Efficacy and safety of various Intravenous Methylprednisolone regimens in Moderate to Severe Thyroid Eye Disease: A systematic review

Abstract

This systematic review aims to assess the efficacy and safety of various intravenous methylprednisolone (IVMP) protocols for treating active moderate to severe thyroid eye disease (TED) and to find the most effective regimen with the least side effects. We conducted a comprehensive literature search adhering to PRISMA guidelines across PubMed, Medline, Embase, Web of Science, and Scopus databases from March 2008 to March 2024 to find relevant studies. Included studies were randomized controlled trials (RCTs), nonrandomized trials, cohort studies, case–control studies, case series, and case reports in English, investigating IVMP usage in adults with active moderate to severe TED. Outcomes focused on disease activity, exophthalmos improvement, diplopia resolution, recurrence, need of additional treatment, and associated adverse events. Of the 274 screened articles, 15 were included, involving 1065 participants. There were six RCTs (two multicentric), six retrospective studies, and three prospective case series from March 2008 to March 2024. Regimens were categorized into low dose (LD) ≤ 2.5 g, medium dose (MD) >2.5 g to 4.5 g, and high dose (HD) >4.5 g, with intervals of daily, weekly (most common), and monthly, over 4 to 26 weeks, typically 12 weeks. The MD (4.5 g) regimen was the most common followed, and it significantly improved Clinical Activity Score and quality of life with low side effects. The main limitations of this study are the heterogeneity of included studies, duration of follow-up, and IVMP regimens, which may affect the comparability and generalizability of the results. The weekly IVMP (4.5 g) regimen optimally treats moderate to severe TED. However, future research should focus on large-scale trials to determine the optimal IVMP regimen while addressing variability in managing recurrence, additional treatments, and the timing of rehabilitative surgeries.

Thyroid eye disease (TED) or Graves’ ophthalmopathy is an autoimmune inflammatory condition affecting the orbit and periorbital tissues and is the most common cause of both unilateral and bilateral exophthalmos in adults. Approximately 25% to 50% of Grave disease (GD) cases develop TED.[1,2] The prevalence of TED globally reveals rates of 10.36% for hypothyroidism, 7.9% for euthyroidism, and 86.2% for hyperthyroidism.[3,4] The management approach for TED relies on assessing its activity and severity, typically evaluated using the European Group on Graves’ Orbitopathy (EUGOGO) scale and the Clinical Activity Score (CAS).[5] The EUGOGO scale, found in Supplementary Tables 1 and 2, is commonly preferred for guiding primary treatment strategies.

Supplementary Table 1.

Assessment of Clinical Activity Score (CAS) as per the EUGOGO Guidelines Clinical activity score (CAS) is the sum of all the parameters enlisted.

Parameters Assessed	Points/Score
Spontaneous retro-orbital pain	1
Gaze evoked orbital pain	1
Eyelid swelling	1
Eyelid erythema	1
Conjunctival congestion	1
Conjunctival Edema	1
Inflammation of caruncle or plica	1
A CAS Score of >3/7 at baseline indicates active TED
Increase of >2 mm in proptosis	1
Decrease in uniocular ocular excursion in any one direction of >8°	1
Decrease of visual acuity equivalent to 1 Snellen line	1
A CAS Score of >4/7 on follow-up indicates active TED

From: Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marinò M, Vaidya B, Wiersinga WM; EUGOGO †. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur J Endocrinol. 2021 Aug 27;185(4):G43-G67.

Supplementary Table 2.

Grades or Severity of Thyroid Eye Disease(TED)

Grades	Clinical Features
Mild TED,	Lid retraction Mild softtissue involvement Proptosis <3mm No diplopia or transient diplopia Exposure keratopathy responsive to lubrication
Moderate to severe TED	Lid retraction >2 mm Moderate to severe softtissue involvement Constant or inconstant diplopia Exophthalmos >3 mm
Sight-threatening TED	Presence of optic neuropathy Presence of corneal decompensation

From: Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marinò M, Vaidya B, Wiersinga WM; EUGOGO †. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur J Endocrinol. 2021 Aug 27;185(4):G43-G67.

Methylprednisolone, a corticosteroid with potent anti-inflammatory properties, has been employed to mitigate the inflammatory response associated with TED, aiming to alleviate symptoms and prevent disease progression.[6] While immunosuppression by intravenous methylprednisolone (IVMP) plays a pivotal role in managing moderate to severe cases of TED, there remains a spectrum of treatment regimens characterized by varying doses, durations, side effects, and response rates. This study was designed to investigate the efficacy and safety of reported regimens of IVMP in patients with moderate to severe active TED.

