D‐Dimer Elevation in Spontaneous Urticaria and Bullous Pemphigoid, Two Chronic Inflammatory Skin Diseases

We have read with interest the consensus guidance by Tripodi et al. on the appropriate use of D-dimer measurement in clinical practice, providing a comprehensive review of both the strengths and the limitations of D-dimer measurement [1]. We agree with the authors that D-dimer elevation should be considered in combination with pre-test clinical probability to exclude venous thromboembolism (VTE) and it can be found in association with several clinical conditions not related to ongoing thromboembolism. However, in this context, we would like to draw attention to two chronic inflammatory skin disorders, namely chronic spontaneous urticaria (CSU) and bullous pemphigoid (BP), not explicitly discussed in the guidance. In these diseases, elevated D-dimer is common, and in our experience, many patients with CSU or BP, evaluated in the emergency room or outpatient clinic, have undergone extensive diagnostic workup for VTE, which ultimately led to its exclusion. This observation should prompt a reflection on the meaning of elevated D-dimer in CSU and BP. Indeed, we showed that both CSU and BP are often associated with activation of coagulation and fibrinolysis that parallels disease activity [2-6]. CSU is a mast cell-driven skin disorder characterized by the recurrent eruption of short-lived wheals accompanied by redness and itching for at least 6 weeks. In this disease, mast cells release histamine and other inflammatory mediators following activation by IgG autoantibodies against the high affinity IgE receptor (FcεRI) or IgE as well as following activation by autoreactive IgE against several autoallergens [7]. Activation of coagulation and complement is also involved in the disease pathogenesis [8]. BP is an autoimmune disease occurring mainly in elderly patients and presenting with blisters and urticaria-like skin lesions due to autoantibodies directed against two hemidesmosomal antigens, BP180 and BP230, with complement/coagulation activation and leukocyte skin infiltration [5, 9]. Biomarkers of coagulation activation, that is, the prothrombin fragment F1 + 2 and D-dimer, are elevated during the acute phase of both CSU and BP, with higher levels in the latter [6]. Clinical improvement of CSU was associated with D-dimer normalization [4]. Hence, D-dimer has been considered as potential biomarker of CSU severity, reflecting skin and systemic inflammation and endothelial activation in the microcirculation rather than intravascular thrombosis [10, 11]. Similarly to CSU, BP is often characterized by marked D-dimer elevations that, also in this case, reflect extravascular fibrin formation and fibrinolysis in affected skin and do not reflect ongoing thrombosis [5]. Comorbidities in elderly BP patients may further increase D-dimer levels, creating diagnostic uncertainty. In a multicenter retrospective study, we have found an increased risk for VTE in BP patients [12], an observation that has been recently confirmed in a nationwide US cohort study, showing that BP was associated with a 2-fold increased incidence of VTE after controlling for VTE risk factors [13]. The above findings highlight the central message of the SISET guidance, that is the lack of specificity of D-dimer elevation and the need not consider the increase of D-dimer as evidence of VTE outside structured diagnostic pathways. CSU and BP represent clinically common scenarios where elevated D-dimer reflects chronic inflammation, and treatment of the underlying inflammatory skin disease reliably decreases D-dimer levels. We suggest including CSU and BP among the conditions frequently associated with increased D-dimer levels, in which D-dimer elevation may be explained by chronic inflammation rather than by an ongoing thrombotic event. Future studies could evaluate the predictive value of D-dimer measurement in CSU and BP patients since epidemiological studies have recently shown increased risk of VTE both in CSU [14] and BP [13]. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.