Tocilizumab as a potential therapeutic option for children with severe, refractory juvenile localized scleroderma

Rheumatology key message Tocilizumab may have a role in the management of refractory juvenile localized scleroderma. Sir, Scleroderma causes chronic inflammation in the skin and soft tissues leading to fibrosis and eventually atrophy. Complications such as joint contractures, limb length discrepancy and facial atrophy can occur and the disease can have marked psychological and functional impact [1]. Optimal treatment for juvenile localized scleroderma (JLS) is unknown and there have been few therapeutic trials. First line medical treatment for active JLS is often MTX with corticosteroids supported by data arising from a randomized placebo-controlled trial and observational cohort studies [2, 3]. MMF is increasingly used, although evidence is restricted to a single case series [4]. A wide range of DMARDs and biologics are used off-label in refractory cases [5]. The pathophysiology of localized scleroderma is poorly described. Cytokines including IL-6 have been suggested to play an important role [6]. A randomized placebo-controlled trial of subcutaneous tocilizumab in adult systemic sclerosis demonstrated a trend towards skin thickness reduction compared with placebo [7]. We therefore hypothesized that tocilizumab may have a role in patients with refractory JLS. Patients were treated with tocilizumab following persistent active disease despite escalation to maximum tolerated doses of MTX and one other DMARD/biologic, and clinician decision to treat with tocilizumab in conjunction with informed consent/assent from the patient and family. Outcome measures were collected prospectively as part of routine clinical care at baseline and approximately 3-monthly intervals to assess disease activity, damage, quality of life and functional status and reviewed as part of a service evaluation. Ethical approval was therefore not required, in accordance with the UK National Health Service Health Research Authority guidelines. The dosing regime was 8 mg/kg (children weighing ⩾30 kg) and 12 mg/kg (those <30 kg) given at 0, 2 and 4 weeks and then at 4-weekly intervals. Regular blood monitoring was performed as per local guidelines. Adverse events were enquired about at 3-monthly review. Data were analysed descriptively and where appropriate, statistical analysis done using Wilcoxon’s signed-rank test. Five patients with long-standing disease that remained active despite multiple doses of i.v. corticosteroids alongside other treatments received tocilizumab. Details of patients and outcomes are summarized in Table 1. Details and outcomes of patients treated with tocilizumab Various pulsed methylprednisolone regimes were used. All doses were 30 mg/kg to a maximum dose of 1 g. Typical regime for new or flaring patient would be three consecutive daily doses then weekly for 4 weeks then monthly pulse to complete 6 months. Three patients were subsequently treated with steroids for disease flare after the initial 12 months of treatment with TCZ. Patient 2 was reviewed after 18 months and i.v. MP was planned for evidence of disease flare. However, the MP was not started until after a further review where disease activity was felt to have reduced. Due to concern about ‘grumbling’ disease activity, i.v. MP was started anyway at 30 mg/kg monthly for 6 months with TCZ. Patient 3 was started on i.v. MP after 13 months. Patient 5 developed significant disease activity after 15 months of treatment and was started on a reducing course of high-dose oral steroids (initial dose 50 mg for 4 weeks) with good response. Patient 3 was re-started on MTX treatment after 5 months treatment with TCZ due to concerns regarding disease activity. It was stopped after 17 months due to intolerance and MMF was started. MMF was stopped after 4 months due to deemed inefficacy and at the time of writing MTX had been re-started at a lower dose with folic acid and ondansetron. The p-value in bold indicates a statistically significant level. CDLQI: children’s dermatology life quality index; CHAQ: childhood HAQ; LoSDI: disease damage measured by localized scleroderma damage index; mLoSSI: modified localized scleroderma skin activity index; MP: methylprednisolone; PGA-A: physician global assessment of activity on visual analogue scale; PGA-D: physician global assessment of disease damage on visual analogue scale; TCZ: tocilizumab. Details and outcomes of patients treated with tocilizumab Various pulsed methylprednisolone regimes were used. All doses were 30 mg/kg to a maximum dose of 1 g. Typical regime for new or flaring patient would be three consecutive daily doses then weekly for 4 weeks then