Rituximab para la oftalmopatía asociada a la tiroides
Resumen
Antecedentes
La oftalmopatía asociada a la tiroides (OAT) es la manifestación extratiroidea más frecuente de la enfermedad de Graves y afecta a hasta el 50% de los pacientes. Tiene una gran repercusión sobre la calidad de vida. El rituximab (RTX) es un anticuerpo monoclonal quimérico humano/murino que actúa sobre el receptor CD20 de los linfocitos B. Trabajos preliminares han mostrado que bloquear este receptor CD20 con RTX podría afectar al curso clínico de la OAT al reducir la inflamación y el grado de proptosis.
Objetivos
Esta actualización de la revisión, publicada originalmente en 2013, evalúa la eficacia y la seguridad del RTX para el tratamiento de la OAT.
Métodos de búsqueda
Se realizaron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials, CENTRAL; 2022, número 2), que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión (Cochrane Eyes and Vision Trials), Ovid MEDLINE, Ovid Embase, la base de datos Latin American and Caribbean Health Science Information (LILACS), el registro ISRCTN, ClinicalTrials.gov y en la Plataforma de registros internacionales de ensayos clínicos (ICTRP) de la OMS. No hubo restricciones de idioma en las búsqueda electrónicas de ensayos. Se buscó por última vez en las bases de datos electrónicas el 22 de febrero de 2022.
Criterios de selección
Se incluyeron ensayos controlados aleatorizados (ECA) de RTX administrado por infusión intravenosa utilizando cualquier pauta de tratamiento de la OAT activa en adultos, en comparación con el tratamiento con placebo o glucocorticoides.
Obtención y análisis de los datos
Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Dos autores de la revisión exploraron de forma independiente los títulos y resúmenes y examinaron los informes de texto completo de los estudios potencialmente relevantes. Los desenlaces de interés en esta revisión fueron: puntuación de actividad clínica (clinical activity score; CAS), escala de gravedad NOSPECS, proptosis (mm), apertura palpebral (mm), motilidad extraocular (grados o escala de calificación de la diplopía), calidad de vida y efectos adversos.
Resultados principales
Se identificaron dos estudios que cumplieron los criterios de inclusión en esta actualización de revisión. En ambos estudios, la media de edad de los participantes fue de 55 años y el 77% fueron mujeres.
RTX comparado con metilprednisolona por vía intravenosa (MPIV)
Un estudio, realizado en Italia, comparó el RTX (n = 15 tras el retiro de un participante) con MPIV (n = 16) para la OAT activa (CAS ≥ 3 de 7 o 4 de 10). Se consideró que este estudio tenía un bajo riesgo de sesgo en la mayoría de dominios, pero se interrumpió antes de tiempo debido a la reactivación de la enfermedad en el grupo de comparación (5/16 participantes). Este estudio aportó evidencia de certeza baja de que el RTX podría dar lugar a una mejora de la CAS a las 24 semanas en comparación con la MPIV (15/15 versus 12/16 mejoraron en ≥ 2 puntos; razón de riesgos [RR] 1,32; intervalo de confianza [IC] del 95%: 0,98 a 1,78). Solo se dispuso de evidencia de certeza muy baja para los otros desenlaces: Mejora de la NOSPECS en 2 o más clases (3/15 versus 3/16; RR 1,07; IC del 95%: 0,25 a 4,49); mejora de la proptosis en 2 mm o más (0/15 versus 1/16; RR 0,35; IC del 95%: 0,02 a 8,08); mejora de la apertura palpebral en 3 mm o más (2/15 versus 0/16; RR 5,31; IC del 95%: 0,28 a 102,38); mejora de la motilidad en 1 clase o más (3/15 versus 3/16; RR 1,07; IC del 95%: 0,25 a 4,49); y mejora en la escala de calidad de vida de la oftalmopatía de Graves en al menos 6 puntos para "funcionalidad" (5/14 versus 8/13; RR 0,58; IC del 95%: 0,25 a 1,32), y "aspecto" (9/14 versus 6/13; RR 1,39; IC del 95%: 0,69 a 2,82). Los eventos adversos fueron más frecuentes en el grupo de RTX (RR 1,39; IC del 95%: 0,90 a 2,13; evidencia de certeza baja). Se observaron efectos adversos de carácter menor (reacciones leves a la infusión) en la primera infusión en la mayoría de las personas que recibieron RTX. Dos participantes experimentaron una reacción importante a la infusión, probablemente el síndrome de liberación de citoquinas.
RTX en comparación con placebo
Un estudio, realizado en los Estados Unidos, incluyó a 25 participantes con OAT activa (CAS ≥ 4 de 7) y comparó RTX (13 participantes) con placebo. Se consideró que este estudio presentaba un bajo riesgo de sesgo en la mayoría de los dominios, pero se interrumpió antes de tiempo debido a problemas de reclutamiento. Proporcionó evidencia de certeza muy baja sobre los siguientes desenlaces a las 24 semanas: Mejora del CAS en 2 o más puntos (4/13 RTX versus 3/12 placebo; RR 1,23; IC del 95%: 0,34 a 4,40); mejora del NOSPECS en 2 o más clases (2/13 versus 2/12; RR 0,92: IC del 95%: 0,15 a 5,56); mejora de la proptosis en 2 mm o más (2/13 versus 4/12; RR 0,46; IC del 95%: 0,10 a 2,08); mediana de cambio de la apertura palpebral (0 mm en el grupo de RTX, en ambos ojos por separado, frente a ‐0,5 mm y 0,5 mm en el grupo de placebo del ojo derecho e izquierdo, respectivamente); mediana de puntuación de la diplopía de la motilidad (3 versus 2,5); mediana de puntuación del componente físico del SF‐12 (45,9 versus 40,3) y mediana de puntuación del componente mental (52,8 versus 46,1). Más participantes del grupo de RTX presentaron efectos adversos (8/13 versus 3/12; RR 2,46; IC del 95%: 0,84 a 7,18).
Conclusiones de los autores
Actualmente no hay evidencia suficiente para apoyar el uso de RTX en personas con OAT. Es posible que los futuros estudios que investiguen el RTX en personas con OAT activa deban ser multicéntricos para poder reclutar suficientes participantes y emitir una valoración suficiente sobre la eficacia y la seguridad de este nuevo tratamiento.
PICO
Resumen en términos sencillos
Cuáles son los beneficios y riesgos del rituximab (un medicamento que reduce la inflamación) para el tratamiento de la oftalmopatía asociada al tiroides (una enfermedad que afecta a los tejidos que rodean los ojos)
Mensajes clave
‐ No se encontraron pruebas suficientes para demostrar que las personas con oftalmopatía asociada a la tiroides de moderada a grave que reciben tratamiento con rituximab tengan algún desenlace diferente en cuanto a los signos y síntomas de la enfermedad en comparación con los tratados con corticoides o placebo (tratamiento falso).
‐ El rituximab podría causar más efectos adversos (no deseados) en comparación con los corticoides o el placebo, pero no hay certeza de ello.
‐ Se necesitan más estudios para reforzar el conjunto de evidencia e investigar si el rituximab debería utilizarse para el tratamiento de la oftalmopatía asociada a la tiroides.
¿Qué es la oftalmopatía asociada a la tiroides?
La oftalmopatía asociada al tiroides es una enfermedad ocular que afecta a la mitad de las personas que padecen la enfermedad de Graves, un trastorno en el que el sistema inmunitario del organismo ataca a la glándula tiroides y la vuelve hiperactiva. En la oftalmopatía asociada al tiroides, el sistema inmunitario del organismo también ataca los tejidos circundantes a ojos. Los síntomas incluyen dolor, enrojecimiento, tumefacción y protrusión (proptosis) del ojo, visión doble y, en los casos graves, reducción de la visión.
¿Cómo se trata la oftalmopatía asociada a la tiroides?
Las opciones terapéuticas para la oftalmopatía grave asociada al tiroides incluyen medicamentos antiinflamatorios llamados corticosteroides, y radioterapia. Sin embargo, las recaídas son frecuentes. La cirugía para aliviar la presión que se acumula detrás del ojo (descompresión orbital) suele reservarse para los casos que ponen en peligro la visión.
Un posible tratamiento alternativo es un medicamento llamado rituximab que se administra por infusión intravenosa (inyección en una vena) y cuyo objetivo es impedir que el sistema de defensa del organismo (sistema inmunitario) ataque por error a los tejidos sanos y provoque una inflamación.
¿Qué se quería averiguar?
Se querían comparar los beneficios y riesgos del rituximab con los de otros tratamientos para la oftalmopatía asociada a la tiroides.
¿Qué se hizo?
Se buscaron estudios que compararan el rituximab con el tratamiento con placebo (ficticio) o con el tratamiento con corticoides para la oftalmopatía asociada a la tiroides. Se compararon y resumieron los resultados de estos estudios y la confianza en la evidencia se evaluó sobre la base de factores como la metodología y el tamaño de los estudios.
¿Qué se encontró?
Se encontraron dos estudios, realizados en Italia y en Estados Unidos, en los que participaron un total de 56 personas con oftalmopatía asociada a la tiroides. Todas las personas que participaron en el estudio tenían entre 18 y 80 años (una media de 55 años) y el 77% eran mujeres. Un estudio (31 personas) comparó el rituximab por vía intravenosa (dos infusiones de 1000 mg administradas cada dos semanas o una única infusión de 500 mg) con la metilprednisolona por vía intravenosa (corticoide). El otro estudio (25 personas) comparó el rituximab por vía intravenosa (dos infusiones de 1000 mg administradas cada dos semanas) con infusiones de placebo por vía intravenosa. Puesto que los estudios compararon rituximab con distintas alternativas de tratamiento, no fue posible combinar los resultados de los estudios para analizarlos en conjunto.
¿Cuáles fueron los resultados principales de esta revisión?
La evidencia sugiere que el rituximab, comparado con la metilprednisolona por vía intravenosa, podría dar lugar a una mejora en el grado de "actividad" de la oftalmopatía asociada a la tiroides a las 24 semanas del tratamiento, cuando se mide con una escala concreta, pero la evidencia de si había una verdadera diferencia no fue clara. Además, hubo poca o ninguna diferencia cuando la actividad de la oftalmopatía asociada al tiroides se midió utilizando una escala diferente. No hubo evidencia de diferencias en los siguientes desenlaces, medidos a las 24 semanas del tratamiento:
‐ reducción de la protrusión del ojo
‐ reducción de la apertura de los párpados
‐ mejora de los movimientos oculares y de la visión doble
‐ mejora de la calidad de vida
La evidencia sugiere que el rituximab, en comparación con el placebo, produce poca o ninguna diferencia en cualquiera los desenlaces señalados anteriormente, medidos a las 24 semanas del tratamiento.
La cifra de episodios adversos fue mayor en el caso del rituximab en comparación con la metilprednisolona por vía intravenosa y el placebo, pero la evidencia para determinar si hubo una verdadera diferencia no era clara.
¿Cuáles son las limitaciones de la evidencia?
La evidencia solo se basa en dos estudios con pocos participantes, y ambos se finalizaron antes de lo previsto, lo que limita la confianza en los resultados.
¿Cuál es el grado de actualización de esta evidencia?
La evidencia está actualizada hasta febrero de 2022.
