Rituximab for thyroid-associated ophthalmopathy

  • Review
  • Intervention

Authors


Abstract

Background

Thyroid associated ophthalmopathy (TAO) is the most frequent extrathyroidal manifestation of Graves' disease, affecting up to 50% of patients, and has a great impact on quality of life. Rituximab is a human/murine chimeric monoclonal antibody that targets CD20, a transmembrane protein expressed on the surface of pre-B and mature B lymphocytes, but not on stem cells, pro-B lymphocytes or plasma cells. Preliminary work has shown that blocking the CD20 receptor on B-lymphocytes with rituximab affects the clinical course of TAO, by reducing inflammation and the degree of proptosis.

Objectives

The aim of this review was to investigate the effectiveness and safety of rituximab for the treatment of TAO.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to April 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the EU Clinical Trials Register (www.clinicaltrialsregister.eu). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 April 2013. We manually searched references of review articles and used the Science Citation Index to identify additional studies citing trials. We contacted the lead investigators of relevant trials on ClinicalTrials.gov and the WHO ICTRP for information and data from as yet unpublished clinical trials. We contacted experts in the field for information about any ongoing trials. We contacted the manufacturers of rituximab for details of any sponsored trials.

Selection criteria

We sought to include randomised controlled trials (RCTs) of rituximab treatment by intravenous infusion for the treatment of patients with TAO, compared with placebo or intravenous glucocorticoid treatment.

Data collection and analysis

Two review authors independently scanned titles and abstracts, as well as independently screened the full reports of the potentially relevant studies. At each stage, the results were compared and disagreements were solved by discussion.

Main results

No studies were identified that met the inclusion criteria. There are three ongoing studies which are likely to meet inclusion criteria once published, and thus be included in future updates of this review.

Authors' conclusions

There is currently insufficient evidence to support the use of rituximab in patients with TAO. There is a need for large RCTs, investigating rituximab versus placebo or corticosteroids in patients with active TAO to make adequate judgement on the efficacy and safety of this novel therapy for this condition.

Résumé scientifique

Rituximab pour le traitement de l'ophtalmopathie thyroïdienne

Contexte

L'ophtalmopathie thyroïdienne (OT) est la manifestation extrathyroïdienne la plus fréquente de la maladie de Basedow, affectant jusqu'à 50 % des patients, et elle a un impact important sur la qualité de vie. Le rituximab est un anticorps monoclonal chimérique humain/murin qui cible la CD20, une protéine transmembranaire exprimée à la surface des pré-lymphocytes B et des lymphocytes matures, mais pas sur les cellules souches, les pro-lymphocytes B ou les plasmocytes. Des travaux préliminaires ont montré que le blocage du récepteur de la CD20 sur les lymphocytes B avec le rituximab affecte la progression clinique de l'OT, en réduisant l'inflammation et le degré d'exophtalmie.

Objectifs

L'objectif de cette revue était d'étudier l'efficacité et l'innocuité du rituximab pour le traitement de l'OT.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL (qui contient le registre des essais cliniques du groupe Cochrane sur l'œil et la vision) (The Cochrane Library 2013, numéro 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (de janvier 1950 à avril 2013), EMBASE (de janvier 1980 à avril 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (de janvier 1982 à avril 2013), OpenGrey (Système d'information sur la littérature grise en Europe) (www.opengrey.eu/), le méta-registre des essais contrôlés (mREC) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), le système d'enregistrement international des essais cliniques de l'OMS (ICTRP) (www.who.int/ictrp/search/fr) et le registre européen d'essais cliniques (www.clinicaltrialsregister.eu). Pour les recherches électroniques d'essais nous n'avons appliqué aucune restriction concernant la date ou la langue. Nous avons consulté les bases de données électroniques pour la dernière fois le 15 avril 2013. Nous avons effectué des recherches manuelles dans les références des articles de revue et nous avons utilisé le Science Citation Index pour identifier des études supplémentaires citant des essais. Nous avons contacté les chercheurs principaux des essais pertinents sur ClinicalTrials.gov et WHO ICTRP pour obtenir des informations et des données d'essais cliniques non publiés. Nous avons également contacté des experts dans le domaine pour obtenir des informations sur les essais en cours. Nous avons contacté les fabricants de rituximab afin d'obtenir des détails concernant tout essai parrainé.

Critères de sélection

Nous avons cherché à inclure les essais contrôlés randomisés (ECR) sur le traitement par le rituximab par perfusion intraveineuse destiné aux patients atteints d'OT, par rapport à un placebo ou au traitement glucocorticoïdique intraveineux.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment analysé les titres et résumés, ainsi que les rapports complets des études potentiellement pertinentes. À chaque étape, les résultats étaient comparés et les désaccords résolus par des discussions.

Résultats principaux

Aucune étude répondant aux critères d'inclusion n'a été identifiée. Il existe trois études en cours qui sont susceptibles de remplir les critères d'inclusion une fois publiées, et qui seront donc incluses dans les futures mises à jour de cette revue.

Conclusions des auteurs

Il n'existe actuellement pas suffisamment de données en faveur de l'utilisation du rituximab chez les patients atteints d'OT. On a besoin de grands ECR comparant le rituximab à un placebo ou aux corticostéroïdes chez les patients atteints d'OT active pour émettre des jugements adéquats sur l'efficacité et l'innocuité de ce nouveau traitement pour cette affection.

Plain language summary

Rituximab for the treatment of thyroid eye disease

Thyroid eye disease affects 50% of patients with the autoimmune condition, Graves' disease. Symptoms include eye pain, redness, swelling, protrusion (proptosis), double vision, and in severe cases, reduction in vision. Currently treatment options include steroids and radiotherapy, but relapses are common. Surgery is reserved for severe cases. Rituximab is a medication given by intravenous infusion which has been shown to benefit patients with other autoimmune conditions like rheumatoid arthritis. This review was designed to investigate whether rituximab is effective and safe as a treatment option for patients with thyroid eye disease. There is a lack of evidence from randomised controlled trials to support the use of rituximab for thyroid eye disease. Rigorous studies looking at patients with active thyroid eye disease, comparing rituximab treatment with either steroids or placebo, need to be conducted in order to answer this question.

Résumé simplifié

Rituximab pour le traitement de l'ophtalmopathie thyroïdienne

L'ophtalmopathie thyroïdienne est une affection auto-immune affectant 50 % des patients atteints de la maladie de Basedow. Les symptômes comprennent les douleurs oculaires, les rougeurs, le gonflement, la protrusion (exophtalmie), la vision double, et dans les cas sévères, une réduction de la vision. Les options de traitement actuelles comprennent les stéroïdes et la radiothérapie, mais les rechutes sont fréquentes. La chirurgie est réservée aux cas les plus sévères. Le rituximab est un médicament administré par perfusion intraveineuse qui s'est avéré bénéfique pour les patients présentant d'autres affections auto-immunes telles que la polyarthrite rhumatoïde. Cette revue a été conçue pour déterminer si le rituximab est une option de traitement efficace et sûre pour les patients souffrant d'ophtalmopathie thyroïdienne. Il existe une insuffisance de données issues d'essais contrôlés randomisés en faveur de l'utilisation du rituximab pour le traitement de l'ophtalmopathie thyroïdienne. Des études rigoureuses sur des patients souffrant d'une ophtalmopathie thyroïdienne active, comparant le traitement par le rituximab soit aux stéroïdes soit à un placebo, doivent être réalisées afin de répondre à cette question.

