Development of minimum standards of care for

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European Journal of Pediatrics https://doi.org/10.1007/s00431-018-3144-8

REVIEW

Development of minimum standards of care for juvenile localized scleroderma Tamás Constantin 1 & Ivan Foeldvari 2 & Clare E. Pain 3 & Annamária Pálinkás 1 & Peter Höger 4 & Monika Moll 5 & Dana Nemkova 6 & Lisa Weibel 7 & Melinda Laczkovszki 1 & Philip Clements 8 & Kathryn S. Torok 9 Received: 26 September 2017 / Revised: 25 February 2018 / Accepted: 4 April 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract Juvenile localized scleroderma (jLS), also known as morphea, is an orphan disease. Pediatric guidelines regarding diagnosis, assessment, and management are lacking. Our objective was to develop minimum standards of care for diagnosis, assessment, and management of jLS. A systematic review was undertaken to establish the pediatric evidence for assessment and monitoring of jLS. An expert panel, including members of the Pediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and, where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. Recommendations for diagnosis, assessment, and management were developed. Due to a lack of pediatric evidence, these were primarily consensus driven. Careful assessment for extra-cutaneous manifestations including synovitis, brain involvement, and uveitis were key features together with joint assessments between Dermatology and Rheumatology to improve and standardize care. Conclusion: Management of jLS is varied. These recommendations should help provide standardization of assessment and care for those with this rare and potentially debilitating condition. What is Known: • Children with juvenile localized scleroderma (jLS) are managed by a number of specialties including pediatric rheumatologists and dermatologists, sometimes in shared clinics. Studies have shown that management varies considerably and that there are notable differences between specialties [1]. • There is very little published guidance on management of jLS. What is new: • These recommendations aim to standardize diagnosis, assessment, and management through review of pediatric evidence and consensus agreement. Communicated by Nicole Ritz Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00431-018-3144-8) contains supplementary material, which is available to authorized users. * Tamás Constantin [email protected]

Dana Nemkova [email protected]

Ivan Foeldvari [email protected]

Lisa Weibel [email protected]

Clare E. Pain [email protected]

Melinda Laczkovszki [email protected]

Annamária Pálinkás [email protected]

Philip Clements [email protected]

Peter Höger [email protected] Monika Moll [email protected]

Kathryn S. Torok [email protected] Extended author information available on the last page of the article

Eur J Pediatr • Joint review of patients by both pediatric rheumatologists and dermatologists is recommended.

Keywords Localized scleroderma . Diagnosis . Treatment . Guideline Abbreviations AHA Anti-histone antibodies ANA Antinuclear antibody CARRA Childhood Arthritis and Rheumatology Alliance CDLQI Children’s Dermatology Life Quality Index CPK Creatinine phosphokinase CRP C-reactive protein DIET Dyspigmentation, Induration, Erythema, Telengiectasias DMARD Disease-modifying anti-rheumatic drug ECDS En coup de saber EEG Electro-encephalogram ESR Erythrocyte sedimentation rate EULAR European League Against Rheumatism JLS Juvenile localized scleroderma LOCUS Localized Scleroderma Clinical and Ultrasound Study LoSCAT Localized Scleroderma Cutaneous Assessment Tool LoSDI Localized Scleroderma Damage Index LS Localized scleroderma mLoSSI Modified Localized Scleroderma Severity Skin Index MMF Mycophenolate mofetil mRSS Modified Rodnan Skin Score MTX Methotrexate PRES Pediatric Rheumatology European Society P U VA Psoralen ultraviolet A therapy QoL Quality of life SSc Systemic sclerosis UV Ultraviolet

Introduction The disease “scleroderma” is characterized by two distinct clinical diseases: systemic sclerosis (SSc) and localized scleroderma (LS) (also known as morphea), which share in part a common pathophysiology resulting in sclerosis of the skin. In children, the localized form is much more common, with a mean age of onset at 7–9 years, with an incidence of 0.3–3 per 100,000 children, compared to SSc in children with estimated incidence of 1–3 per 1,000,000 children [1–6]. JLS is caused by a chronic inflammatory-driven fibrotic connective tissue reaction. Several subtypes of localized scleroderma, also termed morphea, exist and include the following: linear scleroderma of the trunk/limbs and head, which

is the most frequent subtype in childhood (65%), plaque or circumscribed morphea, generalized morphea, circumscribed deep morphea, pansclerotic morphea, and mixed [4, 7–9]. Although the term “localized scleroderma” and “morphea” can be used interchangeably, pediatric rheumatologists and pediatric dermatologists generally prefer the term localized scleroderma given the high frequency of the linear scleroderma subset of disease in children. Therefore, the term localized scleroderma was utilized at this consensus meeting and for the proposed general guidelines. In general, jLS is an under recognized disease as documented by Weibel et al., being misdiagnosed 70% of the time at initial presentation to a variety of practitioners [2]. Together with the generalized slowly progressive nature of the disease, these factors can lead to a significant delay in diagnosis which likely impacts on outcome [2, 10, 11]. A treatment window may be lost if the degree of inflammatory disease is waning and much damage has accrued. In general, treatment options (topical, systemic, and ultraviolet (UV) radiation), have not been standardized and tend to differ between pediatric rheumatologists and dermatologists [1, 10, 11]. Typical cutaneous changes include initial inflammatory signs with erythema and induration, followed by both atrophy of the tissue (dermal and subcutis), dyspigmentation, and fibrosis. Beyond the cutaneous findings, there exists a significant amount of extra-cutaneous manifestations with potential for impact on structural development and function, especially in growing children where lesions can restrict mobility and cause limb length discrepancy and facial atrophy. If a cosmetically sensitive area is affected, it may also lead to a deterioration in quality of life with or without functional damage. Three studies have assessed quality of life (QoL) in childhood scleroderma using the Children’s Dermatology Life Quality Index (CDLQI) [12, 13]. In one study of 75 children, 28% experienced a moderate or great impact on QoL (CDLQI score > 5) [14]. Other extra-cutaneous manifestations experienced by children with jLS include arthritis, “white” uveitis (without occurrence of redness or pain), and brain involvement, which may worsen the prognosis of the disease or may have implications for treatment decisions [4]. Only a limited amount of evidence-based data is available to support the treatment and management of patients with jLS, including how best to manage and coordinate care between pediatric rheumatology and dermatology providers. Recommendations mostly aimed at adult patients have been published [15]. Given the variety of practice in treatment of jLS, the Childhood Arthritis and Rheumatology Alliance

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(CARRA) group have developed and agreed consensus jLS treatment plans for systemic treatment for children with moderate to severe jLS, which include three arms of agreed therapy, all with a methotrexate base [3]. The aim of this evidence review and consensus led development of recommendations by the Scleroderma Working Party of Pediatric Rheumatology European Society (PRES) was to add to these publications by producing recommendations on diagnosis, assessment of patients, including for extracutaneous manifestations, and on treatment, including systemic, topical, light therapies, and surgical corrections of complications. We hope that through development of such recommendations that a minimum standard of care for children jLS will lead to improved outcomes.

Methods Members of the PRES scleroderma working group were officially invited to participate in the consensus meeting. Additional experts in the field were individually invited: KT, as one of the lead pediatric rheumatology members of the CARRA jLS committee (United States and Canadian rheumatology research alliance); European pediatric and adult dermatology colleagues who have expertise in this field (LW, PH) as representatives for the dermatology perspective. An adult rheumatologist (PC) who is an expert in adult systemic sclerosis outcomes was invited as a convener. The recommendations were constructed using the European League Against Rheumatism (EULAR) standard operating procedures [16]. Before the meeting, each participant reviewed the published literature regarding treatment of jLS. The consensus meeting took place on 4 December 2011 in Hamburg, Germany. Participants met in a face-to-face meeting. Highlights of the relevant literature were presented at the meeting. In the consensus process, topics were discussed and a consensus statement was created and voted on by the participants. The expert panel included six pediatric rheumatologists and two dermatologists. We defined consensus if 75% agreement was achieved, and to ensure that the larger group cannot dominate the meeting, both dermatologists’ agreement was required for reaching consensus, meaning also that dermatologists has the potential to veto any recommendation if it was unacceptable by the dermatologists’ point of view, to guarantee all recommendations were supported by both sub-specialties. There were no items of disagreement among the panel (no perceived dermatology and rheumatology conflict of opinion). Recommendations were presented at the annual meetings of EULAR, PRES, the American College of Rheumatology, and the World Scleroderma Congress. In 2015, LW, TC, and IF reviewed all recommendations and considered all recommendations as clinically useful. The

expert group decided to update the literature review and refine the strength of recommendations. In June 2016, a systematic literature review was performed, which was completed in PubMed/MEDLINE (1 January 1990–27 June 2016). Non-English papers were excluded. Studies with mixed pediatric and adult populations were included and adult studies were also included if pediatric evidence was completely lacking. Adapted classification tables for diagnostic [17] and therapeutic [16, 18] studies were used to determine the level of evidence and strength of each recommendation (see supplementary Tables 1–3 and Fig. 1). Participants of the 2011 consensus meeting reviewed the results of the updated systematic literature review and then they were asked to rate the strengths of each recommendation on a 1–9 scale based on their clinical expertise and based on the results of the updated literature review. The strength of the recommendations based on expert opinion was expressed as follows: median scores in the 1–3 range were considered as weak, those in the 4–6 range were considered as intermediate, and those in the 7–9 range were considered as strong. See results of this survey in Table 1. The median score for 37 of the 37 recommendations was 7 or greater (out of maximum 9), meaning the expert panel considered all recommendations as strong (preferred management in most circumstances).

Results Literature review The literature search yielded 2111 unique papers in 2016. After title/abstract and subsequent full-text screening, 197 articles met the inclusion criteria and were selected for quality scoring: 85 articles for therapy, 101 for diagnosis, and 11 articles for both groups (detailed in supplementary figure/ list). Case reports and adult data were included in the final analysis, if pediatric data or stronger evidence were not available (the final 197 articles included 31 case reports and 108 adult studies).