Authors' conclusions
Summary of findings
| Rituximab compared to intravenous methylprednisolone for thyroid‐associated ophthalmopathy | ||||||
| Patient or population: thyroid‐associated ophthalmopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with intravenous methylprednisolone | Risk with rituximab | |||||
| CAS improvement (decrease) by 2 or more points | 750 per 1000 | 990 per 1000 | RR 1.32 | 31 | ⊕⊕⊝⊝ | |
| NOSPECS improvement (decrease) by 2 or more classes | 188 per 1000 | 201 per 1000 | RR 1.07 | 31 | ⊕⊝⊝⊝ | |
| Proptosis improvement (decrease) by 2 mm or more | 63 per 1000 | 22 per 1000 | RR 0.35 | 31 | ⊕⊝⊝⊝ | |
| Palpebral aperture improvement (decrease) by 3 mm or more | Moderate | RR 5.31 | 31 | ⊕⊝⊝⊝ | ||
| 10 per 1000 | 53 per 1000 | |||||
| Motility improvement (increase) by 1 class or more | 188 per 1000 | 201 per 1000 | RR 1.07 | 31 | ⊕⊝⊝⊝ | |
| Quality of life improvement by at least 6 points | Improvement on GO‐QoL Scale by at least 6 points for "functioning": RR at 24 weeks 0.58 (95% CI 0.25 to 1.32)Improvement on GO‐QoL Scale by at least 6 points for "appearance": RR at 24 weeks 1.39 (95% CI 0.69 to 2.82) | 27 | ⊕⊝⊝⊝ | |||
| Adverse events | 625 per 1000 | 869 per 1000 | RR 1.39 | 31 | ⊕⊕⊝⊝ | In the rituximab group, 2 participants experienced a major infusion reaction, likely cytokine release syndrome. Minor adverse effects (mild infusion reactions) were observed in most rituximab patients at first infusion. In IVMP group, 3 participants experienced deranged liver function test. Minor side effects observed in 7 IVMP participants were dyspepsia, hypotension, insomnia, and mild mood disorders, which did not require specific treatment. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_424436778554984307. | ||||||
| a CAS: clinical activity score; GO‐QoL: Graves’ ophthalmopathy quality of life questionnaire; NOSPECS: scoring system based on no symptoms or signs, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, and sight loss; RCT: randomised clinical trial; SF‐12: Medical Outcomes Study 12‐Item Short Form Health Survey. | ||||||
| Rituximab compared to placebo for thyroid‐associated ophthalmopathy | ||||||
| Patient or population: thyroid‐associated ophthalmopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with Rituximab | |||||
| CAS improvement (decrease) by 2 or more points | 250 per 1000 | 308 per 1000 | RR 1.23 | 25 | ⊕⊝⊝⊝ | |
| NOSPECS improvement (decrease) by 2 classes or more | 167 per 1000 | 153 per 1000 | RR 0.92 | 25 | ⊕⊝⊝⊝ | |
| Proptosis improvement (decrease) by 2 mm or more | 333 per 1000 | 153 per 1000 | RR 0.46 | 25 | ⊕⊝⊝⊝ | |
| Palpebral aperture change | Median change in palpebral aperture in the right eye was 0 mm (IQR ‐1 to 1) in the 13 rituximab group participants and ‐0.5 mm (IQR ‐1 to 1.75) in the 12 placebo participants. Median change in the palpebral aperture in the left eye was 0 mm (IQR ‐1.5 to 1) in the rituximab group and 0.5 mm (IQR ‐1 to 1.75) in the placebo group. | 25 | ⊕⊝⊝⊝ | |||
| Motility | The median diplopia score in the 13 rituximab participants was 3 (IQR 2 to 3.5) compared to 2.5 (IQR 0 to 4) in the 12 placebo participants. | 25 | ⊕⊝⊝⊝ | |||
| Quality of Life | SF‐12 physical: the median score was 45.9 (IQR 43.6 to 50.8) in the 13 rituximab participants and 40.3 (IQR 38.5 to 52.1) in the 12 placebo participants. SF‐12 mental: the median score was 52.8 (IQR 36.1 to 56.7) in the rituximab group and 46.1 (IQR 35.4 to 57.4) in the placebo group. | 25 | ⊕⊝⊝⊝ | |||
| Adverse effects | 250 per 1000 | 615 per 1000 | RR 2.46 | 25 | ⊕⊝⊝⊝ | There were four adverse events in 3 out of 12 placebo patients (1 moderate/severe) and 11 adverse events in 8 out of 13 rituximab‐treated patients (5 moderate/severe). Moderate/severe adverse effects included infections (bronchitis, conjunctivitis), vasculitis, optic neuropathy and gastrointestinal adverse effects including tongue pain, abdominal pain and diarrhoea. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_424437036185390139. | ||||||
| a CAS: clinical activity score; IQR: interquartile range; GO‐QoL: Graves’ ophthalmopathy quality of life questionnaire; NOSPECS: scoring system based on no symptoms or signs, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, and sight loss; RCT: randomised clinical trial; SF‐12: Medical Outcomes Study 12‐Item Short Form Health Survey. | ||||||
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 people with Graves' hyperthyroidism have clinically apparent TAO at the time of diagnosis (Burch 1993, Tanda 2013). 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 people 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 and compressive optic neuropathy, which might lead to visual loss. Even milder forms of ophthalmopathy have a great impact on the quality of life of those affected (Kahaly 2005; Lee 2020).
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 the volume of the intraorbital contents. Thyrotropin receptor autoantibodies (TRAb) and immunoglobulins targeting the IGF‐1 receptor also directly activate pre‐adipogenic fibroblasts with the 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). The European Group on Graves' Orbitopathy (EUGOGO) has recommended a six‐month course of selenium supplementation for mild TAO cases of relatively short duration (Bartalena 2016, EUGOGO 2006). 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 people with the active disease remains controversial, but a Cochrane Review does support its use as monotherapy for moderate TAO (Rajendram 2012) and two studies suggest radiotherapy and intravenous glucocorticoids as dual therapy are more effective than glucocorticoid monotherapy (Bartalena 1983; Ng 2005). 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). There are new emerging immunomodulatory medical therapies such as tocilizumab, an anti‐interleukin‐6 receptor monoclonal antibody, and teprotumumab, a human monoclonal antibody inhibitor of IGF‐1 receptor. Both have shown promising results in reducing proptosis and the Clinical Activity Score (Smith 2017, Douglas 2020, Azzam 2018; Perez‐Moreiras 2018). Surgical treatment includes orbital decompression, strabismus surgery and eyelid surgery. The indications for surgical decompression are sight‐threatening TAO (with the aim of preserving the 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 first received US 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 currently approved by the European Medicines Agency (EMA) and FDA for use (with restrictions) in the treatment of people with non‐Hodgkin's lymphoma (follicular and large B‐cell) (Keating 2010), chronic lymphocytic leukaemia (CLL), severe rheumatoid arthritis (Smolen 2007), granulomatosis with polyangiitis (GPA or Wegener’s granulomatosis) and microscopic polyangiitis (MPA), and moderate to severe pemphigus vulgaris.
Rituximab is administered by intravenous infusion.
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 TRAb, 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 the 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 diseases. 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 the 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. Although the use of rituximab in severe cases of TAO has increased in recent years, 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. The increasing number of emerging medical therapy options such as teprotumumab and tocilizumab highlights the need for a thorough review of the evidence.
Objectives
This review, originally published in 2013 and updated in 2021, assesses the efficacy and safety of using rituximab for the treatment of TAO.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) of rituximab for the treatment of people with TAO in this review.
Types of participants
We included studies with adult participants (age 18 years and over) with active TAO.
Types of interventions
We included studies of rituximab treatment by intravenous infusion using any dosage regimen, compared with placebo or intravenous glucocorticoid treatment.
Types of outcome measures
We evaluated primary and secondary outcomes as follows.
Primary outcomes
The primary outcome for this review was improvement in thyroid‐associated CAS after treatment.
CAS is a validated scoring system, designed to distinguish inflammatory from non‐inflammatory TAO, with a high predictive value for the outcome of immunosuppressive treatment in TAO patients (Mourits 1997). It is based on the classical signs of acute inflammation (pain, redness, swelling, and impaired function). After the first clinical examination, a score out of seven is given. After two consecutive clinical examinations, an activity score can be determined, ranging from nought to 10 points, including three points that rely on assessing the changes in the disease status.
Secondary outcomes
The secondary outcomes for this review were the following after treatment:
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Improvement in NOSPECS* TAO classification score
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Decrease in proptosis (mm)
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Change in palpebral aperture measurement (mm)
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Improvement in extraocular motility (degrees or diplopia rating scale)
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Improvement in quality of life score
We also collected safety outcomes, including adverse events.
*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.
Follow‐up time points
We planned that the time points for all outcomes would be at 4, 6 and 12 months post‐treatment. The ranges of follow‐up time points were from 6 to 18 months in this review.
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for RCTs and controlled clinical trials. There were no language or publication year restrictions. We last searched the electronic databases on 22 February 2022.
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Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 2) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 22 February 2022) (Appendix 1).
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MEDLINE Ovid (1946 to 22 February 2022) (Appendix 2).
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Embase Ovid (1980 to 22 February 2022) (Appendix 3).
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LILACS (Latin American and Caribbean Health Science Information database) (1982 to 22 February 2022) (Appendix 4).
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ISRCTN registry (https://iscrtn.org); searched 22 February 2022 (Appendix 5).
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov); searched 22 February 2022 (Appendix 6).
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 22 February 2022 (Appendix 7).
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 search 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 record 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
Two review authors (SK and SHA) independently extracted the following data, where available, from included studies.
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Methodology (group size, randomisation, blinding (masking), exclusions after randomisation, loss to follow‐up)
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Participant characteristics (age, sex, thyroid status, TRAb levels, smoking status, thyroid volume (mL), TAO activity (CAS), TAO severity (NOSPECS score))
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Intervention (dose, regimen, timing of treatment in relation to diagnosis, timing of treatment in relation to previous interventions, nature of previous interventions)
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Primary and secondary outcomes (CAS, NOSPECS score, proptosis (mm) and extraocular motility (degrees and diplopia rating scale results) at the start of treatment and at each follow‐up time period)
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Adverse events and side effects (number, nature, timing)
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Quality of life scores
Trial authors were contacted, where possible, for more information if data were missing or difficult to interpret. We resolved any discrepancies between authors by discussion and consensus. One review author entered the data into Review Manager 5.4 (Review Manager 2020) and the second author checked the entered data for errors or inconsistencies.
Assessment of risk of bias in included studies
Two review authors (SK and SHA) independently assessed 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 2017). The following six quality parameters were considered in assessing the risk of bias.
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Random sequence generation (selection bias)
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Allocation concealment (selection bias)
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Masking of participants and outcome assessors (performance bias and detection bias)
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Incomplete outcome data (attrition bias)
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Selective outcome reporting (reporting bias)
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Other sources of bias
We assessed each parameter as low risk of bias, high risk of bias, or unclear risk of bias. We resolved discrepancies between review authors by discussion and consensus.
Measures of treatment effect
We reported continuous variables where the data were normally distributed as mean and standard deviation (SD), and where the data were not normally distributed as median and interquartile range (IQR). We planned to report the standardised mean difference (SMD) if the included studies reported the same outcomes but on different valid rating scales. We reported dichotomous variables as risk ratios (RRs) with 95% confidence intervals (CIs). These included any rating scales that were dichotomized based on a clinically relevant cut‐off point and the proportion of participants experiencing each adverse event or side effect.
