Early Use of Steroid-Sparing Agents in the Inactivation of Moderate-to-Severe Active Thyroid eye Disease

A Step-Down Approach

Zuzana Sipkova; Elizabeth A. Insull; Joel David; Helen E. Turner; Shay Keren; Jonathan H. Norris


Clin Endocrinol. 2018;89(6):834-839. 

In This Article


Presented is a retrospective audit of the clinical outcomes of 24 consecutive patients with moderate-to-severe active thyroid eye disease (TED) treated with steroid-sparing agents (SSAs) as first-line therapy. Adjuvant intravenous methylprednisolone (IVMP) was commenced simultaneously as bridge therapy due to slower onset of action of methotrexate and other SSAs. Overall, our results illustrate a substantial reduction in total IVMP dose required compared to standard dose recommended by EUGOGO[4] (Figure 2) alongside a significant improvement in the clinical activity of the disease based on VISA inflammatory index score throughout follow-up (Figure 3). Using our treatment protocol, patients also needed almost 50% fewer visits for intravenous therapy.

A large number of immunosuppressive therapies have been studied to minimize the autoimmune inflammatory phase of the natural course of TED, but no consensus regarding the optimal treatment has been reached.[3] Since the 1950s, glucocorticoids (GC) have been the most common immuno-suppressants used in treatment of active moderate-to-severe TED. Several randomized-controlled trials and meta-analyses have proven their beneficial effect with reported response rate of approximately 80% for intravenous GC and 50% with oral GC.[6] As a result, EUGOGO recommends intravenous methylprednisolone (IVMP) as first-line treatment for moderate-to-severe active TED with starting dose of 0.5 g once weekly for 6 weeks followed by 0.25 g once weekly for 6 weeks and optimal cumulative dose of 4.5–5.0 g.[3,4] Although effective, the use of GC has numerous associated side effects, including hypertension, infections, gastritis, diabetes, osteoporosis, and psychosis.[14] Acute liver damage has been reported in approximately 1% of patients treated with IV GC, resulting in fatal liver failure in a few cases.[15,16]

Several alternative pharmacological steroid-sparing immuno-suppressive agents, including methotrexate (MTX),[5,14,17] ciclosporin,[7] and azathioprine[8] have been studied.[8] More recently, rituximab has been shown to be effective at suppressing inflammation in TED and can be considered a second-line therapeutic option in moderate-to-severe active TED.[4,9,10,18]

In the Oxford multi-disciplinary TED (OxTED) clinic we use a 'step-down' approach in treatment of moderate-to-severe active TED, starting intensive combination therapy of an SSA and IVMP in the early stages of disease and then tapering down once appropriate clinical response is achieved. The aim is to modify natural disease progression early, thus limiting its severity and reducing the requirement for rehabilitative surgery once inactive. This type of regimen has been well studied in early management of rheumatoid arthritis. It showed increased effectiveness without increase in adverse effects in comparison to the step-up approach.[19,20]

We use methotrexate (MTX) as first-line SSA. It has been widely used as the preferred treatment in several autoimmune conditions requiring long-term immunosuppression, such as rheumatoid arthritis. It has anti-inflammatory and immunomodulatory properties when administered at lower doses. By inhibiting dihydrofolate reductase enzyme, MTX leads to enhanced extracellular release of adenosine, thus decreasing the production of inflammatory cytokines.[21] Its clinical usefulness has been previously demonstrated in treatment of noninfectious orbital inflammatory disease in patients failing to respond to systemic GCs.[14]

A small number of retrospective studies have been published showing encouraging results of MTX use as second-line TED treatment.[5,14,17] Strianese et al observed improvement in extraocular motility and significant reduction in clinical activity scores (CAS) in 36 patients with TED who had to stop GC due to side effects.[5] A recent study by Rivera-Grana et al of 14 TED patients with previous history of GC dependence found 64% of patients were able to discontinue GCs completely while on MTX treatment without re-activation of TED. Similar to our approach, higher doses of MTX were given with an average of 15 mg/week orally and 20 mg/week subcutaneously.[17]

In patients with insufficient response to MTX alone, our practice is to add ciclosporin with or without azathioprine. Ciclosporin has been shown to result in greater reduction in TED activity score compared to oral GC alone and lower relapse rate after discontinuation of steroid therapy.[7] Despite a reduction in thyroid-associated antibodies in patients on azathioprine, no difference in clinical findings was found compared to a control group.[8]

The comparable response rate for different disease-modifying agents in treatment of active TED suggests that these are only effective if commenced early in the disease course. This emphasises the importance of EUGOGO recommendations of early referral and treatment in multi-disciplinary TED clinics.[3,4]

Overall, we found the use of SSAs was associated with good safety and tolerability. No serious adverse effects were reported with any of the SSAs we used. A small number of patients taking MTX noted mild, predominantly gastro-intestinal, side-effects such as nausea. These improved on switching from oral to subcutaneous MTX and by administering folic acid on a daily basis instead of weekly. One patient's blood tests showed deranged liver function, which normalized spontaneously after stopping MTX.

The limitations of this study arise from the retrospective nature of data collection which relies on the quality of clinical records. Our sample size was moderate and the study was single-centre. In addition to clinical markers of disease activity, it would have been useful to study the serum TSH receptor antibody (TRAb) levels which have been reported to correlate well with the clinical course of Graves' disease.[9] Although now routinely performed for all patients seen in OxTED clinic, data on pre- and post-treatment TRAb levels was only available for a small proportion of patients included in this study (Table 2).

We report on the effect of SSAs on disease activity as assessed by the VISA inflammatory index score. Unfortunately, the retrospective nature of this study did not permit evaluation of the treatment effect on the overall VISA severity score, which is a major limitation of our study. Further evaluation of the treatment effect on the global VISA score, including 'vision', 'strabismus', and 'appearance' grading would be useful.

We recognise that the natural course of TED is improvement over time and further prospective double-blinded controlled trials with larger sample size are needed to confirm long-term MTX efficacy and safety in treatment of active moderate-to-severe TED.