Potential Role of JAK Inhibitors in the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease: A Narrative Review from Pathogenesis to Real-Life Data

Abstract

Background: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is one of the most relevant complications of SSc and the major cause of death. The pathogenesis of SSc-ILD involves a complex interplay of multiple cell types and different molecular pathways, with both inflammation and fibrosis as pathological hallmarks. To date, there are no treatments able to target both components of the disease. Janus kinase inhibitors (JAKinibs) represent an interesting therapeutic option because they exert both anti-inflammatory and anti-fibrotic properties. Methods: Here, we performed a narrative review concerning the potential role of JAKinibs in SSc-ILD to define the state of art and to evaluate the pathogenetic rationale behind this type of treatment. Results: Currently, few studies investigated SSc-ILD response to JAKinibs treatment. Data were analyzed from three clinical studies and four case reports and progression of SSc-ILD was not evident in 93.5% of patients treated with JAKinibs. Conclusions: Available evidence of efficacy of JAKinibs in SSc-ILD is sparse but promising. JAKinibs could be an interesting treatment in SSc-ILD because of their potential inhibition of the fibrotic processes combined with their anti-inflammatory action. Moreover, JAKinibs were also shown in some studies to have a potential effect on pulmonary arterial hypertension (PAH), another threatening complication in SSc. More data are necessary to define JAKinibs role in SSc-ILD treatment.

Interstitial Lung Disease Associated with Systemic Sclerosis

“…Janus kinase inhibitors may have both antifibrotic and anti-inflammatory actions and are currently being investigated for their potential role in the treatment of SSc-ILD. 180 Belimumab, a monoclonal antibody binding to BLyS, is another promising treatment option. 181 Many studies are currently recruiting (clinicaltrials.gov).…”

Immune-mediated lung diseases: A narrative review

“…The initial phase in the pathophysiology of SSc ILD is thought to originate in response to a chronic insult to the alveolar epithelial and endothelial cells caused by local inflammation or an environmental stimulus ( 21 ). This injury stimulates the recruitment of several inflammatory cells, which infiltrate the alveolar spaces and activate existing immune cells in the lungs ( 22 , 23 ). Evidence of immune cell activation has been validated in studies demonstrating that CCL2 and other chemokines are released after the epithelial cell injury and influence inflammation and the migration of leukocytes, particularly the activation of M1 (pro-inflammatory) and M2 (profibrotic) macrophages ( 24 ).…”

“…JAK inhibitors interfere with the JAK/STAT pathway and halt genetic transcription ( 43 ). JAK inhibitors simultaneously exert anti-inflammatory and antifibrotic effects ( 24 ) and are promising therapeutic options for SSc-ILD with a favorable outcome, as reported in a recent non-systematic review by Fiorentini et al ( 23 ).…”

Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets

“…Finally, Fiorentini et al undertook a narrative review on the potential role of Janus kinase (JAK) inhibitors in the management of SSc-associated ILD [ 20 ]. The authors overviewed the current rationale, supporting that, owing to their ability to inhibit the fibrotic process and their anti-inflammatory properties, JAK inhibitors could represent an interesting therapeutic option in the treatment of SSc-associated ILD [ 20 ]. Of note was the fact that JAK inhibitors were also shown to exert a potential effect on PAH [ 20 ].…”

“…The authors overviewed the current rationale, supporting that, owing to their ability to inhibit the fibrotic process and their anti-inflammatory properties, JAK inhibitors could represent an interesting therapeutic option in the treatment of SSc-associated ILD [ 20 ]. Of note was the fact that JAK inhibitors were also shown to exert a potential effect on PAH [ 20 ].…”