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. 2018 Mar 25;2018(3):CD012984. doi: 10.1002/14651858.CD012984

Tocilizumab for thyroid eye disease

Shirin Hamed Azzam 1,✉, Swan Kang 1, Mario Salvi 2, Daniel G Ezra 3
PMCID: PMC6494409

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The aim of this review is to investigate the efficacy and safety of tocilizumab for the treatment of people with TED.

Background

Description of the condition

Thyroid eye disease (TED) is an autoimmune disorder that constitutes a major clinical and therapeutic challenge. TED occurs in up to 50% of individuals with Graves' disease; however, it may also occur without current or prior hyperthyroidism, or in people who are hypothyroid due to chronic autoimmune (Hashimoto’s) thyroiditis (Bartalena 2008). Graves' disease affects approximately 1% to 2% of the adult population (Weetman 2000), and approximately 20% to 25% of those with Graves' hyperthyroidism have clinically apparent TED at the time of diagnosis (Burch 1993; Minakaran 2013). Reported incidence rates are 16/100,000 for women and 2.9/100,000 for men, and calculated prevalence is 0.25% (Bartley 1995).

The pathophysiology of TED is still not completely understood. Stimulation of inflammatory cytokines causes proliferation of the orbital fibroblasts, which in turn produce collagen and glycosaminoglycans in the extracellular matrix (Prabhakar 2003; Wiersinga 2001). The polyanionic charge and the high osmotic pressure of this matrix substance cause swelling of the extraocular muscles (Wiersinga 2001). In addition, a subgroup of orbital fibroblasts can differentiate into new mature fat cells (adipogenesis), which cause increased orbital tissue volume (Sorisky 1996). There is also a role for the humoral‐mediated immune response (Han 2006) in which thyrotropin receptor autoantibodies and immunoglobulins targeting insulin‐like growth factor‐1 receptors contribute to fibroblast activation and glycosaminoglycan secretion (Eckstein 2009; Ezra 2012).

The symptoms of TED may range from sore, gritty and red eyes to double vision, or reduced or loss of vision. The common clinical signs of TED include lid retraction and proptosis. Levator and Muller muscle inflammation and fibrosis can cause upper eyelid retraction, which is seen in up to 90% of affected individuals (Bahn 2010). Proptosis is caused by the expansion of orbital fat (type 1 orbitopathy), muscles (type 2 orbitopathy), or both (Hiromatsu 2000). TED even in its mild form has a deleterious effect on quality of life (Wickwar 2015), and in its severe form can lead to visual loss in 3% to 7% of affected individuals secondary to compressive optic neuropathy or exposure keratopathy (Bahn 2010; Barrio‐Barrio 2015; Kahaly 2005).

The clinical manifestation of TED can be assessed using several classification systems. The NO SPECS (No physical signs or symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle involvement, Corneal involvement, and Sight loss (due to optic nerve involvement) classification was first reported by Werner in 1969 (Werner 1969). Later, Werner published the modified NO SPECS classification and this has been widely used since (Werner 1977). The NO SPECS classification does not differentiate between inflammatory progressive and non‐inflammatory status, but grades clinical severity. Mourits and colleagues later described the Clinical Activity Score (CAS) classification, which differentiates between the active and quiescent stages of the disease and is based on the classic signs of acute inflammation (pain, swelling, redness and impaired function) (Mourits 1989). It was modified in 1997, which included 10‐points that requires two consecutive clinical examinations as three of these items are scored based on the change in clinical signs (Mourits 1997). Active ophthalmopathy is defined as the score greater than or equal to 3/7 at the first examination, or greater than or equal to 4/10 in successive examination. Later in 2006, European Group On Graves' Orbitopathy (EUGOGO) proposed a modification of this classification in which the clinical score can be obtained after a single clinical examination. This modified system has a total score of 7 and does not include an evaluation of change in visual acuity, diplopia or proptosis (EUGOGO 2006). Currently, the VISA (Vision, Inflammation, Strabismus, and Appearance) classification is widely used in the USA and North America, whereas the (EUGOGO) classification is used in Europe (Barrio‐Barrio 2015). Both these classifications assess the signs of activity and the degree of severity of the disease. As with the classification systems available, the treatment options vary: EUGOGO guidelines emphasise the use of intravenous corticosteroid (IV CS) as the superior treatment (Bartalena 2016), whereas the American Thyroid Association (2011) recommend treating the hyperthyroidism rather than the TED itself (Bahn 2011).

