Global reporting of cases of COVID‐19 in psoriasis and atopic dermatitis: an opportunity to inform care during a pandemic
Authors: S.K. Mahil, Z.Z.N. Yiu, K.J. Mason, N. Dand, B. Coker, D. Wall, G. Fletcher, A. Bosma, F. Capon, L. Iversen, S.M. Langan, P. Di Meglio, A.H. Musters, D. Prieto‐Merino, T. Tsakok, R.B. Warren, C. Flohr, P.I. Spuls, C.E.M. Griffiths, J. Barker, A.D. Irvine, C.H. Smith
Journal: British Journal of Dermatology (2020)

We read with interest the article in the BJD by Gambichler and colleagues 1 about a decline of programmed death (PD)-1 + circulating T regulatory cells (Tregs) predicting clinical outcome in anti-PD-1 therapy.The study highlights the potential and importance of immune monitoring in anti-PD-1 checkpoint therapy in malignant melanoma.However, their conclusion about anti-PD-1 antibody treatment effecting a decline of PD-1 + Tregs is misleading.A decline of a cell population infers 'disappearance', which normally is not the effect of therapeutic blocking antibodies.Their IgG4 backbones save target cells from antibody and/or complement-dependent cell-mediated cytotoxicity and depletion from circulation.The reported 'decrease' of CD4 + CD25 ++ CD127 -PD-1 + T cells thus lacks acknowledging that cell-bound therapeutic anti-PD-1 antibodies may simply interfere with detection by anti-PD1 detection antibodies due to 'steric hindrance'.In fact, it is well established that therapeutic and several clones of detection anti-PD1 antibodies compete for the same epitope. 2,3 Differentiating a 'decrease' from 'not detectable' is important because blocking effects are reversible as soon as trough plasma levels of therapeutic antibodies subside.This implicates possible disease reactivation following treatment discontinuation but also the opportunity to accelerate a washout of the therapeutic antibody if needed.We learned this from natalizumab, an alpha-4 integrin blocking antibody used for the treatment of multiple sclerosis, where discontinuation turned out to be a major problem associated with alpha-4 re-expression dynamics.In contrast, in the case of a rare but fatal treatment complication due to John Cunningham virus reactivation, an accelerated natalizumab washout by plasma exchange allowed a hurrying up of reexpression of alpha-4 for re-establishing immune competence. 4 The question remains as to whether the extent of PD-1 expression is not detectable because of bound therapeutic antibody or because of a true decrease in the form of shedding or internalization of receptor-antibody complexes.Of note, Zelba and colleagues already approached this question and developed a flow cytometry method for quantifying PD-1-expressing T cells including the detection of cell-bound therapeutic antibodies with antihuman IgG4 detection antibodies. 3 Our second point concerns the patient highlighted in Figure 1 in the article by Gambichler et al., 1 showing a paradoxical increase of PD-1 + Treg frequencies under anti-PD-1 therapy.This astonishing observation raises the question of an increased drug-antibody turnover, possibly due to the presence of anti-PD-1 neutralizing antibodies.According to the European Medicines Agency/European Public Assessment Report product information for Opdivo and Keytruda, 5,6 antidrug antibodies occurred in 11% of 2022 nivolumab-treated patients, with neutralizing antidrug antibodies in 0Á7% patients, and in 2% of 2034 pembrolizumab-treated patients with neutralizing antidrug antibodies in 0Á4%.Although rare, anti-PD-1 neutralizing antibodies occur and may contribute to treatment resistance.From earlier studies in multiple sclerosis we know that natalizumab neutralizing antibodies can occur after the first infusion and, importantly, can clear circulating therapeutic antibodies within a few days post infusion. 7