Bone impairment in atypical hemolytic and uremic syndrome treated by long-term eculizumab

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy, related to complement dysregulation, including Factor H deficiency (FH) treated by lifelong eculizumab therapy. Its long-term tolerance is not yet fully described. We report two patients with genetic FH deficiency receiving long-term eculizumab and displaying a peculiar bone phenotype. First case is a 13-year-old girl, presenting with bone pains, arthritis, and deformities, for which X-rays and MRI described multifocal osteochondritis. Bone biopsy revealed an active remodeling bone (many areas of bone formation and resorption) and C3c accumulation on immunohistochemical staining. The second patient is an 11-year-old girl, displaying mechanical bone pains, for which bone scintigraphy found hypofixation of wrists and ankles. These findings could be consistent with a side effect of eculizumab, as C3c accumulation may result from the downstream C5-blockade. Alternatively, bone alterations could be due to the absence of FH, as described in murine models. Further investigations are required to characterize bone disease in aHUS.

Keywords: AHUS; Bone; C3 deposits; Eculizumab.

Fig. 1

Bone abnormalities of the two patients. A–C Histological sections of healthy radius and pathologic ulna from patient 1. A Goldner-stained section showing the abundance of osteoid surfaces and adiposity of bone marrow of healthy radius, magnification × 2.5. B Goldner-stained section of pathological ulna. C Unstained section of healthy radius illustrating the extended labeled surfaces by tetracycline labels. D–I Immunostaining on PFA 4% fixed and paraffin-embedded bone sections with primary anti-C3c (D, E, G, H) or with control isotype antibody (F, I). Briefly, sections were deparaffinized and rehydrated, primary polyclonal rabbit anti-human C3c 1/2000 (ref 0062, Dako Glostrup Denmark) was incubated overnight and then incubated with secondary antibody HRP-conjugated goat anti-rabbit (Envision system, Dako Glostrup Denmark) for 1 h. After washing, sections were revealed by 3,3′-diaminobenzidine and counterstained with Mayer’s hematoxylin. D Healthy radius from patient 1, anti-C3c. E Pathological ulna from patient 1, anti-C3c. F Healthy radius from patient 1, isotype control. G Tibia fragment from control girl (10-year-old), anti-C3c. H Tibia fragment from control girl (14-year-old), anti-C3c. I Tibia fragment from control girl (10-year-old), negative control. In bone from patient 1 a strong staining for C3c was found in bone marrow and on bone surfaces, both in healthy radius and pathological radius (D, E). In contrast, only a weak staining for C3c was found in tibia from the 2 controls (G, H). No staining was found isotype control antibody (F, I). Magnification × s10 for B–I. J–K Bone scintigraphy of the second patient (J). Whole body scintigraphy. K Ankles scintigraphy. L Wrist scintigraphy. Bone scintigraphy described asymmetrical bone perfusion and metabolism, diffusely affecting the left foot and right hand