Background/Purpose: Skin lesion as a side effect of Tocilizumab (TCZ) has not been paid much attention. In the drug information sheets, incidence of dermatological adverse reactions was only 1~2%. However, we experienced several RA cases with development of various skin lesions associated with neutrophil activation after TCZ therapy. Although the precise mechanism is still unclear, of particular interest is the decreased neutrophil counts in peripheral blood have been known after initiation of TCZ in clinical trials, which did not affect the rate of serious infections. On the other hand, we also experienced exacerbation of skin ulcer despite the inflammation, such as activity of rheumatoid arthritis, was absolutely under control. In this study, we try to detect the changes in transcriptome of peripheral blood after TCZ treatment.

Methods: As total of 23 RA cases (43.2 person-years) was completely followed in our single hospital from the initiation of TCZ, their medical records were checked to calculate the incidence of dermatological adverse reactions to TCZ from 2014 to 2018. Meanwhile, to explore the normal response to anti-IL6 therapy, peripheral whole blood at just before (pre) and 3 months after (post) TCZ treatment from 10 RA cases without any dermatological problems were subjected to gene expression study. Total RNAs were then extracted with PAXgene miRNA kit. After quantifying the transcripts, differentially expressed genes (DEGs) were selected by paired comparison (post vs. pre), setting thresholds at 2-fold change up/down and less than P=0.05 in paired T-test. And then, enrichment analysis using gene ontology (GO) terms were performed.

Results: Among 23 patients, 4 cases (9.25/100 person-years) of Skin lesion including neutrophilic dermatosis and leukocytoclastic vasculitis were observed as side effects of TCZ. Although 2 of them required termination of the therapy, others were possible to continue TCZ treatment. We also experienced 2 cases of exacerbation of skin ulcer despite the inflammation was under favorable control. For transcriptome analysis, total of 57571 transcripts were identified and the 52/156 genes of up/down-regulated genes were selected as DEGs from the comparison of post vs. pre treatment of TCZ using paried T-test. Surprisingly, 8 out of the top 10 enriched GO terms in the up-regulated genes were relevant to leukocyte activation such as ‘neutrophil chemotaxis’. On the other hand, 6 out of the top 10 enriched GO terms in the down-regulated genes were related to tissue repair, such as “platelet activation” and “wound healing”.

Conclusion: As the cytokine network is very complicated and an exquisite balance presented in immune and homeostatic system is strictly maintained, inhibition of a multifunctional cytokine signaling such as IL-6 may cause unexpected adverse reactions. Our findings indicate a potential risk of the development of skin lesions associated with neutrophil activation by anti-IL6 therapy. The mechanism may also help the increased margination of neutrophils in normal situation, and it may be a hint for the secret behind the decreased neutrophil counts after TCZ treatment. Anyway, we will not recommend anti-IL6 therapy for the patients with skin ulcers from our experiences.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/skin-lesions-as-a-side-effect-of-anti-il6-therapy-transcriptome-analysis-of-peripheral-blood-shows-a-risk-of-paradoxical-neutrophil-activation-and-exacerbation-of-skin-ulcer/