Juvenile Scleroderma: Staying One Step Ahead of a Rare Disease

The range of outcomes varies greatly for children impacted by juvenile or pediatric scleroderma. In the best case scenario, patients with localized disease may experience mild fibrosis of the skin, often on the extremities, that can resolve by adulthood. Children with systemic scleroderma usually face more severe complications, such as the disease impacting vital organs, including the heart and lungs.

Clare Pain, MD, consultant pediatric rheumatologist in the Department of Rheumatology at Alder Hey Children’s NHS Foundation Trust in Liverpool, England, further explained the disease in an interview with Healio Rheumatology.

“Scleroderma describes a group of rare conditions which are characterized by fibrosis of the skin and soft tissues. The majority of children are affected by localized, rather than systemic scleroderma,” she said.

Due to the rarity of the disease, many children, particularly those with localized disease, are either undiagnosed or misdiagnosed, according to Pain.

“This affects outcomes as children therefore experience a delay in starting effective treatment,” she said. “They can accrue more damage.”

One issue surrounding the disease is uncertainty about whether pediatric patients should be diagnosed and managed the same way as adults, according to Ivan Foeldvari, MD, of Hamburger Zentrum für Kinder und Jugendrheumatologie, Kompetenz-Zentrum für Sklerodermie und Uveitis im Kindes- und Jugendalter, Lehrbereich des Asklepios Campus der Semmelweis-Universität, BudapestAn der Schön Klinik Hamburg Eilbek.

“My research has demonstrated that all pediatric patients fulfill the new adult criteria for systemic sclerosis,” he said.

Healio Rheumatology spoke with experts to describe juvenile scleroderma in its entirety, from epidemiology to advances in therapy.

Overview

Kathryn S. Torok, MD, assistant professor of rheumatology at Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, wrote an overview on juvenile scleroderma in Pediatric Clinics of North America. Consensus opinion is that many experts are uncertain about the causes of pediatric scleroderma. There is some speculation that it involves cells lining small blood vessels. However, it may also be an immune disorder, possibly triggered by elevated collagen levels.

Data from the Cleveland Clinic suggest 5,000 to 7,000 children in the United States have scleroderma. Incidence rates in one U.K. study showed 3.4 per million children per year with localized disease and 0.27 per million children per year with systemic scleroderma, according to Pain.

In Clinical Pediatrics, Hedrich and colleagues wrote that among all presentations of juvenile scleroderma, localized scleroderma is the most common type of the disease, followed by systemic disease and eosinophilic fasciitis. In the post-transplant setting, chronic graft vs. host disease scleroderma-like skin involvement has been reported. The systemic manifestations of these diseases can impact the lungs, gastrointestinal tract, heart and kidneys. The authors added disabilities can result, as can other complications that can lead to death.

Localized Scleroderma

As outlined by Torok, five subtypes of localized scleroderma, also named morphea, are recognized: circumscribed; generalized; linear; pansclerotic; and mixed. Circumscribed morphea is characterized by oval or round circumscribed areas of induration surrounded by a violaceous halo. It is confined to the dermis with only occasional involvement of the superficial panniculus. Sometimes, as in deep morphea, the entire skin feels thickened, taut and bound down. When individual plaques are four or more and become confluent, it is the so-called generalized morphea.

Linear scleroderma, the most common subtype in children and adolescents, is characterized by one or more linear streaks that can extend through the dermis, subcutaneous tissue and muscle to the underlying bone, and cause significant deformities. The upper or lower extremities can be affected but also the face or scalp can be impacted, as in the en coup de sabre variety, so called because the lesion looks like the depression caused by a dueling stroke from a sword. This form can be complicated by central nervous system abnormalities, such as calcifications, vasculitis or simply MRI unspecific abnormalities, dental and even ocular abnormalities. Parry Romberg syndrome, a variety of linear scleroderma of the face, is a type of scleroderma that causes atrophy (loss of substance) to one half of the face.

In patients with linear scleroderma, cosmetic and functional issues often arise, as can growth abnormalities, if the affected area is crossing the joint.

Pansclerotic morphea, an extremely rare but severe subtype, is characterized by generalized full-thickness involvement of the skin of the trunk, extremities, face and scalp with sparing of the fingertips and toes.

“In children, the most frequent form of localized scleroderma is the linear form,” Foeldvari said.