Recommendations Diagnosis Several studies have shown a significant delay in diagnosis in jLS, typically 1–2 years [1, 2, 10, 11]. JLS can cause problems in growing children including joint contractures, leg length discrepancy, and facial deformity, and therefore prompt diagnosis and treatment is essential to improve outcomes and to limit these complications [19, 20]. The diagnosis of jLS is made clinically in most patients based on history and examination of the patient. A clinician with training and familiarity

Eur J Pediatr Figure 1 Search strategies

Search strategy (Pubmed search shown:) (((("Scleroderma, Localized/anatomy and histology"[Mesh] OR "Scleroderma, Localized/blood"[Mesh] OR "Scleroderma, Localized/classificaon"[Mesh] OR "Scleroderma, Localized/complicaons"[Mesh] OR "Scleroderma, Localized/cytology"[Mesh] OR "Scleroderma, Localized/diagnosis"[Mesh] OR "Scleroderma, Localized/drug therapy"[Mesh] OR "Scleroderma, Localized/epidemiology"[Mesh] OR "Scleroderma, Localized/eology"[Mesh] OR "Scleroderma, Localized/genecs"[Mesh] OR "Scleroderma, Localized/immunology"[Mesh] OR "Scleroderma, Localized/microbiology"[Mesh] OR "Scleroderma, Localized/mortality"[Mesh] OR "Scleroderma, Localized/physiopathology"[Mesh] OR "Scleroderma, Localized/prevenon and control"[Mesh] OR "Scleroderma, Localized/radiography"[Mesh] OR "Scleroderma, Localized/rehabilitaon"[Mesh] OR "Scleroderma, Localized/stascs and numerical data"[Mesh] OR "Scleroderma, Localized/surgery"[Mesh] OR "Scleroderma, Localized/therapy"[Mesh]))) OR ((jls[Title/Abstract]) NOT "Jarcho-Levin"[Title/Abstract])) OR (((((((juvenile*[Title/Abstract]) OR child*[Title/Abstract]) OR pediatric*[Title/Abstract]) OR paediatric*[Title/Abstract])) AND ((((((((((((localised[Title/Abstract]) OR localized[Title/Abstract]) OR linear[Title/Abstract]) OR plaque[Title/Abstract]) OR circumscribed[Title/Abstract]) OR deep[Title/Abstract]) OR generalised[Title/Abstract]) OR generalized[Title/Abstract]) OR mixed[Title/Abstract]) OR panscleroc[Title/Abstract]) OR subcutaneous[Title/Abstract]) OR profunda[Title/Abstract])) AND ((scleroderma[Title/Abstract]) OR morphea[Title/Abstract]))) OR ((((((juvenile*[Title/Abstract]) OR child*[Title/Abstract]) OR pediatric*[Title/Abstract]) OR paediatric*[Title/Abstract])) AND ((((("en coup de sabre"[Title/Abstract]) OR "progressive facial hemiatrophy"[Title/Abstract]) OR "progressive hemifacial atrophy"[Title/Abstract]) OR "ParryRomberg syndrome"[Title/Abstract]) OR "eosinophilic fasciis"[Title/Abstract])) AND (("1990/01/01"[PDat] : "2016/06/27"[PDat]))

2111 arcles

Inclusion criteria: Original arcles including explicit data about localized scleroderma

Exclusion criteria: Not about localized scleroderma

English language: 1842 arcles remained 350 arcles Exclusion: adult results, if pediatric data is avalable. 227 arcles

183 arcles

Selecon and full text review

44 case reports

166 arcles

Total papers used for recommendaons

31 case reports

in jLS should make the diagnosis, including pediatric dermatologists and pediatric rheumatologists. 1. Skin biopsy, histology Histopathological evaluation of the skin is usually unnecessary for the diagnosis of jLS. Yet, a skin biopsy may be helpful in atypical cases and occasionally to assess whether lesions are active or inactive. In these cases, a punch biopsy of 3 to 6 mm in diameter should

be taken, preferably from the erythematous border of the lesion. In the case of deep, generalized, or linear scleroderma or suspected eosinophilic fasciitis, an excisional biopsy involving the subcutaneous tissue is recommended [21]. Histopathologic changes can accurately reflect disease activity but are limited by sampling bias, and repeated biopsies are inconvenient and not well accepted by patients. Studies have shown that there is correlation between histopathologic changes and clinical/ultrasound findings [22].

Eur J Pediatr Table 1

The strength of the recommendations based on expert opinion

Number of recommendation

Median score

25 pc

75 pc

SD

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

9 9 8 7 8 9 9 9 9 9 9 7 8 7 6 7 9 9 9 8 9 9 8 8 9 9 8 9 7 9 8 9 9 9 9 7 8

8 9 6 6 7 8 8 9 8 9 5 5 7 7 6 6 9 7 8 8 9 8 8 8 9 9 6 8 7 9 6 9 9 9 8 6 7

9 9 9 9 9 9 9 9 9 9 9 9 9 8 8 9 9 9 9 9 9 9 9 8 9 9 9 9 8 9 9 9 9 9 9 8 8

1.80 1.33 2.83 2.54 1.94 2.29 2.29 1.72 1.69 1.66 2.12 2.28 1.73 1.32 2.07 1.48 1.72 1.94 1.64 1.58 2.33 1.64 1.58 3.03 1.67 1.00 2.65 1.66 1.58 1.33 2.74 1.33 1.67 1.01 1.09 1.62 2.55

Recommendations: 1. Diagnosis is primarily clinical and should be performed by a clinician with expertise in jLS such as a pediatric rheumatologist or pediatric dermatologist (4, D). 2. In atypical cases, a biopsy can be helpful. However, skin biopsy is not necessary in most patients who can be diagnosed by an expert based on typical clinical findings. If a biopsy is needed, a punch biopsy is appropriate. In cases of deep involvement, a deep biopsy may be deemed appropriate (4, D). 2. Laboratory characteristics in children with jLS Routine laboratory studies (including peripheral blood cell counts, acute-phase reactants) in patients with jLS are usually normal, although in more extensive and deep lesions, there may be an elevated white blood cell count or raised ESR

and CRP [4, 23, 24]. ESR can be elevated in up to 20% of children with linear scleroderma [4]. Muscle enzymes are elevated only in 10% children with jLS. When elevated, they may be an indicator of muscle involvement in linear scleroderma, as it has been associated with muscle atrophy and limb shortening in the CARRA jLS cohort of 259 patients [4, 23, 25]. Polyclonal hypergammaglobulinemia may be present in patients with jLS [4, 24]. In a multinational survey, antinuclear antibodies (ANAs) were found in 42.3% of patients with jLS. However, there was no correlation between the presence of ANAs and a particular subtype or the disease course [4]. Previous adult and pediatric studies have reported similar prevalence of ANA (ranges from 20 to 80%) [24, 26–32]. Systemic sclerosis-specific antibodies are rare in localized scleroderma [33]. Previous studies failed to detect these antibodies [26, 30, 34], but more recently published studies have shown that anti-Scl 70 and anti-centromere antibodies are positive in 1.3–7.7% of children with jLS [4, 23, 24, 33, 35]. In these series, none of the patients presented with signs or symptoms of internal organ involvement [4, 23, 32]. Anti-histone antibodies (AHA) were demonstrated in 47% (23/49) of adult patients with localized scleroderma (LS) and prevalence was even higher in patients with generalized morphea (87% (13/15)) [33, 36]. AHA positivity was reported also in pediatric case-series, but precise prevalence and significance is still unknown [37, 38]. Anti-single-stranded DNA antibodies have also been correlated to disease extent (areas affected and depth of lesions) as well as disability (joint contractures) [33, 38–40]. Only one group demonstrated correlation with disease activity [33], while another center demonstrated decrease antibody titer as the disease is treated and the severity score decreases [40]. The frequency of anti-single-stranded DNA antibodies in LS is quite variable from 8 to 50% in the literature in both pediatric onset and adult onset LS [33, 38, 40]. Rheumatoid factor was found in 16–26% of patients with jLS. Clinical significance of the presence or absence of rheumatoid factor is questionable. Zulian et al. found significant correlation with the presence of arthritis, while this has not been confirmed in other studies [4, 23, 24, 35]. Borrelia serology Early phase Lyme borreliosis can be associated with erythema migrans, or rarely borrelial lymphocytoma, both of them easily distinguishable from localized scleroderma. Sclerotic skin lesions strongly resembling morphea can be seen in 10% of patients with acrodermatitis chronica atrophicans, a late manifestation of Lyme borreliosis that is caused by Borrelia burgdorferi [41]. A large and growing body of literature has investigated the relationship between B. burgdorferi infection and LS.