Unit of analysis issues
The treatment is a systemic treatment and as such affects both eyes of each person treated. For this reason, participants rather than eyes were randomised. The CAS and NOSPECS scores were calculated for each participant and so the unit of analysis for these data was the participant. For proptosis, palpebral aperture and extraocular motility data, the unit of analysis was the individual eye. Where studies presented worse eye data, we analysed these separately. Where studies presented individual eye data, we considered these in a separate analysis. The unit of analysis was the participant for demographic characteristics and quality‐of‐life data.
For eligible cluster‐randomised trials, we planned to conduct the analysis at the same level as the allocation. This approach, however, may have reduced the precision of the effect estimate. Statistical analysis at the level of the individual can lead to an inappropriately high level of precision unless methods are used to account for the clustering in the data. Effect estimates and their standard errors from correct analyses of cluster‐randomised trials may be meta‐analysed using the generic inverse‐variance approach.
Had any crossover trials been identified, we would have assessed whether a crossover trial is a suitable method for the condition and intervention in question. We planned to consider different approaches and select the most appropriate method where possible. A possible approach would be to take all measurements from intervention periods and analyse these as if the trial were a parallel‐group trial. Another approach would be to include only data from the first period. We could have attempted to approximate a paired analysis by imputing missing standard deviations.
To include a study with more than two intervention groups in a meta‐analysis, a recommended approach is (i) to omit groups that are not relevant to the comparison being made, and (ii) to combine multiple groups that are eligible as the experimental or comparator intervention to create a single pair‐wise comparison. Alternatively, multi‐arm studies are dealt with appropriately by network meta‐analysis.
Dealing with missing data
Where possible, we contacted the authors to obtain this information. Any missing data that was unobtainable were assumed to be 'missing at random' and 'complete case' analysis was performed.
Assessment of heterogeneity
We did not assess the between‐study heterogeneity.
Had we identified sufficient trials, we would have assessed heterogeneity by examining the study characteristics and forest plots of the results. We would have used the I2 statistic to assess the impact of statistical heterogeneity, interpreting an I2 value of 50% or more as substantial.
Assessment of reporting biases
Had we identified sufficient trials for this update, we would have used a funnel plot to examine publication bias.
Data synthesis
Meta‐analysis was not possible in this review as there was only one study for each comparison. Had we identified sufficient trials with substantial clinical or statistical heterogeneity between them (I2 > 50%), rather than combining the results, we would have presented an estimate of effect and associated CI for each individual trial. Had we identified sufficient trials with little variation between them, we would have combined the results in a meta‐analysis using a random‐effects model, or a fixed‐effect model if there were very few trials.
Subgroup analysis and investigation of heterogeneity
Had we identified sufficient trials, we would have: (i) performed subgroup analyses to identify possible sources of heterogeneity and (ii) stratified by treatment dosage and thyroid status, as both are potential effect modifiers.
Sensitivity analysis
Had sufficient data been available, we would have conducted sensitivity analyses to determine the impact of the exclusion of studies with lower methodological quality and industry‐funded studies.
Summary of findings and assessment of the certainty of the evidence
The GRADE approach incorporates assessment of indirectness, study limitations, inconsistency, publication bias and imprecision. We assessed the certainty of the evidence (high, moderate, low, and very low) using these five GRADE considerations and, if required, downgraded the evidence by one, two or three levels using assessments at each stage of our analysis. This approach gives an overall measure of how certain we can be that our estimate of effect is correct.
One review author (SK) used GRADEpro software (GRADEpro GDT), to create a 'Summary of findings' table for each comparison (www.guidelinedevelopment.org/). A second author (SHA) assessed the judgements made and consensus was reached through discussion.
The two comparisons are included in the summary of findings tables:
1. Rituximab compared to IV methylprednisolone for thyroid‐associated ophthalmopathy.
2. Rituximab compared to placebo for thyroid‐associated ophthalmopathy.
The following outcomes are presented in the summary of findings tables:
1. CAS at 24 weeks
2. NOSPECS
3. Proptosis
4. Palpebral aperture
5. Motility
6. Quality of life
7. Adverse events
Results
Description of studies
Two prospective, randomised, double‐masked trials are included in this review, one comparing rituximab with IVMP and the other with placebo.
Results of the search
The original searches were undertaken in April 2013 (Minakaran 2013), and 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 and read 13 full‐text copies of papers reporting on eight studies. None of these were suitable for inclusion. See Characteristics of excluded studies for details.
An updated electronic search in February 2022 identified a further 648 reports of studies (Figure 1). The Cochrane Eyes and Vision Information Specialist removed 137 duplicates, pre‐screened 511 records and removed 447 references which were not relevant to the scope of the review. We screened the remaining 64 reports and obtained four full‐text reports of studies of potential interest. Of these, two studies were deemed suitable for inclusion (Salvi 2015; Stan 2015). There are two ongoing RCTs (EUCTR2011‐000899‐33‐SE; ChiCTR2000036239) that are likely to meet the inclusion criteria for the review when the results are available in the future. We will assess these studies for potential inclusion when complete.
Included studies
Two studies were included in this review.
Salvi 2015 conducted a prospective, randomised, double‐masked trial comparing rituximab (RTX) to intravenous methylprednisolone (IVMP). They included people with active TAO (CAS ≥ 3 out of 7 or 4 out of 10) that was moderate to severe according to the NOSPECS scheme. Participants were randomised to receive either IVMP (7.5 g) or RTX (2000 or 500 mg). One participant randomised to receive RTX subsequently withdrew from the study. The trial authors had initially planned to recruit 60 participants (30 RTX and 30 IVMP). However, the study was discontinued based on an interim analysis on 32 participants (16 RTX and 16 IVMP) that showed a high proportion of disease reactivation in the IVMP group. The study was supported by the Italian Ministry of Education, University and Research, Rome, Italy, and by Fondazione Ca' Granda Istituto di Ricovero e Cura a Carattere Scientifico (Ca' Granda research hospital), Milan, Italy.
Stan 2015 performed a prospective, randomised, double‐masked trial comparing rituximab to placebo. Twenty‐five people with active (defined as CAS of 4 of 7 or greater) moderate to severe Graves’ orbitopathy were enrolled (13 RTX and 12 placebo), and 21 completed the study to the primary endpoint. The participants were given either two rituximab infusions (1000 mg each) or two saline infusions two weeks apart. The study was funded by the National Institutes of Health (NIH). Please see the 'Characteristics of included studies' table for further details.
Participants
The two included studies comprised a total of 56 adult participants with active TAO. In the study comparing RTX with IVMP, there were 15 people in the RTX group and 16 in the IVMP group. In the study comparing RTX with placebo, there were 13 RTX and 12 placebo participants. Forty‐three participants (77%) in the two included studies were female. Salvi 2015 included younger participants (mean age of 51 years compared with 57.6 years in Stan 2015). In addition, Salvi 2015 included a higher proportion of smokers (56.2% and 66.7% in the IVMP and RTX groups, respectively, compared with 16.7% and 15.4% in the placebo and RTX groups, respectively, in Stan 2015). Duration of TAO was much shorter in Salvi 2015, with a mean of 4.6 (SD 2.6) months and 4.5 (SD 2.9 months in the IVMP and RTX groups, respectively, compared to a median of 299 (interquartile range (IQR 253 to 595) days and 373 (IQR 240 to 1080) days in the placebo and RTX groups, respectively, in Stan 2015. The mean baseline CAS was 4.4 (SD 0.7) points in the RTX group in Salvi 2015 versus 4.9 (SD 1) points in Stan 2015. Both studies mandated a period of steroid cessation (at least 12 weeks for Salvi 2015 and 4 weeks for Stan 2015) prior to enrolment.
Types of interventions
One study (Salvi 2015) compared intravenous RTX to intravenous methylprednisolone (IVMP) and another (Stan 2015) compared intravenous RTX to intravenous saline (placebo). Both studies gave 1 g of RTX twice with a two‐week interval, although the dose was reduced to a single 500 mg of RTX after the first 12 participants in Salvi 2015 based on the evidence of complete B cell depletion from a very low dose of RTX (100 mg). The study with the IVMP control group (Salvi 2015) followed the EUGOGO protocol of a treatment schedule with weekly 830 mg IVMP administered for 6 weeks followed by 415 mg for another 6 weeks for a cumulative dose of 7.47 g.
Types of outcome measures
In Salvi 2015, the primary outcome was a decrease in CAS by 2 or more points or disease inactivation defined as CAS below 3 points at 24 weeks.
The secondary endpoints were the following signs of disease severity.
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Reduction in NOSEPECS by at least 2 classes
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Decrease in proptosis by at least 2 mm
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Reduction in lid fissure width by at least 3 mm
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Improvement in total eye score (TES) (obtained by multiplying each NOSPECS class by the severity grade)
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Improvement in eye motility according to the Gorman score for diplopia by 1 class or greater, eye muscle duction by 8 degrees or greater measured with the Foerster‐Goldman perimeter, and the total motility score (TMS)
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Disease reactivation at 24 weeks and the number of surgical procedure required after 12 months
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Improvement in either function or appearance components of the Graves’ ophthalmopathy quality of life questionnaire (GO‐QoL) by at least 6 points when compared to baseline.
NOSPECS score and adverse events related to either treatment were also documented. Most outcomes were recorded at 6 months and 12 months follow‐up. Residual disease severity and requirement for further treatment were evaluated at 18 months.
For Stan 2015, the primary endpoint of interest was CAS reduction assessed as a continuum and separately as an improvement by 2 or more points.
The secondary endpoints were as follows.
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Success rate (defined as a decrease in CAS by 2 or more points and no additional therapy)
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Change in lid fissure width
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Change in lagophthalmos
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Change in proptosis
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Change in orbital fat and/or muscle volume by CT
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Change in subjective diplopia score according to the Gorman scale
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Change in quality of life according to the Physical and Mental Component Summary scores of the Medical Outcomes Study 12‐Item Short Form Health Survey (SF‐12).
Additionally, NOSPECS scores and adverse reactions were recorded. The outcome measurements were documented at 6 months and 18 months follow‐up.
Excluded studies
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 (n = 8) overall looking at rituximab in TAO, these studies are detailed in Characteristics of excluded studies. The additional tables Table 1, Table 2, Table 3, and Table 4 describe the excluded studies which are non‐randomised controlled trials, non‐randomised case series, case reports, and a meta‐analysis, respectively.
