Effect of the Janus kinase inhibitor tofacitinib in the treatment of juvenile scleroderma: A single‐center experience

Juvenile scleroderma (JS) is a group of diseases characterized by increased skin thickness and fibrosis. It is the third-most common rheumatic condition in childhood. There are two major forms of the disease: juvenile localized scleroderma (JLS) and juvenile systemic sclerosis (JSSc), both classified into different subtypes depending on the extent of the disease and the depth of the lesions.1 JLS, also known as morphea, affects only the skin and subdermal tissues, while JSSc also includes fibrous changes in internal organs such as the esophagus, intestines, heart, lungs, and kidneys. Although the precise cause is still not completely clear, skin thickening and related health issues are attributed to the dysregulation of the immune system, which leads to inflammation, vascular damage, and fibrosis.2 The pharmacological management of JS is challenging because no drug is of unequivocal benefit to either children or adults with the disease.1 Treatment regimens vary according to disease form and severity, but targeted therapies are still missing.3 The standard first-line treatment for moderate-to-severe JLS is a mix of steroids and methotrexate (MTX), while topical treatment might be an option in less severe cases. Mycophenolate mofetil (MMF) can be a good alternative, especially in cases of refractory disease or methotrexate intolerance.1 Since JSSc progression leads to severe systemic complications, therapy must be more aggressive and based on the management of organ involvement. In addition to systemic steroids and immunosuppressants (such as MTX, MMF, and cyclophosphamide), other drugs have been used off-label with varying degrees of success.2 Biologic agents were reported to be effective for refractory JLS and JSSc, while Janus kinase (JAK) inhibitors (e.g., tofacitinib) have shown effectiveness for morphea and systemic sclerosis.4, 5 The aim of this study was to describe the experience on tofacitinib use at the Rheumatology Service of the Institute for Maternal and Child Health IRCCS Burlo Garofolo Hospital in Trieste, Italy, both in terms of the safety and its effect on disease progression. Patient 1 was a girl diagnosed with JSSc at the age of 13. Her history began at the age of 10 with the occurrence of Raynaud's phenomenon associated with scleroderma pattern at the videocapillaroscopy (reduction and tortuosity of the vessels). Due to clinical worsening and appearance of joint stiffness, she was referred to our hospital. She presented with mostly hyperchromic skin with some dyschromic areas, livedo reticularis on the lower limbs, finger ulcers, sub-palpebral skin atrophy, and thin lips. Blood tests showed elevated ESR (39 mm/h) in association with high levels of gamma globulins (IgG 1870 mg/dL), antinuclear antibodies (ANA, 1:2560), and anti-Scl70 antibodies (>600 U/mL). Furthermore, there we recorded a high interferon (INF) score (16, normal value: <3), which is a transcriptomic index reflecting the exposure of peripheral blood cells to an inflammatory environment dominated by interferons.6 Spirometry showed a restrictive pattern (forced vital capacity [FVC] 56%, forced expiratory volume 1 [FEV1] 66%, Tiffenau Index 119%). A chest CT scan ruled out pulmonary and cardiac fibrosis. Therefore, diffuse cutaneous systemic sclerosis (dcSSc) was diagnosed, and the girl was treated with prednisone (0.4 mg/kg/day), MMF (12.5 mg/kg twice daily), and rituximab (375 mg/mq). However, the girl has an anaphylactoid reaction to the first infusion of rituximab, so it was suspended and treatment with tofacitinib (5 mg twice daily orally) was started instead. The girl's clinical conditions progressively improved: joint stiffness decreased, digital ulcers disappeared, inflammatory markers normalized, and spirometry values improved. After 2 years, therapy with the JAK inhibitor was stopped while MMF was continued, with good control of the disease. Patient 2 was a girl diagnosed with JLS at the age of 11. She presented with disabling joint stiffness of the left hand and wrist that appeared after a major injury and progressively worsened. At the physical examination, there were many areas of blue, thickened, and hairless skin on the dorsal and palmar surfaces of the upper limb, extending to the middle third of the left arm. Serum immunoglobulins, antibodies, and inflammatory markers were normal, but nailfold capillaroscopy showed twisted and low-density capillaries associated with avascular areas. There was no lung and heart involvement. On MRI, the carpal spongiosa and the proximal end of the third metacarpal were swollen and phlogistic, associated with peritendinous effusions of extensor and flexor tendons. Thus, JLS was diagnosed, although the joint involvement was suspicious of a borderline systemic form of the disease. Because of the rapid worsening of clinical features, she started a treatment with prednisone (0.35 mg/kg/day), MTX (8.5 mg/m2/week), and tofacitinib (5 mg twice daily orally). At later clinical checks, her conditions consistently improved: the skin became less thick, and the violaceous coloration disappeared, joint stiffness gradually resolved, with good recovery of wrist and finger flexion-extension mobility. Corticosteroid therapy was progressively reduced and discontinued after 6 months, while MTX and tofacitinib were discontinued after 1 year due to noticeable clinical and radiological improvement. From before tofacitinib treatment to 12 months thereafter, the patient's modified Localized Scleroderma Skin Activity Index (mLoSSI) score improved from 6 to 0/45, while her Localized Scleroderma Damage Index (LosDi) score improved from 8 to 1/45. Patient 3 was a girl diagnosed with JLS at the age of three, after a 2-year history of skin lesions on the right leg, initially interpreted as atopic dermatitis. She presented with hyperchromic, thickened skin patches with dyschromic areas located on the right leg and right half of the face, without evidence of systemic involvement. Blood tests showed increased inflammatory