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Yves Allenbach, Lois Bolko, Ségolène Toquet, Océane Landon-Cardinal, Olivier Benveniste, Reply: Janus kinase 1/2 inhibition with baricitinib in the treatment of juvenile dermatomyositis, Brain, Volume 142, Issue 3, March 2019, Page e9, https://doi.org/10.1093/brain/awz006
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Sir,
In their letter Papadopoulou et al. (2019) report the case of a severe juvenile dermatomyositis (JDM) case refractory to several lines of conventional immunosuppressants (methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus and ciclosporin), biological agents (infliximab, rituximab and adalimumab) and intravenous immunoglobulins, who was dramatically improved (skin and muscular involvement) by a Janus Kinase 1/2 (JAK1/2) inhibitor (baricitinib). At last follow up, corticosteroids were tapered and the patient was in remission.
Interestingly, the patient relapsed when his medications (baricitinib and corticosteroids) were discontinued and subsequently rapidly improved after JAK inhibitor reintroduction, highlighting its efficacy.
This is the second report of a JDM case successfully treated with JAK1/2 inhibitor. Recently, Aeschlimann et al. (2018) describe a very severe refractory juvenile patient dramatically improved by ruxolitinib, another JAK1/2 inhibitor. To our knowledge there are no other published cases of JDM treated with JAK inhibitors.
These observations are in line with previous reports in adult refractory dermatomyositis patients (n = 17) who improved with JAK inhibitors (Allenbach et al., 2018). Recently, preliminary results of an open label pilot study evaluating tofacitinib (JAK1/2/3 inhibitor) in refractory adult dermatomyositis patients were presented (Paik et al., 2018). All patients (n = 9) met the primary endpoint (definition of improvement based on International Myositis Assessment Clinical Studies) and half of them demonstrated a moderate improvement (based on American Congress Rheumatology/European League Against Rheumatism criteria) (Aggarwal et al., 2017).
The rationale of JAK inhibitor use is provided by the strong interferon (IFN) pathway activation displayed in the peripheral blood, the muscular and the skin compartments (Wong et al., 2012) of patients with dermatomyositis and the demonstration in vitro of the pathogenic role of IFN on muscular and endothelial cells (Ladislau et al., 2018). Indeed, the JAK family (encompassing JAK 1, 2 and 3) plays a central role in signalling transduction for multiple cytokines as well as growth factors, and JAK1 proteins mediate intracellular signalling from IFN transmembrane receptor, leading to STAT1 phosphorylation.
Papadopoulou et al. (2019) showed that IFN stimulated gene expression significantly decreased as well as STAT1 phosphorylation in peripheral blood mononucleated cells during treatment with baricitinib. Since baricitinib is a JAK1/2 inhibitor and that JAK 1 and 2 proteins are involved in signalling of other cytokines other than IFN (e.g. IL-2, IL-4 or IL-6) one cannot exclude that the clinical improvement may also involve other pathway blockage.
The patient did not develop infectious adverse event including herpes zoster, which seems specific to JAK inhibitor therapy (Cohen et al., 2014). In addition, Papadopoulou et al. highlighted that the patient growth was normal during baricitinib exposure considering that JAK2 also transduces growth hormone signal. To overcome these adverse events, including JAK2 dependant haematopoietic toxicity, the development of a ‘second generation’ of selective blockade of JAK1 or JAK3 are ongoing, yet disappointing results concerning their toxicity profile has been reported (Gadina et al., 2016).
Another interesting finding in the patient reported by Papadopoulou et al. was the absence of progression of calcification after JAK inhibition, as it was reported in the other JDM case treated with JAK inhibitor (Aeschlimann et al., 2018). This observation suggests an efficacy of JAK inhibitor on the vasculopathy since there is an association between calcinosis and the presence of vascular injury (Valenzuela et al., 2014). Nevertheless, in both cases, JAK inhibitors failed to improve the calcinosis.
Papadopoulou et al. provide a new observation demonstrating yet again the great potential of JAK inhibitor to treat juvenile as well as adult refractory dermatomyositis patients.
Data availability
Data sharing is not applicable to this article as no new data were created or analysed in this work.
Competing interests
The authors report no competing interests.