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| Study name | B lymphocyte depletion with the monoclonal antibody rituximab in Graves’ disease: a controlled pilot study
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| Participants | People with newly diagnosed or relapsed untreated Grave's disease RTX group: 10 participants. Control group: 10 participants 18 women, 2 men Age range: 18 to 65 years No participants had received immunosuppressants. Consecutive eligible people offered RTX and control participants were those who declined
Only 2 participants in RTX group and no participants in control group had active TAO: Participant 1: woman, aged 64, ex‐smoker; CAS 6 Participant 2: woman, aged 35, ex‐smoker; CAS 4/5 (right/left)
Follow‐up: RTX group: 740 (435 to 904) days Control group: 554 (99 to 741) days |
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| Interventions | All participants rendered euthyroid with methimazole for 4 months RTX group: RTX IV infusion 375 mg per m2 body surface area on day 1, 8, 15 and 22 Pretreatment with 1 g oral acetaminophen, 2 mg IV clemastine Control group: no further treatment |
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| Outcome measures | Time to relapse of hyperthyroidism Changes in autoantibody level |
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| Results | 4 patients in RTX group remained in remission with median follow‐up 705 days All participants in control group relapsed by 393 days (P < 0.05) All participants in remission had initial TRAb levels below 5 IU/litre None of 5 participants in control group with corresponding low TRAb levels stayed in remission (P < 0.01)
2 participants in RTX group with active TAO: Participant 1: CAS reduced from 6 to 2 in 8 months; proptosis reduced from 25 mm to 22 mm bilaterally. Participant 2: CAS 4/5 (right/left) reduced to 2/3 at 5 weeks, 2/4 at 5 months and 1/1 at 11 months; proptosis changed from 23 mm bilaterally to 21 mm/23 mm (right/left). Both participants improved in soft tissue changes and eye motility.
Adverse effects: After first infusion only: hypotension (n = 4), nausea (n = 2), fever (n = 1), chills (n = 1), and tachycardia (n = 1) 2 participants had slight pain in the finger joints 1 participant developed ulcerative colitis |
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| Study name | Treatment of Graves’ disease and associated ophthalmopathy with the anti‐CD20 monoclonal antibody rituximab: an open study | |
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| Participants | People with Grave's disease and TAO RTX group: 9 participants 7 women, 2 men Age range: 31 to 51 years. 5 smokers, 2 ex‐smokers, 2 non‐smokers 2 participants mild signs; 6 moderate; 1 severe Steroid group: 20 participants 17 women, 3 men Age range: 30 to 82 years 12 smokers, 4 ex‐smokers, 4 non‐smokers 3 participants mild TAO, 13 moderate, 4 severe |
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| Interventions | RTX group: RTX IV infusion 1000 mg over 4 hours 15 minutes, twice with a 2‐week interval. 1 g oral paracetamol and 10 mg oral chlorpheniramine administered prior to RTX treatment. 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 participant 5 months, 8 participants 12 months or more Steroid group: 12 months |
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| Outcome measures | Change in CAS Change in NOSPECSa score Thyroid function Lymphocyte count |
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| Results | RTX group: All participants had peripheral B‐cell depletion with first infusion. Depletion lasted 4 months in 3 participants, 5 months in 5 participants, and 1 still depleted at 5 months. Thyroid function not affected Change in TgAb, TPOAb and TRAb not significant and not correlated to CD20+ lymphocyte depletion Mean CAS before 4.7 (SD 0.5), reduced to 1.8 (SD 0.8) at 30 weeks (P < 0.0001) Proptosis (NOSPECSa class 3) reduced significantly in participants with active TAO, from 22.4 (SD0.5) to 20.9 (SD0.6) (P < 0.0001) and in Graves' disease with lid signs, from 19.0 (SD 0.7) to 17.3 (SD0.9) (P < 0.003) at 30 weeks Soft tissue inflammation (NOSEPCSa 2) decreased significantly (P < 0.001) Degree of motility impairment (NOSPECSa 4) reduced (P < 0.05) No relapse at time of B cell return and in subsequent 5 to 7 months of follow up One participant 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 16.3 (SD 4.9) U/L before and 9.3 (SD 3.6) U/L after (non‐significant). No difference compared to RTX at 30 weeks. Mean CAS 4.1 (SD 0.03) before and 2.0 (SD0.4) at 30 weeks (P < 0.0001) Significantly more change in CAS with RTX than with IVGC (P < 0.05) Mean proptosis reduced from 22.6 (SD 0.6) to 22.1 (SD 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 participants did not respond to IVGC and one underwent acute orbital decompression for optic neuropathy 2 participants also had relapse of TAO 6 to 8 weeks after IVGC withdrawal
Adverse effects: RTX: minor side effects in 3 participants with first infusion (nose and throat itching, mild temperature elevation) Steroids: adverse effects more frequent (9 participants) and of greater clinical significance (flushing, insomnia, dyspepsia, hyperglycaemia, serum aminotransferases or GGT increase) |
| CAS: clinical activity score; GGT: gamma‐glutamyl transferase; IV: intravenous; IVGC: intravenous glucocorticoids; RTX: rituximab; SD: standard deviation; TAO: thyroid‐associated ophthalmopathy; TgAb: thyroglobulin antibodies; TPOAb: thyroid peroxidase antibodies; TRAb: thyrotropin receptor autoantibodies | ||
aThe 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.
| Study name | Rituximab in relapsing Graves’ disease, a phase II study |
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| Participants | 13 people with relapsing Graves' disease 9 women, 4 men Mean age: 39.5 (SD 9.5) years Previously adequately treated with at least 1 year antithyroid medications Median CAS was 0 (range 0 to 2) 3 participants had NOSPECSa 2a3040
Follow up: 26 weeks |
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| Interventions | RTX IV infusion 1000 mg, twice with a 2‐week interval. Pre‐medication 10 mg IV dexamethasone plus 2 mg IV clemastine |
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| Outcome measures | Absence of hyperthyroidism Relapse free survival time |
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| Results | All participants had decrease in C19 and MS4A1 (lymphocyte populations) 4 participants no response Other 9 participants: FT4 decreased at 16 weeks (P = 0.001) and TSH increased (P = 0.011) At follow‐up 14 to 27 months, 9 participants still euthyroid with normal FT4 (P < 0.001) and TSH (P = 0.008)
Adverse effects: 2 participants had temporary joint pains |
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| Study name | Rituximab treatment of patients with severe, corticosteroid‐resistant thyroid‐associated ophthalmopathy |
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| Participants | 6 people with severe progressive TAO unresponsive to steroids 4 women, 2 men Mean age: 54.3 (SD 9.1) years 3 current smokers
Follow‐up: 12 weeks |
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| Interventions | RTX IV infusion 1000 mg, twice with a 2‐week interval Pre‐medication 100 mg IVMP, 1 g oral acetaminophen plus 50 mg oral diphenhydramine |
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| Outcome measures | Change in CAS Change in proptosis Change in strabismus Side effects Quantification of regulatory T cells |
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| Results | Mean CAS improved from 5.5 (SD 0.8) to 1.3 (SD 0.5 )at 2 months after treatment (P < 0.03) CAS remained quiescent in all participants (0.7 (SD 0.8); P < 0.0001) at mean follow‐up of 6.2 (SD 4.5) months Vision improved bilaterally in all 4 participants with dysthyroid optic neuropathy (DON) None of the 6 participants experienced disease relapse after RTX infusion Mean proptosis by Hertel measurement remained stable (24 (SD 3.7) mm before therapy and 23.6 (SD 3.7) mm after therapy (P = 0.17)) 1 participant experienced progressive strabismus after RTX treatment No participants had improvement in extraocular motility The abundance of T regulatory cells, assessed in 1 participant 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 participant had cardiac arrest and died 3 months after treatment. |
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| Study name | Rituximab for thyroid eye disease |
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| Participants | 12 people with active TAO (CAS of ≥ 4) 7 women, 5 men Age range: 34 to 80 years 4 smokers 4 participants had never previously been treated with steroids
Follow‐up: 52 weeks |
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| Intervention | RTX IV infusion 1000 mg, twice with a 2‐week interval Pre‐medication 1 g oral acetaminophen plus 50 mg oral diphenhydramine Note: 2 participants were still on oral glucocorticoids during the study |
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| 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 |
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| Results | Mean CAS improved from 5.5 (SD 1.2) to 0.8 (SD 1.4) at 52 weeks after treatment (P < 0.001) Mean TAOS improved from 10.4 (SD 5.7) to 2.4 (SD 4.6) at 52 weeks (P < 0.001) No change in TSH or TSI levels before and after treatment
Adverse effects: none |
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| Study name | The effect of B cell depletion therapy on anti‐TSH receptor antibodies and clinical outcome in glucocorticoid refractory Graves’ orbitopathy |
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| Participants | 9 people with steroid‐refractory TAO 8 women, 1 man Median age: 62 years (range 37 to 87) All participants had pulsed IVMP for a median of 3 months prior to RTX treatment (range 2 weeks to 6 months) 8/9 participants had CAS greater than 4/10 (median 6.5, range 4 to 8). 1 participant had CAS 1. 4 participants had sight‐threatening TAO (NOSPECSa 6)
Follow‐up: 16 months or more (median 29 months, range 16 to 46 months) |
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| Intervention | RTX infusion 1000 mg, twice with a 2‐week interval (3 participants), or 500 mg, twice with a 2‐week interval (6 participants) One participant not B cell depleted after second 500 mg infusion so received third 500 mg infusion Premedication 500 mg IVMP, 10 mg IV chlorpheniramine and 1 g oral paracetamol |
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| Outcome measures | Thyroid function tests B cell count Thyroid autoantibody levels Change in CAS |
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| Results | No effect on TFTs TBII reduced in all participants CAS improved in all participants 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 participants had minor side effects following first infusion: 2 headache, 1 headache and chills without pyrexia, 1 mild myalgia |
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| Study name | Efficacy of rituximab in patients with Graves' orbitopathy: a retrospective multicenter nationwide study |
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| Participants | 32 people with moderate to severe TAO who are corticosteroid resistant or corticosteroid dependent 21 women, 11 men Mean age: 51.2 (SD 10.7) years |
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| Interventions | All participants received 2 IV injections of 1 g of RTX 2 weeks apart, with oral paracetamol (1 g), oral antihistamine treatment, and IV glucocorticoid (1 mg/kg) |
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| Outcome measures | Improvement in at least 1 of the 3 dysfunctional parameters (inflammatory, oculomotor, and visual) without deterioration of the other(s) |
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| Results | The proportion of participants presenting signs of inflammatory activity (CAS ≥ 3) significantly diminished (74% before treatment, 45% at 12 weeks (P < 0.05), 29% at 24 weeks (P < 0.001)). The proportion of participants with visual dysfunction significantly diminished (39% before treatment, 19% at 12 weeks, then 16% at 24 weeks (P < 0.05)). 1 case had improvement in oculomotor dysfunction. Mean CAS significantly decreased after treatment, from 3.29 (SD 1.16) at week 0 to 1.59 (SD 1.12) at week 24 (P < 0.001).