Pain suggested the main challenges faced by clinicians dealing with juvenile localized scleroderma are assessing whether the disease remains active and, consequently, amenable to treatment.

“Advances in the development of outcome measures for juvenile localized scleroderma, in particular the localized scleroderma cutaneous assessment tool (LoSCAT), provide accessible tools for clinicians to use in routine clinical practice to define disease activity and damage,” she said. “Differences in treatment approaches have been shown, particularly between dermatologists and pediatric rheumatologists. Better collaborative working between dermatologists and pediatric rheumatologists will further improve outcomes for children with this condition.”

Several recent studies have challenged the historic view that juvenile localized scleroderma burns out after a few years, according to Pain.

“These studies have highlighted that many adults with pediatric-onset disease have continuing disease activity despite treatment as children,” she said. “Many are left with functional impairments and damage. When to stop treatment safely in growing children remains to be defined.”

Case reports regarding the use of fat transfer and leg lengthening procedures show promise in juvenile localized disease, according to Pain. However, the timing of those approaches, particularly in light of variables in disease activity and patient age, has yet to be determined.

“Although juvenile localized scleroderma is a rare disease, the outcomes of poorly controlled disease can be catastrophic for the patient, leading to deformity and functional impairment,” Pain said.

Clinical Measures

The Childhood Arthritis and Rheumatology Research Alliance (CARRA) has focused on collaborative projects among a cross-section of experts in pediatrics and rheumatology in North America, according to Torok.

“Their goal is to establish specific clinical measures to assess activity and damage, which will assist in monitoring progression and disease state in [localized scleroderma],” she wrote. “These projects are in the process of assessing clinical measures like the LoSCAT and identifying others through multicentered studies with the Localized Scleroderma Clinical and Ultrasound Study group (LOCUS).”

Torok wrote the aim of the LOCUS group is to rank clinical variables in terms of disease activity.

“There was more than 75% consensus agreement and high content validity (modified kappa statistic 0.88–1) regarding four activity parameters: the appearance of new lesions; expansion of current lesions; erythematous/violaceous hue at the border; and skin induration at the border of a lesion,” she wrote.

Besides the clinical scores, other instrumental methods may be used in localized scleroderma.

Laser Doppler flowmetry is a noninvasive method to measure cutaneous microcirculation, according to Francesco Zulian, MD, associate professor of pediatrics and director of the Pediatric Rheumatology Unit and the Department for the Woman and Child Health at the University of Padua, Italy.

“It has been used to investigate a range of medical conditions, such as inflammatory skin disorders, vasospastic vascular disorders, neuropathies, the response of microcirculation to neurotransmitters etc.,” he said. “In juvenile localized scleroderma, blood flow measured by laser Doppler flowmetry is significantly increased in clinically active lesions with a sensitivity of 80% and specificity of 77%.”

However, Zulian said this approach is not being used in juvenile localized disease because it records a slight increase in blood flow, even in clinically inactive lesions.

“It remains unclear whether this is clinically relevant,” he said. “Therefore, for the routine monitoring, we prefer the clinical scoring combined with infrared thermography and computerized skin scoring.”

“The use of outcome measures, such as laser Doppler and thermography, were limited by their availability,” Pain added.

Treatment Options

While there is no cure for juvenile localized scleroderma, it may be managed with timely and accurate diagnosis and treatments tailored to each child.

“During the last decade, more scientific evidence supports the use of methotrexate for the treatment of juvenile localized scleroderma,” Zulian said. “So far, one multicenter placebo-controlled trial, as well as three prospective and four retrospective studies, has been published.”

Zulian and colleagues conducted the only existing randomized placebo-controlled study of methotrexate, which was published in 2011. The data set included 70 patients with active localized disease who received the drug orally at a dose of 15 mg/m², with a maximum of 20 mg or placebo. There were 46 patients in the treatment group and 24 patients in the placebo group. Oral prednisone at 1 mg/kg/day, with a maximum of 50 mg, was added in both groups for the first 3 months. Results indicated relapses in 32.6% of patients in the methotrexate group and 70.8% of those in the placebo group.