Notes de traduction

Traduit par: French Cochrane Centre
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Description of the condition

Thyroid-associated ophthalmopathy (TAO) is the most frequent extrathyroidal manifestation of Graves' disease, an autoimmune thyroid disorder that also affects the connective tissue of the orbit and skin. Graves' disease affects approximately 1% to 2% of the adult population (Weetman 2000), and approximately 20% to 25% of patients with Graves' hyperthyroidism have clinically apparent TAO at the time of diagnosis (Burch 1993). In total, TAO affects up to 50% of these patients clinically (Wiersinga 2002), and in 70% magnetic resonance imaging (MRI) or computed tomographic (CT) scanning reveals extraocular muscle enlargement (Enzmann 1979; Villadolid 1995). It may also occur in patients with euthyroid or hypothyroid chronic autoimmune thyroiditis (Bartalena 2008). 

TAO is characterised by inflammation of the orbital connective tissue, inflammation and fibrosis of the extraocular muscles, and adipogenesis within the orbits (Bahn 2010). Clinically this may result in periorbital oedema, lid lag and retraction, chemosis, exophthalmos and dysmotility. Severe TAO leads to exposure keratopathy, diplopia and compressive optic neuropathy, which might cause visual loss. Even milder forms of ophthalmopathy have great impact on the quality of life of these patients (Kahaly 2005).

The pathophysiology of TAO is still incompletely understood, but appears to involve both the humoral and cell-mediated immune responses (Han 2006). Orbital fibroblasts are thought to be key players in the condition. Stimulation by inflammatory cytokines causes the fibroblasts to secrete large quantities of the glycosaminoglycan hyaluronan (Prabhakar 2003), a chief component of the extracellular matrix, and a subgroup of orbital fibroblasts that can differentiate into mature adipocytes (Sorisky 1996). This leads to an increase in volume of the intraorbital contents. Thyrotropin receptor autoantibodies (TRAb) and immunoglobulins targeting IGF-1 receptor also directly activate pre-adipogenic fibroblasts with additional secretion of pro-inflammatory cytokines and glycosaminoglycans (Eckstein 2009; Ezra 2012). 

Current treatment options for TAO include oral or intravenous glucocorticoids (Krassas 2010a), orbital radiation (Rajendram 2012), surgical decompression (Boboridis 2011) or a combination of these. There is also emerging evidence that the anti-oxidant selenium may play a role in the medical management of mild TAO (Marcocci 2011). Glucocorticoids are the mainstay of immunosuppressive therapy of TAO, with intravenous pulse administration being preferable in terms of efficacy and side-effect profile (Stiebel-Kalish 2009), although the optimum dose is still subject to investigation (Bartalena 2012). The role of orbital radiotherapy for patients with active disease remains controversial, but an ongoing trial is evaluating its effectiveness (Rajendram 2008). In the case of both glucocorticoids and orbital radiotherapy, their impact on the course and final outcome of the disease is not yet determined and recurrences are common after discontinuation of treatment (Marocci 2001; Zoumalan 2007). Surgical treatment includes orbital decompression, eye-muscle surgery and eyelid surgery. The indications for surgical decompression are sight-threatening TAO (with the aim of preserving optic nerve function) and late-stage rehabilitative reconstructive surgery after the disease has burnt out (Bartalena 2008).

Description of the intervention

Rituximab (RTX) is a human/murine chimeric monoclonal antibody that targets CD20, a transmembrane protein expressed on the surface of pre-B and mature B lymphocytes, but not on stem cells, pro-B lymphocytes or plasma cells (Reff 1994; Shen 2013). The binding of rituximab to CD20 antigen therefore blocks the activation and differentiation of B-cells, and in so doing, leads to specific elimination of B cells without affecting their regeneration from stem cells and the production of immunoglobulins from plasma cells. 

Rituximab, sold under the trade names Rituxan and MabThera, was developed by IDEC Pharmaceuticals in 1986. It received Food and Drug Administration (FDA) approval in 1997 for the treatment of non-Hodgkin B-cell lymphoma resistant to other chemotherapy agents (Boye 2003). It is now used, in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) chemotherapy, as standard therapy in the initial treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas (Keating 2010). It has also been shown to benefit patients with autoimmune disorders including rheumatoid arthritis (Smolen 2007). It has FDA approval for use in combination with methotrexate for adult patients with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to one or more anti-TNF-alpha therapies.

How the intervention might work

There are a number of proposed theories as to how rituximab may work in TAO. Rituximab works by depleting B-cells, the precursors of the autoantibody-producing plasma cells. Some authors have suggested that, since Graves' disease is in part an autoantibody-mediated disease involving TRAbs, it is through this mechanism that there may be a potential benefit of rituximab therapy in this condition (Hasselbach 2003; Wang 2006). Studies have suggested that TRAb levels decrease following B-cell depletion to a similar extent to that seen following treatment with methimazole or prednisolone (El Fassi 2007; Heemstra 2008; Salvi 2007).

B-cells are highly efficient antigen-presenting cells (APCs) (Lanzavecchia 1985) and clinical trials of rituximab in T-cell-mediated immunity have shown that rituximab targets the APC functions of B-cells (Pescovitz 2009). Attenuation of antigen-presentation by B-cells is a possible explanation for clinical effect of rituximab in TAO, which is a T-cell-mediated process.

B-cells are also capable of producing a variety of cytokines, and some of these may be involved in the mechanism of action of rituximab in TAO. In rheumatoid arthritis, for example, B-cell depletion results in the elevation of IL-8 levels (Keren 2009).

Furthermore, B-cell depletion in TAO may lead to clinical benefit through altered levels of Tregs, unique T-cells that can modulate autoimmune responses (Liossis 2008; Vignali 2008). Their impact on human immunity remains uncertain, but they seem to act in a large part through the transforming growth factor-beta pathway. Their frequency is reduced in autoimmune disease. Rheumatoid arthritis improves with B-cell depletion in patients demonstrating increasing levels of Tregs (Boisser 2009; Reis 2009).

Preliminary work has shown that blocking the CD20 receptor on B-lymphocytes with rituximab affects the clinical course of TAO, by reducing inflammation and the degree of proptosis (El Fassi 2006; Salvi 2006). It has been shown that reduction of B-cells infiltrating affected tissues is an important indicator of successful rituximab therapy in other disease processes (Kavanaugh 2008). In TAO, it has been shown that depletion of intra-orbital CD20 lymphocytes, proven through immunohistochemical analyses of orbital tissue, is associated with clinical improvement with rituximab treatment (Khanna 2010; Salvi 2009).