Methods

The Ethics Committee of Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, determined that approval was not required for this study.

Search strategy

We conducted a comprehensive literature search from March 2008, when the EUGOGO[7] protocol was introduced, using various electronic databases including PubMed, Medline, Embase, Web of Science, and Scopus up to the end of March 2024, without restrictions on place or language, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[8] The research utilized the following keywords: “Thyroid eye disease (TED) OR Moderate OR Severe Thyroid eye disease (TED) Thyroid-associated ophthalmopathy OR Thyroid-associated orbitopathy OR Graves’ ophthalmopathy OR Graves’ orbitopathy” AND “Methylprednisolone OR Intravenous methylprednisolone OR (IVMP)”. Boolean operators (AND, OR) were used to combine relevant terms. Additionally, we searched gray literature, conference proceedings, and reference lists of included studies for potential additional sources.

Eligibility criteria

The inclusion criteria for this review are listed below:

1. Patients of age 18 years and above.

2. Diagnosed with active moderate to severe TED.

3. Studies giving information on safety and efficacy outcomes of different IVMP protocols. These protocols should include dosage, frequency, duration, and adjunctive therapies.

4. Prospective and retrospective studies presenting randomized controlled trials (RCTs), nonrandomized controlled trials, observational studies, cohort studies, and case series were considered.

5. The studies are published in English or have English translations available.

During the search process, there were no restrictions or limits in terms of language or country of origin. However, studies published from March 2008 onward were included to correspond with the initiation of EUGOGO protocol.

The exclusion criteria for this review are listed below:

1. Studies involving patients with TED classified as mild or sight-threatening or without clear severity grading

2. Studies lacking detailed descriptions of the IVMP protocols utilized

3. Studies in which patients underwent primary radiotherapy or primary surgery

4. Studies focusing solely on pediatric populations

5. Studies comprising review articles, editorials, book chapters, conference abstracts, and case reports with insufficient data. Additionally, studies with overlapping patient populations or duplicated data were excluded to ensure the integrity and relevance of the findings.

Recurrence was defined as the reappearance or worsening of the symptoms in at least one eye after successful treatment. This includes deterioration in two or more parameters such as an increase in CAS score ≥2, worsening of exophthalmos by more than 2 mm, new or aggravated diplopia, deterioration of extraocular motility, and development of dysthyroid optic neuropathy.[9,10,11,12]

Two authors (A.A. and D.S.) independently followed the search strategy; screened the abstracts, then the full text, and also the quality of evidence of the selected articles; and finally included the articles for the systematic review. Additionally, these reviewers were responsible for collecting data from the reports. Disagreement was resolved by the involved senior author (R.A.), who also confirmed data collection with the study investigator. The reference list of the included papers was reviewed to identify additional reports and citations of both published and unpublished research.

Data extraction

The information gathered and recorded included the authors’ names and publication years, study design, IVMP protocol used, cumulative dose of IVMP given, overall improvement, deterioration, a decrease in Clinical Activity Score (CAS), a decrease in exophthalmos, improvement in diplopia, recurrence, requirement of additional treatment, and side effects.

Synthesis of evidence

Quality assessment findings were recorded alongside extracted data, ensuring comprehensive documentation of study methodologies and enabling context-based interpretation of study findings. The systematic documentation of study selection and data extraction processes facilitated transparency, reproducibility, and robust analysis in evaluating the efficacy and safety of IVMP protocols for moderate to severe TED. Meta-analytic methods were not applicable due to the variability in study designs and outcomes.

Results

Out of 274 initially screened articles, 239 studies were selected, the full texts of 89 were reviewed, and 15 papers were finally included, encompassing a combined participant pool of 1065. Fig. 1 presents a PRISMA flow chart illustrating the process of identifying, screening, and selecting studies based on the predetermined inclusion and exclusion criteria. There were six RCTs among which two were multicentric, six retrospective studies, and three prospective case series spanning from March 2008 to March 2024. After thorough evaluation, 15 studies were identified [Table 1]. Broadly, the various cumulative doses used in these studies can be divided into three groups: Low Dose (LD) IVMP, which is ≤2.5 g; Medium Dose (MD) IVMP, which is >2.5 g to 4.5 g; and High Dose (HD) IVMP, which is >4.5 g. These regimens were further classified based on their administration intervals: Daily regimens: Administered over consecutive days within a treatment cycle (e.g., 500 mg IVMP for 3–5 consecutive days per week for 2–4 weeks). Weekly regimens: Spanning from 4 to 26 weeks, with 12 weeks being the most common duration. Monthly regimens: Administered in cycles with intervals of 20–30 days, often paired with tapering oral glucocorticoids (OGCs) or other adjunct therapies.

