Background/Purpose: Response to immunosuppression is highly variable in systemic sclerosis (SSc) related interstitial lung disease (ILD), and there are no widely accepted clinical or biological parameters that predict response to treatment. The interferon (IFN) signature is the most prominent gene expression profile in the peripheral blood cells of SSc patients. We have previously identified 6 serum chemokines that highly correlate with the IFN transcript profile. Herein, we determined whether a composite serum IFN chemokine score has predictive significance for response to immunosuppression in SSc-ILD.

Methods: In the Scleroderma Lung Study (SLS) II (Tashkin et al. Lancet Resp Med. 2016), 142 SSc-ILD patients were randomized to receive either mycophenolate mofetil (MMF) for 2 years or oral cyclophosphamide (CYC) for 1 year followed by 1 year of placebo. The % predicted forced vital capacity (FVC%) was the primary clinical outcome and was measured every 3 months. Baseline serum samples were available in 135 participants. Serum from 45 unaffected controls matched for age, gender, and race in a 1 to 3 ratio to SLS II participants was also investigated. The serum levels of 6 IFN inducible chemokines (IP-10, MIG, MCP-2, B2M, MIP-3 beta, TNFR2) were measured using multiplex assays in a CLIA certified laboratory. A serum IFN composite score was calculated based on the levels of these six chemokines using a previously described method (Bauer et al. Arthritis Rheum. 2009). Similar to the primary outcome analysis in SLS II, a joint model of longitudinal measurements (serially obtained FVC%) and non-ignorable missing data was conducted in order to investigate the predictive significance of the baseline IFN chemokine score for response to treatment.

Results: In this study, 78 (57.8%) participants had diffuse cutaneous disease with a mean baseline FVC% of 66.3%. As shown in Figure 1, the IFN chemokine score was significantly higher in SSc-ILD (fold change= 1.62, p< 0.001) than in controls and decreased significantly in both treatment arms from baseline to 12-months. There was no significant correlation between baseline IFN chemokine score and baseline FVC% (p=0.197). As shown in Table 1, higher baseline IFN chemokine score predicted better response based on higher serial FVC% 3 to 12 months after initiation of treatment in CYC (b=0.91, p=0.009), and MMF (b=0.41, p=0.001) arms, after adjustment for baseline FVC%. In contrast, higher baseline CRP predicted progression of ILD based on significantly lower FVC% after treatment start in the CYC arm (b=-0.56, p< 0.001) and showed a similar trend for lower FVC% 3 to 12 months in the MMF arm (b=-0.15, p=0.091).
Consistent with the different treatment approaches during the second year of SLS II, higher IFN chemokine score at 12 month showed a trend for predicting lower serial FVC% 15-24 months during the placebo treatment period of the CYC arm (b=-0.61, p=0.068) while it continued predicting better response to immunosuppression in the MMF arm (b=0.28, p=0.029).

Conclusion: Higher serum IFN chemokine score in SSc-ILD predicts better response to immunosuppression with MMF and CYC and could be potentially used for identify patients who may derive the most benefit from these two treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-interferon-chemokine-score-predicts-better-response-to-immunosuppression-in-systemic-sclerosis-related-interstitial-lung-disease/