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When prescribing low-dose methotrexate, frequent serological testing is recommended in the dermatologic literature, although much of the supporting data is extrapolated from non-dermatologic conditions. We performed a retrospective cohort study to determine the cumulative incidence and timing of low-dose methotrexate-associated serological abnormalities over the first year of therapy, in a pragmatic cohort of patients with dermatologic compared to non-dermatologic diagnoses. Laboratory values recorded included white blood cell count, hemoglobin, platelet count, estimated glomerular filtration rate, alanine aminotransferase, and aspartate aminotransferase. Among 1376 patients, there were no cases of methotrexate-associated grade 4/very severe lab abnormality or fatality. Baseline risk factors associated with moderate-to-severe lab abnormalities included non-dermatologic diagnoses, low hemoglobin, low estimated glomerular filtration rate, and elevated transaminases. The incidence of moderate-to-severe lab abnormalities was 4.4% among all patients, 3.1% among patients with dermatologic diagnoses, and 2.3% among patients with normal baseline lab values. Lab abnormalities led to discontinuation of therapy in 0.8% of patients. Serious changes did not occur in the first two weeks of therapy. We conclude that the cumulative incidence of low-dose methotrexate-associated lab abnormality was lower in patients with dermatologic diagnoses or normal baseline testing and these factors may be used to adjust monitoring practices.

Atopic dermatitis (AD) is a Th2 biased disease with elevated expression of Th2 cytokines that responds to Th2 signaling blockade. Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase with innate antiviral activity. In our previous studies, we showed that Trim32 null mice developed Th2 biased skin inflammation in response to imiquimod and associated low level of TRIM32 with AD. In this study, we provide evidence that TRIM32 deficiency contributes to enhanced Th2 cell differentiation in vitro. Analysis of TRIM32-associated proteins from public databases identified PKCζ as a TRIM32-associated protein that contributes to the regulation of Th2 signaling. We demonstrated that PKCζ was specifically ubiquitinated by TRIM32, and further, that PKCζ stability tended to be increased in Th2 cells with a Trim32 null background. Furthermore, Prkcz null mice showed compromised AD-like phenotypes in the MC903 AD model. Consistently, a high PKCζ and low TRIM32 ratio was associated with CD4(+) cells in AD human skin compared with healthy controls. Taken together, these findings suggest that TRIM32 functions as a regulator of PKCζ that controls the differentiation of Th2 cells important for AD pathogenesis.