Why it is important to do this review

Thyroid-associated ophthalmopathy is the most common extrathyroidal manifestation of Graves' disease and a serious and potentially sight-threatening one. Current treatment methods include glucocorticoids, radiotherapy and surgery. However, it is unclear whether these treatments alter the natural course of the condition and relapses are common. In addition, many patients suffer significant complications of treatment with high dose intravenous and oral corticosteroids, which are often needed for prolonged periods of time. This means that there is a real, unmet clinical need for effective steroid-sparing-agents that are effective in TAO. Rituximab is a biological agent that has been used successfully in other autoimmune conditions including rheumatoid arthritis. Recently in the literature and at conferences, the potential for the use of this drug in TAO has been discussed but the evidence for its use is still in its infancy and as such no guidelines have been published outlining recommendations. It is therefore important to review systematically all the evidence that is currently available as well as any new evidence to allow for robust conclusions to be made regarding the use of rituximab in the management of this condition.

Objectives

The aim of this review was to investigate the effectiveness and safety of rituximab for the treatment of TAO.

Methods

Criteria for considering studies for this review

Types of studies

This review was designed to include RCTs that use rituximab for the treatment of patients with TAO.

Types of participants

We searched for trials involving adults (age 18 years and over) with active TAO (clinical activity score (CAS) ≥ 4).

Types of interventions

We searched for trials of rituximab treatment by intravenous infusion using any dosage regimen, compared with placebo or intravenous glucocorticoid treatment.

Types of outcome measures

Primary outcomes

The primary outcome for this review was improvement in thyroid-associated CAS at four, six and 12 months post treatment.

CAS is a validated scoring system, designed to distinguish inflammatory from non-inflammatory TAO, and has a high predictive value for the outcome of immunosuppressive treatment in TAO patients (Mourits 1997). It is based on the classical signs of inflammation: pain (two points), redness (two points), swelling (four points), and impaired function (two points). After two consecutive clinical examinations, an activity score can be determined, ranging from nought to 10 points. Because determination of CAS requires two clinical examinations, a modification was proposed that allows determination of CAS in a single session (EUGOGO 2006). This modified CAS system includes seven items and is referred to as the seven-item CAS. The two methods differ in evaluation of visual acuity, diplopia, and proptosis, which are all part of the 10-item CAS and are not included in the seven-item CAS.

Secondary outcomes

The secondary outcomes for this review were the following at four, six and 12 months post treatment:

  1. Improvement in NOSPECS TAO classification score.

  2. Decrease in proptosis (mm).

  3. Change in palpebral aperture measurement (mm).

  4. Improvement in extraocular motility (degrees).

  5. Improvement in quality of life score.

We also collected safety outcomes, including all adverse events and side-effect profiles, and economic data.

The NOSPECS score is a scoring system based on: no symptoms or signs, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement and sight loss, graded as O, A, B or C.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 3, part of The Cochrane Library. www.thecochranelibrary.com (accessed 15 April 2013), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to April 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the EU Clinical Trials Register (www.clinicaltrialsregister.eu). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 April 2013.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), OpenGrey (Appendix 5), mRCT (Appendix 6), ClinicalTrials.gov (Appendix 7), WHO ICTRP (Appendix 8) and the EU Clinical Trials Register (Appendix 9).

Searching other resources

We manually searched the reference lists of review articles and used the Science Citation Index to identify additional studies citing trials. We contacted the lead investigators of relevant trials on ClinicalTrials.gov and WHO ICTRP for information and data from as yet unpublished clinical trials. We contacted experts in the field for information about any ongoing trials. We contacted the manufacturers of rituximab for details of any sponsored trials. We did not handsearch conference proceedings for this review.

Data collection and analysis

Selection of studies

Two review authors independently inspected the titles and abstracts resulting from the electronic and manual searches and classified each abstract as relevant, potentially relevant or not relevant for this review. We obtained full-text copies of articles identified as relevant or potentially relevant. Two review authors independently assessed each article and applied the inclusion criteria to determine final eligibility. We resolved discrepancies through discussion and consensus. We documented the excluded studies and reasons for exclusion.

Data extraction and management

There were no eligible studies for inclusion in this review. In future updates of the review, two review authors will independently extract data and the following details from included studies.

  1. Methodology (group size, randomisation, blinding (masking), exclusions after randomisation, losses to follow-up).

  2. Participant characteristics (age, sex, thyroid status, TRAb levels, smoking status, thyroid volume (ml), TAO activity (CAS score), TAO severity (NOSPECS score)).

  3. Intervention (dose, regimen, timing of treatment in relation to diagnosis, timing of treatment in relation to previous interventions, nature of previous interventions).

  4. Primary and secondary outcomes (CAS score, NOSPECS score, proptosis (mm) and extraocular motility (degrees) at the start of treatment and at each follow-up time period).

  5. Adverse events and side-effects (number, nature, timing).

  6. Quality of life issues.

  7. Economic data.

We will contact trials authors for more information if data are missing or difficult to interpret. We will resolve any discrepancies between authors by discussion and consensus. One review author will enter the data into Review Manager 5 (Review Manager 2012) and the second author will check the entered data for errors or inconsistencies.

Assessment of risk of bias in included studies

In future updates of the review, two review authors will independently assess the methodological quality of the selected trials according to the methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Intervention ( Higgins 2011). The following six quality parameters will be considered in assessing the risk of bias.

  1. Random sequence generation (selection bias).

  2. Allocation concealment (selection bias).

  3. Blinding (masking) of participants and outcome assessors.

  4. Incomplete outcome data (attrition bias).

  5. Selective outcome reporting.

  6. Other sources of bias.

We will assess each parameter as: low risk of bias, high risk of bias, and unclear risk of bias. We will contact the authors of trials for additional information on domains judged to be unclear. We will resolve discrepancies between review authors by discussion and consensus.

Measures of treatment effect

In future updates of the review, we will report continuous variables where the data are normally distributed as mean and standard deviation (SD), and where the data are not normally distributed as median and inter-quartile range. These will include changes in thyroid-associated CAS, NOSPECS score, proptosis (mm), palpebral aperture measurements (mm), extraocular motility (degrees) and quality of life scores. If different measurement scales are used to assess the same outcome, we will use standardised mean differences (SMDs). We will report dichotomous variables as risk ratios (RRs) with 95% confidence intervals (CIs). These will include the proportion of patients experiencing each adverse event or side-effect.

Unit of analysis issues

The treatment is a systemic treatment and as such will affect both eyes of each patient. Patients rather than eyes are randomised. The CAS and NOSPECS scores are calculated for each patient and so the unit of analysis for these data will be the patient. For proptosis, palpebral aperture and extraocular motility data, the unit of analysis will be the individual eye. Where studies present worse eye data, we will analyse these separately. Where studies present individual eye data, we will consider these in a separate analysis. The unit of analysis will be the patient for demographic characteristics, quality of life and economic data.