Smoking and unstable thyroid function levels are risk factors for TED. Smoking, even the history of smoking, is an independent risk factor associated with an impaired response to TED treatments such as IV CS (Xing 2015). In addition, radioiodine therapy is a significant risk factor for the development or worsening of TED; worsening of the condition can be prevented by use of prophylactic glucocorticoids in individuals with pre‐existing TED (Li 2016).

Individuals with TED usually receive advice on lifestyle modification, such as smoking cessation (Thornton 2007), together with a variety of medical and surgical treatment modalities ranging from immunosuppression with glucocorticoids (Kahaly 2005) to focal radiotherapy (Bartalena 2002) to surgical decompression (Kingdom 2015). Somatostatin analogues and immunomodulators, such as cyclosporine, have been trialled with limited success (Yang 2011). Oral glucocorticoid therapy tapered over 10 to 24 weeks is used frequently, although parenteral steroid administration appears to be superior in efficacy with improved quality of life (Stan 2012). A systematic review of the effectiveness of orbital irradiation found that treatment with a combination of radiotherapy and steroids is superior to steroid monotherapy (Rajendram 2008). Surgical interventions include orbital decompression, strabismus surgery and eyelid surgery. Surgical decompression is usually reserved for individuals with significant proptosis and sight‐threatening compressive optic neuropathy. Several surgical techniques have been used for orbital decompression and the endonasal approach appears to have a low complication rate (Boboridis 2015).

Description of the intervention

Tocilizumab is a recombinant humanised antihuman monoclonal antibody of the immunoglobulin G1 subclass directed against the interleukin (IL)‐6 receptor, produced by recombinant DNA technology (Perez‐Moreiras 2014). Tocilizumab specifically binds to the receptors of IL‐6 (IL‐6R), both the soluble and membrane‐bound forms (IL‐6RM). IL‐6 has been shown to inhibit both IL‐6RM and IL‐6‐mediated trans‐signalling through IL‐6R. Tocilizumab is sold under trade names such as Actemra and RoActemra and is approved by the European Medicines Agency and US Food and Drug Administration for the treatment of individuals with active moderate‐to‐severe rheumatoid arthritis that is unresponsive to standard therapies (Firestein 2003; Rose‐John 2007; Smolen 2003). It is administered intravenously at a dose of 4 to 8 mg/kg every four weeks. Many large‐scale global studies have demonstrated the efficacy and safety of tocilizumab for the treatment of individuals with rheumatoid arthritis, and in April 2008 the drug was first approved in Japan for this indication (Kaneko 2013).

How the intervention might work

There are a number of proposed theories as to how tocilizumab may work in TED. IL‐6 is a proinflammatory cytokine produced by various cell types, including T and B lymphocytes, monocytes and fibroblasts (Jyonouchi 2001; Lehmann 2008). IL‐6 is involved in various physiological processes, such as T‐cell activation, induction of immunoglobulin secretion, induction of the hepatic synthesis of acute‐phase proteins and the stimulation of haemotopoiesis. IL‐6 is present in high concentrations in individuals with TED and plays an important role in the pathogenesis of the disease, as previous in vitro and ex vivo experiments have shown (Anvari 2010; Hiromatsu 2000; Slowik 2012). Immune cells such as B and T lymphocytes play an important role in the early stages of TED. Further disease progression is postulated to involve the recruitment of T cells into the orbit to engage in reciprocal immune activation and amplify B‐cell responses, resulting in inflammatory processes such as the production of cytokines (including IL‐6) and prostaglandins that lead to the tissue expansion and remodelling that is characteristic of the orbital soft tissue expansion seen in TED (Lehmann 2008).

