Comparison of the therapeutic effects of 15 mg and 30 mg initial dosage of prednisolone daily in patients with subacute thyroiditis: protocol for a multicenter, randomized, open, parallel control study

Subacute thyroiditis (SAT), also named subacute granulomatous or subacute painful thyroiditis or de Quervain thyroiditis, is a transient inflammatory thyroid disease [1]. SAT is the most common painful thyroid disease and the prevalence of SAT is nearly 5% in the population with abnormal thyroid function [2]. According to the data from the Rochester Epidemiology Project in Olmsted County, Minnesota, the incidence of SAT was reported as 12.1 cases per 100,000/year with a higher incidence in females than in males (19.1 and 4.1 per 100,000/year, respectively) [3, 4]. Over 95% of people with SAT often present with moderate-to-severe pain [3], which may be limited to the region of thyroid or radiate to the upper neck, jaw, throat, upper chest, or ears. The pain may begin focally and spread from one side to the other of the gland over several weeks. Patients may also have fever, fatigue, malaise, anorexia, and myalgia.

SAT is a self-limiting disease and the primary treatment is to relieve thyroid pain. Several clinical guidelines, such as the American Thyroid Association (ATA) [5] and the Chinese Endocrinology Association [6], recommend anti-inflammatory agents based on the severity of symptoms. Non-steroidal anti-inflammatory drugs (NSAIDs) are initially used, particularly for mild cases. Oral glucocorticoids (prednisolone [PSL]) are suggested when patients fail to respond, or present initially with moderate to severe pain and/or thyrotoxic symptoms. ATA and UpToDate Clinical Consultants recommend that patients who fail to respond to full doses of NSAIDs over several days (2–3 days) should be treated instead with oral corticosteroid therapy. PSL of 40 mg daily for 1–2 weeks followed by a gradual taper over 2–4 weeks or longer is the most popular recommendation [5]. According to the Chinese Endocrinology Association, the initial PSL dosage of 20–40 mg daily is recommended [6].

However, albeit strong recommendations, the treatment protocol is based on low-quality evidence [3, 7‐11] and high-quality clinical trials are lacking with respect to the optimal initiation dosage and usage of corticosteroids. Considering the short- and long-term adverse effects on many organ systems and that the risk is both dose- and duration-dependent [12‐16], it is essential to consider the possibility of starting with a minimal dosage of corticosteroid and stop for a short duration. A recent observational study showed that the treatment protocol of PSL 15 mg daily as the initial dosage with tapering by 5 mg every 2 weeks was effective and safe for Japanese patients [17]. In addition, a retrospective study found that PSL treatment with mean dose of 15.0 mg/day (range = 14–16 mg/day) was superior to NSAIDs with regard to resolution of symptoms [18]. Based on the findings, we hypothesized that a low initial dosage of PSL seemed effective in the treatment of SAT; unfortunately there was a lack of high-quality well-designed clinical trials.

Therefore, in the present randomized controlled trial (RCT), we will use 15 mg/day of PSL as the initial dosage for treatment in patients with SAT who fail to respond to full doses of NSAIDs or present initially with moderate to severe pain, with the aim of evaluating whether 15 mg/day of PSL could provide non-inferiority effectiveness but with lower risk and more safety compared with 30 mg/day of PSL.

Corticosteroids are important in the treatment of subacute thyroiditis; however, numerous adverse effects have been attributed to corticosteroids. Several retrospective reports have shown that long-term use of corticosteroids, even in low doses, is a significant independent predictor of adverse effects [12‐16]. For example, a study found that the average daily prednisone dose was the strongest predictor of an adverse effect potentially attributable to glucocorticoid therapy (odds ratio = 4.5 for 5–10 mg and 32.3 for 10–15 mg) [12]. Studies also suggest that even short-term use of glucocorticoids may be associated with serious adverse effects. For example, a retrospective cohort study included 327,452 adults aged < 65 who received at least one short-term prescription over a 3-year period; results showed that there was an increase in the rates of sepsis, venous thromboembolism, and fracture [16]. Adverse effects may be not necessarily serious but displeasing to patients (e.g. Cushingoid appearance), life-threatening (e.g. serious infections), symptomatic (e.g. gastrointestinal ulcer), or largely asymptomatic until a later manifestation develops that requires medical attention (e.g. acute vertebral collapse). However, due to the relative short-term study period in the present trial, some long-term AEs cannot be collected and we may have difficulty in comparing adverse effects between groups, which is the limitation of the study. Meanwhile, because the risk is both dose- and duration-dependent, the time period of PSL usage was chosen as the primary endpoint; if non-inferior results are obtained, a lower initial dosage of PSL with a non-inferior time period will theoretically indicate reduced adverse effects.

This article presents the rationale and design of a RCT to test the effectiveness and safety of 15 mg daily of PSL versus 30 mg daily of PSL as the initial dosage in patients with SAT. This is the first RCT on this topic in Chinese people; by providing high-quality evidence, the present study will try to address the question of whether a lower initial dosage of PSL could provide non-inferiority effectiveness but with lower risk and more safety. If confirmed, our clinical practice may be modified to some extent, and patients may ultimately benefit.