Rituximab for the Treatment of Graves’ Orbitopathy
TRAb, and eventually needed radioiodine therapy. Perhaps the lack of control subjects has prevented the authors from providing a more conclusive interpretation of their findings on a potential role of RTX on GD hyperthyroidism remission rates.
Effects of Rituximab on Lymphocytes in the Peripheral Blood and Infiltrating Target Tissues In patients with GO, data on peripheral B- and T-cell changes after RTX treatment have been reported in the studies of Salvi et al.32,34,49 Heemstra et al.43
and
peripheral B-cell depletion in most patients.34,35,43 clinical response to RTX in both GD43
In general, RTX has been shown to induce total Interestingly, the bore no clear
and GO patients34
correlation with either CD20+ cell depletion or return in the peripheral blood. When studied, B-cells were not detected in the periphery at the time of second dose of 1,000 mg RTX at two weeks.32,34
Peripheral B-cell
depletion has generally been reported to last 16–18 weeks. Very recently, we have observed total peripheral depletion of CD20+ and CD19+ cells 45–60 minutes after infusing only 100 mg of RTX in three patients with active GO.41
Table 3 shows the B-cell depletion patterns in
In addition, the self-reactive B-cell residing in the bone marrow will not be altered by RTX treatment because B-cell receptor selection occurs before CD20 expression.50
these three patients. B-cell depletion lasted 16 weeks, similar to what has been observed in patients treated with the full course of RTX therapy (1,000 mg RTX repeated once after a two-week interval). Typically, no changes were observed in the percentages of peripheral CD3+, CD4+ and CD8+ cells. Although most studies focus on the measurement of peripheral blood B-cells before and after RTX therapy, their analysis might yield findings of limited significance because B-cells in the peripheral blood represent <2 % of total mature B-cells in the body.3
C D
Figure 3: Immunohistochemistry View of Eye Muscle (A, B) and of Fat Tissue of the Orbit (C, D) of a Patient Treated with Rituximab
A B
A: an interstitial infiltrate of CD3 immunostained T lymphocytes. B: immunostaining for CD20 in an analogous field shows no immunoreactive cells. C: rare CD3 immunostained T lymphocytes infiltrating fibro-fatty tissue. D: immunostaining for CD20 in an analogous field of fibro-fatty tissue shows the complete absence of immunoreactive B cells. All pictures are taken at x200 magnification.
Of interest, we have recently observed significant infiltration of CD68+ macrophages after either full-dose or low-dose RTX.41
After performing
Therefore, in organ-specific autoimmune disease, the therapeutic effect of RTX is likely depending on the interaction of RTX with the lymphocytic infiltrates within the target organs—e.g., the thyroid in GD and the orbit in GO. Until now, data on the effect of RTX within target organs in autoimmune disease,51
including GD and GO, are limited to single case
reports. While B-cells have been reported to be completely absent from thyroid tissue specimens of one patient with GD one week after RTX therapy,52
in another patient, CD20+ cells have been shown to be present in the thyroid five months after RTX therapy.32
This discrepancy might be
due to the different time of tissue sampling, since the latter study has been carried out at the time of B-cell return in the peripheral blood.
Orbital tissue specimens, usually obtained at surgical decompression, have also been studied in single patients. Orbital tissue depletion of both B- and T-cells 10 months after RTX therapy was first reported by Salvi et al.,32
and similar findings were recently confirmed as early as 12 days
Incomplete orbital tissue B- and T-cell depletion was observed in another two patients studied at approximately six months after RTX therapy,49,53
after treatment.35 both also characterised by incomplete peripheral
B-cell depletion. This may result from long-lasting inactivation of autoreactive B-cell-induction of inflammation by RTX, since, in both patients, GO became rapidly inactive and remained so at follow-up. Complete CD20+ cell depletion and either complete or near complete absence of CD3+ lymphocytes in the orbit may depend on the time elapsed from RTX therapy (see Figure 3).
US ENDOCRINOLOGY
What is B-cell Depletion Showing us in Autoimmune Disease?
Based on the evidence obtained with RTX therapy in both animals and humans, B-cells may contribute most significantly to the initiation of autoimmune disease, as was observed early in the course of diabetes in non-obese diabetic (NOD) mice,55
in which it was not possible to reverse
disease progression once inflammation had begun. This is because B-cell depletion in vivo has been shown to significantly decrease autoantigen-specific CD4+ T-cell proliferation in NOD mice, but not to inhibit T-cell expansion once fully initiated.2
further staining for CD1a and CD163, CD1a was found negative, indicating an absence of dendritic cells, while CD163—a marker of type 2 macrophages—was well expressed and was particularly abundant in the two patients in whom RTX had been administered more recently.41 By comparison, control patients only had focal CD68+ and CD163+ cell infiltration. Recruitment of type 2 macrophages might be involved in the mechanism of action of RTX in GO and would offer an explanation for its rapid effect. In the work of Khanna et al.,35
GO improvement and
stabilisation after RTX was also associated with the detection of an abundance of CD25 cells (T regs) in the peripheral blood, which have been shown to be predictive of RTX therapeutic success in RA.54
More studies are needed
to determine the significance of B-cell depletion therapy in humans by comparison with experimental animal models. B-cells, T-cells, and autoantibodies are all known to be involved in autoimmune disease pathogenesis, with B-cells likely to contribute the most during early disease, while T-cell activation and autoantibody production may independently mediate disease progression.2
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