However, in addition to an immunomodulatory function, there is evidence that IL‐6 targeting may also affect mesenchymal cells, which could alter extracellular matrix remodelling. Recent studies have shown that IL‐6 increases the expression of the thyrotropin receptor in orbital preadipocytes (Jyonouchi 2001). Furthermore, high levels of IL‐6 produced by differentiated adipocytes and fibroblasts stimulate B lymphocytes and produce thyroid‐stimulating immunoglobulin (TSI). Fibroblasts present in the orbit, when activated by TSI and tumour growth factor‐beta, may differentiate into myofibroblasts or adipocytes, leading to glycosaminoglycan production, adipogenesis and inflammation or fibrosis (Prabhakar 2003; Smith 1997). Reducing the effect of IL‐6 by blocking its receptors may play a role in lowering TSI blood levels, and in improving proptosis and extraocular motility.

Given the role in TED of IL‐6 expression in adipocytes (Jyonouchi 2001), fibroblasts and macrophages, and the existing experience of the use of different biological therapies, the proposed theory is that inhibition of IL‐6 may be an effective treatment in TED by directly reducing the inflammatory response and fibroblast activity, and hence altering extracellular matrix remodelling.

Why it is important to do this review

TED is the most common extrathyroidal manifestation of Graves' disease and, in its severe form, it can cause visual loss. Current treatment options for moderate‐to‐severe TED include immunotherapy (mainly glucocorticosteroids), orbital radiotherapy (Rajendram 2012) and decompression surgery (Boboridis 2011). Limited drugs of proven efficacy are available for the treatment of individuals with TED. The side‐effect profiles of the currently available treatments are undesirable, especially those of the most commonly used first‐line agents ‐ glucocorticosteroids ‐ which are associated with adverse effects such as diabetes mellitus, hypertension, acute heart failure, weight gain, osteoporosis and acute liver failure.

In addition, there is an unmet need for a new treatment that can modify the natural course of the disease and reduce the incidence of late complications that can occur as a result of fibrosis following inflammation. Tocilizumab is a biological agent that has been used successfully in other autoimmune conditions including rheumatoid arthritis. Some recent studies have demonstrated the efficacy of tocilizumab in the treatment of individuals with active moderate‐to‐severe TED, but there are no clear guidelines regarding its use. It is therefore important to systematically review all the current evidence in order to draw conclusions on the use of tocilizumab in the management of TED.

Objectives

The aim of this review is to investigate the efficacy and safety of tocilizumab for the treatment of people with TED.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) that investigate the use of tocilizumab in the treatment of people with TED.

Types of participants

We will include trials involving adults (aged 18 years and over) with active TED (CAS ≥ 3 at baseline, ≥ 4 at subsequent visits).

Types of interventions

We will include trials of tocilizumab administered by intravenous infusion using any dosage regimen, compared with placebo or intravenous glucocorticoid therapy.

Types of outcome measures

Primary outcomes

  • Change in TED as defined by investigators, at 3 months (range 2 to 6 months) and 12 months (range 6 to 18 months) post treatment. This may include classification scores such as CAS, EUGOGO, NOSPECS, VISA.

Secondary outcomes

The secondary outcomes for this review are the following at 3 months (range 2 to 6 months) and 12 months (range 6 to 18 months) post treatment:

  • Change in proptosis (measured in mm) (if change in proptosis is not reported and only one time‐point measurement of proptosis is reported then the final values will be collected)

  • Change in extraocular motility (measured in degrees) (if change in extraocular motility is not reported and only one time‐point measurement of extraocular motility is reported then the final values will be collected)

  • Change in palpebral aperture measurements (measured in mm) (if change in palpebral aperture measurements is not reported and only one time‐point measurement of palpebral aperture is reported then the final values will be collected)

  • Number of relapses (per participant)

  • Development of optic neuropathy (as defined by the trial investigators)

  • Change in quality of life score: we will use any validated measure, for example Graves' Orbitopathy Quality of Life Questionaire (GO‐QOL) score or EuroQol EQ‐5D score

Adverse effects

We will report any adverse effects identified in the included trials.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist will search the following electronic databases for RCTs and controlled clinical trials. We will impose no language or publication year restrictions.

  • Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (latest issue) (Appendix 1)

  • MEDLINE Ovid (1946 to present) (Appendix 2)

  • Embase Ovid (1980 to present) (Appendix 3)

  • LILACS (Latin American and Caribbean Health Science Information Database (1982 to present) (Appendix 4);

  • OpenGrey (opengrey.eu/) (Appendix 5)

  • ISRCTN registry (isrctn.com/editAdvancedSearch (Appendix 6)

  • US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov (clinicaltrials.gov) (Appendix 7);

  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (who.int/ictrp) (Appendix 8)

  • EU Clinical Trials Register (clinicaltrialsregister.eu) (Appendix 9)

Searching other resources

We will manually search the reference lists of review articles and use the Science Citation Index to identify additional studies citing trials. We will contact the lead investigators of relevant trials on ClinicalTrials.gov and the WHO ICTRP for information and data from as yet unpublished clinical trials. We will contact experts in the field for information about any ongoing trials. We will contact the manufacturers of tocilizumab for details of any sponsored trials.

Data collection and analysis

Selection of studies

Using Covidence, two review authors will independently inspect the titles and abstracts resulting from the electronic and manual searches and classify each abstract as relevant, potentially relevant or not relevant for this review. We will obtain full‐text copies of articles identified as relevant or potentially relevant. Two review authors will independently assess each article and apply the inclusion criteria to determine final eligibility. We will resolve discrepancies through discussion and consensus. We will document the excluded studies and reasons for exclusion.

Data extraction and management

Two review authors will independently extract data from the included studies (see Appendix 10). We will use Covidence (Covidence 2015) to screen the citation, review full texts, perform 'Risk of bias' assessments, and extract study characteristics and outcomes. We will contact trial investigators for missing data and when data are difficult to interpret. We will resolve any discrepancies between authors through discussion and consensus. One review author will import the data from Covidence into Review Manager 5 (Review Manager 2014) and a second author will check the entered data for errors or inconsistencies. We will collect data using a pre‐piloted data extraction template.

Assessment of risk of bias in included studies

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

1. random sequence generation (selection bias) 2. allocation concealment (selection bias) 3. blinding (masking) of participants and outcome assessors (performance bias and detection bias) 4. incomplete outcome data (attrition bias) 5. selective outcome reporting (reporting bias) 6. other sources of bias We will assess each parameter to be at: low risk of bias, high risk of bias or unclear risk of bias. We will contact the authors of trials for additional information on domains we judge to be at unclear risk of bias. We will resolve discrepancies between review authors by discussion and consensus.

Measures of treatment effect

We will report continuous variables where the data are normally distributed as means and standard deviations (SD), and where the data are not normally distributed as medians and interquartile (IQ) ranges. Medians and IQ ranges will not be meta‐analysed. Such variables will include changes in thyroid‐associated CAS, proptosis, palpebral aperture measurements, extraocular motility and quality of life scores. If there are more than two studies and different measurement scales are used to assess the same outcome across the included studies, we will use the standardised mean difference (SMD). We will report dichotomous variables as risk ratios (RR) with 95% confidence intervals (CI). Such variables will include the proportion of participants experiencing each adverse effect.

Unit of analysis issues

The treatment is a systemic treatment and as such will affect both eyes of each participant. Included studies will randomise participants rather than eyes. The CAS score is calculated for each participant and so the unit of analysis for these data will be the participant. For proptosis, palpebral aperture and extraocular motility data, the unit of analysis will be the individual eye. If participants are randomly allocated to treatment but only one eye per person is reported then there will be no unit‐of‐analysis issues. In these cases, we will document how the eye was selected. If participants are randomly allocated to treatment but both eyes are included and reported, we will analyse them as "clustered data" (i.e. with adjustments for within‐person correlation). We may have to contact the trial investigators for further information in order to do this. The unit of analysis will be the participant for quality of life.

Dealing with missing data

If there are missing data, we will contact the authors to obtain this information. If individual patient data is available from the authors, we will perform imputation by Multiple Imputation by Chained Equations (MICE) approach (Resche‐Rigon 2016). If standard deviations are missing, we will attempt to calculate them from the reported statistics (e.g., confidence interval, t‐statistics) (Higgins 2011b). We will perform sensitivity analyses by comparing the results with and without imputed data to assess the impact of imputation.

Assessment of heterogeneity

We will examine heterogeneity by examining study characteristics and forest plots of the results. We will use the I2 statistic to assess the proportion of the variance in the plot or analysis that reflects variation in true effects. We will interpret an I2 value of 50% or more as substantial heterogeneity.