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Although literature is highly conclusive against this hypothesis with most papers concluding that B. burgdorferi is not a causative agent for LS, it is still common practice in some centers to use antibiotics (even parenteral penicillin) for weeks during the initial treatment of jLS [42–47]. Although the clinical evaluation of patients with morphea and interpretation of Borrelia serology can be challenging [41, 48], the studies which reported a correlation, included only a limited number of patients [49, 50]. These results therefore need to be interpreted with caution. Rates of seropositivity were reported low in some case series [51, 52]. Results of PCR-based studies do not support a significant association of B. burgdorferi with LS [44, 53–57]. It is therefore unlikely that such connections exist between LS and B. burgdorferi infection. Recommendations: 3. Laboratory studies are not routinely needed to confirm a diagnosis of jLS (4, D). 4. In case of elevated laboratory results (e.g., ESR, CRP, CPK, aldolase, rheumatoid factor or eosinophilia) it is reasonable to repeat abnormal parameters during disease follow-up (3, C). 5. Evaluation of autoantibodies are not routinely recommended as a standard of clinical care as they are not disease specific, and there is no clear evidence for correlation between the presence of autoantibodies and disease course (2, B). 6. There is no clear evidence for pathogenetic role of Borrelia in jLS; therefore, routine serological testing for Borrelia infection is not supported (2, B). 3. Extra-cutaneous manifestations of jLS Extra-cutaneous manifestations are not uncommon in patients with jLS. In a cross-sectional survey by Zulian et al., approximately 20% of the reviewed patients had reported extra-cutaneous manifestations [4]. The most frequent extracutaneous symptom was arthritis, reported in 12% of children. In one fourth of this group of patients, arthritis was unrelated to the site of the skin lesion. Other studies reported a similar prevalence of arthritis/arthralgia [23, 24, 28]. Internal organ involvement, as seen in systemic sclerosis, is rare in patients with jLS. Gastro-esophageal reflux was reported as 1.6% [4, 58, 59]. These patients were symptomatic [58]. The same or even higher rate of gastro-esophageal reflux may occur in the general pediatric population (general prevalence rate 1.8–8%) [60]. Only 1% of patients were reported with respiratory symptoms (restrictive lung disease) in this PRES cohort, lower than expected in the general pediatric population (9%) [61]. Although none of these patients had other clinical features of

juvenile SSc or the presence of SSc-specific autoantibodies at the time of disease onset, the definitive diagnosis, cause of these observations, and the relationship with the jLS are not clear [58]. Less than 1% of patients had cardiac complications or renal involvement [58]. In a prospective study, including 20 children with jLS, Holter monitoring revealed no clinical relevant arrhythmias [62]. An observational study showed subclinical, not severe, cardiac abnormalities in adult patients with juvenile-onset disease [63]. There are only isolated case reports describing the co-existence of LS and SSc or the progression of LS to SSc [64–68]. Recommendations: 7. Routine screening for cardiopulmonary involvement (for example echocardiogram and pulmonary function tests) is not required in jLS (2, B). 8. Investigation for organ involvement should be considered in children presenting with symptoms or signs suggestive of systemic involvement as deemed appropriate by the clinician (4, D). 9. In the rare subgroups of pansclerotic morphea an evaluation for systemic involvement is suggested (4, D). 4. Cerebral imaging using MRI in children with craniofacial scleroderma In a large retrospective study of 130 patients, 23% (30) had craniofacial scleroderma. In this group, neurological involvement was reported in 21 patients and included seizures, recent onset headache, vascular malformations, behavioral changes, neuroimaging abnormalities, and EEG alterations [4]. It is important to highlight that 10 patients had neurological involvement unrelated to the site of scleroderma as has also been documented in other studies [23]. Neuroimaging was only performed in symptomatic patients so frequency of abnormalities may be higher [58]. Seizures were reported in 3/58 patients in a multi-center cohort, 2 with either en coup de saber (ECDS) or Parry–Romberg type disease [24]. In a retrospective chart review of 136 pediatric LS patients, involvement of the central nervous system was found overall in 10.2% of patients. Headaches were the most common feature and predominantly occurred in patients with ECDS [31]. Marzano et al. examined, retrospectively, 239 patients (113 adults and 126 children) with LS. Neurologic abnormalities were found in around 50% of children with craniofacial linear scleroderma or the mixed forms mentioned above. Brain MRI abnormalities were demonstrated in six patients, three of whom also showed neurologic symptoms, including seizures, hemiparesis, and muscle weakness episodes, respectively. Two other children complained of neurologic disturbances, such as migraine headaches and trigeminal neuralgia,

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respectively [28]. Brain cavernomas have been described in two children with ECDS. Both were associated with a hemorrhage, but it is unclear whether this was related to on-going inflammation [69]. The above studies show an association of craniofacial jLS with cerebral abnormalities. However, it is unclear of the progression or significance of asymptomatic changes and from these studies the authors do not comment on whether treatment was changed as a direct result of MRI or EEG abnormalities.

[72]. The difference in height on the affected side will continue to increase as the disease progresses, causing more obvious facial asymmetry, malocclusion of the teeth, and unilateral posterior cross bite. Also, radiographically, the teeth may have atrophic roots causing delayed tooth eruption, mixed dentition, and crowding [72]. The application of an individually designed functional dental hybrid appliance may delay and/or limit the degree of atrophy of the mandible by stimulating mandibular growth [73–75]. Recommendations:

Recommendations: 10. In a child with jLS affecting the head (face or scalp), a brain MRI with contrast is recommended at baseline and if any new neurological symptoms develop (3, C—based on pediatric data; 2, B—extrapolated from adult studies). 5. Uveitis “White Uveitis,” where inflammation occurs without overt symptoms of eye pain or erythema, is a known phenomenon to pediatric rheumatologists, as it is seen in patients with some forms of juvenile idiopathic arthritis. This kind of uveitis occurs in around 3.2–8.3% of the patients with jLS [58, 70]. Twenty-four out of 750 children (3.2%) revealed a significant ocular involvement without a standardized screening protocol, the majority of which had ECDS (66.7%) [58]. Of the 24 patients with eye involvement, 10 patients (41.7%) reported adnexa (eyelids and eyelashes) abnormalities, 7 (29.2%) anterior segment inflammation (5 anterior uveitis, 2 episcleritis), and 3 central nervous system-related abnormalities [71]. JLS patients, especially those with head lesions, have a significant risk of developing uveitis (3, C) [70]. However, the outcome of jLS-associated uveitis is poorly documented due to the lack of prospective studies. Recommendations: 11. In craniofacial jLS, uveitis screening every 6 months with slit-lamp examination is recommended for the first 4 years of the disease (4, D). 12. In non-facial jLS, uveitis screening every 12 months is recommended for the first 4 years (4, D). 6. Dental assessment. Dental abnormalities are not uncommon in facial jLS, especially when the onset of disease is less than 10 years of age due to the immature (growing) mandible, maxilla, and dentition. Hypoplasia of the maxilla and mandible on the affected side are described in Parry–Romberg

13. Dental assessment is suggested for any child with craniofacial jLS (3, C). 14. Baseline dental assessment, including panoramic radiographs, is recommended as early detection of abnormalities and a functional dental appliance may result in clinically significant morphologic changes (4, D). 15. Continued dental assessment with serial panoramic radiographs is supported as clinically indicated, but the group did not specify exact interval (4, D). 7. Temporomandibular joint (TMJ) involvement in children with facial scleroderma There is limited published data on the prevalence of TMJ involvement in children with localized scleroderma affecting the face. However, general articular involvement in general (47.2%) was the most common extra-cutaneous manifestation noted in a large international cohort of children with jLS [58] and oral changes are common in craniofacial involvement [28]. In a UK cohort of jLS, jaw involvement (including one patient with ankylosis) occurred in 3/31 (10%) patients with facial lesions [24]. In the cohort of Foeldvari et al., 9/47 (20%) had TMJ involvement, and 6 of these patients had skin involvement involving the face (unpublished data). Obtaining a history and physical assessment of the TMJ is simple and recommended for screening to avoid long-term effects of TMJ arthritis. Signs and symptoms of TMJ arthritis include the following: a history of jaw stiffness/pain, clicking of the jaw, pain with chewing, findings on examination of tender TMJ, pain in the TMJ at maximal mouth opening, decreased oral aperture, or asymmetrical mouth opening on examination. When these findings are present, imaging of the TMJs with contrast-enhanced MRI is recommended. Screening all subjects with jLS of the head with an MRI of the TMJs is not recommended as there is a relatively high false-positive rate of TMJ effusion and more minor subset of synovial enhancement in healthy subjects [76, 77]. Recommendations: 16. In a patient with jLS affecting the face, a physical examination of the temporomandibular joint by a

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pediatric rheumatologist is suggested at least 6 monthly (3, C). 17. There is no evidence to suggest screening for TMJ involvement, e.g., by MRI, in the absence of any abnormality detected by history and clinical examination alone (4, D). 8. Combined assessment Patients with all forms of jLS are first seen mainly by general practitioners or pediatricians, and then referred to pediatric dermatologists and/or pediatric rheumatologists [2, 10]. To our knowledge, no exact numbers exist of how many patients with jLS are seen by a dermatologist or a pediatric rheumatologist, but it seems to be likely that patients with only superficial localized scleroderma are mostly seen by a dermatologist/pediatric dermatologist and not a pediatric rheumatologist. The children with the more severe forms of jLS, such as linear scleroderma, are seen mainly by a pediatric rheumatologist, but also by dermatologists. In some settings, there are combined scleroderma clinics or patients are seen by both disciplines at separate times. Studies have shown that dermatologists more often tend to treat with topical and light-based therapies whereas pediatric rheumatologists more often treat jLS with systemic therapy [2]. Some of the differences in the approaches from these specialties stem from the different treatment approaches to the different LS subtypes. Linear scleroderma involving face and limbs or crossing any joint can be disfiguring and potentially disabling without systemic therapy. On the other hand, a superficial lesion, which does not lead to cosmetic changes or contracture does not require systemic immunosuppression. To avoid over- or under-treatment it would be wise to see patients in a combined assessment at least once a year. When there is no possibility of a combined clinic, each discipline should see the patient once a year. Recommendations: 18. All patients with jLS, except for those with solitary small superficial plaque scleroderma, should be seen at baseline and minimum of every 12 months by a pediatric rheumatologist and (pediatric) dermatologist ideally in a combined clinic (4, D). 9. Outcome measures to assess cutaneous involvement Current cutaneous clinical assessments of localized scleroderma include the DIET (Dyspigmentation, Induration, Erythema, Telengiectasias), modified Rodnan Skin Score (mRSS), modified Localized Scleroderma Skin Index (mLoSSI), and Localized Scleroderma Damage Index (LoSDI) outcome scoring measures. There are also available

