Association between a History of Inhibitors and Delays in Skeletal Maturation in Adolescents with Hemophilia.
Authors: Donfield Sharyne M. , Lail Alice , Gomperts Edward D. , Hoots W. Keith , Berntorp Erik , Lynn Henry S. 
Published: April 2020

Abstract
The development of inhibitory antibodies to factor VIII or factor IX is the most serious complication of replacement therapy for people with hemophilia. Inhibitors decrease effectiveness of treatment, increasing risk of morbidity including bleeding frequency and arthropathy, and mortality. The current study examined the association between history of inhibitors and physical growth measured by skeletal maturation (bone age, BA) in participants enrolled in the longitudinal Hemophilia Growth and Development Study (HGDS). The HGDS is a population-based multicenter study of children and adolescents enrolled between 1989 and 1990. Participants not skeletally mature (n=306) were included in this investigation. Their mean age was 12, range 7–18 years. Seventy-five percent had severe hemophilia, 19% moderate, and 6% mild. Eighteen percent (n=54) had a history of inhibitors, with maximum lifetime Bethesda titers ranging from 1 to 2048. In general, HGDS participants received on-demand therapy prior to and during study follow-up. Skeletal maturation was determined centrally from x-rays of the hand-wrist according to the Fels method. Readers were masked to the clinical status of participants. Growth delay was defined as chronological age (age) minus BA and modelled using a longitudinal mixed effects polynomial model including age, race, HIV and inhibitor status, and their interactions. P-values were adjusted for multiple comparisons using Scheffe’s method. At every year evaluated (10 through 16), growth delay was greater among HIV-negative subjects with a history of inhibitors compared to HIV-negative subjects without inhibitors (p-values ranged from 0.042 to 0.12). The greatest differences, 9 to 10 months, were observed during the period of expected maximum growth velocity, 12 through 14 years of age (all p&lt;0.05). At ages 15 and 16, subjects with inhibitors lagged approximately 9 months behind those without inhibitors in their skeletal maturation (p=0.067 and 0.12). The predicted BA of HIV-negative adolescents without inhibitors was quite similar to age during this period. At 12, 13, 14, 15 and 16 years, they were 11.9, 13.1, 14.3, 15.4, and 16.4 respectively. Previous investigations from the HGDS have reported delays in skeletal maturation associated with HIV. In this study, delays were greater among HIV-positive subjects with an inhibitor compared to HIV-positive subjects without an inhibitor at every age, but perhaps due to intervening effects of HIV, the differences were generally small (1 to 2 months) and not statistically significant. In conclusion, the differences in bone age relative to chronological age between the HIV-negative groups suggest that a history of inhibitors is associated with delays in onset of puberty. Further investigation of this association and other growth parameters is a priority. If confirmed, the observation has important clinical, epidemiologic and therapeutic implications for the children and adolescents most severely impacted by hemophilia.