Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis

Abstract

Objective: To report on the clinical response to canakinumab in a patient with sporadic nucleotide-binding oligomerization domain-containing protein 2 (NOD-2)-associated pediatric granulomatous arthritis (Blau syndrome) and severe resistant panuveitis, and to describe gene expression profile changes throughout such treatment.

Methods: A 4-year-old boy was diagnosed as having Blau syndrome on the basis of typical clinical features, histologic evidence of noncaseating granulomas, and a NOD2 mutation. Ocular involvement was initially controlled by topical and oral corticosteroids, but over the years visual impairment and complications, such as macular edema and retinal detachment, progressed. Ocular disease remained persistently active despite treatment with multiple different immunosuppressants; therefore, canakinumab treatment was started. Before and during the first 6 months of treatment, the gene expression profile was determined each month.

Results: Canakinumab treatment was well tolerated and led to rapid quiescence of uveitis, which had been continuously active before this treatment. Gene expression profiling analysis of the patient's blood prior to initiation of interleukin-1 (IL-1) blockade revealed differential expression of 1,993 transcripts when compared to healthy controls, and among the up-regulated transcripts, pathway analysis showed that the predominant network consisted of innate immunity-related transcripts. The transcriptional signature of the patient overlapped with the transcriptional signature of patients with systemic-onset juvenile idiopathic arthritis, and canakinumab treatment led to the normalization of most of these transcriptional changes.

Conclusion: The pathogenesis of Blau syndrome may be mediated by IL-1, and canakinumab may be useful when this disorder is unresponsive to more conventional treatments.

Figure 1

Serial retinal angiograms showing the evolution of peripapillary granulomas in both eyes. Fluorescein angiography reveals severe leakage from the granulomas before treatment, while after treatment the inflammatory leakage is reduced, although residual fluorescein staining in the granulomas is still evident. A and B, Early-phase retinal angiography (at 43 seconds) (A) and late-phase retinal angiography (at 220 seconds) (B) of the right eye, prior to canakinumab treatment. E and F, Early-phase retinal angiography (at 26 seconds) (E) and late-phase retinal angiography (at 231 seconds) (F) of the left eye, prior to canakinumab treatment. C and D, Early-phase retinal angiography (at 38 seconds) (C) and late-phase retinal angiography (at 251 seconds) (D) of the right eye, after canakinumab treatment. G and H, Early-phase retinal angiography (at 48 seconds) (G) and late-phase retinal angiography (at 267 seconds) (H) of the left eye, after canakinumab treatment.

Figure 2

Whole blood transcriptional profile of the patient with Blau syndrome compared to controls. A, Expression values of transcripts from 1 time point pretreatment and 1, 2, 3, 4, and 5 months after initiation of canakinumab therapy (V1–5) were log₂ transformed and normalized to the median value in 4 healthy controls. Fold change analysis of the sample from the untreated patient with Blau syndrome and 4 healthy controls resulted in 1,993 differentially expressed transcripts. Hierarchical clustering of these probes was generated using the Pearson correlation method. B, Modular analysis of samples from the patient with Blau syndrome was performed. The results revealed up-regulation of neutrophil and inflammation modules and down-regulation of adaptive immune responses. A t-test was performed for each (baseline and followup) time point and for the healthy controls, with an assumption of equal variance in an error model. Each column corresponds to 1 time point. Within each module, numbers of significant genes were identified and their percentage represented as up-regulated or down-regulated. The transcript composition for each module has been described elsewhere (9). DC = dendritic cell; NK = natural killer. In A and B, red signifies up-regulation and blue signifies down-regulation. C, In the sample from the untreated patient with Blau syndrome, 496 up-regulated transcripts were analyzed by IPA. An inflammatory response network centered around Toll-like receptor 2, inflammasome components, interleukin-1/interleukin-18 signaling, and neutrophil-encoded transcripts was predominant.

Figure 3

Whole blood transcriptional profile of the patient with untreated Blau syndrome overlaps with that of systemic-onset juvenile idiopathic arthritis (SoJIA) patients. A, Expression values of transcripts from the patient with Blau syndrome at baseline (as in Figure 1A) were compared with those from patients with systemic-onset JIA (normalized to values in 18 matched healthy controls). In this analysis, 1,560 transcripts were included as they were common to the 2 Illumina bead array chips used in original analyses of Blau syndrome and systemic-onset JIA. As shown in the boxed area, only 46 transcripts were up-regulated in Blau syndrome but not in systemic-onset JIA. B, The 46 genes were analyzed by IPA. A leptin receptor–centered network was revealed. See Figure 2 for other definitions.