Adverse effect: 1 participant had a cytokine release syndrome |
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| Study name | Low‐dose rituximab for active moderate to severe graves' orbitopathy resistant to conventional treatment |
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| Participants | 15 people with active moderate to severe TAO who were resistant to conventional treatment (IVMP, oral corticosteroids and orbital radiotherapy). 11 women, 4 men Age: 46 years (range 29 to 58) |
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| Interventions | Low‐dose RTX infusions (100 mg) |
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| Outcome measures | CAS decreased by 2 points or < 4/10, at 3 to 4 months after the first infusion of RTX Proptosis Lid fissure width Eye motility |
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| Results | 15 participants received 100 mg RTX doses (cumulative dose 100 to 400 mg) Mean CAS decreased from 4.6 (SD 0.89) to 2.0 (SD 1.65) at 17.1 weeks, after a mean of 2.3 infusions (range 1 to 4) of 100 mg RTX. Mean CAS was 1.3 (SD 1.76) at last visit at 63.6 weeks (range 44.3 to 87.5). RTX was effective in 13 participants, within 2 months of treatment initiation. In all responders except 1, TAO remained inactive after 1 year of follow‐up. RTX was ineffective in 2 participants, according to unchanged CAS after 2 infusions. All participants were euthyroid at the time of RTX treatment. Mean duration between the end of IVMP and RTX treatments was 16 months. Mean duration between the end of orbital radiotherapy and RTX treatments was 15 months. RTX was not clinically significant on proptosis, lid fissure width, and eye motility. |
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| Study name | Early low‐dose rituximab for active thyroid eye disease: An effective and well‐tolerated treatment. |
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| Participants | 12 people with active TAO (VISA (vision, inflammation, strabismus, appearance) CAS ≥ 3) 8 women, 4 men Age: 49 years (range 24 to 79) |
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| Interventions | Low‐dose RTX infusion (100 mg). If clinically indicated, further doses of 500 mg IVMP were administered weekly. Depending on disease activity and severity, a steroid‐sparing agent was started (1st line methotrexate, 2nd line cyclosporin) |
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| Outcome measures | CAS VISA overall severity score OX‐TED (Oxford‐Thyroid Eye Disease) QoL scores TSH receptor antibodies B cell subsets |
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| Results | Mean CAS was significantly reduced at the initial follow‐up between 1 and 3 months (from 5.08 to 3.5, P < 0.05) Mean CAS at last follow‐up was 1.58 (P < 0.001) CAS was not initially reduced in 4 participants. Mean VISA severity score decreased significantly (from 12 to 6, P < 0.001). Average quality of life score was reduced post treatment (from 45/70 to 37/70) at an average of 6 months follow‐up. Thyrotropin receptors were reduced in all participants post treatment but not significantly. 8 participants were checked for B cell subsets pre‐ and post‐ treatment, and all showed depletion of CD19 post RTX treatment (0.26 X 109/L to 0.04 X 109/L, P < 0.001)
Adverse effects: No serious adverse events were noted. 4 patients had minor infusion‐related rashes that resolved with 10 mg IV chlorphenamine. |
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| Study name | Efficacy profile and safety implications of very low dose rituximab in patients with Graves' orbitopathy |
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| Participants | 17 people with active moderate to severe TAO (9 people were unresponsive to IVMP, 8 people were newly diagnosed with TAO). 14 women, 3 men Mean age: 51.5 (SD 11.6) years (range 28 to 72) |
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| Interventions | A single RTX infusion of 100 mg over 1 hour and 15 minutes. Oral paracetamol (1 g), chlorphenamine (10 mg) and IV hydrocortisone (100 mg) were given 1 hour prior to RTX infusion |
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| Outcome measures | Participants were assessed at baseline and at 4, 8, 12, 16, 24, 32, 40, and 76 weeks post treatment: Decrease of 2 or more points in CAS Prevalence and time of disease inactivation (number of patients with CAS < 3) Composite ophthalmic score for severity at 24 weeks TSH receptor antibodies Long‐term surgical treatment Quality of life |
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| Results | Mean baseline CAS was 4.56 (SD 0.96), decreasing to 1.25 (SD 1.14) at 24 weeks (P = 0.001). 13 participants (86.6%) had inactive TAO at 12 weeks (CAS < 3) Participants with longer disease duration responded to RTX as well as those with short duration. After 4 weeks, the responses of the long disease duration group were overall better (P < 0.0001). Composite ophthalmic score for severity at 24 weeks improved in 58.3% of participants. All participants had peripheral depletion of CD20+ and CD19+ cells at the end of RTX infusion (60 minutes). A decrease of TSH receptor antibodies was observed at 12 weeks (P = 0.14), and a significant decrease was observed at 24 weeks (P = 0.015). 2 participants required orbital decompression.
Adverse events: 1 participant had urticaria which resolved with low dose steroids. 1 participant had cytokine release syndrome. |
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| CAS: clinical activity score; FT4: free thyroxine; IV: intravenous; IVMP: intravenous methylprednisolone; QoL: quality of life; RTX: rituximab; SD: standard deviation; TAO: thyroid‐associated ophthalmopathy; TBII: thyrotropin receptor binding inhibitory immunoglobulin; TFTs: thyroid function tests; TSH: thyroid‐stimulating hormone; TSI: thyroid‐stimulating immunoglobulin |
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aThe 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.
| Study name | Failure of rituximab treatment in a case of severe thyroid ophthalmopathy unresponsive to steroids | |
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| Summary | Case unilateral severe TAO (Grave's disease then euthyroid after treatment). TRAb high. TgAb and TPOAb 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. |
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| Study name | Small dose of rituximab for Graves orbitopathy: new insights into the mechanism of action | |
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| Summary | 3 patients treated with one‐off low dose RTX infusion 100 mg
Patient 1: woman age 43 years, CAS 5/10. At day 1, CAS decreased to 1/10 and proptosis reduced from 24.5 to 23 mm in the right eye and 31 to 28 mm in the left eye.
Patient 2: woman age 67 years, CAS 6/10. Vision improved within 3 hours from counting fingers to 10/10. At week 1, CAS decreased to 3 and proptosis from 27.5 to 26 mm in the right eye and 29.5 to 27 mm in the left eye.
Patient 3: woman 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 |
| CAS: clinical activity score; RTX: rituximab; TAO: thyroid‐associated ophthalmopathy; TgAb: thyroglobulin antibodies; TPOAb: thyroid peroxidase antibodies; TRAb: thyrotropin receptor autoantibodies | ||
| Study name | Meta‐analysis of the efficacy of rituximab in thyroid‐associated ophthalmopathy. |
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| Participants | 6 studies: 2 RCTs and 4 cohort studies |
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| Interventions | Meta‐analysis on RTX clinical studies in moderate to severe thyroid‐associated ophthalmopathy |
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| Outcome measures | CAS before and after RTX treatment |
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| Results | CAS reduced significantly (SMD ‐5.04, 95% CI ‐7.08 to ‐3.01; P < 0.00001) |
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| CAS: clinical activity score; CI: confidence interval; RCT: randomised controlled trial; RTX: rituximab; SMD: standard mean difference |
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Risk of bias in included studies
Overall, the risk of bias was considered low across all domains except for the bias introduced by the early termination of both studies. The allocation concealment was not clearly described in the study by Salvi 2015. See Figure 2 for the summary of the risk of bias assessment.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Both included studies performed block randomisation to allocate treatment (low risk). The allocation concealment was adequate (low risk) for Stan 2015 but was not clearly described in Salvi 2015.
Blinding
Both participants and ophthalmologists were masked in both studies (low risk). Regarding masking of outcome assessments, we considered the risk of bias to be low in both studies.
Incomplete outcome data
The attrition rate was broadly equal between the two treatment arms for both studies, and all pre‐specified outcomes were reported (low risk).
Selective reporting
All pre‐specified outcomes were reported in both studies (low risk).
Other potential sources of bias
Neither study achieved the target sample size. Salvi 2015 was terminated early based on the evidence of frequent disease reactivation in the IVMP arm. Furthermore, Salvi 2015 amended the rituximab infusion protocol after the first 12 participants. In Stan 2015, the study was concluded before reaching full enrolment due to recruitment difficulties.
Effects of interventions
See: Summary of findings 1 Summary of findings table ‐ Rituximab compared to intravenous methylprednisolone for thyroid‐associated ophthalmopathy; Summary of findings 2 Summary of findings table ‐ Rituximab compared to placebo for thyroid‐associated ophthalmopathy
Rituximab compared to intravenous methylprednisolone
See: summary of findings Table 1 and Table 5
| Outcomea | Study | RTX | IVMP | RR (95% CI) | ||
|---|---|---|---|---|---|---|
| n | N | n | N | |||
| CAS improvement (decrease) by 2 or more points | 15 | 15 | 12 | 16 | 1.32 (0.98 to 1.78) | |
| NOSPECSb improvement (decrease) by 2 or more classes | 3 | 15 | 3 | 16 | 1.07 (0.25 to 4.49) | |
| Proptosis improvement (decrease) by 2 mm or more | 0 | 15 | 1 | 16 | 0.35 (0.02 to 8.08) | |
| Palpebral aperture improvement (decrease) by 3 mm or more | 2 | 15 | 0 | 16 | 5.31 (0.28 to 102.38) | |
| Motility improvement (increase) by 1 class or more | 3 | 15 | 3 | 16 | 1.07 (0.25 to 4.49) | |
| Quality of life: improvement on GO‐QoL scale by at least 6 points for "appearance" | 9 | 14 | 6 | 13 | 1.39 (0.69 to 2.82) | |
| Quality of life: improvement on GO‐QoL scale by at least 6 points for "functioning" | 5 | 14 | 8 | 13 | 0.58 (0.25 to 1.32) | |
| Adverse events | 13 | 15 | 10 | 16 | 1.39 (0.90 to 2.13) | |
| CAS: clinical activity score; CI: confidence interval;GO‐QoL: Graves' ophthalmopathy quality of life; IVMP: intravenous methylprednisolone; n: number of events; N: number of participants; RR: risk ratio; RTX: rituximab | ||||||
aAll outcomes measured at 24 weeks apart from adverse events at any time period
bThe 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.
Primary outcomes
CAS
CAS improvement (decrease) by 2 or more points was assessed at 24 weeks. Salvi 2015 found that rituximab may result in an improvement in CAS compared with IVMP (RR 1.32, 95% CI 0.98 to 1.78). Using the GRADE approach, we downgraded the certainty of the evidence by two levels to low (one level for serious risk of bias as the study was stopped early, and one level for imprecision because we noted a wide confidence interval that includes no effect).
Secondary outcomes
NOSPECS
NOSPECS improvement (decrease) by 2 or more classes was assessed at 24 weeks. Salvi 2015 showed that rituximab may have little or no effect on NOSPECS (RR 1.07, 95% CI 0.25 to 4.49). We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision because it is a small study with few events and the confidence interval is very wide, including no effect).
Proptosis
Proptosis improvement (decrease) by 2 mm or more was assessed at 24 weeks. The evidence of Salvi 2015 on the effect of rituximab on proptosis is inconclusive (RR 0.35, 95% CI 0.02 to 8.08). We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision because it is a small study with few events and the confidence interval is very wide, including no effect).
Palpebral aperture
Palpebral aperture improvement (decrease) by 3 mm or more was assessed at 24 weeks. The evidence on the effect of rituximab on palpebral aperture in Salvi 2015 is inconclusive (RR 5.31, 95% CI 0.28 to 102.38). We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision because it is a small study with few events and the confidence interval is very wide, including no effect).
Motility
Salvi 2015 assessed the motility outcome as an improvement (increase) by 1 class or more at 24 weeks. The evidence on the effect of rituximab on motility measured by the Gorman scale is inconclusive (RR 1.07, 95% CI 0.25 to 4.49). We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision because it is a small study with few events and the confidence interval is very wide, including no effect).
Quality of life
Salvi 2015 used the GO‐QoL to assess quality of life at 24 weeks. The evidence on the effect of rituximab on quality of life is inconclusive. The risk ratio for improvement by at least 6 points was 0.58 (95% CI 0.25 to 1.32) for "functioning" and 1.39 (95% CI 0.69 to 2.82) for "appearance". We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, one level for imprecision as it is a small study with wide confidence intervals including no effect, and one level for inconsistency as effects on quality of life are inconsistent in two domains assessed).
