Childhood Systemic Sclerosis
Francesco Zulian; Giorgia Martini Curr Opin Rheumatol. 2007;19(6):592-597. ?2007 Lippincott Williams & Wilkins
Abstract and Introduction
Purpose of review: Juvenile systemic
sclerosis has a variety of clinical manifestations, sometimes different
from the adult form. Early recognition, proper classification and
treatment may improve the long-term outcome.
Juvenile systemic sclerosis (JSSc) is a chronic multisystemic connective tissue disease characterized by symmetrical thickening and hardening of the skin, associated with fibrous changes in internal organs. Although rare in children, it represents one of the most severe rheumatic conditions in pediatric rheumatology practice.
In the past few years, a few published papers have characterized the clinical features of patients with JSSc based on experiences with large cohorts of patients. One publication on pediatric-specific classification criteria was also recently published.
In this paper, we review these important studies along with some new developments on disease monitoring, treatment and long-term outcome. Although many of these studies focus on adult onset systemic sclerosis (SSc), the recommendations may be applicable to children with modifications.
To date, no classification criteria are available for children. According to the 1980 American Rheumatism Association criteria for adults, the SSc classification requires the presence either of the major criterion (fibrosis/induration involving areas proximal to the metacarpo-phalangeal or metatarso-phalangeal joints) or two minor criteria (sclerodactyly, digital pitting scars, bibasilar pulmonary fibrosis). This classification was designed to be specific rather than sensitive to minimize false-positive ascertainment. Subsequently, the widespread use of nailfold capillary microscopy, the more precise autoimmune serologic tests, and the early detection of Raynaud's phenomenon in patients who, years later, developed SSc has raised the need for a more comprehensive and pediatric-specific classification.
The lack of classification criteria for children has posed a barrier to the initiation of clinical trials and to a standardized clinical approach to the patients' care. Using clinical data from real patients in combination with a consensus-based methodology, an ad-hoc Committee on Classification Criteria for Juvenile Systemic Sclerosis - a combined effort of the Pediatric Rheumatology European Society, the American College of Rheumatology and the European League Against Rheumatism (EULAR) - developed new classification criteria to help standardize the conduct of clinical, epidemiological and outcome research for this rare pediatric disease.[2??] These criteria, which will supplant the adult criteria that have been used until now, will help ensure an accurate diagnosis of SSc and not other similar conditions such as overlap syndromes, a localized form of scleroderma or genetic sclerodermatous conditions such as progeria.
The criteria were developed in three phases, the first of which included the retrospective collection of information on demographic, clinical, and laboratory features of patients diagnosed with SSc before age 16 from pediatric rheumatology centers worldwide. In phase II, the Classification Committee developed questionnaires based on the data collected in phase I and sent them to 14 pediatric and adult rheumatologists with expertise in JSSc. The experts selected the parameters essential for classification of the disease based on their experience and, among those with the highest final scores, the variables with a prevalence of at least 50% at the time of diagnosis were selected as major criteria; the remaining criteria were listed as minor.
In the third phase, the provisional criteria were tested in a Consensus Conference using the clinical profiles of 160 actual patients with a variety of diagnoses, including 100 from patients with definite JSSc collected in phase I. Of 86 different provisional classification criteria tested on the case profiles of the 127 patients, the criterion with the highest ranking was that which required the presence of proximal skin sclerosis/induration and at least two minor criteria ( Table 1 ). This set of criteria showed sensitivity of 90%, specificity of 96%, and Cohen K value of 0.86.
Although validated with actual patient data, the new classification criteria must undergo validation in an external prospective trial.
New Insights in Clinical Presentation and Distinctive Features From Adult Form
Two main studies helped to clarify the clinical picture of SSc in children of large populations.[3?,4??] Onset in childhood is very uncommon: children under 16 years of age account for less than 5% of all cases[3?] and fewer than 10% of all patients develop SSc before the age of 20. The onset occurs at a mean age of 8.1 years and the peak age is between 10 and 16 years.[3?,4??] The disease is almost four-fold more frequent in females and there is no racial predilection.[4??]
The onset is often insidious. The mean time between the first sign of the disease and the diagnosis of JSSc is between 1.9 and 2.8 years with a range between 0 and 12.2 years.[3?,4??] Overlap syndromes, most frequently with polymyositis-dermatomyositis, accounted for 29% of all cases in a large study.[3?]