instruments to assess localized scleroderma lesions, such as the computerized skin score (2, B), durometer (2, B), ultrasonography (2, B), thermography (3, C), and laser Doppler flowmetry (2, B); however, these devices are either not available at most institutions or do not have a trained investigator at the site [78–83]. They do not fulfill currently the OMERACT criteria [84]. Many of these have been used as complementary tools to cutaneous physical examination, but are not the main outcome measures directing management. Therefore, the focus of the discussion was on clinical assessment involving measures obtained from basic clinical examination. The DIET assessment includes a combination of parameters of activity, such as erythema and induration, and damage, such as dyspigmentation and telangiectasia. DIET was originally used to monitor treatment response of topical agents [85]. Potential issues with this assessment are the lack of telangectasias in jLS and that the score is a combination of disease activity and damage parameters. The mRSS is almost universally used to monitor skin thickness in SSc, which typically associates with internal organ severity. It possesses good interrater reliability with training: 0.58–0.87 [86]. However, in LS, skin thickness is only one of the components of perceived skin activity. A LS specific skin scoring system was developed and further validated by the Localized Scleroderma Clinical and Ultrasound Study (LOCUS) group, the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). This measure has two separate components, an activity score termed the modified Localized Scleroderma Severity Skin Index (mLoSSI) and a damage score termed the Localized Scleroderma Damage Index (LoSDI). The mLoSSI captures the following disease activity parameters: new lesion, expanding lesion, erythema/violaceous color, and skin thickness. These variables were determined as core features of disease activity in LS when the LOCUS group was surveyed using mean rank, consensus agreement, and content validity index, with resulting consensus agreement > 75% and item level CVI 0.88–1.00, supporting content validity [87]. Intra- and inter-rater reliability were demonstrated to be excellent (ICC 0.78–0.99) and improved with minimal training and practice [87]. The mLoSSI correlated moderately (rs = 0.49) with the Physician Global Assessment of Disease Activity (PGA-A), which is considered the “surrogate” gold standard for disease activity in LS; therefore, supporting convergent construct validity. One of the more important features of the mLoSSI score is its sensitivity to change demonstrated in patients with active disease with clinical responsiveness, demonstrating a standardized response mean of 1.35 (considered large) and standard effect size of 0.95 (considered large) within 3 months of systemic therapy [87, 88]. A recent publication describes the ability of the mLoSSI to differentiate between groups of LS subjects who have responded to therapy and have changed from active status to inactive status (compared to no change in activity status), with a minimal clinically

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important difference of 6 points (IQR 4–8), which correlated strongly and significantly to the change in PGA-A (rs = 0.783, p < 0.01) [89]. The LoSDI captures the following disease damage parameters: dermal atrophy, subcutaneous atrophy, and dyspigmentation (hyper- or hypopigmentation). In a similar manner to the development and validation of the mLoSSI, the LoSDI variables were determined as core features of disease damage in LS when the LOCUS group was surveyed using mean rank, consensus agreement, and content validity index, with resulting consensus agreement > 75% and item level CVI 0.88–1.00, supporting content validity for LS cutaneous damage [90]. The reliability of LoSDI was excellent with intra-rater reliability (ICC 0.99) and intra-rater reliability (ICC 0.96). The convergent construct validity of LoSDI is supported by moderate correlation (r s = 0.58) with the physician Global Assessment of Disease Activity (PGA-D) [90].

(a) Child/parent global assessment of disease severity on a visual analogue scale of 0–10 cm. (b) Children’s Dermatology Life Quality Index completed by patient or when not applicable due to the age of the child by the parent.

Treatment 1. Antibiotic treatment Available and relevant literature does not suggest a causative link between LS and B. burgdorferi infection; therefore, antibiotic treatment is not recommended in jLS. Recommendations: 21. There is no scientific evidence available to support the use of antibiotic treatments for jLS (4, D).

Recommendations: 2. Topical therapy for jLS 19. Physician Global—Activity (PGA-A) and Physician Global—Damage (PGA-D) and the LoSCAT, with mLoSSI component for disease assessment of activity and the LoSDI component, are acceptable tools for capturing cutaneous disease activity and damage (2, B). . 10.Quality of life measures in children with JLS The group agreed the importance of measuring quality of life (QOL) as an outcome measure and consensus agreement was to use the Children’s Dermatology Life Quality Index (CDLQI). This generic skin QOL measure was chosen because it is simple to complete, widely used, reliable, and validated in many European languages [91]. Two studies have assessed quality of life in childhood scleroderma using CDLQI [12–14]. In the most recent study, of the 75 children evaluated, 28% experienced a moderate or greater impact on QOL (CDLQI score > 5) [14]. The group also agreed on that patient/parent global assessment of disease severity on a visual analogue scale (VAS) on a horizontal line of 10 cm should form part of routine assessment. There is lacking data on the use of this tool in jLS, although parent- and child-reported VAS for pain and global health is widely reported in juvenile idiopathic arthritis where it is quick, easy, and widely accepted by patients and families. Recommendations: 20. Patient-related outcome measures should be considered as an adjunct to clinical outcome measures and the following are recommended for serial measurements (2, B):

JLS can cause functional and cosmetic deformity, including secondary joint contractures and/or limb length discrepancy. It is widely accepted that widespread, progressive, deep lesions, lesions crossing joints, and/or those on a cosmetically sensitive location should be treated with systemic immunosuppressant [92]. However, early lesions of plaque-type or guttate morphea can be amenable to topical therapy. Topical therapy of LS lesions consists mainly of four different types of agents: calcipotriol, corticosteroids, imiquimod, and calcineurin inhibitors, which may be used either alone or in combination. Topical calcipotriol In an uncontrolled trial of topical calcipotriene (0.005%, twice daily under occlusion), all 12 patients (aged 12 to 38 years) were reported as having exhibited improved skin scores after 1–3 months [85]. In a second uncontrolled trial, calcipotriol ointment was used without occlusion, but in combination with UVA-1 in 19 children and showed improvement in 19/19 children [93]. It is therefore unclear whether the reported improvement was attributable to calcipotriol, UVA, a combination of both, or spontaneous remission [94]. In an uncontrolled study of six patients (age range 15–59 years) with plaque-type morphea, a combination of calcipotriol plus betamethasone dipropionate ointment was reported to be “effective” and well tolerated [95]. Topical corticosteroids Although widely used in clinical practice, there are no published studies on the effectiveness of topical steroids in LS except a study in adults where betamethasone was used in combination with calcipotriol [95]. Topical steroids that might be considered are those with a favorable risk/benefit ratio, i.e., those with a therapeutic

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index of 2.0 (i.e., prednicarbate, methylprednisolone, mometasone). Due to the risk of skin atrophy with prolonged use, topical corticosteroid use on a daily basis should be limited. Topical calcineurin inhibitors The efficacy of topical tacrolimus ointment (0.1%) was assessed in a controlled trial involving seven adult patients [96]. Tacrolimus was applied twice daily under occlusion (overnight) and resulted in resolution of early inflammatory lesions and softening of late sclerotic lesions after 3 months. Topical imiquimod Imiquimod is an inducer of interferon. A study of imiquimod 5% cream used three to seven times per week in 12 patients (age range 6–77 years) with different types of LS, including linear circumscribed superficial, general plaque morphea, for up to 6 months showed improvement of dyspigmentation, induration, and erythema in all cases [97]. A further clinical trial examined the topical application of imiquimod 5% cream for 9 months in nine children and revealed decreasing thickening of plaque morphea and states that this treatment is safe for pediatric use [98]. Recommendations: 22. Topical treatments (tacrolimus 0.1%, calcipotriol 0.005%, topical corticosteroids, imiquimod) without systemic immunosuppression may be appropriate in patients with small-circumscribed superficial nonprogressive morphea which does not cross a joint and occurs in non-cosmetically sensitive areas (1A, B—extrapolated from adult studies; 3, C—pediatric studies). 23. All other types of jLS require systemic immunosuppression (4, D). 3. Phototherapy and UV therapy. UVA therapy may represent an alternative to systemic therapy in some cases of profound or linear scleroderma after the age of 12 years. Unfortunately, only a few randomized controlled studies assessing LS treatment have been published so far, and even fewer of these addressed either topical or UV therapy, and virtually none of those published reported the efficacy (and safety) of topical or UV therapy in children [94, 99]. Therapeutic options presented here are thus largely based on the results from case series on adult patients only. Different types of UV therapy have been described as effective in adult LS. While PUVA therapy (psoralen ultraviolet A) should not be used in children and adolescents because of

concerns of long-term carcinogenicity, narrowband UVB (UVBNB, 308 nm) and UVA-1 (340–400 nm) have been demonstrated in a controlled study to be efficacious in adult LS [100]. Sixty-four patients were randomized to receive either low-dose UVA-1 (total dose, 800 J/cm2), medium-dose UVA1 (2000 J/cm2), or UVBNB (0.1–1.5 J/cm2 according to skin type) three times weekly for 8 weeks. All patient groups responded with a significant decrease in skin scores. UVBNB seems to be more efficacious for superficial lesions, while UVA-1 is also active against deeper LS lesions and even joint contractures [94, 99]. These studies support the efficacy of different UVA/B modalities in adult LS which may be extrapolated to jLS; however, potential safety concerns are unknown. Optimum doses and treatment regimens still need to be established as well. Recommendations: 24. For circumscribed small superficial non-progressive lesions, which are not crossing a joint and occur in non-cosmetically sensitive areas (preferentially in children above the age of 12) light treatment, preferably UVA-1 or alternatively UVB narrowband, is a treatment option. However, PUVA therapy should be avoided (1B, A—extrapolated from adult studies; there is no available pediatric evidence). 4. Systemic treatment Optimal therapy for jLS is not known. Methotrexate (MTX) is often the first choice of therapy based on previous retrospective evaluations, clinical experience, and consensus [23, 99, 101], and was chosen by Zulian et al. as the treatment for the active arm of the only randomized placebo controlled trial in jLS. All children were treated with 3 months of oral prednisolone and all responded in the target lesion, but in some new lesions occurred. At 1 year, there was disease relapse in 32.6% of the MTX group compared to 70.8% of the placebo (p < 0.005) [102]. There are differences in practice and between specialties with pediatric rheumatologists tending to use mores systemic therapies such as MTX whereas dermatologists tend to use topical treatments more commonly [92, 94, 99, 102, 103]. Interestingly, when asked to detail their recommendations for the treatment of a hypothetical patient with moderate to severe linear scleroderma, although there was strong agreement for the use of MTX in combination with a corticosteroid, there was a large diversity in the exact treatment regimen among pediatric rheumatologists in the USA and Canada [92].