Figure 1.

Search Strategy. This was done using Peer Review of Electronic Search Strategy (PRESS) Guideline

Table 1.

Overview of IVMP Studies

Author et al., (year)	Type of Study	Study IVMP†	Cumulative dose and duration of t/t¶	Sample size	Improved (n%)	Deteriorated (n%)	Major Adverse-events (n%)	Conclusion
Geest, 2008[13]	RCT*	Four weekly v/s Placebo	6 g and 3 months	15	5 (83) vs 1 (11)	1 (16) vs 4 (44)	0	IVMP (6 gm) is better.
Ortiga[14]	Retrospective	Weekly vs 2 Weekly	4.5 g vs 4.9-7.4 g and 12 weeks vs 16 weeks	24	11 (92) vs 11 (100)	0	1 (9) vs 2 (18)	IVMP (4.5 gm) is better.
Tambe, 2010[15]	Retrospective	3 days + OGC§	3.7 g-4.26 g and 4 weeks	36	30 (83)	6 (17%)	0	IVMP+OGC is safe but has a higher recurrence.
Bartalena, 2012[11]	RCT, Multicentre	Weekly (250 mg vs 540 mg vs 830 mg)	2.25 g vs 4.98 g vs 7.47 g and 12 weeks	159	15 (28) vs 19 (35) vs 27 (52)	6 (11) vs 6 (11) vs 4 (8)	02 (4) vs 03 (06) vs 05 (10)	4.98 g is better. 7.47 g has short term benefits with high S/E. 2.25 g has higher relapse.
Zhu, 2014[16]	RCT	Weekly v/s Daily	4.5 g vs 4.5 g and 12 weeks vs 4 weeks	80	30 (77) vs 17 (41)	8 (21) vs 9 (23)	0 vs 2 (5)	Weekly protocol is better.
Yang, 2014[17]	Retrospective	Weekly	4.5 to 5 g and 12 weeks	32	12 (38)	5 (15)	1 (3)	Efficacious
Xing, 2015[18]	Retrospective	Weekly	4.5 g and 3 months	92	50 (54)	NA	NA	Nonsmokers responded better to IVMP
Liu, 2016[19]	Prospective, Case Series	20 days cycle (‡HD)	4.5 g – 9 g and 60 days	58	50 (86)	6 (10)	1 (2)	HD IVMP safe and effective
He, 2017[9]	RCT	Monthly vs Weekly	6 g vs 4.5 g and 3 months vs 12 weeks	40	13 (77) vs 10 (67)	3 (18) vs 4 (27)	0 vs 0	Both regimen are safe and effective
Kahaly, 2018[12]	RCT, Multicentre	Weekly v/s Weekly IVMP + Oral Mycophenolate	4.5 g v/s 4.5 g+120 g and 12 weeks vs 24 weeks	164	36 (49) vs 48 (63)	4 (5) vs 5 (6)	11 (14) vs 13 (16)	IVMP + Mycophenolate is better.
Mu, 2020[20]	RCT	Daily (+OGC) vs Weekly	4.3 g vs 4.5 g And 12 weeks	90	(78) vs (64)	0 vs 2 (4)	0 vs 0	Daily IVMP is better.
Beleslin, 2020[10]	Retrospective	IVMP + OGC vs Weekly IVMP	3 g+7.2 g vs 4.5 g And 6 months	140	43 (65) vs 37 (51)	4 (6) vs 9 (12)	2 (3) vs 1 (1)	IVMP + OG efficacious but more side effects.
Xu, 2020[21]	Prospective, Pilot Study	Weekly	4.5 g and 12 weeks	30	13 (87)	NA	0	Decreases Inflammatory markers.
Li, 2021[22]	Prospective, Case Series	Weekly	4.5 g and 12 weeks	40	17 (85)	NA	0	Improves ‖CAS and biomechanical property.
Lai, 2023[23]	Retrospective	Weekly	2.25 g vs 4.5 g and 6 weeks vs 12 weeks	65	NA	NA	0	12 weekly (4.5 g) is better.

