Thyroid Disorders
It is questionable whether disease deterioration was caused by the therapy: optic neuropathy might have been subclinical and due to the patient’s unresponsiveness to steroids, and RTX was perhaps given too late to prevent further worsening of GO severity.
optic neuropathy was described in one patient who was unresponsive to high-dose steroids.40
Besides being limited in number, the population of GO patients treated with RTX so far is also heterogenous in terms of their thyroid status, baseline disease severity and previous (often unsatisfactory) response to immunosuppressive treatment. A novel treatment for GO is most needed, and only controlled studies will provide firm evidence on the efficacy and safety of RTX. These studies will also help us decide whether RTX should be used as first-line therapy in all patients with active GO, or only in those with severe disease unresponsive to other treatments.
A different—and potentially successful—approach is suggested by a very recent report from Salvi et al., who found that the doses of RTX currently used to treat GO may be needlessly excessive.41
Unfortunately, in that study, peripheral B-cells after RTX therapy were not measured, and thus changes in serum TRAb and other autoantibodies could not be studied in relation to B-cell depletion or return in the peripheral blood.46
The open study by Salvi et al.34 mainly addressed the therapeutic
potential of RTX in active GO. It nevertheless reported a decrease of serum TRAb levels in both the RTX- and the glucocorticoid-treated patients with active GO after 30 weeks, but the change was not significantly related to the time elapsed from therapy and did not correlate with either peripheral B-cell depletion or repopulation. Follow-up was at 12 months after RTX therapy in eight patients, and at five months in one patient. RTX had no effect on thyroid function, since GD patients who were hyperthyroid and untreated showed no improvement in their thyroid function, and had to be started on MMI.
In a recent follow-up study, Vannucchi et al.47 For the first
time, it was shown that a low dose of RTX (100 mg) caused effective peripheral B-cell depletion and induced long-term remission of GO without further treatment. There had been no data previously reported in the literature on the time required to attain total B-cell depletion after RTX infusion in autoimmune disease. This was observed after RTX was discontinued in two patients because of strong infusion-related reactions. The patients had mean baseline CAS of 5.3, which decreased to 1.6 at 16 weeks after only 100 mg of RTX, similarly to what has been reported after treatment with a total dose of 2,000 mg. During follow-up, the amelioration of GO was stable. A study employing low-dose RTX is now ongoing in a larger group of patients to confirm these unexpected preliminary findings, potentially interesting also from the point of view of the safety concerns arising from the use of high doses of a potent immunosuppressive agent such as RTX.
Effects of Rituximab on Hyperthyroidism and Circulating Autoantibodies One controlled study42
and two open studies34,43 could not demonstrate a
distinct effect of RTX on serum TSAb autoantibodies, also measured as Ig-stimulation of cAMP by TSHR-transfected CHO cells, which appeared to be unchanged and to fluctuate with an identical pattern compared to serum TRAb in either hyperthyroid or euthyroid GD patients. These discrepancies may be due to the sera coming from a number of patients too small for it to contain sufficiently high TRAb levels for an accurate analysis, and possibly to the heterogeneity of the clinical characteristics of the patients included in these studies—i.e., thyroid function, disease duration, and presence or absence of GO. Again, larger and controlled studies are needed before drawing significant conclusions.
Serum anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were also shown to decline after RTX therapy,34
but
the change was not significant and did not correlate with either B-cell depletion or return in the peripheral blood. Similar data were reported by El Fassi et al.,42
who were not able to observe a change of serum TPOAb in relation to treatment with RTX in a series of GD patients, while they did not examine TgAb.
have addressed the
effects of RTX on the hyperthyroidism of GD, but data are inconsistent. In the controlled study, El Fassi et al.42
treated 10 patients suffering from
newly diagnosed and untreated hyperthyroidism with methimazole (MMI) and RTX, and 10 with MMI only, until they became euthyroid. Within one year of follow-up, all patients treated with MMI alone, but only six of the 10 patients treated with MMI and RTX, experienced hyperthyroidism relapse. Patients euthyroid at 30 months after MMI and RTX had serum TRAb levels not greater than 5 IU/l, which could be predictive of sustained remission.
Subsequently, El Fassi et al.44 have reported that RTX treatment in GD
patients may favourably affect disease remission by distinctively acting on the thyroid stimulating antibody (TSAb) subpopulation with TRAb. In that study, an 84 % decrease in cyclic adenosine monophosphate (cAMP) production by TSHR-transfected Chinese hamster ovary (CHO) cells was obtained with sera from patients treated with RTX after 20 weeks, but not with sera from patients treated with MMI. When explaining their findings, the author postulated that RTX may specifically affect autoreactive short-lived TSAb-producing plasma cells.45
134
Other autoantibodies directed against putative orbital autoantigens, derived mainly from eye muscles,48
have been measured in patients with
active GO. No significant change from baseline was observed after RTX therapy in any of the circulating antibodies against the three orbital antigens calsequestrin, XIII collagen, and flavoprotein subunit of succinate dehydrogenase (FP-SDH).47
In an uncontrolled study, Heemstra et al.43 treated 13 patients with
in the GD patients who remained euthyroid, serum TRAb levels before RTX therapy were relatively low (median 4 IU/l, range 0.2–6.3). What is not explained by the results is why RTX treatment would have no effect on 31 % of GD patients who were more hyperthyroid, with higher serum thyroid hormone concentrations and
relapsing GD, of whom three (23 %) had mild thyroid-associated ophthalmopathy (TAO). On follow-up examination at 26 weeks after RTX, four patients had a relapse of hyperthyroidism despite RTX treatment and received radioiodine therapy, while the remaining nine patients became euthyroid and remained so for a median of 18 months. In that study, serum TRAb levels decreased significantly in nine patients, but did not correlate with B-cell depletion. Consistent with the data from El Fassi et al.,42
US ENDOCRINOLOGY
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