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New Insights in the Pathogenesis of Erdheim‐Chester Disease: Comment on the Article by Los Arcos‐Bertiz et al

estimates were compromised by the significant limitations of studies in the literature, including the high disparity across studies. This disparity did not allow us to use more sophisticated statistical tests. Although we also acknowledge that it is difficult to determine the true frequency of a clinically significant aPL profile in the general population with pregnancy morbidity, our estimates reflected the best available synthesis to date. The studies mentioned by Clark and Laskin were from a different population (obstetric APS) than those that were analyzed for the primary objective of our analysis, which was to estimate the frequency of aPL in the general population with pregnancy morbidity. Second, most published obstetric APS studies recruited women experiencing 3 early pregnancy losses and thus did not fulfill the updated Sapporo classification criteria (1). Early pregnancy loss is a rather common event; in a 2009 national US survey, 526,000 annual pregnancy losses were reported, mainly occurring in the first gestational stages (2). Thus, it is not surprising that, according to our estimates, aPL positivity, irrespective of actual aPL titer and confirmation, could be observed in 50,000 women experiencing 1 pregnancy losses every year in the US. Clearly, this does not in any way imply that 50,000 patients can be diagnosed with obstetric APS every year in the US. Third, we believe that, while cautious interpretation is warranted (as discussed in the original article), our numbers may help us understand the magnitude of the clinical implications of positive aPL. Indeed, it is rather common in everyday clinical practice to see women referred, and sometimes even treated, for purported obstetric APS despite not fulfilling the updated Sapporo classification criteria, e.g., presenting with only 1 pregnancy loss and/or with an insignificant aPL profile. Surely, aPL positivity is necessary, but not sufficient, to diagnose APS; the autoantibody profile, the titer, the persistency, and the clinical manifestations should all be considered by expert physicians. Moreover, we agree that an exhaustive evaluation of hormone, anatomic, genetic, infectious, and thrombophilic etiologies of pregnancy loss should be carried out in all patients with or without obstetric APS diagnosis. In summary, we cannot estimate the frequency of a clinically significant aPL profile or obstetric APS based on the updated Sapporo classification criteria in the general population with pregnancy morbidity because of the lack of robust data. However, we can estimate the impact of aPL positivity in both research and clinical practice. We hope that our article will encourage researchers to pursue the true Herculean task of conducting high-quality collaborative research studies in obstetric APS based on improved clinical research standards.