*RCT: Randomized Controlled Trial, ^†IVMP: Intravenous Methylprednisolone, ^‡HD: High Dose, ^§OGC: Oral Glucocorticoid, ‖CAS: Clinical Activity Score, ^¶t/t: Treatment. This table summarizes the details of various studies on Intravenous Methylprednisolone (IVMP), including study type, dosage, sample size, outcomes, and conclusions.

The studies suggest that different regimens have varying impacts. The key findings from these studies are summarized below.

Decrease in Clinical Activity Score (CAS)

Two studies compared low-dose IVMP regimen. A multicentric RCT[11] evaluated three different IVMP doses (2.25 g, 4.98 g, and 7.47 g). Each group began with a starting dose (250 mg in the 2.25 g group, 540 mg in the 4.98 g group, 830 mg in the 7.47 g group) for the first six infusions, which was then halved (125 mg in the 2.25 g group, 290 mg in the 4.98 g group, 415 mg in the 7.47 g group) for the remaining six infusions. They found that the CAS significantly decreased earlier in the 7.47 g group compared to 4.98 g and 2.25 g groups. However, at the end of treatment, the disease was inactive (CAS ≤ 2) in 65% of the 4.98 g group, 60% in the 7.47 g group, and 45% of the 2.25 g group. Lai et al.[23] documented that a 12-week IVMP (4.5 g) regimen showed a significant improvement in CAS compared to a 6-week (2.25 g) regimen (P < 0.05). The 6-week regimen included 3 weeks of 500 mg IVMP, followed by 3 weeks of 250 mg IVMP.

Among medium-dose IVMP regimens, we found four combination studies using IVMP with either OGC or mycophenolate mofetil. In a retrospective study conducted in 2010,[15] IVMP (3 g) regimen, consisting of 1 g of IVMP administered over 3 consecutive days, followed by 40–60 mg of oral prednisolone tapered over 4 weeks, demonstrated improvement in 75% of patients after the initial treatment course. However, 8% of cases required a repeat cycle. Zhu et al.[16] compared weekly versus daily regimens of IVMP (4.5 g) where the daily protocol included 500 mg of IVMP daily for 3 consecutive days per week for 2 weeks, followed by 250 mg daily for 3 consecutive days per week for another 2 weeks, and subsequent tapering with oral prednisone. They found that CAS response with the weekly protocol was better, though the difference was not statistically significant. Similarly, Mu et al.[20] compared daily IVMP (4.3 g) with weekly IVMP (4.5 g). The daily regimen consisted of 500 mg IVMP daily for 5 consecutive days, followed by oral methylprednisolone for 3 months. They found that both the groups had similar significant decreases in CAS score (P < 0.01). In 2018, a study was conducted to compare weekly IVMP (4.5 g) versus weekly IVMP (4.5 g) with mycophenolate mofetil, and they documented that CAS score decreased significantly more in the combination treatment group than in the monotherapy group (P = 0.047).[12]

Among the studies that examined high-dose IVMP regimens, Geest et al.[13] compared IVMP (6 g) with placebo group. The regimen involved administering 500 mg of IVMP for 3 consecutive days, followed by four cycles at 4-week intervals. They documented significant improvement in the CAS score in the IVMP (6 g) group compared to the placebo group (P = 0.005). A similar protocol was used by He et al.,[9] where they compared monthly IVMP (6 g) versus weekly IVMP (4.5 g) regimen and found that CAS decreased significantly in both (47% vs 40%); however, 20% of patients deteriorated in the weekly group. Another retrospective study in 2020 compared a weekly IVMP (4.5 g) regimen with IVMP (3 g) + OGC (7.2 g) regimen, which included 500 mg IVMP for 2 alternative days, followed by OGC in tapering dose for the next 5 months. This study reported similar improvements in CAS by at least two points between the IVMP+OGC (10.2 g) and IVMP (4.5 g), P = 0.700.[10] Liu et al.[19] studied the role of IVMP (4.5–9 g), consisting of 0.5–1 g IV MP administered three times every other day and repeated every 20 days for three cycles and reported that CAS values reduced significantly from 8.24 ± 1.81 one month after therapy.

Decrease in exophthalmos

Among the studies that examined low-dose IVMP regimens, Bartalena et al.[11] found no significant differences occurred in exophthalmos among the 7.47 g, 4.98 g, and 2.25 g groups (21% vs 20% vs 32%), with deterioration at 12 weeks occurring in 12%, 13%, and 4% of patients in the respective groups. Lai et al.[23] reported that a 12-week IVMP regimen (4.5 g) led to a significant improvement in exophthalmos compared to a 6-week regimen (2.25 g) (P < 0.05).