Dealing with missing data

In future updates of the review, if there are missing data, we will contact the authors to obtain this information. If this is not successful, we will impute data where possible using available information such as P values and CIs. This will form an available case analysis. We will not use imputation to create an intention-to-treat (ITT) analysis.

Assessment of heterogeneity

We will examine heterogeneity by examining study characteristics and forest plots of the results. We will use the I2 statistic to assess the impact of statistical heterogeneity. We will interpret an I2 value of 50% or more as substantial.

Assessment of reporting biases

We will use a funnel plot to examine publication bias if sufficient trials are identified.

Data synthesis

If there is substantial clinical or statistical heterogeneity (I2 > 50%), we will not combine study results and instead will present an estimate of effect and associated CI for each individual trial. If there is little variation between trials, we will combine the results in a meta-analysis using a random-effects model, unless there are a very small number of trials when we will use a fixed-effect model.

Subgroup analysis and investigation of heterogeneity

We planned to stratify by treatment dosage and thyroid status, as both are potential effect modifiers. In future updates of the review, we will perform subgroup analyses to identify possible sources of heterogeneity.

Sensitivity analysis

We planned to conduct sensitivity analyses to determine the impact of the exclusion of studies with lower methodological quality and industry-funded studies.

Results

Description of studies

Results of the search

The electronic database search yielded a total of 524 references (Figure 1). The Trials Search Co-ordinator scanned the search results, removed duplicates and removed 148 references which were not relevant to the scope of the review. We screened the remaining 308 reports to identify potentially relevant studies. We obtained 13 full-text copies of reports of studies for further investigation. After reading the full-text records we excluded the 13 papers which reported on eight studies. Reasons for excluding the studies after full-text assessment are listed in the 'Characteristics of excluded studies' table. There are no completed RCTs comparing rituximab treatment to placebo or intravenous corticosteroids for TAO. There are three ongoing RCTs (EUCTR2011-000899-33-SE; NCT00595335; EUdraCT 2007-003910-33) which are likely to meet the inclusion criteria for the review. We will assess these studies for potential inclusion when the studies are completed. We have contacted the trialists who have stated that data are not currently available for these studies.

Figure 1.

Results from searching for studies for inclusion in the review.

Included studies

There were no completed RCTs that met the inclusion criteria.

Excluded studies

There were no RCTs that met our inclusion criteria. Whilst we did not perform a separate electronic search for study designs less rigorous than the RCT, several non-RCTs, interventional case series and case reports were identified. Given the small number of studies overall looking at rituximab in TAO, these studies are detailed in the table 'Characteristics of excluded studies', despite being non-randomised.

Risk of bias in included studies

No studies were included.

Effects of interventions

No studies were included.

Discussion

Summary of main results

The aim of this review was to investigate the effectiveness and safety of rituximab for the treatment of TAO. As there were no complete RCTs, no reliable conclusions can be made.

There are three ongoing studies which are likely to meet inclusion criteria once published. NCT00595335 is a phase 2/3 randomised, double-masked trial of rituximab versus intravenous saline in patients with moderate to severe TAO (CAS ≥ 4), who have been euthyroid for at least six weeks. There are 15 patients in each treatment arm, receiving either two intravenous infusions of 1000 mg rituximab, two weeks apart, or two intravenous infusions of saline, two weeks apart. The primary outcome measure is improvement in CAS by 2 or more points. EUCTR2011-000899-33-SE is a phase 2/3 randomised, open trial of rituximab+methotrexate versus oral steroids+methotrexate in 50 patients with moderate to severe TAO (CAS ≥ 4), who have relapsed six weeks after responding to a 12 week course of weekly intravenous steroid infusions. Patients must have been euthyroid for at least six weeks prior to starting treatment with intravenous steroid. The primary outcome measure is improvement in CAS by 2 or more points. EUdraCT 2007-003910-33 is a randomised, double-masked trial of rituximab versus intravenous methylprednisolone in 60 patients with moderate to severe TAO (CAS ≥ 4), who have been euthyroid for at least six weeks. The primary outcome measure is reduction of CAS by 2 or more points or below CAS = 3.

There were a number of non-randomised studies (two non-RCTs (Table 1) and four case series (Table 2)) that did not meet the inclusion criteria, reporting benefit of rituximab in treatment of patients with TAO. There were a few case studies also with mixed findings (Table 3).

Table 1. Non-randomised controlled trials
El Fassi 2007Study nameB Lymphocyte Depletion with the Monoclonal Antibody Rituximab in Graves’ Disease: A Controlled Pilot Study
 Participants

Patients with newly diagnosed or relapsed untreated Grave's disease

RTX group: 10 patients.

Control group: 10 patients

18 female, 2 male

Age: 18 to 65 years

No patients had received immunosuppressants.

Consecutive eligible patients offered RTX and control patients were those who declined

Only 2 patients in RTX group and no patients in control group had active TAO:

Patient 1: Female age 64 ex smoker; CAS 6

Patient 2: Female age 35 ex smoker; CAS 4/5 (R/L)

Follow-up:

RTX group: 740 (435 to 904) days

Control group: 554 (99 to 741) days

 Interventions

All patients rendered euthyroid with methimazole for 4 months

RTX group: Rituximab iv infusion 375 mg per m2 body surface area on day 1, 8, 15 and 22

Pretreatment with 1g acetaminophen po, 2 mg clemastine iv

Control group: no further treatment

 Outcome measures

Time to relapse of hyperthyroidism

Changes in autoantibody level

 Results

4 patients in RTX group remained in remission with median follow-up 705 days

All patients in control group relapsed by 393 days (P < 0.05)

All patients in remission had initial TRAb levels below 5 IU/litre

None of 5 patients in control group with corresponding low TRAb levels stayed in remission (P < 0.01)

2 patients in RTX group with active TAO:

Patient 1: CAS reduced from 6 to 2 in 8 months; proptosis reduced from 25 mm to 22 mm bilaterally.

Patient 2: CAS 4/5 (R/L) reduced to 2/3 at 5 weeks, 2/4 at 5 months and 1/1 at 11 months; proptosis went from 23 mm bilaterally to 21 mm/23 mm (R/L).

Both patients improved in soft tissue changes and eye motility.

Adverse effects:

After 1st infusion only: hypotension (n = 4), nausea (n = 2), fever (n = 1), chills (n = 1), and tachycardia (n = 1)

Two patients had slight pain in the finger joints

One patient developed ulcerative colitis

   
Salvi 2007Study name

Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an

open study

 Participants

Patients with Grave's disease and TAO

RTX group: 9 patients

7 female, 2 male

Age: 31 to 51 years.

5 smokers, 2 ex-smokers, 2 non-smokers

2 patients lid signs; 6 patients moderate; 1 patient severe

Steroid group: 20 patients

17 female, 3 male

Age: 30 to 82 years

12 smokers, 4 ex-smokers, 4 non-smokers

3 patients mild TAO, 13 moderate, 4 severe

 Interventions

RTX group: rituximab iv infusion 1000 mg over 4h 15 minutes, twice at 2 weekly intervals. Pre treatment with 1 g paracetamol po and 10 mg chlorpheniramine po.

