Juvenile localized scleroderma (jLS) and juvenile systemic sclerosis (jSS) are both orphan diseases, with jLS around 10 times more frequent than jSS. In recent years the time gap between the appearance of symptoms and diagnosis has become significantly shorter. This review focuses on the new classifications of jSS and jLS, and on the developments and adaptations of the outcome measures for certain organ involvements whereby progress has been made regarding pediatric patients.
Key points
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The main organ, and that which is always involved in juvenile localized scleroderma (jLS) and juvenile systemic sclerosis (jSS), is the skin.
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The Modified Rodnan Skin Score was developed to assess the skin involvement in adult patients with systemic sclerosis, and is a primary outcome measure in therapeutic trials. It is a simple bedside examination to measure skin thickening (not tethering) in 17 anatomic areas and score it from 0 to 3.
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Ultrasonography combined with Doppler is nowadays a readily available and noninvasive imaging modality that has great potential to aid monitoring of localized scleroderma disease activity and, eventually, jSS, because it allows for the evaluation of both superficial and deep soft tissues.
Introduction
Juvenile localized scleroderma (jLS) and juvenile systemic sclerosis (jSS) are both orphan diseases, with jLS around 10 times more frequent than jSS. According a more recent cross-sectional national survey from the United Kingdom and Ireland, the incidence rate per million children per year is 3.4 (95% confidence interval [CI] 2.7–4.1) for jLS, including an incidence rate of 2.5 (95% CI 1.8–3.1) for linear scleroderma, and 0.27 (95% CI 0.1–0.5) for jSS. According the German National Pediatric Rheumatology Registry (Kerndokumentation), in 2011 19 of 14 million children in Germany had documented jSS, which would give a prevalence of 1.36 per million children in Germany (Dr Kirsten Minden, Deutsche Rheumaforschungszentrum, 2013, personal communication).
It still takes some time to be diagnosed with the systemic and localized forms of juvenile scleroderma. According the cross-sectional survey conducted around 2003/2004 by Martini and colleagues, the median time to be diagnosed with jSS was 1 year (range 0.2–18.8 years). The time gap between the appearance of symptoms and diagnosis is becoming significantly shorter; according to a current assessment in the United Kingdom this is 7 months for jSS (range 0–50 months), but the range is still impressively wide. The time to be diagnosed with jLS is longer, with a median delay from onset of symptoms to being seen in a secondary care center varying from 13.1 months (range 6.9–36.5) to 15 months (range 1–103). In a recent study from Switzerland, the mean disease duration until diagnosis was 11.1 months (range 1.8–79) and the mean time to initiation of therapy was after disease duration of 16.6 months (range 1.8–113.4).
This review focuses on the new classifications of jSS and jLS, and on the developments and adaptations of the outcome measures for certain organ involvements whereby progress has been made regarding pediatric patients.
Introduction
Juvenile localized scleroderma (jLS) and juvenile systemic sclerosis (jSS) are both orphan diseases, with jLS around 10 times more frequent than jSS. According a more recent cross-sectional national survey from the United Kingdom and Ireland, the incidence rate per million children per year is 3.4 (95% confidence interval [CI] 2.7–4.1) for jLS, including an incidence rate of 2.5 (95% CI 1.8–3.1) for linear scleroderma, and 0.27 (95% CI 0.1–0.5) for jSS. According the German National Pediatric Rheumatology Registry (Kerndokumentation), in 2011 19 of 14 million children in Germany had documented jSS, which would give a prevalence of 1.36 per million children in Germany (Dr Kirsten Minden, Deutsche Rheumaforschungszentrum, 2013, personal communication).
It still takes some time to be diagnosed with the systemic and localized forms of juvenile scleroderma. According the cross-sectional survey conducted around 2003/2004 by Martini and colleagues, the median time to be diagnosed with jSS was 1 year (range 0.2–18.8 years). The time gap between the appearance of symptoms and diagnosis is becoming significantly shorter; according to a current assessment in the United Kingdom this is 7 months for jSS (range 0–50 months), but the range is still impressively wide. The time to be diagnosed with jLS is longer, with a median delay from onset of symptoms to being seen in a secondary care center varying from 13.1 months (range 6.9–36.5) to 15 months (range 1–103). In a recent study from Switzerland, the mean disease duration until diagnosis was 11.1 months (range 1.8–79) and the mean time to initiation of therapy was after disease duration of 16.6 months (range 1.8–113.4).
This review focuses on the new classifications of jSS and jLS, and on the developments and adaptations of the outcome measures for certain organ involvements whereby progress has been made regarding pediatric patients.