Among the studies that examined medium-dose IVMP regimens, Yang et al.[17] found that a decrease in exophthalmos by more than 2 mm was observed in 28% of cases by 24 weeks among patients receiving weekly IVMP (4.5 g to 5 g). Additionally, Xing et al.[18] reported that 68% of nonsmokers showed significant improvement compared to 32% of smokers receiving IVMP (4.5 g). Li et al.[22] observed a significant reduction in exophthalmos, from 18.9 ± 2.42 mm before treatment to 16.9 ± 2.41 mm after treatment (P < 0.001), using a weekly IVMP regimen (4.5 g). In a 2022 study utilizing a matching-adjusted indirect comparison between teprotumumab, IVMP, and placebo, teprotumumab demonstrated a greater reduction in exophthalmos compared to IVMP, with a difference of -2.31 mm (95% CI, -3.45 to -1.17 mm).[24]

Among studies using the high-dose regimen, Geest et al.[13] documented that exophthalmos improved in 40% of patients receiving 6 g IVMP regimen compared to 28% in placebo group (P = 0.68). However, a new onset of exophthalmos was seen in four placebo groups. He et al.[9] compared monthly (6 g) and weekly (4.5 g) IVMP regimens and found that exophthalmos reduction was comparable in both the groups (35% vs 33%); however, five patients in each group experienced deterioration.

Among the four studies on IVMP plus OGC regimens, Tambe et al.[15] reported a mean exophthalmos improvement of 1.31 mm (range 0–3 mm) with IVMP (3 g)+OGC regimen. Zhu et al.[16] found that exophthalmos reduction was comparable between daily IVMP (4.5 g)+OGC versus weekly regimen of IVMP (4.5 g). Beleslin et al.[10] found the improvement in exophthalmos between the combined IVMP (3 g)+OGC (7.2 g) and IVMP (4.5 g) groups was not significant (29% vs 22%), (P = 0.58). However, Mu et al.[20] compared daily IVMP (4.3 g)+OGC versus weekly IVMP (4.5 g) and noted no improvement in exophthalmos may be due to short follow-up.

Resolution of diplopia

Among the studies that examined low-dose IVMP regimens, Bartalena et al.[11] found no significant differences in subjective diplopia among 7.47 g group versus 4.98 g versus 2.25 g group.

Among the studies that examined medium-dose IVMP regimens, Yang et al.[17] found that 25% of patients experienced resolution of diplopia by 24 weeks among patients receiving weekly IVMP (4.5 g to 5 g) regimen. Xing et al.[18] reported patients receiving IVMP (4.5 g); nonsmokers were more likely to have improved diplopia compared to smokers (82.6% vs 45.2%). However, a study by Li et al.[22] documented that diplopia did not show significant improvement following weekly IVMP (4.5 g) treatment. In a pilot study done by Xu et al.[21] using weekly IVMP (4.5 g), diplopia did not show a statistically significant improvement (P = 0.129). In a 2022 study using a matching-adjusted indirect comparison, IVMP did not show significant improvement in diplopia response odds over placebo (odds ratio, 2.69; 95% CI, 0.94–7.70), whereas teprotumumab was significantly more effective than IVMP (odds ratio, 2.32; 95% CI, 1.07–5.03).[24] Zhu et al.[16] found that the weekly protocol (44%) showed superior results in improving diplopia compared to the daily (22%) regimen of IVMP+OGC (4.5 g). Mu et al.[20] compared daily IVMP+OGC (4.3 g) versus weekly IVMP (4.5 g) and found that diplopia reduction was 50% in weekly and 63% in the daily group; however, two patients in the weekly group worsened.

In studies comparing high-dose regimens, diplopia improvement was seen in 50% of patients treated with 6 gm IVMP, while no improvement was seen in the placebo group (P = 0.073).[13] He et al.[9] compared monthly (6 g) versus weekly (4.5 g) IVMP regimen, finding that diplopia improvement was more in the monthly (6 g) group (47%) compared to the weekly (4.5 g) group (27%). The improvement in diplopia in Combined OGC+IVMP (10.2 g) versus IVMP (4.5 g) group was comparable (39% vs 34%).[10]

Side effects

Among the studies that examined low-dose IVMP regimens, Bartalena et al.[11] documented that two patients in 2.25 g group suffered major side effects, including new-onset diabetes mellitus and one death resulting from a myocardial infarction.

