How to treat patients with MDA5-associated rapidly progressive interstitial lung disease? Which immunosuppressive therapy for which patients?

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Treating patients with melanoma differentiation-associated gene 5 (MDA5)-associated interstitial lung disease (ILD) remains a huge challenge, with over a third of outcomes fatal at 3 months, particularly in case of rapidly progressive (RP) ILD [1].

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The question is whether tofacitinib (TOF) is more effective than calcineurin inhibitors (CNIs) in all forms of MDA5-ILD and, more importantly, whether it is sufficient compared to bi-immunosuppressive therapy (TOF+CNI) in severe MDA5-RP-ILD https://bit.ly/4bEfTpk

To the Editor:

Treating patients with melanoma differentiation-associated gene 5 (MDA5)-associated interstitial lung disease (ILD) remains a huge challenge, with over a third of outcomes fatal at 3 months, particularly in case of rapidly progressive (RP) ILD [1].

We thus read with great interest the article entitled “Effectiveness and safety of tofacitinib versus calcineurin inhibitor in interstitial lung disease secondary to anti-MDA5-positive dermatomyositis: a multicentre cohort study” from Wu et al. [2], which was recently published in the European Respiratory Journal. The article provides an interesting and valuable perspective on Janus kinase (JAK) inhibitors for patients with MDA5-associated ILD, particularly those with arguments in favour of a less severe disease (i.e. those with course of ILD >1 month, no RPILD, forced vital capacity ≥50% predicted or arterial partial pressure of oxygen to inspired oxygen fraction ratio ≥300 mmHg; see figure 3 in their article).

However, we consider certain aspects that warrant further clarification and consideration so as not to confuse different situations.

• 1) The authors compare effectiveness and safety of tofacitinib (TOF) versus calcineurin inhibitor (CNI) without mentioning the dosage of TOF (5 mg or 10 mg twice daily are reported [3]) or the therapeutic target for CNI (usually 8–10 ng·mL⁻¹ for tacrolimus). Could this information be evaluated in the two retrospective groups? It would be useful to know which dosages were used in this study, and if these align with recommendations and “real-life” observations, or if this retrospective series used different dosing strategies. A discussion of the dosing practices in this cohort could provide deeper insights into the generalisability of the findings.

• 2) It is well-established that MDA5-associated RPILD clearly shows a worse prognosis than MDA5-non-RPILD [4]. This leads to bi-immunosuppressive treatment recommendations (posterior to this study ending in 2023), which might be both TOF and CNI [5].

Here, Wu et al. [2] suggested that TOF has a better efficacy than CNI in MDA5-ILD. However, 1) they address the treatment efficacy (lung transplantation-free survival at 1 year) of both MDA5-ILD and MDA5-RPILD (in half/half proportion in each groups), while almost all the events are reached at 3 months (figure 2) and probably linked to RP-ILD; 2) they conducted analyses suggesting that in patients with MDA5-RPILD, TOF or CNI have similar efficacy (see their figure 3); 3) they excluded 61 patients, having received both TOF and CNIs from their analyses, that probably presented with the most severe RPILD of the entire cohort.

We believe it would be of great interest to give the survival analyses in the RPILD and non-RPILD groups separately, according to TOF or CNI use (four groups) and to include also the survival curve of the 61 patients receiving the two drugs (with clinical description of severity) and log-rank test analyses at both 3 months and 1 year.

These deeper analyses of the outcomes between these different subgroups would certainly be helpful, especially for patients with severe RPILD. This would allow a better comparison of the impact of different therapeutic strategies (TOF, CNI or TOF+CNI): as the recent recommendations from the American College of Rheumatology and the American College of Chest Physicians [5] advocate for bi-immunosuppressive therapy in severely ill patients, it would be valuable for the authors to contextualise their findings within these recent clinical guidelines.

These complementary data would help to avoid confusion and assist clinicians for a better management of patients with MDA5-ILD, providing TOF in the correct manner: TOF may be more suitable for less severe cases of MDA5-associated ILD, TOF and CNI seems similar in RPILD patients but each seems insufficient alone to dramatically increase survival and lung survival at 3 months.

Overall, the study of Wu et al. [2] provides an essential contribution to the ongoing debate about the management of MDA5-associated ILD, and further clarification on these points would strengthen the study's impact and applicability in clinical practice.

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ERJ-00446-2025.Shareable