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Presumably, the best results can be achieved if treatment is initiated before the occurrence of any damage. Long-term follow-up (average 30 years) of patients with juvenile-onset LS from the Morphea in Adult and Children Repository at the University of Texas Southwestern showed that ~ 89% of patients had continued disease activity in adulthood. Most had been treated, with topical steroids only. Fifty-six percent of the patients in this group (all with the linear subtype of the disease) had permanent sequelae, emphasizing the need for early effective treatment [104]. The duration of treatment remains a matter of debate, though in regard to MTX, most pediatric localized scleroderma centers treat for a minimum of remission of disease features for at least 1 year [88, 103].

contractures. Orthopedic complications are reported in approximately 30 to 50% of patients with linear scleroderma of the limb(s). Peterson and colleagues reported mild to moderate disability at follow-up in those with LS of the extremities (mean follow-up time of 9.2 years) [4, 31, 112]. Intensive physical and occupational therapy in conjunction with systemic immunosuppressive therapy is recommended for those with linear or deep scleroderma of the extremities, to help avoid and/or minimize joint contractures [112].

Therapy in MTX non-responders Martini et al. described 10 MTX-resistant patients with jLS successfully treated with mycophenolate mofetil (MMF) [105]. Furthermore, there are case reports of the use of tocilizumab cyclosporine A, abatacept, rituximab, and infliximab [106–110]. The use in clinical practice of other DMARDs and biologics has been documented in clinician surveys [92]. There is some data regarding effectiveness from biologics in skin component of SSc in adults, which could be extrapolated to LS [111].

6. Plastic surgery

Recommendations: 25. Systemic treatment beyond topical treatment is suggested for active disease in all subtypes of jLS except for non-progressive small-circumscribed superficial morphea which are not crossing joints and occur in non-cosmetically sensitive areas (4, D). 26. First-line treatment should be with methotrexate 15 mg/m2/week, max 25 mg/week either orally or subcutaneously (1B, A). 27. A minimum of 3 months of corticosteroid therapy while MTX induction occurs is recommended (4, D). 28. Systemic treatment should be changed if disease inactivity is not achieved after 6 months or there is no response after 3 months (4, D). 29. There is currently limited evidence for second line therapies for MTX non-responders. Options including MMF (either switching or in addition to MTX) (3, C) or biologics, such as abatacept and infliximab (4, D—extrapolated from adult case series, no pediatric evidence is available). 5. Physiotherapy Of particular concern in jLS is that permanent shortening or atrophy of the limb can occur commonly with joint

Recommendations: 30. Physiotherapy and/or occupational therapy are recommended for any patients with decreased range of motion in any joints or with muscle weakness (4, D)

Surgical interventions may be considered in LS. Joint contractures might be amenable to surgical release. In Parry– Romberg syndrome, plastic surgical intervention aims at reconstitution of deep atrophic skin areas through fat grafting techniques, particularly in the periorbital and cheek area. The optimal time point for intervention still needs to be established [113]. Early intervention may have a role to decrease psychological impact of facial dysmorphia. Currently, autologous microfat grafting is emerging as a new effective technique to correct dystrophic changes in the face [114, 115]. Recommendations: 31. Reconstructive surgery may be appropriate in individual cases. However, any surgery should be undertaken with caution and ideally with at least 6 months of disease inactivity (4, D) 7. Treatment of extra-cutaneous manifestations Extra-cutaneous manifestations need systemic therapy in most cases and should be treated with MTX or other immunosuppressive agents according to evidence base and best practice for the given association, such as uveitis or arthritis [116]. Seizure medication should be given by a pediatric neurologist according to neuropediatric guidelines. Recommendations: 32. Extra-cutaneous manifestations associated with jLS should be treated according to treatment guidelines for the given association (e.g., uveitis, arthritis, seizures) (4, D).

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8. Active disease There are several definitions of active disease, which include the appearance of a new lesion, extension of existing lesions, erythema throughout the lesion, or the presence of an erythematous/violaceous rim [82, 117]. Other modalities beyond skin examination are helpful in determining disease status, such as ultrasound and thermography. However, these are not available at all institutions and require training; therefore, they can support evaluation of disease activity but are not necessary to define active disease [80, 82, 103, 117, 118]. 9. Inactive disease The definition of disease inactivity has been described as no new lesions, no extension of prior lesions, and lack of erythema. Inactivity in deeper lesions can be harder to define by these parameters. Recommendations: 33. The aim of treatment is to reach disease inactivity (4, D). 34. Disease inactivity is defined as (4, D): (a) (b) (c) (d) (e) (f)

No erythema No new lesions over past 3 months No enlarging lesions over past 3 months No worsening of skin thickness No worsening of joint contractures Physician global assessment on visual analogue scale (VAS) of 0 (where 0 represents no disease activity, 100 represents worst disease activity) (g) No active extra-cutaneous involvement (such as uveitis, arthritis, neurological involvement)

10.Remission There are no universally accepted definitions of remission in jLS. Clinical remission does require completely inactive disease, either on or off medications. As a clinical recommendation, our group suggested a 12-month period of disease inactivity representing remission. This was based on consensus only. Recommendations: 35. Remission is defined as 12 months of disease inactivity (4, D). 36. Systemic treatment should not be stopped before at least 12 months of disease inactivity (4, D).

37. There is currently no evidence to suggest whether systemic treatment should be stopped or tapered at this stage (4, D).

Discussion This paper presents a multidisciplinary effort to create a proposal for diagnosis, assessment, and treatment of jLS. It is part of an on-going process to improve the standard of care for children with this potentially disfiguring disease. It is very important to foster collaboration between pediatric rheumatology and dermatology/pediatric dermatology to establish common pathways of care, which are acceptable to both specialties and allow the best outcomes for children. We invited pediatric dermatologists and pediatric rheumatologists, from different countries and institutions, to represent the diversity in current management, as shown in previous studies [3, 11, 92]. Diagnosis of jLS is usually based on clinical judgment, although skin biopsy can be helpful in unusual cases. Laboratory tests (inflammatory markers, full blood count, autoantibodies) are usually of limited value as do not tend to correlate with disease activity or severity. Organ involvement as usually seen in SSc are not observed in jLS, and therefore routine screening for these manifestations are not recommended. However, musculoskeletal involvement, and in patients with facial/scalp LS, TMJ, dental, eye, and CNS involvement should be evaluated. This review and development of recommendations highlights the paucity of robust evidence to define the efficacy and safety of treatments of jLS with only one randomized controlled trial being identified in children. There are smaller non-controlled and prospective studies; however, the recommendations developed from this consensus group are largely based on expert opinion. Comparison of various therapeutic modalities is challenging due to the non-homogenous patient groups and differences in definitions of disease activity/ inactivity. There are many available instruments to assess LS lesions, such as mRSS, durometer, ultrasonography, thermography, and laser Doppler flowmetry. The availability of some of these devices is limited in routine clinical practice. Currently available cutaneous clinical assessments of LS include DIET, mRSS, and the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). LoSCAT has two separate components, an activity score (mLoSSI) and a damage score (LoSDI). Pediatric rheumatologists and some academic dermatologists mostly use the LoSCAT, which is a validated tool in pediatric LS [89, 90]. The LoSCAT and other cutaneous scoring systems do not capture the important extra-

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cutaneous component of the disease, which occurs at 22.4% in the largest survey in this patient population [4]. Tools to evaluate extra-cutaneous manifestations are currently being developed by various pediatric rheumatology and dermatology investigators. On-going collaboration between dermatologists and pediatric rheumatologists on a national and international level is vital to facilitate prospective and robust clinical trials to better define treatment plans to improve the outcomes of children with jLS. The widespread use of validated outcome measures for assessment of response to treatment in clinical practice and in clinical studies is key. The optimum corticosteroid regimen to facilitate rapid disease control needs to be defined, as does the role of topical therapies, particularly as an adjunct to systemic therapies. Efficacious and well-tolerated treatments for MTX nonresponders are required. Some promising therapies supported by more recent case series include tocilizumab [110] and abatacept [119]. These recommendations will need review as further evidence on the treatment of jLS becomes available. Future research direction:

2.

3.

4.

5. 6.

7.

& & & &

Clinical trials are required to define optimal corticosteroid regimens to induce remission together with the use of MTX. Studies are needed to define efficacious treatments for MTX non-responders. The role of topical therapies and light-based therapies need to be defined. Studies to standardize evaluation of extra-cutaneous manifestations are required.

Authors’ Contributions Kathryn S. Torok is senior author. Ivan Foeldvari designed the initiative. Annamária Pálinkás, Melinda Laczkovszki performed the systematic literature review, supervised by Tamás Constantin. Validity assessment of selected papers was done by Tamás Constantin, Ivan Foeldvari, Clare E Pain, Peter Höger, Monika Moll, Dana Nemkova, Lisa Weibel, Kathryn S. Torok. Recommendations were formulated by Tamás Constantin, Ivan Foeldvari and Clare E Pain. The expert committee consisted of Tamás Constantin, Ivan Foeldvari, Clare E Pain, Peter Höger, Monika Moll, Dana Nemkova, Lisa Weibel, Kathryn S. Torok; they completed the online surveys and participated in consensus meeting. Philip Clements assisted in the preparation of the live consensus meeting and facilitated the consensus procedure using nominal group technique. Tamás Constantin, Clare E Pain and Kathryn S. Torok wrote the manuscript, with contribution and approval of all co-authors.