monthly pulse to complete 6 months. Three patients were subsequently treated with steroids for disease flare after the initial 12 months of treatment with TCZ. Patient 2 was reviewed after 18 months and i.v. MP was planned for evidence of disease flare. However, the MP was not started until after a further review where disease activity was felt to have reduced. Due to concern about ‘grumbling’ disease activity, i.v. MP was started anyway at 30 mg/kg monthly for 6 months with TCZ. Patient 3 was started on i.v. MP after 13 months. Patient 5 developed significant disease activity after 15 months of treatment and was started on a reducing course of high-dose oral steroids (initial dose 50 mg for 4 weeks) with good response. Patient 3 was re-started on MTX treatment after 5 months treatment with TCZ due to concerns regarding disease activity. It was stopped after 17 months due to intolerance and MMF was started. MMF was stopped after 4 months due to deemed inefficacy and at the time of writing MTX had been re-started at a lower dose with folic acid and ondansetron. The p-value in bold indicates a statistically significant level. CDLQI: children’s dermatology life quality index; CHAQ: childhood HAQ; LoSDI: disease damage measured by localized scleroderma damage index; mLoSSI: modified localized scleroderma skin activity index; MP: methylprednisolone; PGA-A: physician global assessment of activity on visual analogue scale; PGA-D: physician global assessment of disease damage on visual analogue scale; TCZ: tocilizumab. To date, all patients remain on i.v. tocilizumab and have been treated for between 12 and 25 months. All patients tolerated tocilizumab with no serious adverse reactions. Patients showed some improvement in disease activity scores with statistically significant improvement in physician’s global assessment of activity (PGA-A) at 6 months. Improvements in disease damage, function and quality of life were not seen. Patient 3 was re-started on MTX and MMF but all other patients were treated with tocilizumab as monotherapy. Patients and families were extremely positive about treatment with tocilizumab. Patient 1 described it as the ‘best treatment they had had’; patient 4 described ‘softer skin’ which is ‘not aching any more’; patient 5 described their scleroderma as ‘the best it has ever been’. This case series is encouraging, indicating a potential new therapeutic option for children with the most severe and refractory JLS where standard treatments have failed and recurrent corticosteroid courses are necessary. Importantly, three patients did not require any concomitant corticosteroid treatment with commencement of tocilizumab because of rapid disease control. Two patients did not require any corticosteroids for disease flare over 25 and 17 months treatment, respectively. Three patients required methylprednisolone for disease flare after 12 months of treatment with tocilizumab. Some patients may benefit from dual therapy with a DMARD/biologic. All patients have remained on tocilizumab and four patients had intolerance of previous treatments. Whilst improvement in PGA-A was statistically significant at 6 months, changes in modified localized scleroderma skin activity index (mLoSSI) were not statistically significant. Many of our patients had low mLoSSI scores at baseline. The mLoSSI measures activity in skin by three domains [8]. Several of our patients had deep longstanding lesions, including facial haemiatrophy where skin changes are often minimal. The mLoSSI does not capture deeper tissue disease activity and PGA-A may be more appropriate in these patients. Damage scores were unaffected by treatment with tocilizumab; this might be expected as changes from previous disease activity may have less potential to be reversible. It may be prudent to focus future studies of tocilizumab in children at an earlier stage in their disease course. Limitations include the small number of patients treated and the non-controlled nature of this case series. Data were collected in a real-world setting and not in the context of a clinical trial, and therefore the outcome measures were collected within 2 months of the specified time point. However, these preliminary data indicate that future clinical studies of the efficacy and safety of tocilizumab should be considered, particularly given the paucity of therapeutic trials in this potentially disfiguring disease. In summary, these results suggest that i.v. tocilizumab is safe, well tolerated and may have therapeutic benefit in patients with severe, refractory JLS. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. We would like to acknowledge the input of the multidisciplinary team in the management of these patients.