Why Is the Mortality of Bullous Pemphigoid Greater in Europe than in the US?

Abstract

What is the prognosis of bullous pemphigoid (BP)? The answer is critical to provide meaningful information to our patients. Unfortunately, the answer is confusing. The reported mortality of BP is much greater in Europe than in the US. Mortality 1 year after initiation of therapy ranges from 19% to 41% in Europe but is only 6%–12% in the US. This difference is supported by an increasing number of reports which are remarkably consistent in their observations, as summarized in Table I. Five European studies report the 1-year mortality as 19%, 29%, 30%, 40%, 41%, respectively; whereas three reports from the US report it as less than 6%, 11%, and 12%. In our own unpublished observations on 135 sequential BP patients treated in a tertiary referral center in New York City during the past decade, mortality at one year was less than 10%. Joly and his colleagues in this issue of the JID have offered several possibilities to explain this difference in outcome. These include differences in treatment, ethnic differences, age, study size, and patient selection bias. There is an obvious difference in treatment, as the majority of patients reported from Europe are hospitalized for treatment whereas this is the exception in the US. The immediate suspicion that complications of hospitalization is the cause for the higher mortality in Europe is, however, refuted by Garcia-Doval and colleagues who in this issue of the JID indicate that the greatest mortality in their patients occurred after hospital discharge. Other aspects of treating BP in Europe and the US are generally similar, and so do not provide a ready explanation for the differing mortality rates. Nor does difference in age provide a likely explanation for the higher mortality reported in Europe. The average age of patients in two European (Rzany et al, 2002; Garcia-Doval et al, 2005) and one American study (Colbert et al, 2004) is identical, i.e., 77 years. Nonetheless, mortality was still three to four times higher in the European studies. American studies are generally smaller than those conducted in Europe. However, the consistency of the reports, i.e., mortality in all European studies, is higher than in all American studies, and the clear nature of the end-point (death) suggest the reported differences between European and American studies are real. Ethnic differences as the cause for higher mortality in Europe cannot be formally refuted based on available data. This is, however, difficult to accept as the studies conducted in Europe (England, France, Germany, and Spain) and in the US (Boston, Cincinnati/Detroit, New York and Milwaukee) both span a wide range of nationalities and ethnicities. We suspect the most likely explanation for the differences in BP mortality between Europe and the US is a patient selection bias, as initially suggested by Korman (1998). The published evidence suggests that BP studies in Europe were conducted in patients who were generally sicker than those in the US, as was initially argued by Korman (1998). Whether this is because patients with more severe disease or comorbidities are not treated in tertiary medical centers in the US, as suggested by Joly et al (2005), or conversely because such patients are preferentially referred to tertiary centers in Europe as we suspect, the results will be the same—mortality will appear worse in Europe than the US because it is based on a subset of patients with BP who are sicker and/or have more comorbidities. Lastly, the true mortality of BP cannot be discerned from any of these studies, since none is adjusted for the expected mortality of age-matched patients with similar comorbidities.