In JSSc, the clinical features at the onset of the disease mainly include Raynaud's phenomenon and skin induration ( Table 2 ), which develops later and is the second most frequent sign.[4??,5] Therefore, the association of Raynaud's and skin changes, eventually with some signs of internal organ involvement or capillary abnormalities, represent key diagnostic features.
In children with SSc, visceral involvement appears different from the adult form, particularly at the moment of diagnosis. In fact, compared with adults, at diagnosis children show a significantly less frequent involvement of all organs, except for the prevalence of arthritis. Differences with adults become less evident during follow up, with the exception of interstitial lung involvement, gastroesophageal dysmotility, renal involvement, and arterial hypertension, which are significantly more common in adults. Other differences with SSc in adults can be seen in the prevalence of arthritis, which is slightly more common in children, while Raynaud's phenomenon and skin sclerosis are fairly less frequent in the pediatric age group.[4??,5,6] For other internal organs, a similar pattern of involvement has been seen in adult and pediatric patients. Scalapino et al.[3?] observed that muscle inflammation was present in up to 38% of children with SSc and was a distinguishing feature from adult SSc. These results may be influenced by the fact that the population examined in this study included children with overlap syndromes and mixed connected tissue diseases, which have more frequent muscle involvement, as shown in previous studies.
In general, a comparison with adult series is difficult because in children the limited cutaneous form, which is far more frequent in adults, is rare. It has now been shown, however, that a substantial number of patients with childhood-onset SSc have their diagnosis made either during adolescence or as young adults.[3?] Indeed, it is possible that the limited cutaneous subset may be underdiagnosed in younger children because of the lack of a full clinical picture.
High titers of antinuclear antibodies (ANAs) are commonly found with a frequency of 81-97% in children with JSSc.[3?,4??,5] Interestingly, a high proportion of children ranging from 20 to 34% are ANA positive. Antitopoisomerase I autoantibodies are present in 28-34% of patients, while the prevalence of anticentromere antibodies is lower in children compared with adults. Anti-polymyositis-Scl and anti-U1RNP antibodies correlate with conditions such as overlap syndrome with muskulo-skeletal involvement and anti RNA-polymerase III antibodies are very unusual in parallel with the rarity of renal involvement in JSSc.[3?]
The frequency of occurrence of rheumatoid factor and antiphospholipid antibodies is similar in adults and children with SSc.[4??,6]
Another important open issue to be addressed is the lack of validated outcome measures for children with SSc. For this reason, when we follow a child with JSSc we use parameters already established in adults. These organ-specific parameters have been mostly validated in previous studies and in recent randomized controlled trials (RCTs)[7-9] using the Outcome Measures for Arthritis Clinical Trials (OMERACT) filter.
Some outcome measures, such as skin thickness score, measures of Raynaud's, forced vital capacity, diffusing capacity for carbon monoxide (DLCO), Health Assessment Questionnaire disability index and Medical Outcomes survey Short-Form 36 (SF-36) have demonstrated statistically significant changes by treatment groups. During the last OMERACT 8, held in 2006, other parameters, such as high-resolution computed tomography of the lung, 6 min walking test, creatinine clearance and patient reported outcome have been proposed as possible outcome measures for adult SSc.
These outcome measures and other more pediatric-specific measures such as the Modified Rodnan Skin Score (MRSS; adapted for children), the Child Health Questionnaire (CHQ-PF50), the Childhood Health Assessment Questionnaire (CHAQ), the patient/parent self-reported questionnaire and gut permeability test for malabsorption are going to be evaluated in prospective studies involving children with JSSc.
For skin evaluation, a recent study has evaluated MRSS in a group of children with mechanical pain or juvenile idiopathic arthritis (JIA) to establish normal values for the pediatric population. With the limitation of having included in the study patients with 'rheumatic' and not healthy children, the authors found a mean MRSS of 13.9 (range 4-25) that extended well into the 'abnormal' range for adult patients with SSc, as the mean MRSS in healthy adults is 0.[11?] Indeed, since the MRSS in children correlates with the BMI and the Tanner stage, it should be corrected for these two parameters if used as an outcome measure in clinical trials.