Among the studies that examined medium-dose IVMP regimens, Zhu et al.[16] showed that both weekly and daily IVMP+OGC protocols (4.5 g) had common adverse effects like weight gain and hypokalemia. However, severe adverse effects such as impaired liver function and intractable hiccups were noted in the daily protocol group, leading to discontinuation treatment. Mu et al.[20] reported that mild adverse events were more frequent in the in the daily regimen IVMP+OGC (11%) compared to the weekly IVMP protocol (4%), with no major side effects in either group. In a retrospective cohort study[17] involving weekly IVMP (4.5 g to 5 g), side effects were recorded in 47% of cases. Among these, the majority were mild and affected 44% of patients, including skin flushing during infusion (8 cases), minor depression (2 cases), Cushingoid features (2 cases), weight gain (1 case), and gastric symptoms (1 case). There was one significant adverse event where a patient developed diabetes mellitus necessitating hypoglycemic treatment.

In studies comparing high-dose regimens, Geest et al.[13] documented a temporary increase in liver enzymes in some patients in 6 g, which did not lead to serious adverse effects. Similarly, a 2017 study by He et al.[9] found no severe adverse events among IVMP weekly (4.5 g) regimen and monthly (6 g) regimen. However, one patient withdrew from the study due to severe gastric aches and headaches but recovered within a day after stopping the treatment. Additionally, a retrospective series in 2020 indicated significantly more side effects in the IVMP+OGC (10.2 g) compared to the IVMP (4.5 g) group (74% vs 38%, P < 0.001). In this series, two patients in the combined group developed severe infections (herpes zoster infection and pulmonary tuberculosis) and one patient in IVMP group had myocardial infarction.[10] Bartalena et al.[11] found that in the 4.98 g group, three patients developed major side effects: one case of severe depression, one of newly diagnosed diabetes mellitus, and one of profound muscle weakness. Six patients in 7.47 g group experienced major adverse effects, including two cases of severe depression, one case of psychosis, one severe infection necessitating hospitalization, and two instances of newly diagnosed diabetes mellitus. Liu et al.[19] studied the role of IVMP (4.5–9 g) and documented that one patient had serious liver injury who was taking fenofibrate at the same time as the IVMP therapy.

Recurrence

Among the studies that examined low-dose IVMP regimens, Bartalena et al.[11] observed no significant differences in recurrence rate at a 24-week follow-up among different dosage groups: 2.25 g group (40%) versus 4.98 g (21%) versus 7.47 g group (33%).

Among the studies that examined medium-dose IVMP regimens, Zhu et al.[16] reported a higher recurrence rate in the daily IVMP+OGC protocol (4.5 g) group, with 12 (29%) patients needing repeat therapy within 6 months, compared to only 3 (8%) in the weekly protocol group (4.5 g).

Kahaly et al.[12] found that relapses occurred in 11% of patients treated with IVMP (4.5 g) alone, compared to 8% in those receiving IVMP (4.5 g) combined with oral Mycophenolate Mofetil. Additionally, in a pilot study by Xu et al.[21] using weekly IVMP (4.5 g), three patients required a second course of IVMP after completing the initial treatment. In studies comparing IVMP+OGC regimens, recurrence was observed in 69.5% of patients who received IVMP for 3 days (3 g)+OGC over an average period of 15 months.[15]

In studies comparing high-dose regimens, a retrospective analysis comparing weekly IVMP (4.5 g) to a combined IVMP+OGC protocol (10.2 g) found that after 6 months of treatment, relapse of Graves’ orbitopathy (GO) occurred in 10 (26%) patients in the IVMP group, necessitating reinitiation of IVMP, while none of the patients in the IVMP+OGC group experienced a relapse (P < 0.001).[10] Additionally, following the completion of the initial weekly IVMP (4.5 g) cycle, a second course of IVMP with oral steroids was required in 15% of the patients.[22] He et al.[9] reported that a monthly IVMP regimen (6 g) had a lower recurrence rate (29.4%) compared to the weekly regimen (4.5 g) at 53.3%, although the severity of symptoms was higher in the monthly group.

Requirement of additional treatment

Among the studies that examined low-dose IVMP regimens, Lai et al.[23] found a higher percentage of patients in the 6-week (2.25 g) regimen required further treatment than those in the 12-week (4.5 g) regimen (P < 0.05). Bartalena et al.[11] found that at end of the treatment, in the 4.98 g group, 11 patients needed additional treatments, but this was not statistically significant compared to the 7.47 g and 2.25 g groups (8 patients each). Also, rehabilitative surgery (orbital decompression and/or squint surgery and/or eyelid surgery) was performed in all the three groups with no significant differences among them after a long term.