Adverse events
The risk ratio for adverse events in Salvi 2015 was 1.39 with a 95% CI of 0.90 to 2.13. In the rituximab group, two participants experienced a major infusion reaction, likely cytokine release syndrome. Minor adverse effects were observed in most rituximab participants at the first infusion. In the IVMP group, three participants experienced deranged liver function tests. Minor side effects were observed in seven IVMP participants and these included dyspepsia, hypotension, insomnia, and mild mood disorders. We downgraded the certainty of the evidence by two levels to low (one level for serious risk of bias as the study was stopped early, and one level for imprecision as it is a small study and the confidence interval is wide, including no effect).
Rituximab compared to placebo
See summary of findings Table 2 and Table 6
| Outcomea | Study | RTX | Placebo | RR (95% CI) | ||
|---|---|---|---|---|---|---|
| n | N | n | N | |||
| CAS improvement (decrease) by 2 or more points | 4 | 13 | 3 | 12 | 1.23 (0.34 to 4.40) | |
| NOSPECSb improvement (decrease) by 2 or more classes | 2 | 13 | 2 | 12 | 0.92 (0.15 to 5.56) | |
| Proptosis improvement (decrease) by 2 mm or more | 2 | 13 | 4 | 12 | 0.46 (0.10 to 2.08) | |
| Adverse effects | 8 | 13 | 3 | 12 | 2.46 (0.84 to 7.18) | |
| CAS: clinical activity score; CI: confidence interval; n: number of events; N: number of participants; RR: risk ratio; RTX: rituximab | ||||||
aAll outcomes measured at 24 weeks apart from adverse events at any time period
bThe 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.
Primary outcomes
CAS
Improvement (decrease) in CAS by 2 or more points was assessed at 24 weeks. The evidence on the effect of rituximab on CAS compared to placebo is inconclusive (RR 1.23, 95% CI 0.34 to 4.40). We downgraded the certainty of the evidence by thee levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision as it is a small study and the confidence interval is very wide, including no effect).
Secondary outcomes
NOSPECS
NOSPECS improvement (decrease) by 2 or more classes was assessed at 24 weeks. Stan 2015 demonstrated that rituximab may have little to no effect on NOSPECS (RR 0.92, 95% CI 0.15 to 5.56). We downgraded the certainty of the evidence to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision as it is a small study and the confidence interval is very wide, including no effect).
Proptosis
Proptosis improvement (decrease) by 2 mm or more was assessed at 24 weeks. Stan 2015 demonstrated that rituximab may not result in improvement in proptosis (RR 0.46, 95% CI 0.10 to 2.08). We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision as it is a small study and the confidence interval is very wide, including no effect).
Palpebral aperture
Stan 2015 showed that rituximab may have little to no effect on palpebral aperture at 24 weeks. The median change in right eye palpebral aperture at 24 weeks was 0 mm (IQR ‐1 to 1) in the 13 people who received rituximab versus ‐0.5 mm (IQR ‐1 to 1.75) in the 12 people who received placebo. The median change in left eye palpebral aperture was 0 mm (IQR ‐1.5 to 1) in the rituximab group versus 0.5 mm (IQR ‐1 to 1.75) in the placebo group. We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, one level for inconsistency as there were different findings in the right and left eye, and one level for imprecision as it is a small study).
Motility
Stan 2015 produced inconclusive evidence on the effect of rituximab on motility. The median diplopia score in the rituximab group was 3 (IQR 2 to 3.5) compared with 2.5 (IQR 0 to 4) in the placebo group. We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision because it was a small study (fewer than 30 participants) and we were unable to calculate the effect estimate and its precision).
Quality of life
Stan 2015 used SF‐12 physical and mental scores to assess quality of life at 24 weeks, producing inconclusive results. The median score for the physical component was 45.9 (IQR 43.6 to 50.8) in the 13 participants who received rituximab versus 40.3 (IQR 38.5 to 52.1) in the 12 participants who received placebo; and the median score for the mental component was 52.8 (IQR 36.1 to 56.7) in the rituximab group versus 46.1 (IQR 35.4 to 57.4) in the placebo group. We downgraded the certainty of the evidence by three levels to very low certainty (one level for serious risk of bias as the study was stopped early, and two levels for imprecision as it is a small study (fewer than 30 participants) and we were unable to calculate the effect estimate and its precision).
Adverse events
Stan 2015 demonstrated that rituximab may increase adverse effects (RR 2.46, 95% CI 0.84 to 7.18). Three and eight participants experienced adverse effects in the placebo group and the rituximab group, respectively. We downgraded the certainty of the evidence by three levels to very low (one level for serious risk of bias as the study was stopped early, and two levels for imprecision as it is a small study and the confidence interval is very wide, including no effect).
Discussion
Summary of main results
This Cochrane review summarises the key findings from two RCTs meeting the inclusion criteria to assess the efficacy of rituximab. Given the differences in comparator groups (placebo for one study and intravenous steroids for the other), a meta‐analysis was not possible. The two studies included 56 adults with active TAO. We found low‐certainty evidence that rituximab may result in an improvement in CAS compared with IVMP, and very low‐certainty evidence that rituximab may improve or have little to no effect on CAS when compared with placebo. The certainty of evidence was downgraded due to the early termination of the study, the small number of participants and the wide confidence intervals. There was either low‐ or very low‐certainty evidence that rituximab has any effect on secondary outcomes including NOSPECS, proptosis, palpebral aperture, motility and quality of life when compared to either IVMP or placebo. There was low‐certainty and very low‐certainty evidence that rituximab may increase the adverse effects compared to IVMP and placebo, respectively.
The first authors of the two RCTs of RTX in TAO conducted a post‐hoc analysis of their studies (Stan 2017). They concluded that the study participant characteristics differed between the two studies, as the people included in the Italian study were younger, with lower TRAb and shorter disease (favourable factors for better response), although more of them were smokers (associated with poorer response). A severity outcome was reassessed by calculating a composite ophthalmic score proposed by EUGOGO (Bartalena 2012) to quantify the change of severity of the disease after therapy. There was an improvement in disease severity in 60% of participants after RTX compared to 37.5% after steroids (Stan 2017). In addition, the post‐hoc data demonstrated that the long‐term disease relapse rate following treatment with RTX was low. They concluded that RTX might be considered as a second‐line treatment in people with early active moderate to severe TAO that is unresponsive to the initial therapy.
There is one ongoing study that is likely to meet inclusion criteria once published. EUCTR2011‐000899‐33‐SE is a phase 2/3 randomised open trial of rituximab+methotrexate versus oral steroids+methotrexate in 50 people with moderate to severe TAO (CAS ≥ 4) who have relapsed six weeks after responding to a 12‐week course of weekly intravenous steroid infusions. Participants must have been euthyroid for at least six weeks prior to starting treatment with intravenous steroids. The primary outcome measure is improvement in CAS by 2 or more points. However, this study is unlikely to be directly comparable to the two published RCTs due to concomitant methotrexate therapy in the trial protocol.
Overall completeness and applicability of evidence
Evidence was limited to two studies with few participants. No meta‐analysis was possible as there was only one study comparing rituximab with IVMP and another with placebo.
The study populations were different in the two studies. The study by Salvi 2015 enrolled younger, predominantly female patients with shorter disease duration and lower pre‐treatment TRAb levels, which could have influenced the treatment response.
Quality of the evidence
We used the GRADE approach to assess the quality of evidence for this review. The evidence was either low or very low certainty for all outcomes measured for both comparisons. Reasons for downgrading the certainty of the evidence were the early termination of both studies, which increases risk of bias; the small participant numbers and wide confidence intervals including no effect, which increase imprecision; and the inconsistency of reported results for the right and left eyes.
Potential biases in the review process
We conducted a thorough search and two review authors assessed study eligibility and risk of bias of the included studies to minimise potential biases in the review process.
Agreements and disagreements with other studies or reviews
We found no systematic reviews that investigated the efficacy of rituximab in TAO in RCTs. Ostrowski 2015 found variable results with regard to the value of rituximab as a treatment for TAO. Wang 2018 conducted a systematic review and included 11 studies, finding a decline in CAS at 1, 3, 6, and 12 months after rituximab treatment. However, the authors noted that a large, high‐quality study is required.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
| Rituximab compared to intravenous methylprednisolone for thyroid‐associated ophthalmopathy | ||||||
| Patient or population: thyroid‐associated ophthalmopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with intravenous methylprednisolone | Risk with rituximab | |||||
| CAS improvement (decrease) by 2 or more points | 750 per 1000 | 990 per 1000 | RR 1.32 | 31 | ⊕⊕⊝⊝ | |
| NOSPECS improvement (decrease) by 2 or more classes | 188 per 1000 | 201 per 1000 | RR 1.07 | 31 | ⊕⊝⊝⊝ | |
| Proptosis improvement (decrease) by 2 mm or more | 63 per 1000 | 22 per 1000 | RR 0.35 | 31 | ⊕⊝⊝⊝ | |
| Palpebral aperture improvement (decrease) by 3 mm or more | Moderate | RR 5.31 | 31 | ⊕⊝⊝⊝ | ||
| 10 per 1000 | 53 per 1000 | |||||
| Motility improvement (increase) by 1 class or more | 188 per 1000 | 201 per 1000 | RR 1.07 | 31 | ⊕⊝⊝⊝ | |
| Quality of life improvement by at least 6 points | Improvement on GO‐QoL Scale by at least 6 points for "functioning": RR at 24 weeks 0.58 (95% CI 0.25 to 1.32)Improvement on GO‐QoL Scale by at least 6 points for "appearance": RR at 24 weeks 1.39 (95% CI 0.69 to 2.82) | 27 | ⊕⊝⊝⊝ | |||
| Adverse events | 625 per 1000 | 869 per 1000 | RR 1.39 | 31 | ⊕⊕⊝⊝ | In the rituximab group, 2 participants experienced a major infusion reaction, likely cytokine release syndrome. Minor adverse effects (mild infusion reactions) were observed in most rituximab patients at first infusion. In IVMP group, 3 participants experienced deranged liver function test. Minor side effects observed in 7 IVMP participants were dyspepsia, hypotension, insomnia, and mild mood disorders, which did not require specific treatment. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_424436778554984307. | ||||||
| a CAS: clinical activity score; GO‐QoL: Graves’ ophthalmopathy quality of life questionnaire; NOSPECS: scoring system based on no symptoms or signs, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, and sight loss; RCT: randomised clinical trial; SF‐12: Medical Outcomes Study 12‐Item Short Form Health Survey. | ||||||
| Rituximab compared to placebo for thyroid‐associated ophthalmopathy | ||||||
| Patient or population: thyroid‐associated ophthalmopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with Rituximab | |||||
| CAS improvement (decrease) by 2 or more points | 250 per 1000 | 308 per 1000 | RR 1.23 | 25 | ⊕⊝⊝⊝ | |
| NOSPECS improvement (decrease) by 2 classes or more | 167 per 1000 | 153 per 1000 | RR 0.92 | 25 | ⊕⊝⊝⊝ | |
| Proptosis improvement (decrease) by 2 mm or more | 333 per 1000 | 153 per 1000 | RR 0.46 | 25 | ⊕⊝⊝⊝ | |
| Palpebral aperture change | Median change in palpebral aperture in the right eye was 0 mm (IQR ‐1 to 1) in the 13 rituximab group participants and ‐0.5 mm (IQR ‐1 to 1.75) in the 12 placebo participants. Median change in the palpebral aperture in the left eye was 0 mm (IQR ‐1.5 to 1) in the rituximab group and 0.5 mm (IQR ‐1 to 1.75) in the placebo group. | 25 | ⊕⊝⊝⊝ | |||
| Motility | The median diplopia score in the 13 rituximab participants was 3 (IQR 2 to 3.5) compared to 2.5 (IQR 0 to 4) in the 12 placebo participants. | 25 | ⊕⊝⊝⊝ | |||
| Quality of Life | SF‐12 physical: the median score was 45.9 (IQR 43.6 to 50.8) in the 13 rituximab participants and 40.3 (IQR 38.5 to 52.1) in the 12 placebo participants. SF‐12 mental: the median score was 52.8 (IQR 36.1 to 56.7) in the rituximab group and 46.1 (IQR 35.4 to 57.4) in the placebo group. | 25 | ⊕⊝⊝⊝ | |||