Classification criteria of juvenile systemic sclerosis
For a long time there were no specific classification criteria for jSS. As jSS differs in the course of development of organ involvement from adult systemic sclerosis, the pediatric rheumatologic community, in its capacity as the juvenile scleroderma working group of the Pediatric Rheumatology European Society (PRES), initiated a multidisciplinary project using the Delphi method, with the participation of adult rheumatologists and pediatric and adult dermatologists, which ultimately established new proposed classification criteria ( Box 1 ). This new classification is accepted by PRES, the European League Against Rheumatism (EULAR), and the American College of Rheumatology.
Major Criterion (Required)
Proximal skin sclerosis/induration of the skin
Minor Criteria (At Least 2 Required)
Cutaneous
Sclerodactyly
Peripheral vascular
Raynaud phenomenon
Nailfold capillary abnormalities
Digital tip ulcers
Gastrointestinal
Dysphagia
Gastroesophageal reflux
Cardiac
Arrhythmias
Heart failure
Renal
Renal crisis
New-onset arterial hypertension
Respiratory
Pulmonary fibrosis (high-resolution computed tomography/radiography)
Decreased diffusing capacity of carbon monoxide
Pulmonary arterial hypertension
Neurologic
Neuropathy
Carpal tunnel syndrome
Musculoskeletal
Tendon friction rubs
Arthritis
Myositis
Serologic
Antinuclear antibodies
Systemic sclerosis–selective autoantibodies (anticentromere, anti–topoisomerase I [Scl-70], antifibrillarin, anti-PMScl, antifibrillin, or anti–RNA polymerase I or III)
This classification should enable an earlier diagnosis of patients. The first publications to apply these criteria are appearing. This new system has one major criterion, namely proximal skin sclerosis/induration of the skin, and several minor criteria (see Box 1 ). The patient has to fulfill 1 major and at least 2 minor criteria (see Box 1 ). Each criterion was defined in the publication and represents an organ-specific presentation of juvenile scleroderma. This classification system has to be prospectively validated in a larger pediatric cohort. One of the validation projects is the Juvenile Scleroderma Inception Cohort Project ( www.juvenile-scleroderma.com ), in which patients with less than 18 months’ disease duration after the first non-Raynaud symptom are included and prospectively followed with a standardized assessment.
Classification of juvenile localized scleroderma
Localized scleroderma is a distinct entity from systemic sclerosis, and as yet there is no accepted uniform terminology. Dermatologists like to use the word “morphea” and rheumatologists and pediatric rheumatologists the term “localized scleroderma.” In the framework of the PRES Scleroderma Working Group a preliminary proposed classification of jLS was suggested, but this is not as widely accepted as the new classification of jSS. In Table 1 this preliminary proposed classification, which consists of 5 types with some subgroups, is summarized. The classification criteria have not yet been prospectively tested.
| Main Group | Subtype/Definition |
|---|---|
| 1. Circumscribed morphea | A, Superficial |
| B, Deep | |
| 2. Linear scleroderma | A, Trunk/limbs |
| |
| 3. Generalized morphea | Four or more plaques (>3 cm) and involves at least 2 of 7 anatomic sites |
| 4. Pansclerotic morphea | Circumferential involvement of the limbs, affecting all tissue layers including the bone |
| 5. Mixed morphea | Combination of 2 or more previous types |
Outcome measures
A major problem in the care of children with jLS and jSS lies in assessing the activity of the disease, especially in the skin, and vascular involvement. Not even in adults are all organ-involvement assessments validated according to the OMERACT criteria. A good outcome measure should be relevant to the goal of treatment, easy to administer, and easy to score. It should be reliable and valid and at the same time sensitive to change.
Assessment of skin involvement
The main organ, and that which is always involved in jLS and jSS, is the skin. The extent of skin involvement can be palpated with the fingers of the physician and assessed using the Modified Rodnan Skin Score (MRSS). The skin, especially the subcutaneous components, changes during the maturation of the child, therefore the “normal skin score” changes with age.
Modified Rodnan Skin Score
The MRSS was developed to assess skin involvement in adult patients with systemic sclerosis, and is a primary outcome measure in therapeutic trials. It is a simple bedside examination to measure skin thickening (not tethering) in 17 anatomic areas and award a score from 0 to 3. The MRSS has large intraobserver variability and has never been validated in children. Foeldvari and Wierk applied it in 217 consecutive healthy children to establish norm values. Surprisingly, healthy children had a mean MRSS of 13.92, which is significantly elevated. It was suggested that the MRSS should be adjusted according to the age and Tanner stage of the child. The prospective assessment of the MRSS in a larger jSS patient population is pending. It is routinely applied in the Localized Scleroderma Cutaneous Assessment Tool.