Informed consent no confidential data were used regarding this work.

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9. 10.

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References 1.

Johnson W, Jacobe H (2012) Morphea in adults and children cohort II: patients with morphea experience delay in diagnosis and large variation in treatment. J Am Acad Dermatol 67:881–889

16.

Weibel L, Laguda B, Atherton D, Harper JI (2011) Misdiagnosis and delay in referral of children with localized scleroderma. Br J Dermatol 165:1308–1313 Li SC, Torok KS, Pope E, Dedeoglu F, Hong S, Jacobe HT, Rabinovich CE, Laxer RM, Higgins GC, Ferguson PJ, Lasky A, Baszis K, Becker M, Campillo S, Cartwright V, Cidon M, Inman CJ, Jerath R, O'Neil KM, Vora S, Zeft A, Wallace CA, Ilowite NT, Fuhlbrigge RC (2012) Development of consensus treatment plans for juvenile localized scleroderma: a roadmap toward comparative effectiveness studies in juvenile localized scleroderma. Arthritis Care Res 64:1175–1185 Zulian F, Athreya BH, Laxer R, Nelson AM, Feitosa de Oliveira SK, Punaro MG, Cuttica R, Higgins GC, Van Suijlekom-Smit LW, Moore TL, Lindsley C, Garcia-Consuegra J, Esteves Hilario MO, Lepore L, Silva CA, Machado C, Garay SM, Uziel Y, Martini G, Foeldvari I, Peserico A, Woo P, Harper J, Juvenile Scleroderma Working Group of the Pediatric Rheumatology European S (2006) Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology (Oxford, England) 45:614–620 Nouri S, Jacobe H (2013) Recent developments in diagnosis and assessment of morphea. Curr Rheumatol Rep 15:308 Herrick AL, Ennis H, Bhushan M, Silman AJ, Baildam EM (2010) Incidence of childhood linear scleroderma and systemic sclerosis in the UK and Ireland. Arthritis Care Res 62:213–218 Weibel L (2012) Localized scleroderma (morphea) in childhood. Der Hautarzt; Zeitschrift Dermatol, Venerol Verwandte Geb 63: 89–96 Kreuter A, Krieg T, Worm M, Wenzel J, Gambichler T, Kuhn A, Aberer E, Scharffetter-Kochanek K, Hunzelmann N (2009) AWMF guideline no. 013/066. Diagnosis and therapy of circumscribed scleroderma. J Deutschen Dermatol Ges = J German Soc Dermatol: JDDG 7(Suppl 6):S1–S14 Peterson LS, Nelson AM, Su WP (1995) Classification of morphea (localized scleroderma). Mayo Clin Proc 70:1068–1076 Hawley DP, Baildam EM, Amin TS, Cruikshank MK, Davidson JE, Dixon J, Martin NS, Ohlsson V, Pilkington C, Rangaraj S, Riley P, Sundaramoorthy C, Walsh J, Foster HE (2012) Access to care for children and young people diagnosed with localized scleroderma or juvenile SSc in the UK. Rheumatology (Oxford, England) 51:1235–1239 Hawley DP, Pain CE, Baildam EM, Murphy R, Taylor AE, Foster HE (2014) United Kingdom survey of current management of juvenile localized scleroderma. Rheumatology (Oxford, England) 53:1849–1854 Baildam EM, Ennis H, Foster HE, Shaw L, Chieng AS, Kelly J, Herrick AL, Richards HL (2011) Influence of childhood scleroderma on physical function and quality of life. J Rheumatol 38: 167–173 Orzechowski NM, Davis DM, Mason TG 3rd, Crowson CS, Reed AM (2009) Health-related quality of life in children and adolescents with juvenile localized scleroderma. Rheumatology (Oxford, England) 48:670–672 Das S, Bernstein I, Jacobe H (2014) Correlates of self-reported quality of life in adults and children with morphea. J Am Acad Dermatol 70:904–910 Kreuter A, Krieg T, Worm M, Wenzel J, Moinzadeh P, Kuhn A, Aberer E, Scharffetter-Kochanek K, Horneff G, Reil E, Weberschock T, Hunzelmann N (2016) German guidelines for the diagnosis and therapy of localized scleroderma. J Deutschen Dermatol Ges = J German Soc Dermatol: JDDG 14:199–216 Dougados M, Betteridge N, Burmester GR, Euller-Ziegler L, Guillemin F, Hirvonen J, Lloyd J, Ozen S, Da Silva JA, Emery

Eur J Pediatr

17.

18.

19.

20. 21. 22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

P, Kalden JR, Kvien T, Matucci-Cerinic M, Smolen J (2004) EULAR standardised operating procedures for the elaboration, evaluation, dissemination, and implementation of recommendations endorsed by the EULAR standing committees. Ann Rheum Dis 63:1172–1176 Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, Gerster J, Jacobs J, Leeb B, Liote F, McCarthy G, Netter P, Nuki G, Perez-Ruiz F, Pignone A, Pimentao J, Punzi L, Roddy E, Uhlig T, Zimmermann-Gorska I (2006) EULAR evidence based recommendations for gout. Part I: diagnosis. Report of a task force of the standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 65:1301–1311 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, Gerster J, Jacobs J, Leeb B, Liote F, McCarthy G, Netter P, Nuki G, Perez-Ruiz F, Pignone A, Pimentao J, Punzi L, Roddy E, Uhlig T, Zimmermann-Gorska I (2006) EULAR evidence based recommendations for gout. Part II: management. Report of a task force of the EULAR standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 65: 1312–1324 Piram M, McCuaig CC, Saint-Cyr C, Marcoux D, Hatami A, Haddad E, Powell J (2013) Short- and long-term outcome of linear morphoea in children. Br J Dermatol 169:1265–1271 Blaszczyk M, Janniger CK, Jablonska S (1996) Childhood scleroderma and its peculiarities. Cutis 58:141–144, 148–152 (2009) Weedon’s skin pathology. Churchill Livingstone Wortsman X, Wortsman J, Sazunic I, Carreno L (2011) Activity assessment in morphea using color Doppler ultrasound. J Am Acad Dermatol 65:942–948 Beltramelli M, Vercellesi P, Frasin A, Gelmetti C, Corona F (2010) Localized severe scleroderma: a retrospective study of 26 pediatric patients. Pediatr Dermatol 27:476–480 Herrick AL, Ennis H, Bhushan M, Silman AJ, Baildam EM Clinical features of childhood localized scleroderma in an incidence cohort. Rheumatology (Oxford, England) 50:1865–1868 Wu EY, Li SC, Torok KS, Virkud Y, Fuhlbrigge R, Rabinovich CE (2014) A28: Description of the Juvenile Localized Scleroderma Subgroup of the CARRA Registry. Arthritis Rheumatol (Hoboken, NJ) 66(Suppl 11):S43–S44 Uziel Y, Krafchik BR, Silverman ED, Thorner PS, Laxer RM (1994) Localized scleroderma in childhood: a report of 30 cases. Semin Arthritis Rheum 23:328–340 Vancheeswaran R, Black CM, David J, Hasson N, Harper J, Atherton D, Trivedi P, Woo P (1996) Childhood-onset scleroderma: is it different from adult-onset disease. Arthritis Rheum 39: 1041–1049 Marzano AV, Menni S, Parodi A, Borghi A, Fuligni A, Fabbri P, Caputo R (2003) Localized scleroderma in adults and children. Clinical and laboratory investigations on 239 cases. Europ J Dermatol: EJD 13:171–176 Rosenberg AM, Uziel Y, Krafchik BR, Hauta SA, Prokopchuk PA, Silverman ED, Laxer RM (1995) Antinuclear antibodies in children with localized scleroderma. J Rheumatol 22:2337–2343 Takehara K, Moroi Y, Nakabayashi Y, Ishibashi Y (1983) Antinuclear antibodies in localized scleroderma. Arthritis Rheum 26:612–616 Christen-Zaech S, Hakim MD, Afsar FS, Paller AS (2008) Pediatric morphea (localized scleroderma): review of 136 patients. J Am Acad Dermatol 59:385–396 Laxer RM, Zulian F (2006) Localized scleroderma. Curr Opin Rheumatol 18:606–613

33. 34.

35.

36.

37.

38.

39.

40.

41. 42. 43.

44.

45.

46.

47.

48. 49.

50.

51.

52.