Steroid group: methylprednisolone 500 mg iv once a week for 14 weeks then 250 mg once a week for further 2 weeks

Follow-up:

RTX group: 1 patient 5 months, 8 patients 12 months or more

Steroid group: 12 months

 Outcome measures

Change in CAS

Change in NOSPECS score

Thyroid function

Lymphocyte count

 Results

RTX group:

All patients had peripheral B-cell depletion with first infusion. Depletion lasted 4 months in 3 patients, 5 months in 5 patients, and 1 still depleted at 5 months.

Thyroid function not affected

Changed in TgAb, TPOAb and TRAb not significant and not correlated to CD20+ lymphocyte depletion

Mean CAS before 4.7±0.5, reduced to 1.8 ±0.8 at 30 weeks (P < 0.0001)

Proptosis (NOSPECS class 3) reduced significantly in patients with active TAO 22.4±0.5 to 20.9±0.6 (P < 0.0001) and in GD with lid signs 19.0±0.7 to 17.3±0.9 (P < 0.003) at 30 weeks

Soft tissue inflammation (NOSEPCS 2) decreased significantly (P < 0.001)

Degree of motility impairment (NOSPECS 4) reduced (P < 0.05)

No relapse at time of B cell return and in subsequent 5 to 7 months of follow up

One patient clinically responsive to RTX (no change in TRAb) later had thyroidectomy and orbital decompression. B cells found in thyroid tissue but none in orbital tissue.

Steroid group:

Mean serum TRAb before 16.3±4.9 and 9.3±3.6 U/L after (not significant). No difference compared to RTX at 30 weeks.

Mean CAS 4.1±0.03 before and 2.0±0.4 at 30 weeks (P < 0.0001)

Significantly more change in CAS with RTX than with IVGC (P < 0.05)

Proptosis 22.6±0.6 to 22.1±0.6 at 30 weeks (P < 0.014). No significant difference compared to RTX.

Soft tissue inflammation decreased significantly at 30 weeks (P < 0.003) but no significant difference compared to RTX

4 patients did not respond to IVGC and one underwent acute orbital decompression for optic neuropathy

2 patients also had relapse of TAO 6 to 8 weeks after IVGC withdrawal

Adverse effects:

RTX: minor side-effects in 3 patients with first infusion (nose and throat itching, mild temperature elevation)

Steroids: adverse effects more frequent (9 patients) and of greater clinical significance (flushing, insomnia, dyspepsia, hyperglycaemia, serum aminotransferases or GGT increase)

Table 2. Non-randomised case series
Heemstra 2008Study nameRituximab in relapsing Graves’ disease, a phase II study
 Participants

13 patients with relapsing Graves' disease

9 female, 4 male

Age: 39.5±9.5 years

Previously adequately treated with at least 1 year antithyroid medications

Median (range) CAS was 0 (0 to 2)

3 patients had NOSPECS 2a3040

Follow up: 26 weeks

 Interventions

Rituximab iv infusion 1000 mg, twice at 2 weekly interval.

Pre-medication 10 mg iv dexamethasone plus 2 mg iv clemastine

 Outcome measures

Absence of hyperthyroidism

Relapse free survival time

 Results

All patients had decrease in C19 and MS4A1 (lymphocyte populations)

4 patients no response

Other 9 patients: FT4 decreased at 16 weeks (P = 0.001) and TSH increased (P = 0.011)

At follow-up 14 to 27 months, 9 patients still euthyroid with normal FT4 (P < 0.001) and TSH (P = 0.008)

Adverse effects: 2 patients had temporary joint pains

   
Khanna 2010Study nameRituximab Treatment of Patients with Severe, Corticosteroid-Resistant Thyroid-Associated Ophthalmopathy
 Participants

6 patients with severe progressive TAO unresponsive to steroids

4 female, 2 male

Age: 54.3±9.1 years

3 current smokers

Follow-up: 12 weeks

 Interventions

Rituximab iv infusion 1000 mg, twice at 2 weekly intervals

Pre-medication 100 mg iv methylprednisolone, 1 g po acetaminophen plus 50 mg po diphenhydramine

 Outcome measures

Change in CAS

Change in proptosis

Change in strabismus

Side effects

Quantification of regulatory T cells

 Results

CAS improved from 5.5±0.8 to 1.3±0.5 at 2 months after treatment (P < 0.03)

TAO remained quiescent in all patients (CAS, 0.7±0.8; P < 0.0001) at mean follow-up of 6.2±4.5 months

Vision improved bilaterally in all 4 patients with dysthyroid optic neuropathy (DON)

None of the 6 patients experienced disease relapse after RTX infusion

Proptosis remained stable (Hertel measurement, 24±3.7 mm before therapy and 23.6±3.7 mm after therapy (P = 0.17)

1 patient experienced progressive strabismus after RTX Tx

None of patients had improvement in extraocular motility

The abundance of T regulatory cells, assessed in 1 patient who had orbital decompression 12 days after RTX, increased within 1 week of RTX and remained elevated at 18 months of follow-up

Adverse effects: urinary tract infection, hypertension. 1 patient had cardiac arrest and died 3 months after treatment.

   
Silkiss 2010Study nameRituximab for Thyroid Eye Disease
 Participants

12 patients with active TAO (CAS 4 or more)

7 female, 5 male

Age: 34 to 80 years

4 smokers

4 patients had never previously been treated with steroids

Follow-up: 52 weeks

 Intervention

Rituximab iv infusion 1000 mg, twice at 2 weekly intervals

Pre-medication 1 g po acetaminophen plus 50 mg po diphenhydramine

Note 2 patients were still on oral glucocorticoids during the study

 Outcome measures

Change in CAS

Change in thyroid associated ophthalmopathy scale (TAOS)

Pre-infusion CD20+ lymphocyte count

Post-infusion CD19+ lymphocyte count

Thyroid stimulating hormone and thyroid stimulating immunoglobulin levels

 Results

CAS improved from 5.5 (SD 1.2) to 0.8 (SD 1.4) at 52 weeks after treatment (P < 0.001)

TAOS improved from 10.4 (SD 5.7) to 2.4 (SD 4.6) at 52 weeks (P < 0.001)

No change in thyroid stimulating hormone or thyroid stimulating immunoglobulin levels pre/post treatment

Adverse effects: none

   
Mitchell 2013Study nameThe effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid refractory Graves’ orbitopathy
 Participants

9 patients with steroid-refractory TAO

8 female, 1 male

Median age: 62 years (37 to 87)

All patients had pulsed iv methylprednisolone median of 3 months prior to rituximab treatment (2 weeks to 6 months)

8/9 patients had CAS greater than 4/10 (median 6.5, range 4 to 8). 1 patient had CAS 1.

