Volume 6 Issue 1 (2022)

The principal cause of fibrosis in systemic sclerosis is thought to be excessive deposition of extracellular matrix in multiple organs. The main component of matrix is thought to be collagen, especially type I collagen, which is one of the most abundant proteins in the mammalian body. Various factors have been estimated to be involved in the mechanism of their excessive deposition in fibrotic tissues of systemic sclerosis. In this review, we discuss the latest findings on these factors.

Pretibial myxedema (PTM) is an uncommon cutaneous manifestation of Graves’ disease. A 62-year-old obese Japanese man treated for Graves’ disease presented with nodular lesions symmetrically on both pretibial areas. Systemic corticosteroid therapy targeted against simultaneously developing severe Graves’ ophthalmopathy almost completely cleared his skin symptoms. About ten years later, edema of both lower legs recurred, and the right lower leg showed an elephantiasis-like condition with nodules. However, the left leg had less edema and only a few nodular lesions. The skin lesions gradually improved with oral prednisolone. We speculate that our patient’s habit of lying on the right side of the body induced prominent asymmetry of skin lesions by pooling some immune mediators.

A 62-year-old woman reported with progressive pruritus rash that persisted on her buttocks and extremities for a duration of twenty years. She was initially diagnosed with tinea corporis but then the morphological and histological features were consistent with MF. As MF is considered as a “great imitator”, it is important to emphasize that cutaneous characteristics, skin biopsy, histology, and immunohistology may need to be performed in patients with chronic dermatoses resistant to treatment to rule out the underlying malignancy.

Immune checkpoint inhibitors, which promote or suppress the anti-tumor immune response, are becoming the mainstay of cancer treatment. In 2018, CheckMate 214 study showed a higher response rate with ipilimumab and nivolumab combination therapy compared to conventional therapy for advanced renal cell carcinoma. We report a case of complete response and durable response for two years to ipilimumab and nivolumab combination therapy in a patient with postoperative renal cancer recurrence that caused immune-related adverse events such as interstitial pneumonia and hepatotoxicity.

It has been less than a decade since immune checkpoint inhibitors became the mainstay of lung cancer treatment, and 2020 saw the advent of the era of complex immune checkpoint inhibitors. Although clinical trials have shown that the therapeutic effects of complex immune checkpoint inhibitors are favorable, they are associated with an increase in adverse events. The use of combined immune checkpoint inhibitors in clinical practice has progressed slowly, and the frequency and types of adverse events they cause remain unclear. Here we report the adverse events of six patients with lung cancer treated with regimens containing nivolumab and ipilimumab in 2021. Four of the six patients had grade 3 or higher adverse events, including one patient with lung injury and one patient with skin injury, both of whom died. The timing and nature of the adverse events were difficult to predict.

Allergic diseases are currently considered diseases of excessive type 2 inflammation created by orchestration between the innate and acquired immune systems. Since pattern recognition receptors (PRRs) are present in epidermal keratinocytes, it is noteworthy that aggravating factors of allergic diseases act directly on keratinocytes via PRRs. To investigate the relationship between the activation of PRRs and inflammation, we stimulated a keratinocyte cell line (HaCaT cells) with agonists against proteinase-activated receptor-2 (PAR-2), Toll-like receptor (TLR)2, and TLR4, alone or in combination, and we evaluated the changes in inflammatory cytokines and chemokines. Activation of TLR2 or TLR4 alone induced interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) in an agonist concentration-dependent manner. Simultaneous activation of TLR2 and TLR4 induced IL-8 synergistically, MCP-1 in an additive trend, and IL-6 weakly but synergistically. PAR-2 activation of HaCaT cells induced IL-6 and IL-8 but suppressed MCP-1 in an agonist concentration-dependent manner. The enhancement of IL-8 and the suppression of MCP-1 by PAR-2 activation were both neutralized by the PAR-2 antagonist AZ3451, supporting the possibility that PAR-2 activation simultaneously induces the following opposing effects in inflammation: enhancement of IL-8 and suppression of MCP-1. The nuclear factor-κB (NF-κB) pathway inhibitor BAY 11-7082 neutralized the induction of IL-8 but not the suppression of MCP-1 by PAR-2 activation, indicating that PAR-2 activation induces activation of the NF-κB pathway, and that the suppression of MCP-1 by PAR-2 activation is not related to the NF-κB pathway.

Inflammaging is a subject of considerable attention, because aging is characterized by low-grade, chronic, and asymptomatic inflammation, concomitant with increased blood levels of senescence-associated secretory phenotype (SASP) factors, including IL-1, IL-6, IL-8, IL-18, and tumor necrosis factor-α (TNF-α). However, IL-27 is currently not categorized as a SASP factor, although it is known to play pleiotropic roles in inflammation. In this study, we evaluated the interaction between TNF-α and IL-27 in the context of low-grade inflammation using HaCaT cells. TNF-α induced significant upregulation of the mRNA levels of IL-6 and IL-8 at the experimental concentration (~10 ng/ml), while the mRNA levels of IL-1RA, IL-10, and IL-18BP were unchanged. After confirming the expression of functional IL-27 receptors in HaCaT cells, we examined the effects of IL-27 alone on cytokine expression. IL-27 alone significantly upregulated the mRNA levels of IL-10, IL-18BP and IL-6 by 1.61-fold, 1.46-fold, and 2.32-fold, respectively. In the presence of 100 ng/ml of IL-27, the mRNA levels of the anti-inflammatory cytokines IL-1RA, IL-10, and IL-18BP, were significantly upregulated upon treatment with TNF-α at the physiological concentration (1 ng/ml). Taken together, this study indicates that a high concentration of IL-27 exhibits anti-inflammatory effects in the presence of a low concentration of TNF-α in keratinocytes, suggesting that the anti-inflammatory role of IL-27 in inflammaging may be regulated by TNF-α concentration.

Early detection is the key in managing side effects because immune-related adverse events (irAEs) are becoming more serious, and their onset time differs. In our hospital, we conducted an outpatient pharmacist clinic for early detection of irAEs by self-care practice for the cases of immune checkpoint inhibitor administration. As a result of a retrospective survey of 207 cases, the percentage of irAEs found by pharmacist’s suggestion of the outpatient pharmacist clinic increased over time, and a high detection ratio was obtained even for irAEs with a late onset time. The incidence of serious irAEs was higher than that in the immediate post-marketing surveillance, and different factors were considered. Although there were some problems, the outpatient pharmacist clinic had a certain effect.