Takehara K, Sato S (2005) Localized scleroderma is an autoimmune disorder. Rheumatology (Oxford, England) 44:274–279 Sato S, Fujimoto M, Ihn H, Kikuchi K, Takehara K (1994) Clinical characteristics associated with antihistone antibodies in patients with localized scleroderma. J Am Acad Dermatol 31: 567–571 Lo CY, Shyur SD, Chu SH, Huang LH, Kao YH, Lei WT, Cheng CH, Lee KH, Chen CK, Liu LC Juvenile scleroderma: experience in one institution. Asian Pac J Allergy Immunol/ Launched Allergy Immunol Soc Thailand 28:279–286 Parodi A, Drosera M, Barbieri L, Rebora A (1995) Antihistone antibodies in scleroderma. Dermatology (Basel, Switzerland) 191: 16–18 el-Azhary RA, Aponte CC, Nelson AM, Weaver AL, Homburger HA (2006) Antihistone antibodies in linear scleroderma variants. Int J Dermatol 45:1296–1299 Dharamsi JW, Victor S, Aguwa N, Ahn C, Arnett F, Mayes MD, Jacobe H (2013) Morphea in adults and children cohort III: nested case-control study—the clinical significance of autoantibodies in morphea. JAMA dermatology 149:1159–1165 Falanga V, Medsger TA Jr, Reichlin M, Rodnan GP (1986) Linear scleroderma. Clinical spectrum, prognosis, and laboratory abnormalities. Ann Intern Med 104:849–857 Arkachaisri T, Fertig N, Pino S, Medsger TA Jr (2008) Serum autoantibodies and their clinical associations in patients with childhood- and adult-onset linear scleroderma. A single-center study. J Rheumatol 35:2439–2444 Weber K (2009) Is juvenile localized scleroderma related to Lyme borreliosis? J Am Acad Dermatol 61:901 Weide B, Walz T, Garbe C (2000) Is morphoea caused by Borrelia burgdorferi? A review. Br J Dermatol 142:636–644 Fan W, Leonardi CL, Penneys NS (1995) Absence of Borrelia burgdorferi in patients with localized scleroderma (morphea). J Am Acad Dermatol 33:682–684 Dillon WI, Saed GM, Fivenson DP (1995) Borrelia burgdorferi DNA is undetectable by polymerase chain reaction in skin lesions of morphea, scleroderma, or lichen sclerosus et atrophicus of patients from North America. J Am Acad Dermatol 33:617–620 Raguin G, Boisnic S, Souteyrand P, Baranton G, Piette JC, Godeau P, Frances C (1992) No evidence for a spirochaetal origin of localized scleroderma. Br J Dermatol 127:218–220 Vaillant L, Goudeau A (1992) Localized scleroderma is not a Borrelia burgdorferi infection in France. Dermatology (Basel, Switzerland) 184:286–288 Lupoli S, Cutler SJ, Stephens CO, Wright DJ, Black CM (1991) Lyme disease and localized scleroderma—no evidence for a common aetiology. Br J Rheumatol 30:154–156 Eisendle K, Zelger B (2009) The expanding spectrum of cutaneous borreliosis. G Ital Dermatol Venereol 144:157–171 Ozkan S, Atabey N, Fetil E, Erkizan V, Gunes AT (2000) Evidence for Borrelia burgdorferi in morphea and lichen sclerosus. Int J Dermatol 39:278–283 Schempp C, Bocklage H, Lange R, Kolmel HW, Orfanos CE, Gollnick H (1993) Further evidence for Borrelia burgdorferi infection in morphea and lichen sclerosus et atrophicus confirmed by DNA amplification. J Invest Dermatol 100:717–720 Akimoto S, Ishikawa O, Miyachi Y (1996) The absence of antibodies against Borrelia burgdorferi in the sera of Japanese patients with localized scleroderma. J Rheumatol 23:573–574 Espinoza-Leon F, Hassanhi-Hassanhi M, Arocha-Sandoval F, Urbina-Lopez M (2006) Absence of Borrelia burgdorferi

Eur J Pediatr

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65. 66.

antibodies in the sera of Venezuelan patients with localized scleroderma (morphea). Investig Clin 47:283–288 Zollinger T, Mertz KD, Schmid M, Schmitt A, Pfaltz M, Kempf W (2010) Borrelia in granuloma annulare, morphea and lichen sclerosus: a PCR-based study and review of the literature. J Cutan Pathol 37:571–577 Goodlad JR, Davidson MM, Gordon P, Billington R, Ho-Yen DO (2002) Morphoea and Borrelia burgdorferi: results from the Scottish highlands in the context of the world literature. Mol Pathol: MP 55:374–378 Weide B, Schittek B, Klyscz T, Schuz K, Stark M, Rassner G, Wilske B, Garbe C (2000) Morphoea is neither associated with features of Borrelia burgdorferi infection, nor is this agent detectable in lesional skin by polymerase chain reaction. Br J Dermatol 143:780–785 Wienecke R, Schlupen EM, Zochling N, Neubert U, Meurer M, Volkenandt M (1995) No evidence for Borrelia burgdorferispecific DNA in lesions of localized scleroderma. J Invest Dermatol 104:23–26 Ranki A, Aavik E, Peterson P, Schauman K, Nurmilaakso P (1994) Successful amplification of DNA specific for Finnish Borrelia burgdorferi isolates in erythema chronicum migrans but not in circumscribed scleroderma lesions. J Invest Dermatol 102: 339–345 Zulian F, Vallongo C, Woo P, Russo R, Ruperto N, Harper J, Espada G, Corona F, Mukamel M, Vesely R, MusiejNowakowska E, Chaitow J, Ros J, Apaz MT, Gerloni V, MazurZielinska H, Nielsen S, Ullman S, Horneff G, Wouters C, Martini G, Cimaz R, Laxer R, Athreya BH, Juvenile Scleroderma Working Group of the Pediatric Rheumatology European S (2005) Localized scleroderma in childhood is not just a skin disease. Arthritis Rheum 52:2873–2881 Weber P, Ganser G, Frosch M, Roth J, Hulskamp G, Zimmer KP (2000) Twenty-four hour intraesophageal pH monitoring in children and adolescents with scleroderma and mixed connective tissue disease. J Rheumatol 27:2692–2695 Nelson SP, Chen EH, Syniar GM, Christoffel KK (2000) Prevalence of symptoms of gastroesophageal reflux during childhood: a pediatric practice-based survey. Pediatric Practice Res Group. Arch Pediatr Adolesc Med 154:150–154 Akinbami LJ, Moorman JE, Garbe PL, Sondik EJ (2009) Status of childhood asthma in the United States, 1980–2007. Pediatrics 123(Suppl 3):S131–S145 Wozniak J, Dabrowski R, Luczak D, Kwiatkowska M, MusiejNowakowska E, Kowalik I, Szwed H (2009) Evaluation of heart rhythm variability and arrhythmia in children with systemic and localized scleroderma. J Rheumatol 36:191–196 Borowiec A, Dabrowski R, Wozniak J, Jasek S, Chwyczko T, Kowalik I, Musiej-Nowakowska E, Szwed H (2011) Cardiovascular assessment of asymptomatic patients with juvenile-onset localized and systemic scleroderma: 10 years prospective observation. Scand J Rheumatol 41:33–38 Hayashi M, Ichiki Y, Kitajima Y (2009) Coexistence of recurrent generalized morphea and systemic sclerosis. Acta Derm Venereol 89:329–330 Holzmann H, Schlieter A (1994) Coexistence of morphea and systemic sclerosis. Dermatology (Basel, Switzerland) 189:99 Soma Y, Tamaki T, Kikuchi K, Abe M, Igarashi A, Takehara K, Ishibashi Y (1993) Coexistence of morphea and systemic sclerosis. Dermatology (Basel, Switzerland) 186:103–105

67.

68.

69.

70.

71.

72. 73. 74.

75.

76.

77.

78.

79.

80.

81.

82.

Maricq HR (1992) Capillary abnormalities, Raynaud’s phenomenon, and systemic sclerosis in patients with localized scleroderma. Arch Dermatol 128:630–632 Carneiro S, Ramos-e-Silva M, Russi DC, Albuquerque EM, Sousa MA (2011) Coexistence of generalized morphea and lichen sclerosus et atrophicus mimicking systemic disease. Skinmed 9: 131–133 Fain ET, Mannion M, Pope E, Young DW, Laxer RM, Cron RQ, Brain cavernomas associated with en coup de sabre linear scleroderma (2011) Two case reports. Pediatr Rheumatol Online J 9:18 Zannin ME, Martini G, Athreya BH, Russo R, Higgins G, Vittadello F, Alpigiani MG, Alessio M, Paradisi M, Woo P, Zulian F, Juvenile Scleroderma Working Group of the Pediatric Rheumatology European S (2007) Ocular involvement in children with localised scleroderma: a multi-centre study. Br J Ophthalmol 91:1311–1314 Martini G, Foeldvari I, Russo R, Cuttica R, Eberhard A, Ravelli A, Lehman TJ, de Oliveira SK, Susic G, Lyskina G, Nemcova D, Sundel R, Falcini F, Girschick H, Lotito AP, Buoncompagni A, Sztajnbok F, Al-Mayouf SM, Orban I, Ferri C, Athreya BH, Woo P, Zulian F, Juvenile Scleroderma Working Group of the Pediatric Rheumatology European S (2006) Systemic sclerosis in childhood: clinical and immunologic features of 153 patients in an international database. Arthritis Rheum 54:3971–3978 Foster TD (1979) The effects of hemifacial atrophy on dental growth. Br Dent J 146:148–150 You KH, Baik HS (2011) Orthopedic and orthodontic treatment of Parry–Romberg syndrome. J Craniofac Surg 22:970–973 Vig PS, Vig KW (1986) Hybrid appliances: a component approach to dentofacial orthopedics. Am J Orthod Dentofac Orthop 90:273–285 Grippaudo C, Deli R, Grippaudo FR, Di Cuia T, Paradisi M (2004) Management of craniofacial development in the Parry–Romberg syndrome: report of two patients. Cleft Palate Craniofac J 41:95– 104 Tzaribachev N, Fritz J, Horger M (2009) Spectrum of magnetic resonance imaging appearances of juvenile temporomandibular joints (TMJ) in non-rheumatic children. Acta Radiologica (Stockholm, Sweden: 1987) 50:1182–1186 Stoll ML, Guleria S, Mannion ML, Young DW, Royal SA, Cron RQ, Vaid YN (2018) Defining the normal appearance of the temporomandibular joints by magnetic resonance imaging with contrast: a comparative study of children with and without juvenile idiopathic arthritis. Pediatr Rheumatol Online J 16:8 Zulian F, Meneghesso D, Grisan E, Vittadello F, Belloni Fortina A, Pigozzi B, Frigo AC, Martini G, Ruggeri A (2007) A new computerized method for the assessment of skin lesions in localized scleroderma. Rheumatology (Oxford, England) 46:856–860 Poff S, Li SC, Kelsey CE, Foeldvari I, Torok KS (2016) Durometry as an outcome measure in juvenile localized scleroderma. Br J Dermatol 174:228–230 Li SC, Liebling MS (2009) The use of Doppler ultrasound to evaluate lesions of localized scleroderma. Curr Rheumatol Rep 11:205–211 Li SC, Liebling MS, Haines KA (2007) Ultrasonography is a sensitive tool for monitoring localized scleroderma. Rheumatology (Oxford, England) 46:1316–1319 Li SC, Liebling MS, Haines KA, Weiss JE, Prann A (2011) Initial evaluation of an ultrasound measure for assessing the activity of skin lesions in juvenile localized scleroderma. Arthritis Care Res 63:735–742

Eur J Pediatr 83.