4 patients had sight-threatening TAO (NO SPECS 6)

Follow-up: 16 months or more (median 29 months, range 16 to 46 months)

 Intervention

Rituximab infusion 1000 mg twice at two weekly intervals (3 patients) or 500 mg twice at two weekly intervals (6 patients)

One patient not B cell depleted after second 500 mg infusion so received third 500 mg infusion

Premedication 500 mg iv methylprednisolone, 10 mg iv chlorpheniramine and 1 g po paracetamol

 Outcome measures

Thyroid function tests

B cell count

Thyroid autoantibody levels

Change in CAS

 Results

No effect on TFTs

TBII reduced in all patients

CAS improved in all patients

Median improvement in CAS at 3 months: 2 points (range 1 to 6), P = 0.018

Median improvement in CAS at 12 months: 5 points (range 1 to 8), P = 0.0006

Adverse effects: 4 patients had minor side-effects following first infusion: 2 headache, 1 headache and chills without pyrexia, 1 mild myalgia

Table 3. Case reports
Krassas 2010bStudy nameFailure of rituximab treatment in a case of severe thyroid ophthalmopathy unresponsive to steroids
 SummaryCase unilateral severe TAO (GD then euthyroid after Tx). TRAb high. TG and TPO normal. Previously had iv steroids for TAO. RTX 2 infusions 1 g over 4 hours 2 weeks apart. TAO got worse, developed optic neuropathy and had to have orbital decompression.
   
Salvi 2012Study nameSmall Dose of Rituximab for Graves Orbitopathy: New Insights Into the Mechanism of Action
 Summary

3 patients treated with one-off low dose rituximab infusion 100 mg

Patient 1: female age 43 years, CAS 5/10. At day 1, CAS decreased to 1/10 and proptosis reduced from 24.5 to 23 mm OD and 31 to 28 mm OS.

Patient 2: female age 67 years, CAS 6/10. Vision improved w/i 3 hours from CF to 10/10. At week 1, CAS decreased to 3 and proptosis from 27.5 to 26 mm OD and 29.5 to 27 mm OS.

Patient 3: female age 50 years, CAS 6/7. No immediate effects. At 8 weeks, CAS reduced to 3.

No relapse at 32, 55 and 86 weeks follow up respectively

El Fassi 2007 was a prospective, open non-randomised study of 20 patients with newly diagnosed, untreated Grave's disease, including two with TAO. Ten patients received rituximab and 10 did not (control group). All patients were treated with methimazole (MMI) until they became euthyroid. Patients in the rituximab group then received rituximab 375 mg/m2 on days one, eight, 15 and 22. All patients were withdrawn from methimazole at day 22. The two patients with TAO were both in the rituximab group. (The primary outcome measures were time to relapse of hyperthyroidism and changes in autoantibody levels, rather than effect on TAO). Both patients were female ex-smokers who had previously received glucocorticoids and retrobulbar radiation. CAS decreased from 6 to 2 in one patient, and from 5 to 1 in the other at 11 months. Proptosis decreased from 25 mm to 22 mm bilaterally in one patient, and from 23 mm to 21 mm unilaterally in the other (second eye had no change in proptosis). Both patients had improvement in soft tissue changes and eye motility.

Salvi 2007 was a prospective, open non-randomised study of nine patients with Graves' disease treated with rituximab; seven with active TAO (CAS ≥ 3) and two with mild lid signs. These were compared to a case series of 20 consecutive patients with active TAO treated with intravenous glucocorticoids. Five patients were smokers, two were ex-smokers and two never smoked. At the time of rituximab therapy, four patients were hyperthyroid and untreated, five were euthyroid, two were on methimazole and one on levothyroxine for 12 months after previous thyroidectomy. Patients received two intravenous infusions of rituximab 1000 mg administered two weeks apart, or intravenous methylprednisolone 500 mg at weekly intervals for 14 weeks and then 250 mg for another two weeks. In the rituximab group, mean CAS decreased from 4.7±0.5 to 1.8±0.8 at 30 weeks. This change was significantly greater (P < 0.05) than the change in CAS with iv glucocorticoid treatment (mean CAS 4.1±0.3 to 2.0±0.4 at 30 weeks). Soft tissue inflammation and proptosis improved significantly in both groups, with no difference between the groups. Degree of motility impairment also improved in the rituximab group.

Khanna 2010 was a retrospective case series of six patients with severe, progressive TAO unresponsive to corticosteroids. Four patients were female and three were smokers at the time that TAO developed. All patients were euthyroid at the time of rituximab infusion, and previously had received one to three courses of corticosteroids for active TAO. Patients received two intravenous infusions of rituximab 1000 mg administered two weeks apart. Mean CAS improved from 5.5±0.8 to 1.3±0.5 at two months after treatment (P < 0.03). TAO remained quiescent in all patients (CAS, 0.7±0.8; P < 0.0001) at mean follow-up of 6.2±4.5 months. Four of the patients had presented with optic neuropathy. Visual acuity improved in all within four weeks of rituximab therapy and returned to pre-neuropathy vision within two months. Proptosis did not improve significantly (24±3.7 mm to 23.6±3.7 mm, P = 0.17), nor was there any improvement in extraocular motility. One patient demonstrated progressive strabismus.

Heemstra 2008 was a prospective, open interventional study of 13 patients with relapsing Graves' disease, of whom three exhibited mild TAO (NOSPECS score 2a). Patients received two intravenous infusions of rituximab 1000 mg administered two weeks apart. Outcome measures were changes in thyroid function test blood biochemistry and TRAb levels. No changes in TAO measures were reported.

Silkiss 2010 was a prospective, open interventional study of 12 patients with moderate-to-severe TAO (CAS ≥ 4). Eight patients had previously been treated with glucocorticoids, two of whom were still on glucocorticoids during the study. One patient had previously had orbital radiation therapy. Patients received two intravenous infusions of rituximab 1000 mg administered two weeks apart. CAS improved from 5.5 (SD 1.2) to 0.8 (SD 1.4) at 52 weeks after treatment (P < 0.001).

Mitchell 2013 was a retrospective case series of nine patients with steroid-refractory TAO, eight of whom had moderate-to-severe disease (CAS ≥ 4, median CAS 6/10, range 4 to 8). All patients had previously been treated with pulsed intravenous methylprednisolone prior to rituximab (median three months prior, range two weeks to six months). Patients received two infusions of rituximab two weeks apart. Three patients received a dose of 1000 mg at each infusion, and six patients received 500 mg. One of these received a third infusion of 500 mg two weeks later as this patient was not B-cell depleted following the second infusion. CAS improved in all patients, with a median improvement of 2 points at three months (range 1 to 6, P = 0.018), and 5 points at 12 months (range 1 to 8, P = 0.0006). One patient had emergency optic nerve decompression after the first infusion.

Salvi 2012 reported three cases of patients treated with a one-off infusion of low dose rituximab (100 mg), all of whom had clinical improvement in TAO, in two cases within just one day.

One case report, Krassas 2010b, reported failure of rituximab in a patient with unilateral severe TAO, who developed dysthyroid optic neuropathy and had to go on to have orbital decompression.