Durometer
The durometer is a hand-held device that assesses hardness of the skin, expressed in arbitrary units from 0 to 100 in linear distribution. The measurement can be conducted in seconds. In patients with systemic sclerosis a correlation between durometer and MRSS assessments has been found. It has a lower intraobserver variability than the MRSS, and has been used in patients with localized and systemic scleroderma to assess the treatment effect. Merkel and colleagues established norm values for anatomic areas similar to those used in the MRSS. The durometer assessment showed good intraobserver correlation (0.82–0.92), and the baseline durometer values showed a good correlation with the MRSS values ( r = 0.7). Foeldvari and colleagues (unpublished data, 2013) conducted a study to establish norm values for the durometer in children whereby values less than 30 appeared normal and were equivalent to an MRSS score of 0. The durometer cannot be used in all anatomic areas, especially if a bony surface is directly under the skin, such as the dorsal site of the fingers. Otherwise a durometer is a reliable device to access skin thickening more objectively.
Ultrasonography with Doppler to Assess Skin Involvement
Ultrasonography combined with Doppler is nowadays a readily available and noninvasive imaging modality that has great potential to aid monitoring of localized scleroderma disease activity and eventually jSS, because it allows for the evaluation of both superficial and deep soft tissues. Li and colleagues established a protocol to evaluate Doppler ultrasonography in jLS for the assessment of activity. The lesions were assessed by clinicians, and features such as erythema, warmth, violaceous color, new lesion, expansion of lesion, and induration were considered to indicate active disease. The Ultrasound Disease Activity (U-DA) was assessed by a radiologist, comparing the site of the lesion with the control healthy site. The U-DA is a composite score of the echogenicity and vascularity of dermis, hypodermis, and deep tissue. Hypovascularity or hypoechogenicity had a score of −1 compared with the healthy site. No difference from the control site was scored as 0. Increased vascularity was scored 1 to 3, and increased echogenicity was scored depending on the tissue layer: dermis +1, hypodermis 1 to 3, and deep tissue 1 to 2. The U-DA was significantly different between active and inactive skin lesions ( P = .0010) with significant differences found for the parameters total echogenicity, hypodermis echogenicity, and deep tissue layer vascularity ( P = .0014, P = .0023, and P = .0374, respectively). No significant differences were found for tissue layer thickness or the Tissue Thickness Score. The U-DA promises to be a useful tool in the identification of localized scleroderma activity. Ultrasonography is not universally applicable, because it cannot be used over a bony surface situated directly under the lesion, such as on the scalp, near the eyes, or on the shin. The findings of Li and colleagues were confirmed in a further color Doppler study by Wortsman and colleagues, in which the most accurate sonographic signs of lesion activity were increased subcutaneous tissue echogenicity and increased blood flow, with sensitivity and specificity both of 100%. In this study the sonographic findings correlated with histologic findings. Further prospective studies are needed to validate this Doppler ultrasonography scoring system.
Thermography and Laser Color Doppler
Thermography is not a widely available method for the assessment of activity of skin lesions, being time consuming and expensive. Infrared thermography (IRT) is of value for the assessment of the inflammatory changes associated with jLS. Patients need to acclimatize to a standardized room temperature at least for 15 minutes. IRT measures skin temperature as a surrogate measure of blood flow. It is a sensitive technique but can show false-positive results in “older/dystrophic” inactive lesions. In these “burned” lesions the heat conduction is increased and therefore the lesion appears “hot” despite clinical inactivity. Martini and colleagues found that the sensitivity of thermography was 92% and specificity 68%. Full concordance between the 2 clinicians involved was observed in 91% of lesions, with a κ coefficient of 0.82, implying very high reproducibility of this technique.
If IRT is combined with other measurements of activity, it becomes more sensitive. Howell and colleagues combined it with laser Doppler measurement, which assesses the blood flow/vascularity of the lesion by digital photographic techniques to provide a record of the temperature, blood flow, and appearance of each localized scleroderma lesion. These investigators developed norm values for thermography and laser Doppler measurements for certain anatomic areas such as forehead, cheek, abdomen, back, arm, and leg. Of note, a temperature difference of 1°C occurred in contralateral sites in healthy individuals. Zulian and colleagues used thermography measurements as one of the outcome measures in the first controlled trial of jLS with methotrexate.