Weibel L, Howell KJ, Visentin MT, Rudiger A, Denton CP, Zulian F, Woo P, Harper JI (2007) Laser Doppler flowmetry for assessing localized scleroderma in children. Arthritis Rheum 56:3489–3495 84. Boers M, Brooks P, Strand CV, Tugwell P (1998) The OMERACT filter for outcome measures in rheumatology. J Rheumatol 25: 198–199 85. Cunningham BB, Landells ID, Langman C, Sailer DE, Paller AS (1998) Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol 39:211–215 86. Pope JE, Baron M, Bellamy N, Campbell J, Carette S, Chalmers I, Dales P, Hanly J, Kaminska EA, Lee P et al (1995) Variability of skin scores and clinical measurements in scleroderma. J Rheumatol 22:1271–1276 87. Arkachaisri T, Vilaiyuk S, Li S, O'Neil KM, Pope E, Higgins GC, Punaro M, Rabinovich EC, Rosenkranz M, Kietz DA, Rosen P, Spalding SJ, Hennon TR, Torok KS, Cassidy E, Medsger TA Jr, Localized Scleroderma C, Ultrasound Study G (2009) The localized scleroderma skin severity index and physician global assessment of disease activity: a work in progress toward development of localized scleroderma outcome measures. J Rheumatol 36: 2819–2829 88. Torok KS, Arkachaisri T (2012) Methotrexate and corticosteroids in the treatment of localized scleroderma: a standardized prospective longitudinal single-center study. J Rheumatol 39:286–294 89. Kelsey CE, Torok KS (2013) The localized scleroderma cutaneous assessment tool: responsiveness to change in a pediatric clinical population. J Am Acad Dermatol 69:214–220 90. Arkachaisri T, Vilaiyuk S, Torok KS, Medsger TA Jr Development and initial validation of the localized scleroderma skin damage index and physician global assessment of disease damage: a proof-of-concept study. Rheumatology (Oxford, England) 49:373–381 91. Lewis-Jones MS, Finlay AY (1995) The Children’s Dermatology Life Quality Index (CDLQI): initial validation and practical use. Br J Dermatol 132:942–949 92. Li SC, Feldman BM, Higgins GC, Haines KA, Punaro MG, O'Neil KM (2010) Treatment of pediatric localized scleroderma: results of a survey of North American pediatric rheumatologists. J Rheumatol 37:175–181 93. Kreuter A, Gambichler T, Avermaete A, Jansen T, Hoffmann M, Hoffmann K, Altmeyer P, von Kobyletzki G, Bacharach-Buhles M (2001) Combined treatment with calcipotriol ointment and lowdose ultraviolet A1 phototherapy in childhood morphea. Pediatr Dermatol 18:241–245 94. Zwischenberger BA, Jacobe HT (2011) A systematic review of morphea treatments and therapeutic algorithm. J Am Acad Dermatol 65:925–941 95. Dytoc MT, Kossintseva I, Ting PT (2007) First case series on the use of calcipotriol-betamethasone dipropionate for morphoea. Br J Dermatol 157:615–618 96. Mancuso G, Berdondini RM (2005) Localized scleroderma: response to occlusive treatment with tacrolimus ointment. Br J Dermatol 152:180–182 97. Dytoc M, Ting PT, Man J, Sawyer D, Fiorillo L (2005) First case series on the use of imiquimod for morphoea. Br J Dermatol 153: 815–820 98. Pope E, Doria AS, Theriault M, Mohanta A, Laxer RM (2011) Topical imiquimod 5% cream for pediatric plaque morphea: a prospective, multiple-baseline, open-label pilot study. Dermatology (Basel, Switzerland) 223:363–369 99. Fett N, Werth VP Update on morphea: part II. Outcome measures and treatment. J Am Acad Dermatol 64:231–242 quiz 243–234

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112. 113.

114.

Kreuter A, Hyun J, Stucker M, Sommer A, Altmeyer P, Gambichler T (2006) A randomized controlled study of lowdose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma. J Am Acad Dermatol 54:440–447 Vilela FA, Carneiro S, Ramos-e-Silva M Treatment of morphea or localized scleroderma: review of the literature. J Drugs Dermatol: JDD 9:1213–1219 Zulian F, Martini G, Vallongo C, Vittadello F, Falcini F, Patrizi A, Alessio M, La Torre F, Podda RA, Gerloni V, Cutrone M, BelloniFortina A, Paradisi M, Martino S, Perilongo G (2011) Methotrexate treatment in juvenile localized scleroderma: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 63:1998–2006 Weibel L, Sampaio MC, Visentin MT, Howell KJ, Woo P, Harper JI (2006) Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children. Br J Dermatol 155:1013–1020 Saxton-Daniels S, Jacobe HT An evaluation of long-term outcomes in adults with pediatric-onset morphea. Arch Dermatol 146:1044–1045 Martini G, Ramanan AV, Falcini F, Girschick H, Goldsmith DP, Zulian F (2009) Successful treatment of severe or methotrexateresistant juvenile localized scleroderma with mycophenolate mofetil. Rheumatology (Oxford, England) 48:1410–1413 Stausbol-Gron B, Olesen AB, Deleuran B, Deleuran MS (2011) Abatacept is a promising treatment for patients with disseminated morphea profunda: presentation of two cases. Acta Derm Venereol 91:686–688 Perez Crespo M, Betlloch Mas I, Mataix Diaz J, Lucas Costa A, Ballester Nortes I (2009) Rapid response to cyclosporine and maintenance with methotrexate in linear scleroderma in a young girl. Pediatr Dermatol 26:118–120 Ferguson ID, Weiser P, Torok KS (2015) A case report of successful treatment of recalcitrant childhood localized scleroderma with infliximab and leflunomide. Open Rheumatol J 9:30–35 Heiligenhaus A, Michels H, Schumacher C, Kopp I, Neudorf U, Niehues T, Baus H, Becker M, Bertram B, Dannecker G, Deuter C, Foeldvari I, Frosch M, Ganser G, Gaubitz M, Gerdes G, Horneff G, Illhardt A, Mackensen F, Minden K, Pleyer U, Schneider M, Wagner N, Zierhut M (2012) Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Rheumatol Int 32: 1121–1133 Ivan Foeldvari JA, Friswell M, Bica B, de Inocencio J, Aquilani A, Helmus N (2017) Tocilizumab is a promising treatment option for therapy resistant juvenile localized scleroderma patients. J Scleroderma Relat Disord 2:203–207 Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, Karampetsou M, Yiannopoulos G, Andonopoulos AP (2010) Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford, England) 49:271–280 Torok KS (2012) Pediatric scleroderma: systemic or localized forms. Pediatr Clin N Am 59:381–405 Palmero ML, Uziel Y, Laxer RM, Forrest CR, Pope E (2010) En coup de sabre scleroderma and Parry–Romberg syndrome in adolescents: surgical options and patient-related outcomes. J Rheumatol 37:2174–2179 Sautereau N, Daumas A, Truillet R, Jouve E, Magalon J, Veran J, Casanova D, Frances Y, Magalon G, Granel B (2016) Efficacy of

Eur J Pediatr

115.

116.

autologous microfat graft on facial handicap in systemic sclerosis patients. Plastic Reconstr Surg Global Open 4:e660 Magalon J, Daumas A, Veran J, Magalon G, Rossi P, Granel B, Sabatier F (2015) Autologous adipose tissue-derived cells: are we talking about adipose derived stem cells, stromal vascular fraction, or Coleman fat grafting? Cell Transplant 24:2667–2668 Dueckers G, Guellac N, Arbogast M, Dannecker G, Foeldvari I, Frosch M, Ganser G, Heiligenhaus A, Horneff G, Illhardt A, Kopp I, Krauspe R, Markus B, Michels H, Schneider M, Singendonk W, Sitter H, Spamer M, Wagner N, Niehues T (2012) Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis. Clin Immunol 142:176–193

117.

118.

119.

Zulian F, Vallongo C, Patrizi A, Belloni-Fortina A, Cutrone M, Alessio M, Martino S, Gerloni V, Vittadello F, Martini G (2012) A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea). J Am Acad Dermatol 67:1151–1156 Martini G, Murray KJ, Howell KJ, Harper J, Atherton D, Woo P, Zulian F, Black CM (2002) Juvenile-onset localized scleroderma activity detection by infrared thermography. Rheumatology (Oxford, England) 41:1178–1182 Adeeb F, Anjum S, Hodnett P, Kashif A, Brady M, Morrissey S, Devlin J, Fraser AD (2017) Early- and late-stage morphea subtypes with deep tissue involvement is treatable with abatacept (Orencia). Semin Arthritis Rheum 46:775–781

Affiliations Tamás Constantin 1 & Ivan Foeldvari 2 & Clare E. Pain 3 & Annamária Pálinkás 1 & Peter Höger 4 & Monika Moll 5 & Dana Nemkova 6 & Lisa Weibel 7 & Melinda Laczkovszki 1 & Philip Clements 8 & Kathryn S. Torok 9 1

Semmelweis University, Budapest, Hungary

6

Charles University, Prague, Czech Republic

2

Hamburger Zentrum für Kinder- und Jugendrheumatologie, Hamburg, Germany

7

Department of Dermatology, University Children’s Hospital Zurich, Zurich, Switzerland

3

Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

8

4

Department of Paediatric Dermatology, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany

David Geffen School of Medicine at UCLA, Division of Rheumatology, Los Angeles, CA, USA

9

University of Pittsburgh, Pittsburgh, PA, USA

5

University Childrens Hospital, Tuebingen, Germany