New lesions appeared in 6.5% of patients in the study drug group and in 16.7% of those in the placebo group. A decrease in mean skin sore rate was observed in the methotrexate group, from 1 to 0.79. Conversely, this rate increased in patients receiving placebo, from 1 to 1.1. The mean target lesion temperature decreased by 44.4% among those in the study drug group compared with 12.1% in the placebo group.

“At month 12, at the end of the study, a significant clinical as well as infrared thermography improvement was only observed in the study drug group,” Zulian said.

“For localized disease, only one controlled trial is published, which showed the effectiveness of methotrexate,” Foeldvari added.

For Pain, these results are another step toward standardizing therapy, which has previously been variable.

“This first randomized controlled trial in juvenile localized scleroderma has provided further evidence for the use of methotrexate and corticosteroids in active disease,” she said.

Zulian said future applications may include an early combination therapy of methotrexate with mycophenolate mofetil for children with severe cases of systemic disease, especially for those with face and central nervous system involvement.

“The topical use of methotrexate, actually under experimental studies, through functionalized gold nanoparticles delivery, may also be possible,” Zulian said.

Li and colleagues aimed to develop a set of standardized clinical assessments, treatment plans and response criteria for active or moderate to high severity localized sclerosis. The researchers included a group of pediatric rheumatologists and dermatologists along with a lay advisor. CARRA was involved in helping to develop consensus methods and nominal group techniques. The recommendations were affirmed by more than 90% of pediatric rheumatologists responding to a survey. They agreed to use these consensus plans in the treatment of patients.

“The high level of support among pediatric rheumatologists will support future comparative effectiveness studies and enable the development of evidence-based guidelines for the treatment of juvenile localized scleroderma,” the authors wrote.

The prognosis of juvenile scleroderma can vary widely depending on whether it is a localized or systemic disease. Localized juvenile sclerosis progresses in the early stages, but generally stabilizes after 4 years, but can, although rarely, be active up to 34 years.

Juvenile Systemic Sclerosis

Kevin Baszis, MD, a pediatric rheumatologist at Washington University/St. Louis Children’s Hospital, put this information into context.

“Scleroderma in children can present insidiously, so keeping in mind that it often presents with isolated Raynaud’s, arthritis or myositis can lead to earlier diagnosis and treatment and differentiation from other rheumatic diseases of childhood,” he said. “Raynaud’s in scleroderma is often associated with fingernail fold capillary changes or small digital ulcers. These abnormalities can help differentiate children with early scleroderma from children with primary Raynaud’s phenomenon. These vascular changes can be readily seen with an ophthalmoscope and a drop of oil.”

Onset of skin thickening occurs later, according to Baszis.

“Instead, these children often present with hand edema/tightness which can mimic arthritis and tenosynovitis,” he said. “This phase can last for months before skin tightening begins.”

Systemic sclerosis may involve the internal organs, such as the kidneys, heart, lungs and gastrointestinal system, according to Torok and other sources of the consensus opinion. Skin changes and restricted joint movement are mostly seen. Raynaud’s phenomenon can occur in children with systemic sclerosis, along with fatigue, joint pain, difficulty swallowing, various abdominal complaints and shortness of breath. A child with systemic scleroderma should be checked for problems with these internal organs and undergo high blood pressure testing. Evaluation of the lungs and kidneys also should be undertaken.

“Revised [American College of Rheumatology] ACR criteria have been developed for systemic scleroderma, which will hopefully improve diagnosis and recognition,” Pain said. “How these criteria perform in children and adolescents with systemic scleroderma has yet to be defined.”

Pain noted that Foeldvari and colleagues are conducting an international prospective juvenile systemic scleroderma cohort study aimed at understanding organ involvement and outcomes.

“Results from this study are awaited with interest,” she said. “Evidence for treatment of juvenile systemic scleroderma is largely extrapolated from adult studies. While many advances have been made in the treatment of organ manifestations in adults with systemic scleroderma, the efficacy and safety of such treatments in children requires further evaluation.”

Foeldvari built on this point.

“The juvenile disease is different,” he said. “The diffuse subtype dominates. Most medications used in adults with systemic scleroderma are not licensed in children at all. For most of them, there is no validated pediatric dosing at all.”

Consensus opinion from the Cleveland Clinic is that a rheumatologist or dermatologist can diagnose systemic scleroderma based on physical signs, skin changes with skin biopsy, blood tests, radiographs, echocardiography or tests evaluating swallowing function in the esophagus or pulmonary function. However, clinicians also should be aware of other possible diagnostic avenues.

