• Autoimmune Diseases
• Dermatomyositis
• Treatment

Juvenile dermatomyositis (JDM) is a rare autoimmune disorder, affecting mainly muscles and skin. The mainstay of treatment is high dose corticosteroids, combined with other immunosuppressive drugs.1 In about 30% of patients, the disease cannot be controlled despite multiple treatment interventions. Autologous stem cell transplantation (aSCT) has been reported as a last resort treatment in refractory patients with autoimmune diseases.2 The main hypothesis for the underlying immunological mechanism is that aSCT resets the immune system and restores immune tolerance following profound lymphodepletion and immune suppression.3

Here, we report three patients with refractory JDM that received aSCT (Clinical information, table 1). A short-term follow-up with detailed clinical information (including imaging before and after aSCT, and immune reconstitution after aSCT) of two patients describing complete remission was reported previously.4 The current follow-up of these patients is more than 5 years showing sustained remission. A third patient (#3) has a follow-up of nearly 3 years. Indication of aSCT for patient 3 was refractory muscle and skin inflammation comparable to the other two patients. Whole body MRI prior to aSCT confirmed active myositis. As muscle tests improved substantially after aSCT, MRI was not repeated post aSCT in this patient. Immune reconstitution was similar to those published.4 In patient 3 myositis is controlled and the patient is without systemic treatment at the time of publication. However, skin disease persists including calcinosis and contractures. Interestingly, autoantibody levels decreased in those patients with excellent response to aSCT (patients 1 and 2), but remained stable for patient 3 (table 1).

We have recently reported a typical proinflammatory protein plasma profile in patients with active JDM with three markers being highly correlated to disease activity: CXCL10, TNFR2 and Galectin-9.5 We measured these proteins before and at different time points after aSCT to determine kinetics and correlation to disease activity in the context of this intervention. Values of creatine kinase were not elevated in the weeks before aSCT and did not change after, indicating low correlation with actual disease activity. CXCL10, TNFR2 and Galectin-9 were elevated in the patients prior to the conditioning regimen, irrespective of maintenance treatment (figure 1A). After aSCT, these three markers decreased over time in patients 1 and 2 with the most pronounced reduction in levels of Galectin-9 and CXCL10. These levels remained low, even after full reconstitution of the immune system. In parallel, clinical scores improved over time as shown in figure 1B. Pre-existent severe calcinosis disappeared completely in patient 2 after aSCT4 but is still persisting in patient 3. Importantly, only in this patient, CXCL10 and Galectin-9 levels remained elevated after aSCT.

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Figure 1

Protein levels and clinical scores over time in aSCT treated patients with juvenile dermatomyositis. (A) Levels of TNFR2, CXCL-10 and Gal-9 measured in serum (Patient 1) or plasma (Patients 2 and 3) by multiplex immunoassay as described previously.5 In the same paper, cut-off levels for plasma values are described, cut-off values for serum are not yet described, but remission values were compared with those found in healthy adults (unpublished results). Evolution of protein profile over time shows decrease of all markers in patient 1, decrease of Gal-9 and CXCL10 in patient 2 and persisting high levels of Gal-9 and CXCL10 in patient 3. (B) Clinical scores and CK plasma levels. For patient 2, levels at 22 months after aSCT are comparable to those in patients in remission as described earlier.5 CMAS, Childhood Myositis Assessment Scale; MMT, manual muscle testing; PhyGloVAS, physician's global assessment of the patient's overall disease activity on a 100 mm visual analogue scale; CK, creatine kinase; Gal-9, Galectin-9; aSCT, autologous stem cell transplantation.

In contrast to TNFR2, CXCL-10 and Galectin-9 are produced by immune and non-immune cells under inflammatory conditions.6–9 As circulating immune cells are largely depleted during aSCT, our data suggest that CXCL10 and Galectin-9 are mainly produced by tissue cells or tissue infiltrating cells. Therefore, even during profound immunosuppression these markers may reveal ongoing disease activity in the tissues. This is also supported by the observation that CXCL10 and Galectin-9 levels dropped very gradually following aSCT in patients 1 and 2 and mirrored clinical disease improvement.

In conclusion these data demonstrate that aSCT can induce prolonged drug-free disease remission in refractory patients with JDM with regards to the myositis. Furthermore, we show that the proinflammatory signature as measured by TNFR2, CXCL-10 and Galectin-9 leads to a differentiated response after aSCT, with a marked decrease in the two patients with inactive disease but persistent elevation in a patient with skin involvement. Further studies are needed to determine the immunopathogenic role of these proteins in JDM.