Among the studies that examined medium-dose IVMP regimens, HE et al.[9] found that only one patient in the weekly IVMP (4.5 g) group needed orbital decompression surgery at the end of treatment. At the end of 6 months of treatment, Zhu et al.[16] reported that in the daily IVMP regimen (4.5 g), 12 patients needed further treatments including additional IVMP, OGC, surgery, and orbital betamethasone injections, whereas only three patients in the weekly regimen (4.5 g) required repeat injections. In a retrospective cohort study done by Yang et al.,[17] 94% of the patients (30 individuals) required rehabilitative surgery within a 2-year period of IVMP treatment. Nonresponders more frequently underwent orbital decompression and squint surgery, whereas responders commonly had eyelid lengthening procedures. Mu et al.[20] documented that two patients on the weekly protocol IVMP (4.5 g) acquired diplopia with vision loss and needed additional IVMP. In studies comparing IVMP combined with OGC regimens, Tambe et al.[15] reported that at a mean follow-up of 15 months, 25% of patients were treated with IVMP for 3 consecutive days (3 g)+OGC, 25% required a repeat cycle, 67% underwent orbital decompression, and a few received additional treatments like orbital irradiation and steroid-sparing immunosuppression. Notably, decompression was performed after 3 months of completion of treatment.

In studies comparing high-dose regimens, Geest et al.[13] noted that all patients in the placebo group required additional treatment, with 22% needing radiotherapy and oral glucocorticoids and 89% undergoing orbital decompression, while only 33% of patients in the IVMP (6 g) group required orbital decompression at a follow-up of 12 months. Similarly, Liu et al.[19] investigated the impact of high-dose IVMP (4.5–9 g) and found that six participants received orbital irradiation at the end of treatment following IVMP therapy due to inadequate therapeutic outcomes.

Discussion

TED presents a significant disease burden,[25,26,27] impacting their quality of life and causing psychological stress and behavioral changes.[28,29,30,31,32] As a potentially disabling condition, TED can lead to a decrease in vision, diplopia, and progressive disfigurement.[24,33,34,35,36] The complex pathogenesis of TED complicates its management, often leading to dissatisfaction with the treatment outcomes.[25,35,37,38,39,40] As per Rundle’s curve, early immunosuppressive therapy during the active inflammation phase can alter the disease’s course, reducing long-term morbidity such as eyelid retraction, disabling diplopia, and potential visual loss, thereby improving both functional and esthetic outcomes.[6,41,42]

The optimal treatment regimen for TED remains uncertain, with various IVMP protocols reporting variable responses and lacking a clear consensus on dosage, interval, and treatment duration.[6,11,42] Despite its common use to reduce inflammation in TED, no systematic review has evaluated the safety and effectiveness of different cumulative doses of IVMP after EUGOGO protocol initiation. This systematic review aims to determine the safest and most effective treatment regimen for active moderate to severe TED.

Based on the studies, we can categorize the various cumulative doses into three dosage groups: LD at ≤2.5 g, MD between >2.5 g and 4.5 g, and HD at >4.5 g. Administration intervals include daily, weekly (most common), and monthly, with treatment durations ranging from 4 to 26 weeks, typically 12 weeks. The most common protocol compared was Weekly IVMP (4.5 g) for 12 weeks, which may be because it is the recommended treatment.[42] Overall, IVMP has been documented to be more effective and to improve the quality of life more than OGC in TED patients.[43,44]

Low-dose IVMP regimens are less effective in reducing CAS.[11,23] Medium-dose regimens, such as weekly IVMP (4.5 g), show significant improvements in CAS and quality of life, outperforming other protocols. High-dose IVMP regimens are effective but do not significantly surpass the medium-dose regimens.[9,13,19] Combining IVMP with OGC or mycophenolate mofetil does not significantly outperform IVMP alone, suggesting that IVMP monotherapy is effective for CAS reduction.[10,12,15,16,20] While both weekly and monthly IVMP protocols are effective, the weekly regimen is slightly more favorable in terms of CAS response.[9]

For exophthalmos reduction, the weekly IVMP (4.5 g) regimen consistently shows significant improvements and is generally more favorable than other protocols.[5,22,24] Combining IVMP with OGC does not offer additional benefits over IVMP alone.[10,15,16] Low-dose regimens are less effective, and high-dose regimens show similar effectiveness but with higher deterioration rates.[11,19] A 2022 study found that Teprotumumab demonstrated a greater reduction in exophthalmos compared to IVMP, making it potential area of future research.[24]