Weibel and colleagues conducted a study with laser Doppler and thermography to assess the activity of jLS lesions. Seventy-five active lesions (34%) and 147 inactive lesions (66%) were identified clinically. The median relative increase in blood flow measured by laser Doppler flowmetry was +89% (range −69% to +449%) for clinically active lesions and +11% (range −46% to +302%) for clinically inactive lesions ( P <.001). Thermography showed a median difference in temperature of +0.5°C (range −0.1°C to +4.1°C) and +0.3°C (range −1.9°C to +2.7°C) for clinically active lesions and clinically inactive lesions, respectively ( P = .024). Using a cutoff level of 39% to indicate increase in blood flow, a sensitivity of 80% and specificity of 77% to detect clinically active lesions were observed. For thermography, no useful cutoff level was identified. Howell and colleagues showed that a +1°C difference can also occur in healthy skin. The correlation between differences in blood flow and differences in temperature was small, but significant ( r 2 = 0.120, P <.001). In daily practice, thermography seems fairly time consuming, with extensive personnel and cost. Laser Doppler is sensitive in assessing blood flow and vascularity and thus the activity of the lesion, but it is not readily available and, hence, not an ideal tool to assess activity.
Optical Coherence Tomography
A recent publication describes the newly applied method of optical coherence tomography (OCT), in a pilot study in 21 systemic sclerosis patients and 22 healthy controls, as “virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma.” OCT is a powerful imaging technology providing high-contrast images with 4-μm resolution, comparable with microscopy (“virtual biopsy”). OCT uses a low-intensity infrared laser beam and is capable of producing high-contrast images of skin up to 2 mm deep with resolutions of 4 to 10 μm. Both features make it an ideal tool to explore the most superficial layers of the skin. Visualizing the superficial structures of the skin, it can assess the early fibrotic changes (eg, capillary rarefaction and perivascular infiltration) that are foremost represented in the superficial dermis. Indeed, recent work has shown a pivotal interaction between keratinocytes and superficial dermis in early skin fibrosis in systemic sclerosis. Comparisons of OCT images with skin histology indicated a progressive loss of visualization of the dermal-epidermal junction associated with dermal fibrosis. Furthermore, skin affected by systemic sclerosis showed a consistent decrease of optical density (OD) in the papillary dermis, progressively worse in patients with a worse MRSS ( P <.0001). In addition, clinically unaffected skin was also distinguishable from healthy skin for its specific pattern of OD decrease in the reticular dermis ( P <.001). The technique showed an excellent intraobserver and interobserver reliability (intraclass correlation coefficient >0.8). This tool has not yet been not tested in pediatric jLS or jSS patients, but its use seems intriguing because it is not invasive, the interpreter does not need any special training as with ultrasonography, and it is not time consuming (<10 seconds for each site examination).
Composite Index to Assess Localized Scleroderma Skin Damage and Physician Global Assessment of Disease Damage
The composite index was developed because even nowadays, as already described, there is no simple, feasible, or reliable tool to assess activity of jLS. Ultrasonography, thermography, laser Doppler, and OCT all require availability of specific equipment and sometimes special training to use and interpret the results. Arkachaisri and colleagues established the first composite index to assess disease activity in jLS. The Localized Scleroderma Skin Severity Index (LoSSI) ( Table 2 ) consists of the assessment in 18 anatomic areas of the surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension of the localized scleroderma lesions. Interrater reliability was excellent for ER (intraclass correlation coefficient [ICC] 0.71), ST (ICC 0.70), LoSSI (ICC 0.80), and Physician Global Assessment (PhysGA-A) (ICC 0.90), but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. In mLoSSI the SA of the lesion is excluded, because it had low interrater reliability and was not sensitive to change. Examiners’ experience did not affect the scores, but training and practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman ρ = 0.71–0.89) and moderate for SA. The PhysGA-A was based on 4 clinical criteria (appearance of new lesion, extension of existing lesion, erythema, and skin thickening) and 2 laboratory variables (erythrocyte sedimentation rate and C-reactive protein). mLoSSI correlated moderately with PhysGA-A and the Patient Global Assessment of Disease Severity (PtGA-S). Both mLoSSI and PhysGA-A were sensitive to change following therapy. To deal with the age-specific skin thickness, each involved skin area was compared with the contralateral healthy area from the same person. The LoSSI and PhysGA-A appeared to be easy to use in a busy clinic. In the next step the same group established the Localized Scleroderma Skin Damage Index (LoSDI) (see Table 2 ) and the Physician Global Assessment of Disease Damage (PGA-D). Although jLS is not a life-threatening disease, regardless of subtype, it almost always results in chronic and/or irreversible changes in the skin or underlying tissue. Therefore the assessment of damage is important. Damage was defined as irreversible/persistent changes (>6 months) caused by previous active disease/complications of therapy. LoSDI was calculated by summing 3 scores for cutaneous features of damage (dermal atrophy [DAT], subcutaneous atrophy [SAT], and dyspigmentation [DP]) measured at 18 anatomic sites. LoSDI and its domains DAT, SAT, DP, and PGA-D demonstrated excellent interrater and intrarater reliability (reliability coefficients 0.86–0.99 and 0.74–0.96, respectively). PGA-D and PtGA-S were also validated. At each visit patients were instructed to consider the past month for their answers.
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