However, Foeldvari said the modified Ronan skin score and durometer measurements can assess skin involvement well. Ultrasound with Doppler assesses inflammatory activity reflected by increased blood flow.

Scoring Systems

As for scoring systems, Zulian discussed one that is being used in juvenile systemic sclerosis.

“Juvenile systemic sclerosis is often an insidious disease without clear signs of inflammation,” he said. “Therefore, conversely to other inflammatory conditions, the clinical features attributable to vascular changes and connective tissue fibrosis are more difficult to detect and quantify than inflammation.”

The Juvenile Systemic Sclerosis Severity Score — also called J4S — is an instrument aimed to closely monitor disease changes during a period of time, according to Zulian.

“It is based on variables adapted for the pediatric age, scored with coefficients of severity that consider the weight, in terms of clinical importance, of each type of organ involvement. For example, worsening of cardiac function has a different weight, in terms of severity, from an increased skin score.”

Zulian noted the measurement of severity is more appropriate than the measurement of disease activity because the effect of the disease on organ function includes a combination of both reversible (activity) and irreversible (damage) components.

“The J4S, as multidimensional tool tailored for young patients, also can be used in comparative population studies and in identifying potentially reversible aspects of the disease,” he said. “We currently use the J4S in our daily clinical practice as it is a useful aid to the therapeutic decision-making process.”

Treatment Options

Baszis addressed treatments for systemic sclerosis.

“Similar to in adults, juvenile systemic sclerosis is difficult to treat,” he said. “Rather than just inflammation, there is a prominent fibrotic immune response, which does not respond as well to our typical antirheumatic drugs used in other illnesses. Depending on which organ systems are affected, methotrexate, mycophenolate mofetil, azathioprine and cyclophosphamide have all been used.”

There has been some recent success in the treatment of interstitial lung disease in scleroderma with rituximab (Rituxan, Genentech), but there have been no trials in children, according to Baszis.

The adult ASTIS trial of autologous bone marrow transplantation is promising, but no juvenile patients were included, he added.

“Imatinib (Gleevec, Novartis), a protein tyrosine kinase inhibitor that can interfere with the fibrotic pathway, has shown some benefit in uncontrolled trials in improving skin thickness and forced vital capacity. Intravenous immunoglobulin has been associated with skin improvement in some patients. However, in a controlled trial, it was unfortunately not more effective than placebo. Tocilizumab (Actemra, Genentech), an [interleukin] IL-6 receptor antagonist, has been linked with improvement in skin disease and pulmonary fibrosis,” Baszis said.

Foeldvari echoed this point.

“Tocilizumab seems to be effective in the skin involvement of systemic scleroderma,” he said. “Extrapolated from that, it is expected to be effective in localized scleroderma.

For systemic juvenile sclerosis treatment, there are no evidence-based data, according to Foeldvari.

“The EUSTAR/EULAR recommendation are recently updated and will be published in this year,” he said. “We hope to learn more about the effectiveness of these drugs from the prospective collected data from the juvenile scleroderma inception cohort. There are now over 70 patients included, and we are following them prospectively.”

Team Approach

A team approach is recommended for the management of juvenile systemic sclerosis to control the disease and preserve the child’s physical growth and emotional development.

The general management may include family counseling regarding cosmetic, financial, emotional, social or disability issues, according to consensus opinion from the Cleveland Clinic. Skin protection is encouraged. Children should avoid injuries to affected areas. Hands and feet should not become too cold in children with systemic scleroderma. Exposure to smoking should be limited, as should exposure to pseudoephedrine, the sun and astringents. Stretching and other activities that promote flexibility and joint range of motion benefit children with juvenile scleroderma. In rare cases, corrective joint surgery or surgical repair of scars may be used.

For juvenile systemic sclerosis, organ damage can pose the greatest risk, according to the Cleveland Clinic.

“Pulmonary hypertension in juvenile systemic sclerosis can be secondary to interstitial lung disease/fibrosis, which is less common than in adult scleroderma, or it can be secondary to primary damage to the pulmonary vasculature, as scleroderma can lead to vasculopathy in many vessels throughout the body,” Baszis said.

Foeldvri said pulmonary hypertension is part of the disease.