markers and ANA. She received treatment with corticosteroids (betamethasone 0.15 mg/kg/day) and MTX (12 mg/m2 subcutaneously once a week), with initial apparent benefit. Nonetheless, after 1 year, new hyperchromic lesions appeared on her face in association with hemifacial atrophy involving skin and soft tissues, pointing to Parry Romberg syndrome. Brain MRI excluded neurological involvement. Given the disease progression during therapy with DMARDs, tofacitinib was started at a dosage of 5 mg twice a day. After 3 months, the lesions had not progressed, and after 10 months, her clinical picture was improved, with evidence of better trophism of skin lesions on the right lower limb. From before tofacitinib treatment to 10 months thereafter, evaluation by the Localized Scleroderma Assessment Tool (LoSCAT) score showed measurable improvement (activity index from 5 to 0/45, damage index from 17 to 8/45, physician assessment of activity disease from 35 to 0/100, physician assessment of activity damage from 35 to 10/100). Patients' characteristics are shown in Table 1. Dyschromic areas Livedo reticularis on the lower limbs Finger ulcers Atrophy of sub-palpebral skin Thin lips Hyperchromic and thickened skin lesions on the right leg Hyperchromic and slightly depressed linear patches on the right cheek and right side of the chin Hemifacial atrophy involving skin and soft tissues of the right cheek and right side of the chin Other clinical manifestations Raynauds phenomenon Joint stiffness Lung involvement Joint stiffness of left hand and wrist ESR 39 mm/h CRP 3.9 mg/L ANA 1:2560 Anti-Scl70 antibodies >600 U/mL Anti-centromere antibodies negative INF score 16 ESR 2 mm/h CRP 0.8 mg/L ANA negative Anti-Scl70 antibodies negative Anti-centromere antibodies negative INF score negative ERS 69 mm/h CRP 24.9 mg/L ANA 1:320 Anti-Scl70 antibodies negative Anti-centromere antibodies negative INF score negative Resolution of digital ulcers Reduction in joint stiffness Improvement in spirometry values Normalization of inflammatory indices Disappearance of cutaneous discoloration and reduction in skin thickening Resolution of joint stiffness Radiological improvement of soft tissue alterations on wrist MRI Reduction in LoSCAT score No disease progression Better trophism of skin lesions of the right lower limb Reduction in LoSCAT score Normalization of inflammatory indices In our experience, tofacitinib was consistently effective in improving skin manifestations, along with significant improvement in mobility. Nonetheless, in Patient 2 MTX and the JAK inhibitor were started simultaneously, so we cannot conclude with certainty whether the improvement occurred due to one drug or the other. Several studies have reported marked inflammatory activation in the early stages of systemic sclerosis, with increased interferons and interleukin (IL)-6. This inflammation is associated with increased JAK/STAT transducer signaling, which can be controlled by the use of tofacitinib in mouse models.3 Numerous other cytokines are implicated in collagen synthesis and consequently in the development of fibrosis on an autoimmune basis, for example, IL-4/IL-13, IL-12, transforming growth factor (TGF)-β, and INF-γ, which exert their effect via the JAK/STAT signal. This suggests that inhibition of this pathway could have a therapeutic effect in cutaneous scleroderma.2 In the literature, there are many case reports of adult patients with cutaneous scleroderma successfully treated with tofacitinib, whose mechanism of action involves modulation of the JAK/STAT-induced signal, with some reports of clinical and histological regression of fibrosis.2, 7 JAK inhibitors have also recently been found to be effective in treating sclerodermatous cutaneous graft-versus-host disease, which is also characterized by severe cutaneous sclerosis.8 However, there are very few cases of pediatric patients with scleroderma treated with tofacitinib. Recently, Tang et al. reported two of the earliest cases of pediatric morphea effectively treated with tofacitinib.9 Another case report described a 5-year-old male with pansclerotic morphea who did not respond to first-line treatments nor to ruxolitinib, a selective JAK1-2 inhibitor.10 It is not clear whether the lack of response is because ruxolitinib does not have much effect on JAK3. However, in a different study, ruxolitinib was reported to be effective in four patients from three different families who had an autosomal dominant pattern of inheritance of disabling pansclerotic morphea. The drug normalized most immunologic variables and resolved systemic symptoms without any side effects.11 In our experience, the use of tofacitinib was associated with a noticeable improvement in skin manifestations and a decrease in joint stiffness as early as 3 months after the start of treatment. Tofacitinib, either by itself or with methotrexate, may be a valuable option to treat severe forms of morphea and JSSc, especially when the disease does not respond to standard treatment, or the patient cannot tolerate it. The treatment is safe overall, and none of our patients reported any adverse effects during treatment. However, the literature reports an increased risk of infections during treatment, such as a higher risk of reactivation of varicella-zoster virus. Cases of herpes zoster are rare in the pediatric population and are responsive to specific treatment.12 Based on our small group of cases, tofacitinib seems to be effective in stopping the progression of scleroderma in the medium term, with less disease activity and tissue damage (LoSCAT score). Arianna Dagri and Lara Colussi wrote the manuscript. Alessia Pin performed the laboratory analyses of the patients described. Serena Pastore, Andrea Taddio and Alberto Tommasini conceived the idea and revised the article. All authors discussed the results and contributed to the final manuscript. The authors would like to thank all patients and families for their participation in this study. This work was supported by the Ministry of Health, Rome, Italy, in collaboration with the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.