| Adverse effects | 250 per 1000 | 615 per 1000 | RR 2.46 | 25 | ⊕⊝⊝⊝ | There were four adverse events in 3 out of 12 placebo patients (1 moderate/severe) and 11 adverse events in 8 out of 13 rituximab‐treated patients (5 moderate/severe). Moderate/severe adverse effects included infections (bronchitis, conjunctivitis), vasculitis, optic neuropathy and gastrointestinal adverse effects including tongue pain, abdominal pain and diarrhoea. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_424437036185390139. | ||||||
| a CAS: clinical activity score; IQR: interquartile range; GO‐QoL: Graves’ ophthalmopathy quality of life questionnaire; NOSPECS: scoring system based on no symptoms or signs, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, and sight loss; RCT: randomised clinical trial; SF‐12: Medical Outcomes Study 12‐Item Short Form Health Survey. | ||||||
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| Study name | B lymphocyte depletion with the monoclonal antibody rituximab in Graves’ disease: a controlled pilot study
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| Participants | People with newly diagnosed or relapsed untreated Grave's disease RTX group: 10 participants. Control group: 10 participants 18 women, 2 men Age range: 18 to 65 years No participants had received immunosuppressants. Consecutive eligible people offered RTX and control participants were those who declined
Only 2 participants in RTX group and no participants in control group had active TAO: Participant 1: woman, aged 64, ex‐smoker; CAS 6 Participant 2: woman, aged 35, ex‐smoker; CAS 4/5 (right/left)
Follow‐up: RTX group: 740 (435 to 904) days Control group: 554 (99 to 741) days |
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| Interventions | All participants rendered euthyroid with methimazole for 4 months RTX group: RTX IV infusion 375 mg per m2 body surface area on day 1, 8, 15 and 22 Pretreatment with 1 g oral acetaminophen, 2 mg IV clemastine Control group: no further treatment |
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| Outcome measures | Time to relapse of hyperthyroidism Changes in autoantibody level |
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| Results | 4 patients in RTX group remained in remission with median follow‐up 705 days All participants in control group relapsed by 393 days (P < 0.05) All participants in remission had initial TRAb levels below 5 IU/litre None of 5 participants in control group with corresponding low TRAb levels stayed in remission (P < 0.01)
2 participants in RTX group with active TAO: Participant 1: CAS reduced from 6 to 2 in 8 months; proptosis reduced from 25 mm to 22 mm bilaterally. Participant 2: CAS 4/5 (right/left) reduced to 2/3 at 5 weeks, 2/4 at 5 months and 1/1 at 11 months; proptosis changed from 23 mm bilaterally to 21 mm/23 mm (right/left). Both participants improved in soft tissue changes and eye motility.
Adverse effects: After first infusion only: hypotension (n = 4), nausea (n = 2), fever (n = 1), chills (n = 1), and tachycardia (n = 1) 2 participants had slight pain in the finger joints 1 participant developed ulcerative colitis |
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| Study name | Treatment of Graves’ disease and associated ophthalmopathy with the anti‐CD20 monoclonal antibody rituximab: an open study | |
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| Participants | People with Grave's disease and TAO RTX group: 9 participants 7 women, 2 men Age range: 31 to 51 years. 5 smokers, 2 ex‐smokers, 2 non‐smokers 2 participants mild signs; 6 moderate; 1 severe Steroid group: 20 participants 17 women, 3 men Age range: 30 to 82 years 12 smokers, 4 ex‐smokers, 4 non‐smokers 3 participants mild TAO, 13 moderate, 4 severe |
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| Interventions | RTX group: RTX IV infusion 1000 mg over 4 hours 15 minutes, twice with a 2‐week interval. 1 g oral paracetamol and 10 mg oral chlorpheniramine administered prior to RTX treatment. 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 participant 5 months, 8 participants 12 months or more Steroid group: 12 months |
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| Outcome measures | Change in CAS Change in NOSPECSa score Thyroid function Lymphocyte count |
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| Results | RTX group: All participants had peripheral B‐cell depletion with first infusion. Depletion lasted 4 months in 3 participants, 5 months in 5 participants, and 1 still depleted at 5 months. Thyroid function not affected Change in TgAb, TPOAb and TRAb not significant and not correlated to CD20+ lymphocyte depletion Mean CAS before 4.7 (SD 0.5), reduced to 1.8 (SD 0.8) at 30 weeks (P < 0.0001) Proptosis (NOSPECSa class 3) reduced significantly in participants with active TAO, from 22.4 (SD0.5) to 20.9 (SD0.6) (P < 0.0001) and in Graves' disease with lid signs, from 19.0 (SD 0.7) to 17.3 (SD0.9) (P < 0.003) at 30 weeks Soft tissue inflammation (NOSEPCSa 2) decreased significantly (P < 0.001) Degree of motility impairment (NOSPECSa 4) reduced (P < 0.05) No relapse at time of B cell return and in subsequent 5 to 7 months of follow up One participant 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 16.3 (SD 4.9) U/L before and 9.3 (SD 3.6) U/L after (non‐significant). No difference compared to RTX at 30 weeks. Mean CAS 4.1 (SD 0.03) before and 2.0 (SD0.4) at 30 weeks (P < 0.0001) Significantly more change in CAS with RTX than with IVGC (P < 0.05) Mean proptosis reduced from 22.6 (SD 0.6) to 22.1 (SD 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 participants did not respond to IVGC and one underwent acute orbital decompression for optic neuropathy 2 participants also had relapse of TAO 6 to 8 weeks after IVGC withdrawal
Adverse effects: RTX: minor side effects in 3 participants with first infusion (nose and throat itching, mild temperature elevation) Steroids: adverse effects more frequent (9 participants) and of greater clinical significance (flushing, insomnia, dyspepsia, hyperglycaemia, serum aminotransferases or GGT increase) |
| CAS: clinical activity score; GGT: gamma‐glutamyl transferase; IV: intravenous; IVGC: intravenous glucocorticoids; RTX: rituximab; SD: standard deviation; TAO: thyroid‐associated ophthalmopathy; TgAb: thyroglobulin antibodies; TPOAb: thyroid peroxidase antibodies; TRAb: thyrotropin receptor autoantibodies | ||
| aThe 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. | ||
| Study name | Rituximab in relapsing Graves’ disease, a phase II study |
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| Participants | 13 people with relapsing Graves' disease 9 women, 4 men Mean age: 39.5 (SD 9.5) years Previously adequately treated with at least 1 year antithyroid medications Median CAS was 0 (range 0 to 2) 3 participants had NOSPECSa 2a3040
Follow up: 26 weeks |
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| Interventions | RTX IV infusion 1000 mg, twice with a 2‐week interval. Pre‐medication 10 mg IV dexamethasone plus 2 mg IV clemastine |
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| Outcome measures | Absence of hyperthyroidism Relapse free survival time |
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| Results | All participants had decrease in C19 and MS4A1 (lymphocyte populations) 4 participants no response Other 9 participants: FT4 decreased at 16 weeks (P = 0.001) and TSH increased (P = 0.011) At follow‐up 14 to 27 months, 9 participants still euthyroid with normal FT4 (P < 0.001) and TSH (P = 0.008)
Adverse effects: 2 participants had temporary joint pains |
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| Study name | Rituximab treatment of patients with severe, corticosteroid‐resistant thyroid‐associated ophthalmopathy |
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| Participants | 6 people with severe progressive TAO unresponsive to steroids 4 women, 2 men Mean age: 54.3 (SD 9.1) years 3 current smokers
Follow‐up: 12 weeks |
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| Interventions | RTX IV infusion 1000 mg, twice with a 2‐week interval Pre‐medication 100 mg IVMP, 1 g oral acetaminophen plus 50 mg oral diphenhydramine |
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| Outcome measures | Change in CAS Change in proptosis Change in strabismus Side effects Quantification of regulatory T cells |
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| Results | Mean CAS improved from 5.5 (SD 0.8) to 1.3 (SD 0.5 )at 2 months after treatment (P < 0.03) CAS remained quiescent in all participants (0.7 (SD 0.8); P < 0.0001) at mean follow‐up of 6.2 (SD 4.5) months Vision improved bilaterally in all 4 participants with dysthyroid optic neuropathy (DON) None of the 6 participants experienced disease relapse after RTX infusion Mean proptosis by Hertel measurement remained stable (24 (SD 3.7) mm before therapy and 23.6 (SD 3.7) mm after therapy (P = 0.17)) 1 participant experienced progressive strabismus after RTX treatment No participants had improvement in extraocular motility The abundance of T regulatory cells, assessed in 1 participant 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 participant had cardiac arrest and died 3 months after treatment. |
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| Study name | Rituximab for thyroid eye disease |
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| Participants | 12 people with active TAO (CAS of ≥ 4) 7 women, 5 men Age range: 34 to 80 years 4 smokers 4 participants had never previously been treated with steroids
Follow‐up: 52 weeks |
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| Intervention | RTX IV infusion 1000 mg, twice with a 2‐week interval Pre‐medication 1 g oral acetaminophen plus 50 mg oral diphenhydramine Note: 2 participants were still on oral glucocorticoids during the study |
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| 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 |
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| Results | Mean CAS improved from 5.5 (SD 1.2) to 0.8 (SD 1.4) at 52 weeks after treatment (P < 0.001) Mean TAOS improved from 10.4 (SD 5.7) to 2.4 (SD 4.6) at 52 weeks (P < 0.001) No change in TSH or TSI levels before and after treatment
Adverse effects: none |
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| Study name | The effect of B cell depletion therapy on anti‐TSH receptor antibodies and clinical outcome in glucocorticoid refractory Graves’ orbitopathy |
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| Participants | 9 people with steroid‐refractory TAO 8 women, 1 man Median age: 62 years (range 37 to 87) All participants had pulsed IVMP for a median of 3 months prior to RTX treatment (range 2 weeks to 6 months) 8/9 participants had CAS greater than 4/10 (median 6.5, range 4 to 8). 1 participant had CAS 1. 4 participants had sight‐threatening TAO (NOSPECSa 6)
Follow‐up: 16 months or more (median 29 months, range 16 to 46 months) |
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| Intervention | RTX infusion 1000 mg, twice with a 2‐week interval (3 participants), or 500 mg, twice with a 2‐week interval (6 participants) One participant not B cell depleted after second 500 mg infusion so received third 500 mg infusion Premedication 500 mg IVMP, 10 mg IV chlorpheniramine and 1 g oral paracetamol |
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| Outcome measures | Thyroid function tests B cell count Thyroid autoantibody levels Change in CAS |
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| Results | No effect on TFTs TBII reduced in all participants CAS improved in all participants 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 participants had minor side effects following first infusion: 2 headache, 1 headache and chills without pyrexia, 1 mild myalgia |
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| Study name | Efficacy of rituximab in patients with Graves' orbitopathy: a retrospective multicenter nationwide study |
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| Participants | 32 people with moderate to severe TAO who are corticosteroid resistant or corticosteroid dependent 21 women, 11 men Mean age: 51.2 (SD 10.7) years |
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| Interventions | All participants received 2 IV injections of 1 g of RTX 2 weeks apart, with oral paracetamol (1 g), oral antihistamine treatment, and IV glucocorticoid (1 mg/kg) |
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| Outcome measures | Improvement in at least 1 of the 3 dysfunctional parameters (inflammatory, oculomotor, and visual) without deterioration of the other(s) |
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| Results | The proportion of participants presenting signs of inflammatory activity (CAS ≥ 3) significantly diminished (74% before treatment, 45% at 12 weeks (P < 0.05), 29% at 24 weeks (P < 0.001)). The proportion of participants with visual dysfunction significantly diminished (39% before treatment, 19% at 12 weeks, then 16% at 24 weeks (P < 0.05)). 1 case had improvement in oculomotor dysfunction. Mean CAS significantly decreased after treatment, from 3.29 (SD 1.16) at week 0 to 1.59 (SD 1.12) at week 24 (P < 0.001).