Assessment of reporting biases

We will search PubMed, other major reference databases and the internet for a protocol for each included study. If a protocol is available, then we will compare outcomes mentioned in the protocol and in the published report. If no protocol is available, then we will compare the outcomes listed in the methods section of each article with those for which results are reported. We will seek further information from the authors of the study reports. We will use funnel plots to assess the evidence of publication bias if at least 10 suitable studies are available. If there are fewer than 10 studies, the funnel plot will not be appropriate due to the loss of power.

Data synthesis

If there is substantial clinical or statistical heterogeneity (I2 > 50%) we will not combine study results and instead will present an estimate of effect and associated 95% CI for each individual trial. If there is little variation between trials, we will combine the results in a meta‐analysis using a random‐effects model, unless there are a very small number of trials when we will use a fixed‐effect model. If multi‐arm studies are included, we will combine groups to create a single pair‐wise comparison. The formulae in Cochrane 7 of the Cochrane Handbook for Systematic Reviews of Intervention will be used to combine numbers into a single sample size, mean and standard deviation for each intervention group (Higgins 2011c).

Subgroup analysis and investigation of heterogeneity

We intend to stratify our findings by treatment dosage as a potential effect modifier. We will consider high (8 mg/kg) and low (4 mg/kg) dosage for subgroup analysis.

Sensitivity analysis

We plan to conduct sensitivity analyses to determine the impact of the exclusion of studies with lower methodological quality and industry‐funded studies. Studies with low methodological quality are defined as the ones with high risk of bias in one or more domain in Cochrane risk of bias assessment.

Summary of findings

See Table 1 and Table 2 for further details. Two authors will grade independently the certainty of the evidence for each outcome using the GRADE approach. This will take into account the size, consistency and precision of the effects, indirectness of the evidence and potential role of publication bias, (www.gradeworkinggroup.org).

Table 1.

Type of intervention: intravenous tocilizumab treatment versus standard treatment. Type of studies: randomised controlled trials

Outcomes Measure Relative effect Number of participants (studies) Quality of evidence (GRADE*) Comments
Change in TED as defined by investigators Measured in CAS/EUGOGO/NOSPECS/VISA classification at 12 months (range 6 to 18 months) post treatment.
Change in proptosis Measured in millimetres at 12 months (range 6 to 18 months) post treatment.
Change in extraocular motility Measured in degrees at 12 months (range 6 to 18 months) post treatment.
Number of relapses per participant at 12 months (range 6 to 18 months) post treatment.
Development of optic neuropathy as defined by the trial investigators at 12 months (range 6 to 18 months) post treatment.
Change in quality‐of‐life score GO‐QOL score or EQ‐5D score at 12 months (range 6 to 18 months) post treatment. MCID = 6 points
Adverse effects Any adverse effect that is reported at 12 months (range 6 to 18 months) post treatment.
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*The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest. Quality of a body of evidence involves consideration of within‐study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. TED= Thyroid Eye Disease.

CAS = Clinical Activity Score.

EUGOGO= European Group On Graves' Orbitopathy. NOSPECS = No symptoms or signs, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle involvement, Corneal involvement and Sight loss. It is graded as 0, a, b or c.

VISA= Vision, Inflammation, Strabismus, and Appearance classification. GO‐QOL = Graves' Orbitopathy Quality of Life questionnaire.

EQ‐5D= European Quality of life questionnaire.

The treatment effect for each continuous outcomes will be expressed as a mean difference (MD) with 95% CI. Where continuous outcomes are measured using different scales, the treatment effect will be expressed as a standardised mean difference (SMD) with 95% CI.

Table 2.

Type of intervention: intravenous tocilizumab treatment versus placebo. Type of studies: randomised controlled trials

Outcomes Measure Relative effect Number of participants (studies) Quality of evidence (GRADE*) Comments
Change in TED as defined by investigators Measured in CAS/EUGOGO/NOSPECS/VISA classification at 12 months (range 6 to 18 months) post treatment.
Change in proptosis Measured in millimetres at 12 months (range 6 to 18 months) post treatment.
Change in extraocular motility Measured in degrees at 12 months (range 6 to 18 months) post treatment.
Number of relapses per participant at 12 months (range 6 to 18 months) post treatment.
Development of optic neuropathy as defined by the trial investigators at 12 months (range 6 to 18 months) post treatment.
Change in quality‐of‐life score GO‐QOL score or EQ‐5D score at 12 months (range 6 to 18 months) post treatment. MCID = 6 points
Adverse effects Any adverse effect that is reported at 12 months (range 6 to 18 months) post treatment.
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*The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest. Quality of a body of evidence involves consideration of within‐study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. TED= Thyroid Eye Disease.

