The Histopathological Landscape of Synovitis in Hemophilic Arthropathy
Authors: Gualtierotti Roberta , Suffritti Chiara , Pescia Carlo , Giachi Andrea , Spena Silvia , Molfino Federico , Lavorato Stanislao , Semproni Eleonora , Truma Addolorata , Arcudi Sara , Ciavarella Alessandro , Maggioni Marco , Gianelli Umberto , Siboni Simona Maria , Acquati Lozej Jacopo , Solimeno Luigi Piero , Peyvandi Flora 
Published: December 2023

Recurrent joint bleeding leads to chronic arthropathy in severe hemophilia A and B. With the recent introduction of novel therapies and the increased availability of treatments for patients with hemophilia, a very tight control of bleeding is achievable, but some patients still experience synovitis oat target joints. A deeper knowledge of the synovial membranes in hemophilic synovitis may help the personalised treatment. However, very few data are available regarding the histopathological characteristics of the synovial membrane of patients with hemophilic arthropathy.

We studied the histopathological aspects of the synovial membranes of nine patients undergoing orthopedic surgery in order to describe the overall characteristics and the immune infiltrate.

Hematoxylin-eosin coloration was applied. Immunohistochemical analysis was performed and two synovitis scores currently used for rheumatoid arthritis were applied: the Krenn and the Humby scores. Moreover, we evaluated synovial collagen fibrosis by means of Masson trichromic staining, grading subintimal fibrosis semiquantitatively. Iron deposits were parallelly assessed with Perls histochemical stain and graded semiquantitatively. For each case we also evaluated whether iron deposits were mostly found in the intracellular (mainly siderophages) or extracellular compartment.

Nine patients (six affected by severe hemophilia A, one by moderate hemophilia A and two by severe hemophilia B) with a mean age of 41 ± 14 years, were included. All patients were in prophylaxis with replacement drugs. Synovial membrane was collected during surgery (four total knee replacement, one arthroscopic knee synovectomy, two total ankle replacement, two arthroscopic ankle debridement), following good clinical practice. Informed consent was obtained before the procedure.

All the synovial membrane samples were characterised by synovial hyperplasia and hemosiderin deposits. In seven out of nine samples a pauci-immune infiltrate was observed, whereas in two samples a lymphoid-myeloid infiltrate with lymphoid aggregates was present. All cases showed ≥1 grade fibrosis, with eight out of nine cases showing moderate to severe subintimal fibrosis and only one case with lympho-myeloid infiltrate exhibiting mild fibrosis. Iron deposition across the cohort was heterogeneous, with equal distribution of cases with mild (33%), moderate (33%) and severe (33%) iron deposition. Iron deposits were observed mostly in the intracellular compartment (i.e siderophages) with scattered extracellular presence, with the exception of one case with mild and almost exclusive extracellular deposition.

In hemophilic arthropathy, we fount typical characteristics of the blood-induced synovial hyperplasia in the majority of the studied synovial membranes, with a pauci-immune infiltrate resembling degenerative arthropathies such as osteoarthritis. By contrast, lymphoid aggregates similar to inflammatory arthritis were less frequent. Fibrosis and iron deposition were more frequent than in osteoarthritis. It should be noted that all the samples were collected from patients undergoing orthopedic surgery due to long-lasting synovitis. A larger study including patients at different stages of arthropathy may help clarify if a different histopathological landscape may correlate with a different clinical history and predict the response to different therapeutic approaches.