A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has recently been described as an autoinflammatory disease associated with severe adult-onset inflammatory manifestations. The various clinical manifestations include recurrent high-grade fever, neutrophilic dermatoses, cutaneous vasculitis, chondritis of the ear and nose, pulmonary infiltrates, cytopenia, uveitis, gastrointestinal pain or inflammation, aortitis, hepatosplenomegaly, and hematological disorders. VEXAS syndrome is caused by somatic mutations of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene in myeloid-lineage cells. It is characterized by vacuolated myeloid and erythroid progenitor cells seen by bone marrow biopsy. We report the case of a 64-year-old Japanese man with VEXAS syndrome. At age 63, he was referred to us with a recurrent erythema on the hands associated with a general fever of 38-40°C that had persisted for 4 or 5 days and had recurred about once a month for a year. The skin rash appeared 2 or 3 days after the onset of each fever episode. Computed tomography (CT) of the chest revealed bilateral hilar lymphadenopathy (BHL), and the mediastinal lymph nodes were swollen. Sarcoidosis was suspected but was ruled out by several tests. Laboratory examinations showed elevated inflammatory markers. Bone marrow examination showed the vacuolization of myeloid precursor cells. A skin biopsy revealed dense dermal, predominantly perivascular, infiltrates. These consisted of mature neutrophils admixed with myeloperoxidase-positive CD163-positive myeloid cells, lymphoid cells and eosinophils. Sequencing analysis identified the somatic UBA1 variant c.122T > C, which results in p.Met41Thr. Treatment with oral prednisone (15 mg/day) and monthly intravenous tocilizumab injections (400 mg) completely resolved the symptoms. Neutrophils are a major source of reactive oxygen species, and the present case demonstrated numerous neutrophilic infiltrates. We hypothesize that the patient might have had elevated derivatives of reactive oxygen metabolites (d-ROMs). d-ROM quantification is a simple method for detecting hydroperoxide levels, and clinical trials have proven it useful for evaluating oxidative stress. In this study, we measured serum d-ROM before and after oral prednisone and tocilizumab treatment. The levels decreased significantly during treatment.

FTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression.

Sphingosine kinase (SK), a key enzyme in sphingosine-1-phosphate (S1P) synthesis, is known to be overexpressed in various types of cancer cells. The effects of anticancer agents on SK1/S1P signaling have not yet been fully assessed in melanoma cells. In the present study, we investigated the effects of the combination of FTY720, an S1P receptor antagonist, and cisplatin, a DNA-damaging agent, on the induction of the death of human melanoma cells, as well as the molecular mechanisms involved. The viability of various human melanoma cell lines was examined following treatment with anticancer drugs. The cisplatin-resistant SK-Mel-28 and cisplatin-sensitive A375 cell lines were selected for this analysis. Protein expression and apoptotic rates were evaluated by western blot analysis following treatment with cisplatin and/or FTY720. Following treatment with a combination of FTY720 and cisplatin, cell viability significantly decreased and the expression of apoptosis-associated cleaved poly(ADP-ribose) polymerase (PARP) was significantly higher in comparison to treatment with cisplatin alone in the SK-Mel-28 cells. In addition, the combination of FTY720 and cisplatin reduced the protein expression of SK1 and the phosphorylation levels of phosphoinositide 3-kinase (PI3K), Akt and mTOR in the SK-Mel-28 cells; the expression of epidermal growth factor receptor (EGFR) was also markedly reduced. These findings suggest that FTY720 and cisplatin synergistically induce cell death through the downregulation of the PI3K/Akt/mTOR pathway and the decrease in EGFR expression in SK-Mel-28 cells. Thus, the combination of FTY720 and cisplatin may have therapeutic potential for chemotherapy-resistant melanoma, and the effects are likely exerted through the downregulation of S1P signaling.

Efficacy of granulocyte and monocyte adsorption apheresis for treatment of palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is characterized by neutrophilic pustules with erythema, which are limited to the hands and feet. Although granulocyte and monocyte adsorption apheresis (GMA) has shown remarkable effects on generalized pustular psoriasis, there are few reports of PPP treated with GMA. We treated three refractory PPP patients using GMA weekly for 5 weeks. The skin eruptions were assessed by a 5-grade score for scales, pustules, and erythema. GMA decreased the total grade from 9 to 2 in patients 1 and 2, and from 7 to 3 in patient 3. The GMA effects were estimated to be excellent in all three patients. Pustule formation and pain disappeared in all cases. The treatment effect lasted for at least 5 months after GMA. GMA was also effective for relieving the arthralgia in one patient, but it recurred at 6 weeks. Based on these findings, GMA could be an effective therapy for refractory PPP.

Interferon-γ decreases ceramides with long-chain fatty acids: possible involvement in atopic dermatitis and psoriasis.

Ceramide (CER) with long-chain fatty acids (FAs) in the human stratum corneum (SC) is important for the skin barrier functions. Changes in the CER profile have been associated with abnormal permeability of dermatoses such as atopic dermatitis (AD) and psoriasis. In addition, interferon-γ (IFN-γ) has been known to be abundant in both AD and psoriatic skin lesions. In this study, we aimed to identify the mechanism underlying the alteration of FA chain length of CERs in these diseases. Mass spectrometry analysis of CERs in the SC showed that the proportion of CERs with long-chain FAs was significantly lower in AD and psoriasis patients than in healthy controls, and this reduction was more pronounced in psoriasis than in AD. Using cultured human keratinocytes and epidermal sheets, we found that only IFN-γ among various cytokines decreased the mRNA expression of elongase of long-chain fatty acids (ELOVL) and ceramide synthase (CerS), enzymes involved in FA chain elongation. Furthermore, quantitative analysis showed that IFN-γ decreased the levels of CERs with long-chain FAs. These results suggest that IFN-γ decreases CERs with long-chain FAs through the downregulation of ELOVL and CerS and that this mechanism may be involved in the CER profile alteration observed in psoriasis and AD.