CAS = Clinical Activity Score.

EUGOGO= European Group On Graves' Orbitopathy. NOSPECS = No symptoms or signs, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle involvement, Corneal involvement and Sight loss. It is graded as 0, a, b or c.

VISA= Vision, Inflammation, Strabismus, and Appearance classification. GO‐QOL = Graves' Orbitopathy Quality of Life questionnaire.

EQ‐5D= European Quality of life questionnaire.

The treatment effect for each continuous outcomes will be expressed as a mean difference (MD) with 95% CI. Where continuous outcomes are measured using different scales, the treatment effect will be expressed as a standardised mean difference (SMD) with 95% CI.

Acknowledgements

The Cochrane Eyes and Vision has created and will execute the electronic search strategies. We would like to thank Faye Wellington and Jennifer Evans for their comments on the protocol, and Anupa Shah and the editorial team for helping with registration and preparation of the protocol.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Graves Disease] explode all trees #2 MeSH descriptor: [Graves Ophthalmopathy] explode all trees #3 grave* near ophthalm* #4 grave* near orbitopath* #5 (thyroid*) near (ophthalm* or eye*) #6 TED or TAO #7 basedow* next disease* #8 #1 or #2 or #3 or #4 or #5 or #6 or #7 #9 MeSH descriptor: [Antibodies, Monoclonal] explode all trees #10 MeSH descriptor: [Interleukin‐6] this term only #11 MeSH descriptor: [Receptors, Interleukin‐6] this term only #12 (tocilizumab or TCZ) #13 (atlizumab or actemra or roactemra) #14 (anti IL 6 next receptor) #15 (anti interleukin 6 next receptor) #16 monoclonal near/4 antibod* #17 (lymphocyte* or cell*) near/4 agent* #18 #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 #19 #8 and #18

Appendix 2. MEDLINE (Ovid) search strategy

1. randomized controlled trial.pt. 2. (randomized or randomised).ab,ti. 3. placebo.ab,ti. 4. dt.fs. 5. randomly.ab,ti. 6. trial.ab,ti. 7. groups.ab,ti. 8. or/1‐7 9. exp animals/ 10. exp humans/ 11. 9 not (9 and 10) 12. 8 not 11 13. exp graves disease/ 14. exp graves ophthalmopathy/ 15. (grave$ adj3 ophthalm$).tw. 16. (grave$ adj3 orbitopath$).tw. 17. ((ophthalm$ or orbitopath$ or eye$) adj3 thyroid$).tw. 18. (TED or TAO).tw. 19. (basedow$ adj3 disease$).tw. 20. or/13‐19 21. exp antibodies, monoclonal/ 22. Interleukin‐6/ 23. Receptors, Interleukin‐6/ 24. (tocilizumab or TCZ).tw. 25. (atlizumab or actemra or roactemra).tw. 26. ((anti IL 6 or anti interleukin 6) adj1 receptor).tw. 27. (monoclonal adj4 antibod$).tw. 28. ((lymphocyte$ or cell$) adj4 agent$).tw. 29. or/21‐28 30. 12 and 20 and 29