Diplopia improvement was inconsistent across studies; the monthly HD IVMP regimen showed better results with a 47% improvement rate compared to 27% in the weekly IVMP (4.5 g) group.[9] Combining IVMP with OGC showed slightly better results compared to IVMP alone.[10,16,20] However, Teprotumumab showed superior efficacy overall for diplopia improvement.[24]

Adverse events were observed across all the three regimens. Low-dose regimens generally exhibit a safer profile.[11,23] Medium-dose regimens (4.5 g) showed mostly mild side effects with occasional severe side effects like depression and new-onset diabetes mellitus. High-dose regimens and combination therapies generally reported more significant side effects, including severe infections, new-onset diabetes mellitus liver injury, and psychiatric issues.[10,15,16,24] These findings highlight the importance of careful dosage and regimen selection to minimize risks while ensuring treatment efficacy.

Recurrence rates varied across IVMP regimens, with low-dose protocols showing higher rates of 40%[4] compared to medium-dose regimens, where weekly IVMP (4.5 g) demonstrated lower recurrence (8%) than daily IVMP+OGC (29%).[16] High-dose regimens had mixed outcomes, with monthly IVMP (6 g) showing fewer relapses (29.4%) than weekly IVMP (4.5 g; 53.3%),[5] while combination protocols such as IVMP+OGC (10.2 g) reported no relapses compared to 26%.[10] Similarly, IVMP + Mycophenolate Mofetil (8%) had lesser recurrence compared to IVMP alone (11%).[3] These findings suggest better control of recurrence with combination therapies and highlight variability between dosage and administration protocols.

Additional treatment and rehabilitative surgery requirements varied across IVMP regimens. Low-dose protocols were associated with a higher need for additional treatments, though differences in rehabilitative surgery rates were not significant. Medium-dose IVMP (4.5 g) regimens generally required fewer additional treatments, with weekly protocols showing fewer needs than daily regimens. The high-dose regimen showed a lower need for further treatments. Combination therapies with OGC resulted in higher rates of repeat cycles and orbital decompression, often performed after treatment completion. Overall, higher dose or longer duration IVMP regimens required fewer additional treatments.

Limitations

Even though we used standard methods to evaluate indirect comparisons and adjusted for relevant clinical characteristics, comparing results across different studies is still subject to potential bias. At the study and outcome levels, there was significant heterogeneity and risk of bias among the included studies, with varied IVMP regimens and follow-up durations. Overall, among the studies included, two used LD regimens, 13 examined MD regimens, and six employed HD regimens, which created discrepancies and limited direct comparisons between groups. Additionally, most studies did not clearly specify their follow-up periods and the timing of rehabilitative surgeries, making it difficult to assess long-term outcomes and management strategies comprehensively. At the review level, the limitations included incomplete retrieval of identified studies and potential reporting biases, which may affect the comprehensiveness and balance of the review. These gaps highlight areas requiring further research to establish standardized regimens and clearer protocols for follow-up and rehabilitative interventions.

Conclusion

The weekly IVMP (4.5 g) regimen is the most commonly studied and appears to be a safe and effective treatment for moderate to severe TED. However, a limited number of studies on both LD and HD regimens and the differences in duration and dosage of both regimens across studies create challenges in direct interpretation, highlighting the lacunae that future research should address for better comparisons. Additionally, the use of immunomodulatory agents in combination with IVMP represents an emerging area of interest, with promising preliminary results that warrant further investigation.

Future research should focus on large-scale, randomized controlled trials to establish the optimal IVMP dosage, interval, and duration. They should also address the variability in managing recurrence, additional treatments, and the timing of rehabilitative surgeries.

Abbreviations and acronyms

TED: Thyroid Eye Disease, IVMP: Intravenous Methyl Prednisolone, OGC: Oral Glucocorticoid, HD: High Dose, MD: Medium Dose, LD: Low Dose, g: Gram, RCT: Randomized Control Trial, GD: Grave disease, GO: Graves Orbitopathy, GC: Glucocorticoid, PRISMA: Preferred Reporting Items for Systematic Review Guidelines, S/E: Side effects, EUGOGO: European Group on Graves’ orbitopathy, CAS: Clinical Activity Score, CI: Confidence Interval.

Conflicts of interest:

There are no conflicts of interest.

Funding Statement

Nil.