For patient function and quality of life, two child-specific outcome measures already validated in JIA and juvenile dermatomyositis (JDM), CHAQ and CHQ-PF50, could also be extended to JSSc.
The CHAQ is a reliable and sensitive instrument for measuring the functional status in children with JIA. It has been used in a variety of settings and translated into a number of different languages while maintaining excellent reliability, validity, and parent-child correlations. It can be administered to children of all ages and thus is of great potential use in the clinical setting for the long-term follow up of children with JIA, JDM and, probably, JSSc.
The CHQ-PF50 utilizes the same structure and methodological approach as the SF-36 adult version but, being developed specifically for children and adolescents, includes salient domains such as self-esteem and family functioning that are not found in the SF-36. The latest version of CHQ-PF50 consists of 50 items measuring the following domains: physical functioning, bodily pain, emotional/behaviour, mental health, general behaviour, self esteem, parent impact on time and emotion, family limitation and cohesion. It has good psychometric properties, especially in the ability to discriminate between the presence/absence of chronic conditions, and represents a good candidate outcome measure in children with SSc.
Regarding vascular involvement, Raynaud's phenomenon is one of the earliest manifestations of the disease and a very common clinical problem in JSSc.[4??]
In a multicenter retrospective study evaluating the safety and efficacy of iloprost for the treatment of ischemic digits in children with connective tissue disease, including JSSc, response to treatment was assessed by patient/parent Raynaud's phenomenon activity assessment (visual analogue scale - VAS), physician Raynaud's phenomenon activity assessment (VAS), Raynaud's phenomenon frequency (number of attacks/week), Raynaud's phenomenon duration (mean duration of attacks/week). Digital ulcers as a complication of Raynaud's phenomenon or vasculitis were evaluated by both digital ulcer count and pain (VAS). These parameters can be potential markers for disease change evaluation in JSSc.
The pharmacologic management of patients with JSSc is challenging since no drug has been shown to be of unequivocal benefit in either children or adults with SSc. For this reason, a EULAR task force of 18 SSc international experts, including two pediatric rheumatologists and two representatives of patients with SSc, have very recently tried to establish some recommendations to guide clinicians in the management of SSc. This was done, at first, through the definition of a preliminary set of research questions concerning SSc treatment, provided by 74 EULAR Scleroderma Trial and Research (EUSTAR) centers by a Web-based Delphi survey. These questions were presented to the experts who selected a final set of 26 questions for the systematic literature research performed using Pubmed, Medline, EMBASE, and Cochrane databases. Retrieved manuscripts were evaluated according to the Jadad classification and the level of evidence was graded from I to IV. A final set of 14 recommendations for the treatment of SSc included three on SSc-related digital vasculopathy (Raynaud's phenomenon and ulcers), four on SSc-related pulmonary arterial hypertension, three on SSc-related gastrointestinal involvement, two on scleroderma renal crisis, one on SS-related interstitial lung disease and one on skin involvement.
These recommendations were subsequently evaluated by a panel of 18 pediatric experts on JSSc to test their agreement on the appropriateness for children. Through a Dephi survey, they were asked to approve, disapprove or state the lack of experience for each of the 14 recommendations. The results of this survey were recently presented at the Pediatric Rheumatology European Society meeting in Istanbul.
For nine recommendations concerning the use of cyclophosphamide in active interstilial lung disease, prostanoids in digital ulcers, calcium channel blockers in Raynaud's phenomenon, corticosteroids as possible risk factors for scleroderma renal crisis, methotrexate for skin manifestation in the early phase, ACE for renal crisis and proton pump inhibitors for esophageal involvement, prokinetics for symptomatic motility disturbances and rotating antibiotics for malabsorption due to bacterial overgrowth, a consensus greater than 85% among experts was reached. For the recommendation on continuous intravenous epoprostenol for SSc-related pulmonary arterial hypertension (PAH), the majority of experts had no experience. As far as new experimental drugs (i.e. bosentan for PAH and digital ulcers, sitaxentan and sindenafil), the experts expressed interest for future applications in pediatric clinical trials although there was not enough experience at present to recommend their use.
In conclusion, most of the recommendations for the management of SSc in adults can be extended to pediatric-onset SSc. An international cooperation, following a standardized operative procedure, is needed, however, to validate the strength of these and future recommendations.
