Systemic Sclerosis
In SSc, autoimmune inflammation drives fibrosis of body tissues. Juvenile onset SSc (jSSc) is rare, comprising <10% of SSc cases (incidence 0.27-1 per million children per year). Diagnosis of SSc requires skin thickening [25], with other organ involvement including ILD, pulmonary arterial hypertension (PAH), Raynaud’s phenomenon, digital ulceration, myositis, arthritis, esophageal dysmotility, and gastrointestinal reflux. All manifestations are not typically present and needed to make the diagnosis. The average age of onset is 8-11 years, with female predominance (4:1 ratio) [26].
Pulmonary disease, are major causes of morbidity and mortality in SSc, with ILD present in 1/3 of jSSc patients and PAH present in ~2-5% [26]. There are three main subtypes of SSc: limited cutaneous, diffuse cutaneous, and overlap. ILD can be a feature in diffuse and overlap subtypes. In limited cutaneous SSc, vasculopathy, including pulmonary hypertension, is more common [27-29].
With the development of ILD in SSc, imaging abnormalities may precede clinical symptoms. Thus, baseline studies at diagnosis include high-resolution chest CT, PFTs, echocardiogram (to assess for PAH), and esophageal dysmotility studies (to assess for aspiration) [30, 31]. Children with esophageal involvement have been shown to have significantly decreased forced expiratory volume in the first second (FEV1), forced viral capacity (FVC), and vital capacity (VC) [32]. PFTs can also demonstrate restriction and low DLCO [33, 34], but tight facial skin and reduced oral aperture may lead to technically limited PFTs. PFTs have limited sensitivity and specificity in diagnosis ILD in childhood SSc [35]. CT is more sensitive for diagnosis, with findings including parenchymal/subpleural micronodules, ground glass, linear and diffuse centrilobular opacities, honeycombing, and traction bronchiectasis [36]. Lung biopsy is rarely indicated; however, pathologic patterns described include bland interstitial fibrosis, usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD), honeycomb remodeling, pulmonary hypertensive changes, findings compatible with aspiration and rarely, alveolar hemorrhage with capillaritis [37].
There have been several randomized controlled trials for ILD-related outcomes in adults with SSc, with multiple sets of consensus guidelines outlining organ-specific therapeutic approaches. Based on adult trials [38-40] first line therapies to treat alveolar inflammation include cyclophosphamide, mycophenolate mofetil, and tocilizumab. Rituximab has some prospective cohort data to suggest its use as a second line therapy. For patients with fibrosis, nintenadib, an oral tyrosine kinase inhibitor, has shown benefit [41] in adults. As a 3rd/4th line option, autologous hematopoietic stem cell transplantation (HSCT) has been shown to improve cutaneous and pulmonary features based on RCT in Europe [42] and the United States [43] comparing HSCT to cyclophosphamide. Depending on the extent of lung fibrosis, some patients may require lung transplantation. For PAH, endothelin receptor antagonists, PDE5 inhibitors, and intravenous prostacyclins may be used and have additional benefit for severe Raynaud’s [29, 44]. In the pediatric population there is one expert guideline for management [45]. In this guideline for management of heart and lung involvement it is recommended to first treat with mycophenolate mofetil and cyclophosphamide and then if refractory move to biologic treatments. In our practice given fertility considerations and the success of biologic treatments we often add biologics before treating with cyclophosphamide.