“Scleroderma renal crisis is another feared complication, characterized by vascular damage/fibrosis that typically occur in the first 5 years after diagnosis,” Baszis said. “Renal crisis manifests as severe hypertension, acute renal failure and microangiopathic hemolytic anemia. Urinalysis is typically normal, as the glomerulus is not the primary area of involvement.”

However, Foeldvari said renal crisis rarely occurs in children.

“In the 70 patients of the juvenile systemic scleroderma inception cohort, no hypertension and no renal crisis was observed,” he said.

Rapidly progressive skin disease is a risk factor for renal crisis, as is the presence of anti-RNA polymerase III and higher doses of corticosteroids based on adult data, according to Baszis.

“The cardiac conduction system can be infiltrated by fibrosis, leading to conduction defects and arrhythmias, such as ventricular tachycardia,” he said.

Gastrointestinal involvement is another comorbidity of systemic disease.

“Dysphagia, constipation, diarrhea and abdominal discomfort are common,” Baszis said. “Collagen deposition can lead to gastroesophageal reflux, impaired gastric/intestinal motility and nutrient malabsorption leading to malnutrition.”

Baszis added that Raynaud’s disease and digital ulcers can impact quality of life, can be difficult to treat and can increase the risk for secondary cellulitis or osteomyelitis.

“Digital ischemia/necrosis can lead to loss of tissue or need for amputation,” he said.

Moving Forward

In a paper written with McCann, Pain suggested the prognosis for juvenile localized scleroderma has improved in developed nations, possibly due to early diagnosis and treatment with immunosuppressive medications.

“Early recognition of juvenile scleroderma remains a challenge across the world related to the rarity of the disease,” she said. “Close working between specialties, particularly dermatology and rheumatology, is key to improve recognition. This is a potentially treatable disease. We should recognize that there are particular challenges in the growing child that justify the early and aggressive use of immunosuppression to gain disease control and limit complications.”

Baszis echoed this point. “Early referral to a pediatric rheumatologist is ideal,” he said. “Pediatric patients may benefit from early screening for morbidity and targeted therapy.” – Rob Volansky

• References:
• Foeldvari I. Rheum Dis Clin North Am. 2013;doi:10.1016/j.rdc.2013.05.003.
• Hedrich CM, et al. Clin Pediatr (Phila). 2011;doi:10.1177/0009922810396546.
• https://my.clevelandclinic.org/health/diseases_conditions/hic_Scleroderma_An_Overview/hic_Pediatric_Scleroderma
• Li SC, et al. Arthritis Care Res (Hoboken). 2012;doi:10.1002/acr.21687.
• McCann LJ, et al. Indian J Pediatr. 2015. [Epub ahead of print].
• Salehzadeh F. Med Arch. 2015;doi:10.5455/medarh.2015.69.421-422.
• Torok KS. Pediatr Clin North Am. 2012;doi:10.1016/j.pcl.2012.03.011.
• www.jusinet.org
• www.juveline-scleroderma.com
• Zulian F, et al. Curr Opin Rheumatol. 2013;doi:10.1097/BOR.0b013e3283641f61.
• Zulian F, et al. Arth Rheum. 2011;doi:10.1002/art.30264.

• For more information:
• Kevin Baszis, MD, can be reached at One Childrens Place, Suite C, St. Louis, MO 63110; email: paul.suess@bjc.org.
• Ivan Foeldvari, MD, can be reached at Hamburger Zentrum für Kinder- und Jugendrheumatologie, Kompetenz-Zentrum für Sklerodermie und Uveitis im Kindes- und Jugendalter, Lehrbereich des Asklepios Campus der Semmelweis-Universität, Budapest, An der Schön Klinik Hamburg Eilbek, Dehnhaide 120, 22081 Hamburg; email: foeldvari@t-online.de.
• Clare Pain, MD, can be reached at Alder Hey Children’s NHS Foundation Trust, Eaton Road, Liverpool L12 2AP; email: clare.pain@alderhey.nhs.uk.
• Francesco Zulian, MD, can be reached at the University of Padua, Via Giustiniani 3, 35128 Padua, Italy; email zulian@pediatria.unipd.it.

Disclosures: Foeldvari reports he is an advisor for Bayer and Chugai. Baszis, Pain and Zulian report no relevant financial disclosures.