Appendix 3. Embase (Ovid) search strategy

1. exp randomized controlled trial/ 2. exp randomization/ 3. exp double blind procedure/ 4. exp single blind procedure/ 5. random$.tw. 6. or/1‐5 7. (animal or animal experiment).sh. 8. human.sh. 9. 7 and 8 10. 7 not 9 11. 6 not 10 12. exp clinical trial/ 13. (clin$ adj3 trial$).tw. 14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. 15. exp placebo/ 16. placebo$.tw. 17. random$.tw. 18. exp experimental design/ 19. exp crossover procedure/ 20. exp control group/ 21. exp latin square design/ 22. or/12‐21 23. 22 not 10 24. 23 not 11 25. exp comparative study/ 26. exp evaluation/ 27. exp prospective study/ 28. (control$ or prospectiv$ or volunteer$).tw. 29. or/25‐28 30. 29 not 10 31. 30 not (11 or 23) 32. 11 or 24 or 31 33. exp graves disease/ 34. exp endocrine ophthalmopathy/ 35. (grave$ adj3 ophthalm$).tw. 36. (grave$ adj3 orbitopath$).tw. 37. ((ophthalm$ or orbitopath$ or eye$) adj3 thyroid$).tw. 38. (TED or TAO).tw. 39. (basedow$ adj3 disease$).tw. 40. or/33‐39 41. exp monoclonal antibody/ 42. interleukin 6/ 43. interleukin 6 receptor/ 44. (tocilizumab or TCZ).tw. 45. (atlizumab or actemra or roactemra).tw. 46. ((anti IL 6 or anti interleukin 6) adj1 receptor).tw. 47. (monoclonal adj4 antibod$).tw. 48. ((lymphocyte$ or cell$) adj4 agent$).tw. 49. or/41‐48 50. 32 and 40 and 49

Appendix 4. LILACS search strategy

graves or thyroid and ophthalm$ or orbit$ or disease or TED or TAO and monoclonal antibod$ or tocilizumab or interleukin‐6 or IL‐6

Appendix 5. OpenGrey search strategy

tocilizumab

Appendix 6. ISRCTN search strategy

(thyroid eye disease OR thyroid associated orbitopathy OR ophthalmopathy OR TED or TAO) AND Tocilizumab

Appendix 7. ClinicalTrials.gov search strategy

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

Appendix 8. WHO ICTRP search strategy

thyroid eye OR ophthalmopathy OR orbitopathy OR TAO OR TED = Condition AND tocilizumab = Intervention

Appendix 9. EU Clinical Trials Register search strategy

Thyroid AND tocilizumab

Appendix 10. Data on study characteristics

Mandatory items Optional items
Methods
Study design · Parallel group RCTi.e. people randomised to treatment
· Within‐person RCTi.e. eyes randomised to treatment
· Cluster RCTi.e. communities randomised to treatment
· Cross‐over RCT
· Other, specify		 Exclusions after randomisation
Losses to follow up
Number randomised/analysed
How were missing data handled? e.g. available case analysis, imputation methods
Reported power calculation (Y/N), if yes, sample size and power
Unusual study design/issues
Eyes or
unit of randomisation/ unit of analysis		 · One eye included in study, specify how eye selected
· Two eyes included in study, both eyes received same treatment, briefly specify how analysed (best/worst/average/both and adjusted for within‐person correlation/both and not adjusted for within‐person correlation) and specify if mixture one eye and two eye
· Two eyes included in study, eyes received different treatments,specify if correct pair‐matched analysis done
Participants
Country Setting
Ethnic group
Equivalence of baseline characteristics (Y/N)
Total number of participants This information should be collected for total study population recruited into the study. If these data are reported only for the people who were followed up only, please indicate
Number (%) of men and women
Average age and age range
Inclusion criteria
Exclusion criteria
Interventions
Intervention (n= )
Comparator (n= )
See MECIR 65 and 70 		· Number of people randomised to this group
· Drug (or intervention) name
· Dose
· Frequency
· Route of administration
Outcomes
Primary and secondary outcomes as defined in study reports
See MECIR R70 		List outcomes
Adverse events reported (Y/N)
Length of follow‐up and intervals at which outcomes assessed		 Planned/actual length of follow‐up
Notes
Date conducted Specify dates of recruitment of participants mm/yr to mm/yr Full study name (if applicable)
Reported subgroup analyses (Y/N)
Were trial investigators contacted?
Sources of funding
Declaration of interest
See MECIR 69
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Contributions of authors

Drafting the protocol: SHA, SK Drafting the final version of the protocol: DE, MS

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research (NIHR), UK.

    • Richard Wormald, Co‐ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.
    • This protocol was supported by the NIHR, via Cochrane Infrastructure funding to the CEV UK editorial base.

    The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Declarations of interest

None

New

References

Additional references

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