With regards to safety, El Fassi 2007 gave 1 g acetaminophen and 2 mg clemastine pre-rituximab infusion. Half of the patients experienced benign infusion reactions with the first infusion (hypotension (n = 4), nausea (n = 2), fever (n = 1), chills (n = 1), and tachycardia (n = 1)). Two patients had to receive long-term glucocorticoid therapy due to late-onset articular pain. One patient with no infusion reaction experienced worsening of gastrointestinal symptoms, subsequently diagnosed as ulcerative colitis, and axial arthritis. Salvi 2007 gave 1 g paracetamol and 10 mg chlorpheniramine pre-treatment. Three of the nine patients reported mild side-effects during the first infusion such as mild fever, and were treated with 100 mg intravenous hydrocortisone. Khanna 2010 gave 100 mg intravenous methylprednisolone, 1 g acetaminophen and 50 mg diphenhydramine as pre-treatment. One patient developed a urinary tract infection, one worsening hypertension, and one died from a sudden cardiac arrest three months after the second infusion. Heemstra 2008 gave 10 mg dexamethasone and 3 mg clemastine intravenously pre-treatment. Two of the 13 Graves' patients reported temporary joint pains, but it was not clear whether either of these were TAO patients. Silkiss 2010 gave 1 g acetaminophen and 50 mg diphenhydramine pre-treatment. They reported no adverse events. Mitchell 2013 gave 500 mg intravenous methylprednisolone, 10 mg intravenous chlorpheniramine and 1 g oral paracetamol pre-treatment. Four patients reported minor side-effects with the first infusion. Two had headache, one headache and chills without pyrexia and one mild myalgia.

Authors' conclusions

Implications for practice

The published literature regarding the use of rituximab in the treatment of TAO to date only consists of limited non-randomised studies, case series and case reports, and includes a heterogenous cohort of patients. Whilst these studies do seem to indicate efficacy of treatment and, with adequate pre-treatment, an acceptable side-effect profile, the quality of these studies is insufficient to be included in any robust analysis. No reliable conclusions regarding the use of rituximab for TAO can be made.

Implications for research

Larger randomised controlled, double-masked trials need to be conducted to provide the data that can then be utilised to make adequate judgement on the efficacy and safety of this novel therapy in TAO. These trials should be designed to include patients with moderate-to-severe TAO (CAS ≥ 4) who have been euthroid for at least six weeks. Both treatment-naïve patients and patients who have relapsed following previous glucocorticoid therapy could be investigated. Patients should be randomised to receive intravenous rituximab, or to receive intravenous glucocorticoids or intravenous saline/placebo. The primary outcome could be improvement in thyroid-associated CAS at four, six and 12 months post treatment. Secondary outcomes could include decrease in proptosis, change in palpebral aperture measurement and improvement in extraocular motility. Patients should be followed-up long-term and relapse rates recorded. Improvement in quality of life is also an important outcome that future studies should investigate, measured using validated tools such as the SF-36 questionnaire (Ware 1998) and GO-QoL questionnaire (Terwee 2001). Adverse effects and side-effect profiles should be recorded, including longer-term follow-up such as 24 months post treatment. Awaiting such studies, rituximab should be used with caution, and only so when evidence-based therapy has failed or is contraindicated.

This is an exciting area of development, and as more research is conducted to understand further the pathophysiology of TAO and particularly its immune basis, more immune-modulating agents can be developed and trialled to take us one step further in managing this serious and potentially sight-threatening condition.

Acknowledgements

We would like to thank Iris Gordon for creating and executing the electronic searches, and Catey Bunce, Mario Salvi, Richard Wormald, Jennifer Evans, Kostas Boboridis and Anupa Shah for their comments on the protocol and review.

Richard Wormald (Co-ordinating Editor for CEVG) acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Graves Disease
#2 MeSH descriptor Graves Ophthalmopathy
#3 grave* near ophthalm*
#4 grave* near orbitopath*
#5 (thyroid*) near (ophthalm* or eye*)
#6 TED or TAO
#7 basedow* next disease*
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
#9 MeSH descriptor Antibodies, Monoclonal
#10 MeSH descriptor Antigens, CD20
#11 MeSH descriptor B-Lymphocytes
#12 rituximab or RTX
#13 CD20
#14 monoclonal near/4 antibod*
#15 (lymphocyte* or cell*) near/4 agent*
#16 (#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15)
#17 (#8 AND #15)

Appendix 2. MEDLINE (OvidSP) search strategy

1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. exp graves disease/
14. exp graves ophthalmopathy/
15. (grave$ adj3 ophthalm$).tw.
16. (grave$ adj3 orbitopath$).tw.
17. ((ophthalm$ or eye$) adj3 thyroid$).tw.
18. (TED or TAO).tw.
19. (basedow$ adj3 disease$).tw.
20. or/13-19
21. exp antibodies, monoclonal/
22. Antigens, CD20/
23. exp B-Lymphocytes/
24. (rituximab or RTX).tw.
25. CD20.tw.
26. (monoclonal adj4 antibod$).tw.
27. ((lymphocyte$ or cell$) adj4 agent$).tw.
28. or/21-27
29. 20 and 28
30. 12 and 29

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville (Glanville 2006).

Appendix 3. EMBASE (OvidSP) search strategy

1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp graves disease/
34. exp endocrine ophthalmopathy/
35. (grave$ adj3 ophthalm$).tw.
36. (grave$ adj3 orbitopath$).tw.
37. ((ophthalm$ or eye$) adj3 thyroid$).tw.
38. (TED or TAO).tw.
39. (basedow$ adj3 disease$).tw.
40. or/33-39
41. exp monoclonal antibody/
42. exp rituximab/
43. exp CD20 antigen/
44. exp B lymphocyte/
45. (rituximab or RTX).tw.
46. CD20.tw.
47. (monoclonal adj4 antibod$).tw.
48. ((lymphocyte$ or cell$) adj4 agent$).tw.
49. or/41-48
50. 40 and 49
51. 32 and 50

Appendix 4. LILACS search strategy

graves and ophthalm$ or orbit$ or disease or TED or TAO and monoclonal antibod$ or rituximab or CD20

Appendix 5. OpenGrey search strategy

rituximab

Appendix 6. metaRegister of Controlled Trials search strategy

thyroid eye disease OR thyroid associated orbitopathy OR ophthalmopathy OR TED or TAO

Appendix 7. ClinicalTrials.gov search strategy

(Thyroid Eye Disease OR Thyroid Associated Orbitopathy OR Ophthalmopathy OR TED or TAO) AND Rituximab

Appendix 8. WHO ICTRP search strategy

ophthalmopathy OR orbitopathy OR TAO = Condition AND rituximab = Intervention

Appendix 9. EU Clinical Trials Register search strategy

Thyroid AND Rituximab

What's new

DateEventDescription
29 May 2013AmendedLead author's contact details have changed.

