Abstract and Introduction
Abstract
Objective This case series documents the response of nine individuals with glucocorticoid-refractory Graves' orbitopathy (GO) to B cell depletion therapy with rituximab (RTX).
Context Graves' disease (GD) is one of the commonest autoimmune conditions and is frequently associated with inflammatory changes around the eyes (GO). GO frequently results in significant functional visual impairment, and in the most severe cases, it can result in permanent loss of sight. RTX is a therapeutic monoclonal antibody, which targets cell-surface CD-20, resulting in depletion of circulating B lymphocytes. It has been found to be useful for the treatment of a number of autoimmune conditions including, in preliminary studies, GO.
Design and Patients We have treated nine individuals (1 male, 8 female, age range 37–87 years) with glucocorticoid-resistant GO with RTX since 2008. RTX was administered in divided doses at fortnightly intervals, following 500 mg IV methylprednisolone pretreatment.
Measurements Each patient underwent thorough assessment before and after RTX therapy, including thyroid function tests, B cell counts, thyroid autoantibody levels and detailed clinical assessment according to EUGOGO standard protocols. All patients have now been followed up for 16 months or more.
Results There was a significant reduction in thyrotropin receptor binding inhibitory immunoglobulin (TBII) levels in all patients following RTX treatment and a reduction in the clinical activity score (CAS) was seen in all cases. We also report striking improvement in pretibial thyroid dermopathy in one patient following RTX.
Conclusions This case series adds to the growing literature demonstrating that RTX, administered in our patients with concomitant methylprednisolone, is safe and clinically effective in the treatment of active, moderate to severe and sight-threatening GO. Randomized controlled trials are now needed to confirm the efficacy of RTX for GO.
Introduction
Graves' disease (GD) affects 1–2% of the adult female population and 25–50% of individuals with GD develop Graves' orbitopathy (GO), an autoimmune inflammatory disorder of the orbit, characterized by retraction of the upper eyelid, and inflammatory swelling of the periorbital tissue leading to eyeball protrusion. These clinical signs are the result of an immune cell infiltrate in the orbit, with associated tissue glycosaminoglycan accumulation and oedema. GO, independent of thyroid status, has a significant impact upon patients' quality of life and, in the most severe cases, can result in permanent sight loss due to optic nerve damage (termed dysthyroid optic neuropathy: DON). Medical treatment is reserved for those with active, moderate to severe or sight-threatening disease. The clinical activity score (CAS) is used to determine GO inflammatory activity while the NO SPECS score assesses GO severity.
Glucocorticoids, often administered intravenously (IV), are the mainstay of treatment for active moderate to severe GO; however, a recent randomized controlled trial comparing three differing cumulative doses of IV glucocorticoids reports a highest response rate of 52% in those receiving 7·47 g compared with a 35% and 28% response rates in those receiving 4·98 g and 2·25 g, respectively, suggesting that almost half of individuals treated may not respond. Sight-threatening GO is also managed with IV glucocorticoids, with a low threshold to escalate to immediate orbital decompression surgery should visual acuity remain impaired. However, there are limited therapeutic options available to individuals who respond inadequately to glucocorticoids, whose GO progresses despite glucocorticoids or who cannot tolerate glucocorticoids. Other possible treatments for which there is RCT evidence of benefit include ciclosporin and orbital radiotherapy. However, neither of these options has a rapid effect, thus a particular problem remains for those patients with DON who are unfit or unwilling to have orbital decompression surgery, and for rare individuals whose optic nerve function remains compromised following such surgery.
Rituximab (RTX) is a therapeutic monoclonal antibody, which targets the CD-20 transmembrane protein expressed on the surface of B lymphocytes. In preliminary studies, the results of RTX for GO have been promising (Table 1). To date, these studies have demonstrated a fall in disease activity (CAS) in the majority of individuals treated, but little effect on thyroid function tests (TFTs). In all but two studies, TSH-R autoantibody (TBII) levels have not fallen significantly. A further study looked at the stimulatory effect of autoantibodies in vitro following RTX and found this to be reduced in vitro.
Here, we present a series of nine patients treated with RTX for moderate to severe or sight-threatening, steroid-refractory, GO.