Intraorbital tissues effects of rituximab (RTX) treatment in patients with thyroid-associated ophthalmopathy (TAO)
Guia Vannucchi1, Irene Campi1, Stefania Rossi2, Paola Bonara3, Claudio Guastella4, Nicola Currò5, Simona Simonetta5, Clara Sina6, Roberto Ratiglia5, Paolo Beck-Peccoz1 & Mario Salvi1
We previously described a significant response to RTX treatment in patients with active TAO, with no effect on TRAb and hyperthyroidism. In order to study the effect of RTX in the orbit, we analyzed the orbital tissues of 9 patients with TAO at decompression after RTX (n.2) or other treatments. Decompression was carried out in 2 patients for sight threatening optic neuropathy and in 7 for correction of proptosis. Of the RTX treated patients, one was decompressed after 12 months because of optic neuropathy, while the other after 23 months with burnt out disease. Of the other 7 patients, one was decompressed for the second time because of relapse of optic neuropathy that did not respond to steroids and 6 had burnt out disease of 15-175 months of duration. Immunohistochemistry of orbital fat and muscle showed presence of infiltrating immune cells in all patients. Infiltrates were present independently of the duration and the type of treatment of TAO and of thyroid disease. Interestingly, in the orbital fat of the patient who underwent decompression twice, we observed a typical lymphoid aggregate with CD3+ and CD20+ cells. In patients treated with RTX immunohistochemistry and cytofluorimetry were performed. While no cells were observed in the orbital fat of the patient with burnt out disease, we found persistence of CD3+ cells in the muscle of the patient with optic neuropathy at immunohistochemistry. In this patient, RTX induced peripheral CD20+ depletion, but persistence of 3 and 6% CD19+ after the first and a second cycle of treatment, respectively. Cytofluorimetry showed that almost all of these cells were CD19+5+ both in periphery and the orbital fat, suggestive of autoreactive clones. An increase of the absolute and relative numbers of CD19+5+ was observed in relation to the worsening of optic neuropathy, despite the absence of CD20+. These findings suggest that: 1) immune infiltrates are present in the orbital tissues of TAO patients even in long standing disease; 2) RTX may act by depleting CD20+ in the orbit; 3) persistence of autoreactive CD19+5+ clones in the orbit may correlate with an only temporary and partial response to RTX in TAO patients.