Contributions of authors

Conceiving the review: DGE
Designing the review: NM, DGE
Co-ordinating the review: NM
Data collection for the review:
- Designing electronic search strategies: Cochrane Eyes and Vision Group editorial base
- Undertaking manual searches: NM, DGE
- Screening search results: NM, DGE
- Organising retrieval of papers: NM
- Screening retrieved papers against inclusion criteria: NM, DGE
- Appraising quality of papers: NM, DGE
- Extracting data from papers: NM, DGE
- Writing to authors of papers for additional information: NM
- Providing additional data about papers: NM
- Obtaining and screening data on unpublished studies: NM, DGE
Data management for the review:
- Entering data into RevMan: NM
- Checking that data entered into RevMan is correct: NM, DGE
Analysis of data: NM
Interpretation of data:
- Providing a methodological perspective: NM, DGE
- Providing a clinical perspective: NM, DGE
- Providing a policy perspective: NM, DGE
Writing the review: NM, DGE
Providing general advice on the review: DGE
Securing funding for the review: DGE
Performing previous work that was the foundation of the current study: NM, DGE

Declarations of interest

None.

Sources of support

Internal sources

  • NIHR, UK.

    "DGE acknowledges financial support from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health."

External sources

  • No sources of support supplied

Differences between protocol and review

We did not handsearch conference proceedings for additional non-published studies.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    TAO: thyroid-associate ophthalmopathy

El Fassi 2007Non-randomised prospective controlled open trial comparing rituximab to no treatment for Grave's disease (not specifically TAO)
Heemstra 2008Non-randomised prospective open interventional case series investigating rituximab for treatment of Grave's disease (not specifically for TAO)
Khanna 2010Non-randomised retrospective interventional case series investigating rituximab for patients with severe corticosteroid resistant TAO
Krassas 2010bCase study
Mitchell 2013Non-randomised retrospective interventional case series investigating rituximab for patients with glucocorticoid-refractory TAO
Salvi 2007Non-randomised prospective controlled open trial comparing rituximab to intravenous glucocorticoids for TAO
Salvi 2012Case study
Silkiss 2010Non-randomised prospective open interventional case series investigating rituximab for patients with TAO

Characteristics of ongoing studies [ordered by study ID]

EUCTR2011-000899-33-SE

Trial name or titleRituximab (RTX) therapy in steroid resistant patients or patients relapsing after intravenous steroids with active TAO Rescue RTX - rescue RTX
MethodsRandomised, controlled, open clinical trial (phase 2/3)
Participants

All new patients with active TAO and indication for iv steroids

Male or female aged 18 to 70 years

TAO with CAS of = 4 (less than 3 months)

Euthyroid for at least 6 weeks

Interventions

All patients treated 4 x weekly steroid infusions

Non-responders at 4 weeks receive rituximab+methotrexate

Responders at 4 weeks continue weekly iv steroids for total 12 weeks

6 weeks after completing course of iv steroid, those relapsing randomised to rituximab+methotrexate or oral steroid+methotrexate

Outcomes

Primary outcome:

Responder analysis in CAS score. A responder is defined as an improvement in CAS = 2 compared with before treatment. Analysed at four occasions

1. At 4 weeks iv steroid treatment compared to baseline

2. In the responder group 12 weeks compared to baseline

3. In the non-responder group 18 weeks compared to 4 weeks
4. In the relapse group at 32 and 46 weeks compared to 18 weeks

Secondary outcomes:

Compare RTX+MTX versus poGC+MTX on CAS week 32 and 46

Compare RTX+MTX versus poGC+MTX on severity of disease week 32 and 46

Compare quality of life effect of RTX+MTX versus poGC+MTX

Compare the side-effects in RTX+MTX versus poGC+MTX

Describe the number of relapses later than 6 weeks but before 52 weeks after 12 weeks iv steroids

Evaluate if impaired adrenal GC production occurs after 12 weeks iv steroid treatment

Evaluate the QoL in patients on intravenous steroids

Describe side-effects in RTX+MTX and intravenous steroids

Do the side-effects differ according to GCd receptor polymorphism?

To characterise the GC resistant group in the GC receptor, genetic and immunologic markers

Compare genetic and immunological markers in the steroid-responding patients that relapses compared to the non-relapsing patients

Describe how immunologic markers changes under treatment

Starting dateJune 2011
Contact informationhelena.filipsson@telia.com
NotesRecruiting since Jan 2012. Likely to finish recruitment in 2014 (personal communication, 12th November 2012)

EUdraCT 2007-003910-33

Trial name or titleRandomised controlled study of rituximab and steroid treatment in thyroid-associated ophthalmopathy (TAO)
MethodsRandomised, controlled double-masked clinical trial
Participants

Male or female aged 18 to 75 years

Smokers and non smokers

Euthyroid for at least 6 to 8 weeks

TAO with CAS of > 4/10 or > 3/7 and moderate to severe disease severity, as defined by NOSPECS score

Patients with previous steroid treatment, as long as it has been stopped at least 3 month before, may be included in the study

InterventionsRituximab infusion versus intravenous methylprednisolone
OutcomesReduction of clinical activity score > 2 points or below CAS = 3
Starting date 
Contact informationmario@mariosalvinet.it
NotesRecruitment complete Nov 2012 (personal communication, 19th November 2012)

NCT00595335

Trial name or titleTrial of Rituximab for Graves' Ophthalmopathy
MethodsRandomised, controlled, double-masked clinical trial
Participants

Male or female aged 18 to 75 years

Patients with CAS of ≥ 4 and moderate to severe disease severity, as defined by NOSPECS score

Euthyroid for at least 6 to 8 weeks

No immediate need for decompression surgery

Interventions

15 patients will receive 2 infusions of rituximab (1000 mg iv), two weeks apart

15 patients will receive 2 infusions of saline iv, 2 weeks apart

Outcomes

Primary outcome measures:

Improvement in CAS by 2 or more points (Time Frame: 2, 4, 6 and 12 months after the first infusion)

Secondary outcome measures:

Decrease in disease severity (Time Frame: 2, 4, 6 and 12 months after first infusion)

Decrease in proptosis by ≥ 2 mm (Time Frame: 2, 4, 6 and 12 months after first infusion)

Decrease in lid aperture width by ≥ 3 mm (Time Frame: 2, 4, 6 and 12 months after first infusion)

Improvement in extraocular motility by ≥ 8 degrees (Time Frame: 2, 4, 6 and 12 months after first infusion)

Improvement in a GO-specific quality of life score of ≥ 6 points (Time Frame: 2, 4, 6 and 12 months after first infusion)

Failure rate, defined as need for additional therapy (excluding cosmetic surgery) for the eye disease (Time Frame: 52 weeks)

Composite of decrease of CAS ≥ 2 points and no need for additional therapy for the eye disease versus either CAS decrease of < 2 points or need for additional therapy (Time Frame: 52 weeks)

Starting dateJanuary 2008
Contact informationbahn.rebecca@mayo.edu
NotesRecruitment complete October 2012 for 6 months primary endpoint (personal communication 27th August 2012)

Ancillary