPSS version 18.0 software. P values less than 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Patients.

The UK JSLE Cohort Study commenced recruitment in August 2006. Data analysis took place on February 28, 2011, representing 4.5 years of data on the recruited patients. Of the 276 patients recruited, 232 (84%), from 14 of the 16 invited centers from across the UK, had complete baseline data and at least one pBILAG-2004 disease activity score at the time of analysis. The present study cohort of patients with juvenile SLE, who fulfilled ≥4 of the ACR SLE criteria, consisted of 198 (85%) of the 232 patients for whom there were sufficient data at the time of analysis. The remaining 34 patients (15%) had a clinician's diagnosis of juvenile SLE but met only 2 or 3 (but not 4 or more) of the ACR criteria, and therefore these patients were excluded for the purposes of this study.

Demographic data.

Of the 198 patients with juvenile SLE, 168 (85%) were female, with a female-to-male ratio of 5.6:1; among the 41 patients (21%) who were diagnosed at age ≤10 years, the female-to-male ratio was 2.7:1. The median age at diagnosis was 12.6 years (range 1.8–17.9 years, IQR 10.4–14.5 years). The median time from the onset of symptoms to diagnosis was 3.2 months (IQR 1.7–9.6 months), and all patients had symptom onset prior to age 17 years. The median time from diagnosis to data collection was 4.5 years (IQR 2.7–6.9 years). At presentation, the median number of ACR criteria fulfilled was 4 (IQR 4–5), and at the latest (last to date) analysis, the median number of ACR criteria present was 5 (IQR 4–6.5).

Male patients with juvenile SLE were statistically significantly younger (median age 11.1 years [IQR 7.3–13.1 years] at presentation and 15.4 years [IQR 12.4–18.7 years] at the time of analysis) when compared to female patients (median age 12.8 years [IQR 10.9–14.7 years] at presentation and 17.6 years [IQR 15.1–19.7 years] at the time of analysis) (each P < 0.01). Male patients were more likely to have a discoid rash (8 of 30 male patients versus 16 of 168 female patients; P < 0.01) but less likely to have had arthritis (16 of 30 male patients versus 109 of 168 female patients; P < 0.05). No other significant differences in the ACR criteria present were noted between male and female patients.

Caucasian patients made up the majority of the juvenile SLE cohort (103 [52%] of 198 patients) (Table 1). Using ethnicity data from the UK 2001 Census (20), the standardized incidence of juvenile SLE was calculated per 100,000 persons in each UK ethnic population. This demonstrated a marked effect on the proportion of patients with juvenile SLE in the respective UK ethnic minority groups, with standardized incidence rates showing a significantly greater incidence of juvenile SLE in UK non-Caucasian patients compared to the UK Caucasian population (P < 0.05) (Table 1). The incidence of juvenile SLE (expressed per 100,000 persons per UK ethnic group) was highest in UK patients of black African or Asian ethnic origin. Although the differences were not statistically significant, non-Caucasian patients tended to be younger at diagnosis (median age 12.2 years, IQR 10.4–13.7 years) compared to Caucasian patients (median age 13.3 years, IQR 10.9–15.0 years; P = 0.05). There was a notable tendency toward an increased incidence of nephritis at presentation in patients of Chinese, black African, or mixed ethnicity, although this was not statistically significant. No other significant differences in any of the other ACR criteria were noted between Caucasian and non-Caucasian patients.

Table 1. Ethnic distribution of the patients in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort Study (n = 198), and standardized disease incidence rates based on UK 2001 Census data for each ethnic group
Ethnic groupNo. (%) of patientsStandardized incidence per 100,000 persons per UK ethnic population
Caucasian103 (52)0.1
Chinese4 (2)0.8
Bangladeshi5 (2.5)0.9
Black Caribbean8 (4)0.7
Indian18 (9)0.9
Black “other”2 (1)1
Pakistani12 (6)0.8
Mixed race15 (8)1.1
Black African19 (10)2
Asian “other”12 (6)2.5
Not stated0 (0)

Seventy-six patients with juvenile SLE (38%) had a family history of ≥1 autoimmune disease. The autoimmune diseases observed in relatives of patients with juvenile SLE were as follows: lupus in 29 family members (15%), rheumatoid arthritis in 31 family members (16%), thyroid disease in 25 family members (13%), insulin-dependent diabetes mellitus in 14 family members (7%), and a family history of another connective tissue disease in 5 family members (3%).

