B Cell Depletion Therapy in Graves' Orbitopathy
No serious adverse events were recorded during or immediately after the administered RTX infusions. Four patients experienced minor side effects during the first infusion only (2 reported headache, 1 headache and chills without pyrexia and 1 mild myalgia).
Peripheral B lymphocyte counts were assessed in seven of the nine patients before RTX therapy. The mean count of circulating B lymphocytes (expressed as the percentage of CD19 cells in the total circulating lymphocyte count) was 15·7% (range: 8–30%). All patients had peripheral B lymphocyte counts assessed following RTX infusions to confirm B cell depletion. Eight of the nine patients have recovered their peripheral B cell counts at follow-up. The median time to recovery was 9 months (range: 5–13 months). One individual remained B cell depleted 8 months following RTX; however, a repeat measurement was not obtained. To date, only one patient (patient E) has had a slight flare of their eye disease coinciding with the first return of B lymphocytes to her peripheral blood, requiring symptomatic treatment only.
All patients had controlled serum thyroid hormone measurements at the time of RTX treatment (described in Table 2). No effect on thyroid function was noted in any of the patients treated.
TBII levels were assessed in each individual 0–2 months prior to RTX therapy and then repeated 3–15 months after RTX treatment (median 8 months). There was no correlation between the baseline TBII and reduction in TBII concentration when compared with the time since initial thyroid diagnosis. The TBII levels declined significantly following RTX in all individuals (P < 0·001 Wilcoxon signed-rank test) (Fig. 1). There was no significant difference between the reduction in TBII level in those with DON compared with those without DON and the dose of RTX received did not influence the reduction in TBII level. There was also no difference between the mean percentage reductions in TBII in those receiving antithyroid medications with levothyroxine compared with those receiving levothyroxine alone. Finally, the reduction in TBII level was also not related to the baseline B lymphocyte count, nor did it predict the improvement in CAS.
(Enlarge Image)
Figure 1.
Graph to illustrate TBII levels in all patients at baseline and then at follow-up after RTX. The dashed lines represent those individuals receiving antithyroid drugs during treatment (individuals B, C, H and I). The solid lines represent those receiving thyroxine (individuals A, D, E, F, G). The solid line which crosses the y axis at 0.8 U/l represents the minimum detection level for the TBII assay.
Disease Activity. The median CAS prior to treatment was 6/10 (range: 1–8). Eight of the nine patients treated had active disease with a CAS greater than 4/10 (median 6·5, range: 4–8). The patient treated to consolidate treatment had a baseline CAS of 1.
The CAS was improved in all individuals treated, with a median improvement at 3 months post-RTX of 2 points (range: 1–6, P = 0·018 Mann–Whitney U-test) and at 12 months of 5 points (range: 1–8, P = 0·0006 Mann–Whitney U-test) (Fig. 2). In one individual with DON, although a diminution in CAS score was observed (4–3), early improvement in optic nerve function was not optimal and emergency orbital decompression surgery was performed before the second RTX infusion.
(Enlarge Image)
Figure 2.
Graph to illustrate patient CAS scores, out of 10, before RTX (dotted bars), at 3 months after RTX (checkered bars) and at 12 months follow-up (striped bars).
The median improvement in CAS at 3 months and at 12 months did not differ significantly in those with DON compared with those without DON, nor in those on antithyroid drugs and levothyroxine compared with levothyroxine alone. CAS improvement did not correlate with total RTX dose.
Disease Severity. Overall, an improvement in NO SPECS classification was seen in six individuals in the 12 months following BCDT. Two individuals remained static and one individual showed a slight deterioration in diplopia (4iii at baseline, 4i at 3 months, 4iv at 12 months), which could be due to post-inflammatory fibrotic changes in the orbital muscles. All four individuals treated for DON experienced an improvement in NO SPECS score (from grade 6 in all cases to grade 4).
Thyroid Dermopathy. One patient (patient E) had very severe thyroid dermopathy before BCDT affecting the dorsum of both feet and lower legs. The patient also reported an increase in width of the scar over her right knee, synchronously with the development of the dermopathy. These features substantially improved in the year following BCDT (Fig. 3).
(Enlarge Image)
Figure 3.
Thyroid dermopathy of the feet and legs in patient E before (panel A) and 24 months after (panel B) B cell depletion therapy (BCDT). The photographs in panel A were taken just prior to BCDT and show thyroid dermopathy, with oedema and erythema of the right leg and dorsum of right foot compared with the left, and classical appearance of 'peau d'orange' and tethered skin on the right pretibial region. These appearances are clearly improved following BCDT (panel B), particularly in the right leg. The appearance of the hypertrophic scar from a previous right knee replacement operation is also much improved following BCDT.