Adverse effect: 1 participant had a cytokine release syndrome |
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| Study name | Low‐dose rituximab for active moderate to severe graves' orbitopathy resistant to conventional treatment |
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| Participants | 15 people with active moderate to severe TAO who were resistant to conventional treatment (IVMP, oral corticosteroids and orbital radiotherapy). 11 women, 4 men Age: 46 years (range 29 to 58) |
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| Interventions | Low‐dose RTX infusions (100 mg) |
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| Outcome measures | CAS decreased by 2 points or < 4/10, at 3 to 4 months after the first infusion of RTX Proptosis Lid fissure width Eye motility |
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| Results | 15 participants received 100 mg RTX doses (cumulative dose 100 to 400 mg) Mean CAS decreased from 4.6 (SD 0.89) to 2.0 (SD 1.65) at 17.1 weeks, after a mean of 2.3 infusions (range 1 to 4) of 100 mg RTX. Mean CAS was 1.3 (SD 1.76) at last visit at 63.6 weeks (range 44.3 to 87.5). RTX was effective in 13 participants, within 2 months of treatment initiation. In all responders except 1, TAO remained inactive after 1 year of follow‐up. RTX was ineffective in 2 participants, according to unchanged CAS after 2 infusions. All participants were euthyroid at the time of RTX treatment. Mean duration between the end of IVMP and RTX treatments was 16 months. Mean duration between the end of orbital radiotherapy and RTX treatments was 15 months. RTX was not clinically significant on proptosis, lid fissure width, and eye motility. |
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| Study name | Early low‐dose rituximab for active thyroid eye disease: An effective and well‐tolerated treatment. |
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| Participants | 12 people with active TAO (VISA (vision, inflammation, strabismus, appearance) CAS ≥ 3) 8 women, 4 men Age: 49 years (range 24 to 79) |
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| Interventions | Low‐dose RTX infusion (100 mg). If clinically indicated, further doses of 500 mg IVMP were administered weekly. Depending on disease activity and severity, a steroid‐sparing agent was started (1st line methotrexate, 2nd line cyclosporin) |
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| Outcome measures | CAS VISA overall severity score OX‐TED (Oxford‐Thyroid Eye Disease) QoL scores TSH receptor antibodies B cell subsets |
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| Results | Mean CAS was significantly reduced at the initial follow‐up between 1 and 3 months (from 5.08 to 3.5, P < 0.05) Mean CAS at last follow‐up was 1.58 (P < 0.001) CAS was not initially reduced in 4 participants. Mean VISA severity score decreased significantly (from 12 to 6, P < 0.001). Average quality of life score was reduced post treatment (from 45/70 to 37/70) at an average of 6 months follow‐up. Thyrotropin receptors were reduced in all participants post treatment but not significantly. 8 participants were checked for B cell subsets pre‐ and post‐ treatment, and all showed depletion of CD19 post RTX treatment (0.26 X 109/L to 0.04 X 109/L, P < 0.001)
Adverse effects: No serious adverse events were noted. 4 patients had minor infusion‐related rashes that resolved with 10 mg IV chlorphenamine. |
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| Study name | Efficacy profile and safety implications of very low dose rituximab in patients with Graves' orbitopathy |
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| Participants | 17 people with active moderate to severe TAO (9 people were unresponsive to IVMP, 8 people were newly diagnosed with TAO). 14 women, 3 men Mean age: 51.5 (SD 11.6) years (range 28 to 72) |
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| Interventions | A single RTX infusion of 100 mg over 1 hour and 15 minutes. Oral paracetamol (1 g), chlorphenamine (10 mg) and IV hydrocortisone (100 mg) were given 1 hour prior to RTX infusion |
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| Outcome measures | Participants were assessed at baseline and at 4, 8, 12, 16, 24, 32, 40, and 76 weeks post treatment: Decrease of 2 or more points in CAS Prevalence and time of disease inactivation (number of patients with CAS < 3) Composite ophthalmic score for severity at 24 weeks TSH receptor antibodies Long‐term surgical treatment Quality of life |
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| Results | Mean baseline CAS was 4.56 (SD 0.96), decreasing to 1.25 (SD 1.14) at 24 weeks (P = 0.001). 13 participants (86.6%) had inactive TAO at 12 weeks (CAS < 3) Participants with longer disease duration responded to RTX as well as those with short duration. After 4 weeks, the responses of the long disease duration group were overall better (P < 0.0001). Composite ophthalmic score for severity at 24 weeks improved in 58.3% of participants. All participants had peripheral depletion of CD20+ and CD19+ cells at the end of RTX infusion (60 minutes). A decrease of TSH receptor antibodies was observed at 12 weeks (P = 0.14), and a significant decrease was observed at 24 weeks (P = 0.015). 2 participants required orbital decompression.
Adverse events: 1 participant had urticaria which resolved with low dose steroids. 1 participant had cytokine release syndrome. |
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| CAS: clinical activity score; FT4: free thyroxine; IV: intravenous; IVMP: intravenous methylprednisolone; QoL: quality of life; RTX: rituximab; SD: standard deviation; TAO: thyroid‐associated ophthalmopathy; TBII: thyrotropin receptor binding inhibitory immunoglobulin; TFTs: thyroid function tests; TSH: thyroid‐stimulating hormone; TSI: thyroid‐stimulating immunoglobulin |
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| aThe 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. | ||||
| Study name | Failure of rituximab treatment in a case of severe thyroid ophthalmopathy unresponsive to steroids | |
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| Summary | Case unilateral severe TAO (Grave's disease then euthyroid after treatment). TRAb high. TgAb and TPOAb 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. |
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| Study name | Small dose of rituximab for Graves orbitopathy: new insights into the mechanism of action | |
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| Summary | 3 patients treated with one‐off low dose RTX infusion 100 mg
Patient 1: woman age 43 years, CAS 5/10. At day 1, CAS decreased to 1/10 and proptosis reduced from 24.5 to 23 mm in the right eye and 31 to 28 mm in the left eye.
Patient 2: woman age 67 years, CAS 6/10. Vision improved within 3 hours from counting fingers to 10/10. At week 1, CAS decreased to 3 and proptosis from 27.5 to 26 mm in the right eye and 29.5 to 27 mm in the left eye.
Patient 3: woman 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 |
| CAS: clinical activity score; RTX: rituximab; TAO: thyroid‐associated ophthalmopathy; TgAb: thyroglobulin antibodies; TPOAb: thyroid peroxidase antibodies; TRAb: thyrotropin receptor autoantibodies | ||
| Study name | Meta‐analysis of the efficacy of rituximab in thyroid‐associated ophthalmopathy. |
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| Participants | 6 studies: 2 RCTs and 4 cohort studies |
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| Interventions | Meta‐analysis on RTX clinical studies in moderate to severe thyroid‐associated ophthalmopathy |
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| Outcome measures | CAS before and after RTX treatment |
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| Results | CAS reduced significantly (SMD ‐5.04, 95% CI ‐7.08 to ‐3.01; P < 0.00001) |
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| CAS: clinical activity score; CI: confidence interval; RCT: randomised controlled trial; RTX: rituximab; SMD: standard mean difference |
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| Outcomea | Study | RTX | IVMP | RR (95% CI) | ||
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| n | N | n | N | |||
| CAS improvement (decrease) by 2 or more points | 15 | 15 | 12 | 16 | 1.32 (0.98 to 1.78) | |
| NOSPECSb improvement (decrease) by 2 or more classes | 3 | 15 | 3 | 16 | 1.07 (0.25 to 4.49) | |
| Proptosis improvement (decrease) by 2 mm or more | 0 | 15 | 1 | 16 | 0.35 (0.02 to 8.08) | |
| Palpebral aperture improvement (decrease) by 3 mm or more | 2 | 15 | 0 | 16 | 5.31 (0.28 to 102.38) | |
| Motility improvement (increase) by 1 class or more | 3 | 15 | 3 | 16 | 1.07 (0.25 to 4.49) | |
| Quality of life: improvement on GO‐QoL scale by at least 6 points for "appearance" | 9 | 14 | 6 | 13 | 1.39 (0.69 to 2.82) | |
| Quality of life: improvement on GO‐QoL scale by at least 6 points for "functioning" | 5 | 14 | 8 | 13 | 0.58 (0.25 to 1.32) | |
| Adverse events | 13 | 15 | 10 | 16 | 1.39 (0.90 to 2.13) | |
| CAS: clinical activity score; CI: confidence interval;GO‐QoL: Graves' ophthalmopathy quality of life; IVMP: intravenous methylprednisolone; n: number of events; N: number of participants; RR: risk ratio; RTX: rituximab | ||||||
| aAll outcomes measured at 24 weeks apart from adverse events at any time period bThe 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. | ||||||
| Outcomea | Study | RTX | Placebo | RR (95% CI) | ||
|---|---|---|---|---|---|---|
| n | N | n | N | |||
| CAS improvement (decrease) by 2 or more points | 4 | 13 | 3 | 12 | 1.23 (0.34 to 4.40) | |
| NOSPECSb improvement (decrease) by 2 or more classes | 2 | 13 | 2 | 12 | 0.92 (0.15 to 5.56) | |
| Proptosis improvement (decrease) by 2 mm or more | 2 | 13 | 4 | 12 | 0.46 (0.10 to 2.08) | |
| Adverse effects | 8 | 13 | 3 | 12 | 2.46 (0.84 to 7.18) | |
| CAS: clinical activity score; CI: confidence interval; n: number of events; N: number of participants; RR: risk ratio; RTX: rituximab | ||||||
| aAll outcomes measured at 24 weeks apart from adverse events at any time period bThe 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. | ||||||
