Anti-Interferon-Inducible Protein 16 Antibodies Associate With Digital Gangrene in Patients With Scleroderma

Abstract

Objective: To examine the association between anti-interferon-inducible protein 16 (anti-IFI-16) antibodies and clinical features of scleroderma.

Methods: Sera from a discovery sample of 94 patients with scleroderma and 47 healthy controls were assayed for anti-IFI-16 antibodies by enzyme-linked immunosorbent assay, and associations were examined using regression analyses. Since anti-IFI-16 autoantibodies were found to be strongly associated with digital gangrene in the discovery sample, a subsequent case-control study (with subjects matched 1:1 on disease duration) was designed for further exploration. Cases were patients with scleroderma and digital gangrene, while controls were patients with scleroderma and Raynaud's phenomenon alone (n = 39 matched pairs). Nonparametric, unadjusted matched pairs analysis as well as univariate and multivariable conditional logistic regression analyses were performed.

Results: In the discovery sample, anti-IFI-16 antibodies were more prevalent in patients with scleroderma than in healthy controls (18% versus 2%; P = 0.01). Patients with anti-IFI-16 antibodies, compared to anti-IFI-16 antibody-negative patients, were more likely to have limited scleroderma (77% versus 46%; P = 0.03), a longer disease duration (median 15.2 years [interquartile range 10.6-18.3] versus 6.0 years [interquartile range 3.4-13.8]; P < 0.01), digital gangrene (24% versus 4%; P = 0.02), and a low diffusing capacity for carbon monoxide (DLco) (P < 0.01). In the case-control study, 35 (45%) of 78 patients were anti-IFI-16 antibody positive. Anti-IFI-16 antibody levels were significantly higher in cases with digital gangrene than in matched controls (P = 0.02). In analyses adjusted for age, cutaneous scleroderma subtype, smoking, and DLco, high anti-IFI-16 antibody levels were associated with the presence of digital gangrene (adjusted odds ratio 2.3, 95% confidence interval 1.0-5.6, P = 0.05). The odds of having digital gangrene increased with higher anti-IFI-16 antibody titers, in a dose-dependent manner.

Conclusion: Anti-IFI-16 antibodies are associated with digital gangrene in patients with scleroderma. Longitudinal prospective studies exploring anti-IFI-16 antibodies as a disease biomarker, and biologic studies investigating the pathogenicity of these antibodies, are warranted.

Figure 1. Anti-IFI16 antibody levels are significantly higher in scleroderma patients compared to healthy controls, and associate with a lower DLCO

(A) Anti-IFI16 antibody levels in patients with scleroderma and healthy controls were assayed by ELISA. Calibrated optical density levels are significantly higher (p=0.01) in patients with scleroderma than healthy controls (n=94 scleroderma, n=47 controls). (B) Amongst scleroderma patients, DLCO is significantly lower (p<0.01) in anti-IFI16 antibody positive patients compared to those without this specificity (antibody positive, n = 17; antibody negative, n = 77).

Figure 2. Anti-IFI16 antibody levels in cases and controls

Anti-IFI16 antibody levels are significantly higher in patients with scleroderma and digital gangrene (n=39) than in scleroderma controls with Raynaud’s and no history of digital ischemic events (maximum Raynaud’s Medsger severity score of 1) (n=39) (p=0.02).

Figure 3. Anti-IFI16 antibody levels are highest in patient sera drawn within 6 months of the event

Mean anti-IFI16 antibody levels in patients with digital gangrene who are positive for anti-IFI16 antibodies (n=30/62) are shown. Patients were binned by the time interval between serum draw and clinical visit for digital gangrene. Anti-IFI16 antibody levels are higher in scleroderma patients with digital gangrene and blood drawn within 6 months of the event (n=20/39) compared to levels in patients who had blood drawn within 6–24 months of the event (n= 10/23).