Background
Thyroid-associated ophthalmopathy (TAO) is an autoimmune inflammatory orbital disease, which usually is caused by 20–50% of patients with Graves’ disease (GD) [
1] and has the symptom of bilateral or unilateral eyeball protrusion, eyelid swelling, edema of periorbital tissue, and upper or lower eyelid retraction [
2]. It was reported that lymphocytes B played an important role in TAO [
3]. B cells could induce immune function via antigen presentation, co-stimulatory molecules expression and antibodies production. They can also be differentiated into antibody-producing plasma cells, which not only caused host defense, but also identified their own tissues, resulting in autoimmunity [
4]. In addition, B cells produced cytokines that induced fbroblasts to generate glycosaminoglycan causing fluid and periorbital edema. In recent years, there have been many treatments for TAO, but adverse effects in follow-up should be cautious, such as hypertension, diabetes, stress ulcer, and osteoporosis during immunosuppressive therapies [
5], retinopathy, neuropathy, and cataracts in single radiation therapy or combining with oral or intravenous steroids [
6], around 20% to 25% of nonresponders after intravenous pulses of corticosteroids [
7].
Rituximab (RTX) is a chimeric mouse monoclonal anti-human CD20 antibody against B-cell proliferation and maturation. RTX has been allowed since 2006 for treating rheumatoid arthritis and had a chance to become a candidate for the treatment of some other autoimmune diseases [
8]. In recent years, although some case series have shown that RTX treatment in severe TAO may benefit patients, its application was restricted to case reports and uncontrolled studies, which was a lack of large-scale prospective studies and the effectiveness was still inconsistent. Therefore, we did a systematic review and aimed to check whether the CAS activity improved 1 month or more after RTX treatment for persons with TAO.
Discussion
Thyroid-associated ophthalmopathy was the main extrathyroidal manifestation of Graves’ disease. Treatment was depended on the evaluation of the activity and severity of TAO and focused on the patient’s living quality. In this systematic review and meta-analysis, we showed that RTX treatment may confer a favorable improvement against TAO. The improvement of TAO remained stable during the follow-up.
Regarding CAS, which may indicate whether these patients benefit or not from RTX therapy. Pain, redness, swelling and impaired function improved in most patients at 1 month after RTX treatment, and sustained during the 12-month follow-up. As shown in a previous study, there were evident reductions from the mean baseline CAS score 5.5 to finally approximate 1.0 for weeks 4, 8, 16, 24, 36, and 52 [
16]. A high CAS could help select targeting patients who will benefit from RTX treatment. The eyelids became swollen and visual acuity decreased. The serious signs and symptoms in the baseline may result from the inflammation caused by the autoimmune course. Orbital fibroblasts were also considered to be vital in the pathogenesis [
10]. Decreased CAS in the majority of individuals meant favorable therapeutic effects. The long-term reduction in CAS scores may suggest it may depend upon the late effects of the drug in some cases.
Recently, unchangeable proptosis was visible in Khanna et al. study [
15]. It should be interpreted seriously because the study was only 6 patients and uncontrolled. But in this study, RTX therapy was effective in ameliorating disease severity, as seen in the significant improvement of proptosis and soft tissue inflammation. Furthermore, previous study found that RTX associated with the consumption and resistance of mature B lymphocytes, contributing to control inflammation [
25].
Besides CAS, reduction in TRAbs level was observed at 6-month and 12-month observation period after RTX use. However, it was reported that serum TRAbs levels were not changed significantly, and was slightly negatively associated with time during 75-week follow-up [
14]. Vannucchi et al. found that serum TRAbs have not reduced obviously in TAO cases before 30 weeks since treatment [
17]. Based on the previous limited TAO cases treated by RTX, the pooled changes in current results may because TRAb were associated significantly with TAO clinical activity [
26]. During the different disease phase, participants with severe TAO have more serum TRAb levels than those with mild-moderate TAO [
27]. Although it was possible to include the involvement of B cells, TRAb and cytokines, the detailed mechanism of decreased TRAb levels was still unknown [
28]. In addition, the fluctuation of TSH concentration also existed in short- and long-term observation period.
There was a weakly reduced trend in IL-6, which were around the normal range. However, it was different from the prior studies [
29]. IL-6 secreted by diverse cells like T and B lymphocytes, monocytes, and fibroblasts could participate in stimulating T cell, triggering immunoglobulin secretion, also have impacts in fibroblasts and macrophages in TAO [
30,
31]. It was likely that blocking IL-6 might be a promising therapy in TAO. But the inapparent results in current meta-analysis could be owing to the small number of participants. Thus large-scale researches were needed in order to make reliable conclusions.
There were several limitations of our review that should be interpreted. First, we have only limited sample size to hardly explore the potential impact of other risk factors such as age, gender, smoking status, dosage of RTX. Second, the orbital variation after RTX treatment could be susceptible to the previous medication of intravenous or oral corticosteroid. Third, subgroup analysis was on the basis of aggregate data, which could mask diversity within individual level and interaction between factors.
In spite of these, the strengths of this review were that we had a systematic search according to prespecified strategies, and tried to find additional studies. We cross-checked methodological decisions and the influence of each study through sensitivity analyses, and showed the robust results, which were similar to those previous trials, making the results more faithworthy in practice in many countries.