Rituximab for the Treatment of Graves’ Orbitopathy
Table 3: Percentages of Peripheral Lymphocytes at Baseline and at Different Follow-up Time-points after a Single Small Dose of Rituximab in Three Patients with Active Graves’ Orbitopathy
Time Patient 1 Baseline
45 minutes 1 week 3 weeks 6 weeks 10 weeks 13 weeks
Patient 2 Baseline
60 minutes 1 week 3 weeks 7 weeks 11 weeks 16 weeks
Patient 3 Baseline
45 minutes 1 week 4 weeks 8 weeks 16 weeks 24 weeks
CD20+ 10.2
0.4 0 0 0 0 0
13 0 0 0 0
0.6 1.9
13.6 0.1 0.1 0 0
1.6 2.2
CD19+ 9.9
0.7 0 0 0 0 0
12.7 3.2 0 0 0
0.6 1.8
13.9 3.1 0.2 0 0
1.6 2.3
CD19+5+ 1.4
0.1 0 0 0 0 0
1
0.2 0 0 0
0.1 0.6
2.1 0.4 0 0 0
0.5 0.8
CD3+ 84.2
92.5 84.2 88.6 90.1 91.4 90.7
81
88.9 94.8 93.5 94
92.8 90.7
69.7 69.1 82.8 79.4 76.7 82.4 78.3
CD4+ 62.3
68.5 59.5 65 64
67.6 60.7
73.6 81.9 87.7 85.8 83.9 85.5 83.9
44.9 45.8 51.5 49.9 51
54.3 53.2
CD8+ 24.1
26
32.3 29.1 28.4 28.2 30.2
9.9 8.1 9.4
10.8 11.8 9.4
10.2
29.9 33.9 37.0 40 35
34.8 30.7
in a stable and consistent way after only two doses of RTX, suggesting that the drug did impact the active phase of the disease.
Subsequently, Salvi et al.34 conducted an open study and treated, with a
1 g dose of RTX repeated after a two-week interval, a group of nine patients with active GO, of whom two had mild GO with only lid signs, and compared it with a group of 20 patients treated with the standard intravenous methylprednisolone therapy (see Table 2). All patients responded to RTX therapy, compared with 80 % who responded to the glucocorticoid. With RTX, CAS values had significantly decreased from 4.7 to 1.8 at the end of the follow-up period, and decreased more rapidly than with the glucocorticoid. Proptosis, eye muscle motility, and signs of soft tissue inflammation also improved significantly with RTX. Relapse of active GO was not observed in the patients treated with RTX, but occurred in 10 % of those treated with the glucocorticoid. More patients on the glucocorticoid than on RTX experienced side effects (45 % versus 33 %, respectively).
More recent data have confirmed the therapeutic effects of RTX in active GO. Khanna et al.35
have reported that, in six patients with
active and severe GO unresponsive to glucocorticoid therapy, RTX had had a rapid and sustained therapeutic effect on both disease activity and severity. In their study, RTX was also given intravenously as a 1 g dose repeated after a two-week interval, along with steroid therapy. The CAS had decreased from 5.5 to 1.8 at eight weeks after treatment and remained low at six months. No patient showed any improvement of extra-ocular motility or proptosis, but, in four patients who had optic neuropathy, visual acuity improved within four weeks
US ENDOCRINOLOGY
of treatment and had returned to pre-morbid values at eight weeks after treatment. Tapering of glucocorticoids after treatment was not followed by relapse of inflammatory signs. Two patients experienced minor side effects and one had sudden cardiac death later on, unlikely related to treatment.
Another recent open study, conducted by Silkiss et al.,36 has shown
significant improvement of active GO in 12 patients after administration of one dose of 1 g RTX repeated two weeks later. The mean CAS decreased from 5.5 to 1.9 at 16 weeks, and the mean scores on the Thyroid Associated Ophthalmopathy Scale (TAOS)—as modified by Dolman and Rootman (VISA Classification)37
—decreased from 10.4 to 7.1. Improvement
was further recorded up to 52 weeks after treatment, without evidence of relapse of inflammatory signs. Interestingly, no side effects were reported.
There has been an unpublished report of an ongoing open study in Newcastle, UK, by Mitchell et al.,38
in which RTX was administered at 1 g
or at an even lower dose of 500 mg (and repeated two weeks later) to six patients with active, steroid-refractory GO. GO improved fairly rapidly in five patients, with a decrease of the CAS from 5.5 to 2 at 16 weeks, and remained unchanged in one, without any occurrence of side effects.
Single case reports of RTX treatment have also been recently published. A significant therapeutic effect of RTX was observed in one patient with active GO, stiff person syndrome, and diabetes, with complete and persistent inactivation of GO and amelioration of the spastic paresis characteristic of the muscular disease.39
In contrast to all previous studies, failure of RTX in improving GO and subsequent progression to 133
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