Mycophenolate mofetil (MMF) has been successfully used for early diffuse scleroderma and lung disease.[20?] The apparent safety and tolerability of this drug was confirmed in a recent retrospective study. Data from 109 patients with diffuse cutaneous systemic sclerosis treated with MMF were compared with those of 63 controls receiving other immunosuppressive drugs. MMF was discontinued due to disease stabilization in 9%, side effects in 8% or no effects on disease activity in 14%. A lower frequency of clinically significant pulmonary fibrosis and better 5-year survival from disease onset were reported. According to the authors' conclusion, MMF appears to be at least as effective as the other current therapies for diffuse SSc, providing support for further evaluation in prospective clinical trials.
Rituximab, an anti-CD20 monoclonal antibody, has been used, in combination with cyclophosphamide, in a small series of six patients with severe refractory JSSc. All patients, followed for 3-12 months (mean 8.33 months) reported subjective improvement in skin tightness and sense of well being. No changes in DLCO were observed, although one patient with mild PAH showed improvement in pulmonary artery pressures. The therapy was well tolerated, with the exception of mild infusion reactions responsive to premedication. Although this therapeutic approach is of interest, larger and longer-term studies are needed to evaluate efficacy.
Recent studies have shown that the prognosis of SSc in children appears better than in adults. The survival of childhood onset SSc at 5, 10, 15 and 20 years after diagnosis is 89%, 80-87.4%, 74-87.4% and 69-82.5%, respectively, and is significantly higher than in adult onset disease.[3?,23]
The commonest causes of death in children are related to the involvement of cardiac, renal, and pulmonary systems. Indeed, cardiomyopathy is a leading cause of early death, especially in children. This complication is rare and usually associated with diffuse cutaneous disease and features of polymyositis. An aggressive immunosuppressive treatment has been shown to be effective on muscle, skin and lung involvement, but does not impair progression of myocardial dysfunction.
In children with poor prognosis, diagnosis is made earlier as probably clinical manifestations are clear since the onset of the disease and severe enough to lead rapidly to death, as shown by the fact that most of the deaths occurred in the first 5 years after diagnosis. In children, therefore, SSc may have two possible evolutions: few children have a rapid development of internal organ failure leading to severe disability and eventually to death, while other patients experience a slow insidious course of the disease with lower mortality.
Compared with studies in adults[25,26] in which the diffuse cutaneous SSc subset is considered a risk factor for higher mortality, this does not appear so relevant in children. Probably this observation is influenced by the fact that in children a clear-cut differentiation between the various subsets is difficult as the limited cutaneous form is rare.[4??] Similarly, in adult series the presence of antitopoisomerase I and anti-RNA polymerase III antibodies, and the male gender have been associated with poorer survival, while in children no clear relationship was found between serological features, age at onset, gender and mortality.
Important contributions over the past few months have included the descriptions of clinical manifestations of children with SSc, highlighting the fact that, in comparison to adult-onset disease, JSSc appears to be less severe with less internal organ involvement, has a less specific autoantibody profile and better long-term outcome. New approaches to the monitoring and treatment of JSSc have been presented and require further study.
As soon as disease activity and damage outcome measures are defined and validated, we should be able to measure accurately the effects of new drug regimens in controlled clinical trials and better compare patient groups.
Table 1. Preliminary Classification Criteria for Juvenile Systemic Sclerosis (SSc)
Table 2. Prevalence of Clinical Features in Juvenile Systemic Sclerosis at the Time of Diagnosis and During the Overall Course of the Disease
Papers of particular interest, published within
the annual period of review, have been highlighted as:
CHQ-PF50 = Child Health Questionnaire; JIA = juvenile idiopathic arthritis; JSSc = juvenile systemic sclerosis; MMF = mycophenolate mofetil; MRSS = Modified Rodnan Skin Score; SF-36 = Medical Outcomes survey Short-Form 36; SSc = systemic sclerosis
Correspondence to Francesco Zulian, MD, Professor, Chief, Pediatric Rheumatology Unit, Department of Pediatrics, Via Giustiniani 3, 35128 Padova, Italy Tel: +39 049 8213583; fax: +39 049 8218088; e-mail: email@example.com
Francesco Zulian, and Giorgia Martini, Pediatric Rheumatology Unit, Department of Pediatrics, University of Padova, Italy