Organ involvement.

Organ involvement in patients with juvenile SLE was assessed according to the presence of the ACR classification criteria for SLE at the latest date (time of analysis, as shown in Figure 1). The most common ACR criteria among the patients with juvenile SLE were immunologic features, hematologic features, nonerosive arthritis, and malar rash. In addition, 98% of the patients were positive for antinuclear antibodies. The ACR hematologic criterion, met by 144 (73%) of the 198 patients with juvenile SLE, was examined in further detail. Hematologic features included lymphopenia in 144 patients (73%), leukopenia in 63 patients (32%), hemolytic anemia in 54 patients (27%), and thrombocytopenia in 39 patients (20%). The ACR immunologic criterion was met by 167 patients (84%), and included the presence of anti–double-stranded DNA antibodies in 137 patients (69%), anti-Sm antibodies in 43 patients (22%), and antiphospholipid antibodies (either levels of anticardiolipin antibodies above the normal laboratory range or positivity for lupus anticoagulant) in 71 patients (36%).

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Figure 1. Number and percentage of patients in the juvenile systemic lupus erythematosus (SLE) cohort meeting the American College of Rheumatology (ACR) classification criteria for SLE at the time of latest analysis. ANA = antinuclear antibodies.

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In addition to the ACR criteria, organ involvement was characterized using scores on each of the pBILAG-2004 organ domains. The first (baseline) and latest (last to date) pBILAG-2004 scores were used to describe the progressive change/onset of organ involvement in each individual patient over the study period. For the juvenile SLE cohort, 176 patients had a followup pBILAG-2004 score by the time of data analysis. Figure 2 presents the distribution of organ involvement as identified by the alphabetical scores on the pBILAG-2004 index from the baseline and latest assessments.

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Figure 2. Number and percentage of patients (among 176 patients with sufficient data) in the juvenile systemic lupus erythematosus (SLE) cohort with organ involvement at the baseline (first) and followup (last) assessments, according to scores for each organ-based domain in the pediatric adaptation of the 2004 British Isles Lupus Assessment Group (BILAG) disease activity index. Scores were assigned alphabetically as A, B, C, D, or E, where score A = severe disease activity (i.e., requiring urgent change in corticosteroid and/or disease-modifying immunosuppressant therapy), score B = moderate disease activity (i.e., demanding close attention, often with symptomatic therapy, such as low-dose corticosteroids or hydroxychloroquine), score C = stable disease activity present in the organ, but not requiring treatment alterations, score D = inactive disease, but previous organ involvement, and score E = no organ involvement ever.

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The results of this analysis among the patients with juvenile SLE showed that, for example, 47% of the patients (83 of 176) had evidence of renal involvement at presentation (defined as a pBILAG-2004 score ranging from A to D in the renal domain), which progressed to 80% of the patients showing renal involvement (141 of 176) at the time of latest analysis. Of note, this degree of renal involvement, indicated by a pBILAG-2004 score of A–D, demonstrated markedly greater actual organ involvement than was indicated by the frequency of patients meeting the relevant ACR criterion (i.e., presence of nephritis in only 36% of the patients with juvenile SLE at the latest analysis). This trend of greater organ involvement demonstrated by the pBILAG-2004 disease activity index when compared to that predicted by the ACR criteria was similarly seen for other organ systems, including the neurologic system, in which the latest pBILAG-2004 score for neurologic manifestations showed involvement in 26% of patients, as compared to only 10% of patients meeting the ACR criterion of neurologic involvement at the latest assessment.

Disease activity.

Disease activity assessed using the pBILAG-2004 index was compared between the baseline visit and the visit at 12 months (range 10–14 months) after presentation, to determine change in disease activity over time. Among the 198 patients with juvenile SLE, 110 (56%) had a followup pBILAG-2004 score within the appropriate time interval up to the time of analysis. The median baseline pBILAG-2004 score in these patients was 8.5 (range 0–53, IQR 4–16.3), and at followup 12 months later, the median pBILAG-2004 score was 2 (range 0–16, IQR 1–4). This indicated that there was a statistically significant improvement (P < 0.01, by Wilcoxon's signed rank test) in disease activity over the defined period. When disease activity was measured using the SLEDAI, a statistically significant change in the SLEDAI score from first review to 12 months of followup was also seen in the patients (median SLEDAI score 12 [range 0–32, IQR 6.8–21] at baseline versus median SLEDAI score 4 [range 0–24, IQR 2–10] at followup; P < 0.01).

