Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common cholestatic liver diseases. While PBC is generally accepted to be an autoimmune disorder characterized by pathognomonic autoantibodies against mitochondrial antigens, the pathogenesis of PSC is less precisely defined; however, some degree of altered immunity toward autoantigens has been suggested. Follicular T helper (Tfh) cells, a distinct clusters of differentiation (CD)4 T‐cell subset specialized in facilitating antibody responses, have been shown to contribute to humoral autoimmunity in various disorders; yet, there is only limited information on possible alterations of Tfh cells in the context of cholestatic liver diseases. Thus, we addressed this important question by analyzing the frequency, activation status, and function of Tfh cells and frequencies of regulatory follicular T helper (Tfr) cells in well‐defined cohorts of patients with PBC and patients with PSC. Interestingly, we observed a significant increase in circulating chemokine (C‐X‐C motif) receptor 5 (CXCR5)+programmed death 1 (PD‐1) +CD4+ Tfh cells in patients with PBC but not in those with PSC. Although the frequency of potentially pathogenic chemokine (C‐C motif) receptor 7 (CCR7)lowCXCR5+PD‐1+CD4+ Tfh cells was increased in both disorders compared to healthy donors, the increase was significantly more pronounced in PBC. Furthermore, in patients with PBC, Tfh cells displayed stronger expression of the activation markers OX40 and inducible costimulator of T cells, correlated with anti‐anti‐mitochondrial antibody M2 and immunoglobulin M titers, and were most significantly increased in patients with cirrhosis. Tfr cell numbers were similarly increased; however, Tfh/Tfr ratios were unaltered in PSC and PBC. These alterations did not correlate with increased secretion of the Tfh signature cytokine interleukin‐21 in sorted CD4 T cells. Conclusion: Significant alterations occur in the Tfh cell compartment in cholestatic liver diseases, suggesting that Tfh cells influence the pathogenesis of PBC and to a lesser extend PSC.

ZUSAMMENFASSUNGDie diabetische Stoffwechsellage korreliert häufig mit einer Dyslipidämie, die sich typischerweise durch erhöhte Triglyzeride, niedriges HDL-Cholesterin und eine hohe Konzentration an small dense LDL-Cholesterin (LDL: low-density lipoprotein) auszeichnet. Zur kardiovaskulären Risikostratifizierung bei Diabetes mellitus Typ 2 eignet sich die Verwendung von Non-HDL-Cholesterin (HDL: high-density lipoprotein), um sämtliche potenziell atherogene Lipoproteine – VLDL (very-low-density lipoprotein), IDL (intermediate-density lipoprotein), LDL, Lipoprotein(a), Chylomikronen, Remnants – zu erfassen.

Targeted therapy with BRAF‐ and MEK‐Inhibitors (BRAFi, MEKi) provides an excellent therapeutic option for patients with malignant melanomas with a BRAF‐Mutation. Mild cutaneous adverse events have been common under the BRAF‐ and MEK‐Inhibitor therapy, on the contrary, severe cutaneous adverse reactions to drugs (SCARs) are rarely reported. We present the case of a 59‐ year‐old female patient who after the resection of cutaneous in‐transit metastases of a malignant melanoma received one adjuvant cycle of Nivolumab followed by a switch of the therapy to an oral BRAFi/MEKi therapy. 3–4 Weeks after the therapy switch she developed high fever, chills, progredient general weakness, headaches, abdominal complaints, generalised rash as well as thrombocytopaenia, eosinophilia, elevated liver enzymes, declining kidney, and pulmonary function as well as a maculopapular exanthema. She was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS) and quickly started recovery after initiation of a high steroid substitution. Under steroid dose reduction, the exanthema worsened and toxic epidermal necrolysis (TEN) was histologically diagnosed. After a series of unsuccessful therapeutic approaches (high dose steroid, human immunoglobulins and ciclosporin) the patient received a single dose of the TNF‐alpha inhibitor etanercept, which led to a quick recovery. This case demonstrates that DRESS and TEN can present a spectrum of possibly transitioning SCARs providing a diagnostic and therapeutic challenge. Nevertheless, in a such complicated therapeutic setting, etanercept may be lifesaving even after multiple previous unsuccessful therapies. This effective approach provides evidence SCARs due to BRAF/MEK targeted therapy may be driven by TNF‐alpha.

No abstract