Results
Adverse Events With Rituximab
No serious adverse events were recorded during or immediately after the administered RTX infusions. Four patients experienced minor side effects during the first infusion only (2 reported headache, 1 headache and chills without pyrexia and 1 mild myalgia).
Effects of Rituximab on B Cells
Peripheral B lymphocyte counts were assessed in seven of the nine patients before RTX therapy. The mean count of circulating B lymphocytes (expressed as the percentage of CD19 cells in the total circulating lymphocyte count) was 15·7% (range: 8–30%). All patients had peripheral B lymphocyte counts assessed following RTX infusions to confirm B cell depletion. Eight of the nine patients have recovered their peripheral B cell counts at follow-up. The median time to recovery was 9 months (range: 5–13 months). One individual remained B cell depleted 8 months following RTX; however, a repeat measurement was not obtained. To date, only one patient (patient E) has had a slight flare of their eye disease coinciding with the first return of B lymphocytes to her peripheral blood, requiring symptomatic treatment only.
Effects of Rituximab on Biochemical Results
All patients had controlled serum thyroid hormone measurements at the time of RTX treatment (described in Table 2). No effect on thyroid function was noted in any of the patients treated.
Effect of Rituximab on Immunological Results
TBII levels were assessed in each individual 0–2 months prior to RTX therapy and then repeated 3–15 months after RTX treatment (median 8 months). There was no correlation between the baseline TBII and reduction in TBII concentration when compared with the time since initial thyroid diagnosis. The TBII levels declined significantly following RTX in all individuals (P < 0·001 Wilcoxon signed-rank test) (Fig. 1). There was no significant difference between the reduction in TBII level in those with DON compared with those without DON and the dose of RTX received did not influence the reduction in TBII level. There was also no difference between the mean percentage reductions in TBII in those receiving antithyroid medications with levothyroxine compared with those receiving levothyroxine alone. Finally, the reduction in TBII level was also not related to the baseline B lymphocyte count, nor did it predict the improvement in CAS.
(Enlarge Image)
Figure 1.
Graph to illustrate TBII levels in all patients at baseline and then at follow-up after RTX. The dashed lines represent those individuals receiving antithyroid drugs during treatment (individuals B, C, H and I). The solid lines represent those receiving thyroxine (individuals A, D, E, F, G). The solid line which crosses the y axis at 0.8 U/l represents the minimum detection level for the TBII assay.
Clinical Effect of Rituximab in GO
Disease Activity. The median CAS prior to treatment was 6/10 (range: 1–8). Eight of the nine patients treated had active disease with a CAS greater than 4/10 (median 6·5, range: 4–8). The patient treated to consolidate treatment had a baseline CAS of 1.
The CAS was improved in all individuals treated, with a median improvement at 3 months post-RTX of 2 points (range: 1–6, P = 0·018 Mann–Whitney U-test) and at 12 months of 5 points (range: 1–8, P = 0·0006 Mann–Whitney U-test) (Fig. 2). In one individual with DON, although a diminution in CAS score was observed (4–3), early improvement in optic nerve function was not optimal and emergency orbital decompression surgery was performed before the second RTX infusion.
(Enlarge Image)
Figure 2.
Graph to illustrate patient CAS scores, out of 10, before RTX (dotted bars), at 3 months after RTX (checkered bars) and at 12 months follow-up (striped bars).
The median improvement in CAS at 3 months and at 12 months did not differ significantly in those with DON compared with those without DON, nor in those on antithyroid drugs and levothyroxine compared with levothyroxine alone. CAS improvement did not correlate with total RTX dose.
Disease Severity. Overall, an improvement in NO SPECS classification was seen in six individuals in the 12 months following BCDT. Two individuals remained static and one individual showed a slight deterioration in diplopia (4iii at baseline, 4i at 3 months, 4iv at 12 months), which could be due to post-inflammatory fibrotic changes in the orbital muscles. All four individuals treated for DON experienced an improvement in NO SPECS score (from grade 6 in all cases to grade 4).
Thyroid Dermopathy. One patient (patient E) had very severe thyroid dermopathy before BCDT affecting the dorsum of both feet and lower legs. The patient also reported an increase in width of the scar over her right knee, synchronously with the development of the dermopathy. These features substantially improved in the year following BCDT (Fig. 3).
(Enlarge Image)
Figure 3.
Thyroid dermopathy of the feet and legs in patient E before (panel A) and 24 months after (panel B) B cell depletion therapy (BCDT). The photographs in panel A were taken just prior to BCDT and show thyroid dermopathy, with oedema and erythema of the right leg and dorsum of right foot compared with the left, and classical appearance of 'peau d'orange' and tethered skin on the right pretibial region. These appearances are clearly improved following BCDT (panel B), particularly in the right leg. The appearance of the hypertrophic scar from a previous right knee replacement operation is also much improved following BCDT.
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