Medication usage.

Use of disease-modifying antirheumatic drugs or biologic drugs at any time during followup was determined (Figure 3). Among the 198 patients in the juvenile SLE cohort, 189 (95%) were currently receiving, or had received, hydroxychloroquine at some point, 184 (93%) had received oral prednisolone, 95 (48%) had received intravenous methylprednisolone, 92 (46%) had received mycophenolate mofetil, 91 (46%) had received azathioprine, 47 (24%) had received intravenous cyclophosphamide, 45 (23%) had received methotrexate, 26 (13%) had received rituximab, 5 (3%) had received cyclosporine, and 2 (1%) had received infliximab. Other medications for which use was reported at any time during the followup included the following: an angiotensin-converting enzyme inhibitor in 48 patients (24%), angiotensin receptor blocker in 24 patients (12%), aspirin in 41 patients (21%), a calcium channel blocker in 37 patients (19%), diuretics in 28 patients (14%), intravenous immunoglobulins in 12 patients (6%), warfarin in 4 patients (2%), thyroxine in 3 patients (2%), bisphosphonates in 3 patients (2%), and current or previous use of statin medication in 3 patients (2%).

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Figure 3. Use of corticosteroids and immunomodulatory medication among patients in the juvenile-onset systemic lupus erythematosus cohort at any time over the course of the study. IV Methylpred = intravenous methylprednisolone; MMF = mycophenolate mofetil; AZA = azathioprine.

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Table 2 summarizes the key demographic and clinical features of the patients in the juvenile SLE cohort. The data demonstrated a predominance of female patients, significant family history of autoimmune disease, significant changes in the pBILAG-2004 disease activity score, and a significant accumulation of disease damage according to the SLICC/ACR Damage Index over the 4.5 years of followup.

Table 2. Key clinical characteristics of the patients in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort Study (n = 198)*
  • *

    Except where indicated otherwise, values are the number (%) of patients. SLE = systemic lupus erythematosus; ACR = American College of Rheumatology; anti-dsDNA = anti–double-stranded DNA; pBILAG-2004 = pediatric adaptation of the 2004 British Isles Lupus Assessment Group disease activity index; SLEDAI = SLE Disease Activity Index; SLICC = Systemic Lupus International Collaborating Clinics.

Sex 
 Female168 (85)
 Female:male ratio5.6:1
Mean age, years 
 At diagnosis12.6
 At data analysis17.4
Caucasian103 (52)
Family history 
 Autoimmune disease76 (38)
 SLE29 (15)
Mean no. of ACR criteria present at latest analysis5
Anti-dsDNA positive137 (69)
pBILAG-2004 index, median score 
 At presentation8.5
 At 12 months2
SLEDAI, median score 
 At presentation12
 At 12 months4
Medication use 
 Corticosteroids184 (93)
 Antimalarials189 (95)
SLICC/ACR Damage Index 
 Median (range) score0 (0–5)
 Patients with score ≥156 (28)
Mean duration of followup, years4.5

Disease damage.

The damage accrued secondary to juvenile SLE was quantified annually in the patients using SLICC/ACR Damage Index assessment forms. Table 3 presents the damage accrued, by organ system and by subcategories of damage symptoms. Among the juvenile SLE cohort, a total of 56 patients (28%) had disease-associated damage at the time of data analysis, with a total sum of 95 SLICC/ACR Damage Index criteria met and a SLICC/ACR damage score range of 0–5. Even within the short followup period (median 4.5 years, IQR 2.7–6.9 years), notable organ damage had already accrued in the juvenile SLE cohort. There was a predominance of neurologic damage, with 15 patients (8%) showing neurologic manifestations, of whom 6 (3%) had experienced at least 1 cerebrovascular accident. Severe scarring alopecia was recorded in 20 patients (10%), and 7 patients (4%) had renal damage, mainly consisting of persistent heavy proteinuria, but also established renal failure in 1 child.

Table 3. Organ damage accrued, as identified by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index, in patients in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort Study*
Organ system involved, subcategory symptomNo. (%) of patients with SLICC/ACR organ damage
  • *

    Data are based on the 56 patients with juvenile-onset systemic lupus erythematosus who had a SLICC/ACR damage score of ≥1, indicating notable disease-related damage, over the study period. The number of patients shown in each of the organ categories is independent of each other category, as some of the 56 patients experienced damage in more than one organ category. Within each organ-specific category, a patient may have more than one subcategory symptom. eGFR = estimated glomerular filtration rate.

Ophthalmic5 (3)
 Ocular cataract4 (2)
 Retinal change1 (0.5)
Neurologic15 (8)
 Cognitive impairment/psychosis5 (2.5)
 Seizures >6 months4 (2)
 Cerebrovascular accident6 (3)
 Cranial/peripheral neuropathy3 (1.5)
 Transverse myelitis1 (0.5)
Renal7 (4)
 Reduced eGFR <50%1 (0.5)
 Persistent proteinuria7 (3.5)
 End-stage renal disease1 (0.5)
Pulmonary2 (1)
 Pulmonary hypertension2 (1)
 Pulmonary fibrosis1 (0.5)
 Pulmonary shrinking lung on radiography1 (0.5)
 Pleural fibrosis on radiography1 (0.5)
 Pulmonary infarction0 (0)
Cardiac2 (1)
 Cardiomyopathy1 (0.5)
 Pericarditis >6 months1 (0.5)
Vascular5 (3)
 Minor tissue loss1 (0.5)
 Venous thrombosis4 (2)
Gastrointestinal5 (3)
 Gastrointestinal infarction4 (2)
 Mesenteric insufficiency1 (0.5)
 Pancreatic insufficiency1 (0.5)
Musculoskeletal12 (6)
 Muscular atrophy3 (1.5)
 Arthritis6 (3)
 Osteoporosis4 (2)
 Avascular necrosis2 (1)
Cutaneous22 (11)
 Alopecia20 (10)
 Panniculum2 (1)
 Skin ulceration >6 months4 (2)
Other 
 Diabetes2 (1)

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The UK JSLE Cohort Study is important in presenting the clinical characteristics of a large, national, multicenter collaborative cohort of patients with new-onset juvenile SLE. As such, it represents a significant inception cohort of children and young people with juvenile SLE whose primary characteristics include significant organ involvement, a high prevalence of disease activity, and a frequent requirement for corticosteroid and immunosuppressant therapy, all of which can be compared with published data from adult cohorts (1, 12, 17, 18).

Consistent with the observations in other pediatric lupus cohorts (1, 7), the sex distribution of 5.6 females to every male in our juvenile SLE cohort is typical of childhood-onset disease, although this predominance in young female patients is less striking than has been observed in female patients with adult-onset SLE (18). Within our group, the median age at diagnosis was 12.8 years, with 41 patients (21%) diagnosed at age 10 years or younger and no patients diagnosed in the infantile period (age <1 year). Younger patients are known to present with a more severe disease phenotype, with infantile-onset SLE having an extremely high mortality rate (28). Previous studies have demonstrated a tendency for more internal organ involvement, such as cardiac, renal, or respiratory disease, in patients with a younger age at disease onset, in contrast to an increased incidence of musculoskeletal or cutaneous disease in postpubertal patients, when the substantial shift toward disease preponderance in females also occurs (29). Consistent with this preponderance of juvenile SLE in female patients in the peri- or postpubertal stage, male patients in our cohort were significantly younger than the female patients at the time of diagnosis, and patients under the age of 10 years had a less striking between-sex difference in the preponderance of juvenile SLE.

The high incidence of autoimmune diseases in family members of the patients with juvenile SLE was notable. This, in itself, can be associated with a worse outcome in patients (30). The generally more severe clinical phenotype in juvenile SLE as compared to that in adult-onset SLE, the very early age at disease onset, the shorter time of exposure to potential environmental triggers of lupus, the relatively high male-to-female sex ratio of disease preponderance in the younger age group, and the strong family history of autoimmunity all point toward probable genetic factors being important in the pathogenesis of juvenile SLE as compared to that in later-onset disease (31).

Although, numerically, the UK JSLE Cohort Study consisted predominantly of Caucasian children, adjustment against national standardized ethnicity data demonstrated a significantly higher incidence of juvenile SLE, as well as important differences in disease characteristics, in non-Caucasian patients, as has also been noted in previous, smaller UK-based cohorts (7). Recognition of this national preponderance of juvenile SLE in UK ethnic minority groups could influence efforts to ensure the availability and provision of specialist care in these communities. The impact of ethnicity on disease phenotype is also important to recognize in the future development of interventional trials involving patients with juvenile SLE, as there may be an influence of ethnicity on disease outcomes or response to treatment. For example, a recent phase III trial of belimumab in patients with adult-onset SLE demonstrated differences in drug efficacy based on ethnic origin (32). The influence of ethnicity on disease phenotype is likely to be better determined in the UK JSLE Cohort Study as the cohort increases in size over time.

Approximately 50 percent of the patients were diagnosed as having juvenile SLE during the teenage years, a critical time for adolescent growth, puberty, education, and emotional maturation. This emphasizes the importance of access to specialist, multidisciplinary pediatric and adolescent holistic care for patients with juvenile SLE (33). The challenge of diagnosing SLE in the pediatric age group should not be underestimated (34). The median time from symptom onset to juvenile SLE diagnosis was 3.2 months (range 0–111 months, IQR 1.7–9.6 months), reflecting, in part, the gradual, nonspecific onset of disease and, in part, the challenge of recognition and diagnosis in this age group. Our national study also aims to capture the evolving nature of lupus in those children who, at presentation, have fewer than 4 ACR SLE classification criteria, which will form the focus of a future study. Further consideration and validation of SLE diagnostic criteria in children/young people is required.

A higher incidence of arthritis, nephritis, neurologic manifestations, and hematologic involvement was evident in this national cohort of patients with juvenile SLE as compared to previously described cohorts of patients with adult-onset SLE (35, 36). These observations are in line with published data from other pediatric lupus cohorts (19). After a median followup of 4.5 years among the patients with juvenile SLE, 80% had, at any time (current or past), experienced renal involvement, 91% had experienced hematologic manifestations, 82% had experienced musculoskeletal disease, and 26% had experienced neurologic disease. A similar pattern of these predominant clinical manifestations and severe phenotype has been found repeatedly in juvenile SLE cohorts (1).

Importantly, the pBILAG-2004 disease activity tool was utilized here, for the first time, to provide a helpful and detailed description of the organ involvement seen in patients with juvenile SLE. Numerous composite scores have been developed for adult-onset SLE cohorts to standardize assessment of disease activity (37). Reflecting the complexity and multisystem nature of the clinical characteristics of SLE, the BILAG Study Group developed the BILAG disease activity tool, the reliability and validity of which have been demonstrated in patients with adult-onset SLE (38). The BILAG index provides more detailed information on specific organ involvement when compared to other SLE disease activity scoring systems, such as the SLEDAI (27, 39). More recently, the updated version of the index, the BILAG-2004, has been widely used in clinical trials in patients with adult-onset SLE (32).

In an effort to adapt the BILAG disease activity index to provide parameters and parameter definitions more suitable to pediatric age groups, preliminary validation of the original BILAG index in a small cohort of children was undertaken, along with use of other activity tools, including the SLEDAI (21, 26). A pediatric adaptation of the subsequent 2004 update of the index (25, 40), the pBILAG-2004, was adapted for use in the present study. Prospective validation of the pBILAG-2004 index is currently under way.

Among the patients with juvenile SLE in the present study, differences were found in the occurrence of organ involvement identified using the ACR classification criteria for SLE and that noted using the pBILAG-2004 index. The pBILAG-2004 index collects more detailed information about organ-related disease activity than that incorporated within the ACR criteria. A total of 34 patients were deemed, by experienced clinicians, to have probable or definite lupus, but these patients had not yet strictly fulfilled the ACR criteria, which were devised as classification, not diagnostic, criteria in SLE. Ongoing evaluation of specific diagnostic criteria in juvenile SLE is warranted. The BILAG index may be too sensitive to discriminate between organ manifestations, or the ACR criteria may not be specific enough for childhood disease. Nevertheless, our study did demonstrate a significant reduction in disease activity as measured by the pBILAG-2004 index at a time point 12 months after diagnosis, which may be of relevance as an outcome measure of response to treatment in future interventional studies.

In this UK national cohort, patients with juvenile SLE experienced a high burden of corticosteroid use, and a significant number of patients required cytotoxic immunosuppression. This underlines once again the burden of disease in the pediatric age group, together with the importance of developing steroid-sparing regimens based on robust randomized controlled trials of new interventions in juvenile SLE. In a study undertaken by Brunner et al, similarly high levels of corticosteroid use were observed in patients with juvenile SLE; immunosuppressive medications were used in 66% of patients with childhood-onset SLE but in only 37% of patients with adult-onset SLE (17). Alternative therapies to relieve the burden of corticosteroids in this population are urgently required. The use of potentially toxic immunosuppressive treatment was evident, with 24% of the patients requiring treatment with cyclophosphamide, a drug associated with serious long-term side effects, including malignancy and infertility (41). Almost one-half of the cohort had received either mycophenolate mofetil or azathioprine. Use of rituximab, a therapy with steroid-sparing potential, was reported in 13% of our cohort, demonstrating the clinical impression that it has a key role in management of juvenile SLE despite a paucity of well-conducted studies supporting its use (42, 43).

Over a relatively short followup period in this study, scores on the SLICC/ACR Damage Index highlighted important disease-related damage in our cohort. The damage seen in this pediatric age group is likely to have a significant, long-lasting physical and/or psychosocial impact and consequences. We demonstrated a predominance of neurologic and renal damage within our cohort, similar to that observed in other international studies (44). However, the reported rates of end-stage renal failure have been higher in other juvenile SLE cohorts (8, 44). This may be attributed to ethnic variations in renal disease severity or efficacy of treatment in non-Caucasian ethnic groups, as has been seen in trials involving adult patients with lupus nephritis (45–47). Severe persistent alopecia was frequently seen and may have devastating effects on patients who are already adapting to taking medications, attending hospital, trying to gain peer acceptance, and trying to attain educational qualifications. Determining the effect of lupus-associated damage on the developing child requires large, prospective long-term studies, together with improved disease biomarkers, to assess the true physical and psychosocial impact of this condition. The extent of the damage in our cohort may be underestimated, and further detailed evaluation is needed. However, in contrast to the damage in patients with adult-onset SLE, which is generally steroid-associated, as, for example, in the development of cataracts or osteoporosis, damage in our juvenile SLE cohort was predominantly disease-related (48).

In conclusion, the UK JSLE Cohort Study provides a detailed, national, prospective description of the demographics, disease activity, organ involvement, and outcome (to date) in a large inception cohort of children with juvenile SLE. The UK JSLE Study Group, and its established multicenter collaborative infrastructure, provides a model of a multidisciplinary research network that will also facilitate future clinical trials in juvenile SLE. Ongoing recruitment and long-term followup of both the JSLE Study Cohort and the cohort of patients with probable juvenile SLE is continuing, with the principal aim of improving the care of patients with juvenile SLE across the UK. The complex and severe nature of juvenile SLE requires multidisciplinary pediatric management that carefully considers issues related to disease activity and damage and choice of medications, along with growth, puberty, educational development, and psychosocial well-being.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

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 published. Dr. Beresford 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. Watson, Leone, Pilkington, Rangaraj, Wilkinson, Tizard, Armon, Davidson, Baildam, Cleary, McCann, Beresford.

Acquisition of data. Watson, Pilkington, Tullus, Rangaraj, McDonagh, Gardner-Medwin, Wilkinson, Tizard, Armon, Sinha, Ioannou, Archer, Bailey, Davidson, Baildam, Cleary, McCann, Beresford.

Analysis and interpretation of data. Watson, Leone, Gardner-Medwin, Riley, Tizard, Armon, Baildam, Cleary, McCann, Beresford.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We would like to thank all of the patients and their families for participating in this study, and acknowledge the support given by all of the multidisciplinary teams within each pediatric center, represented herein by the respective principle investigators. In addition, special recognition is made to Lupus UK for providing financial support for the coordination and database development, as well as private benefactors and the Alder Hey Kidney Fund. We appreciate the support of the National Institute of Health Research (NIHR) Medicines for Children Research Network, the nurses and staff of the NIHR Local Research Network, the staff of the NIHR Comprehensive Local Research Network, and all those who are part of and have supported the work of the UK JSLE Study Group to date. In addition, grateful acknowledgment is made to Professors David Isenberg and Ian Bruce, adult rheumatology advisors to the UK JSLE Study Group, who, along with Professor Caroline Gordon and the BILAG Group, have shown significant support for this initiative, and also Dr. Ruth Murphy, consultant dermatologist. Specific acknowledgment goes to the clinical teams, consultants, research nurses, and clinical nurse specialists in each center, including Louise Hanna, Gill Jackson, Louise Spencer-Walsh, Nicola Daly, Lucinda Dawson, Jenna Shaw, Mandy Aspinall, Ann McGovern, Vicky Stevenson, Beverley Thomas, Natalie Fineman, Kay Riding, Anna Frost, Emma Innes, Liz Reus, Kit Tranter, Fiona Thompson, and Sue Doyle. Special recognition goes to Duncan Appleby for database and information technology support.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
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