Is There a Safe Systemic Corticosteroid Dose?

Systemic corticosteroids (CS) are an essential, frequently used therapy for patients with a variety of sight-threatening inflammatory eye diseases (IEDs). Although CS therapy is effective and often induces rapid control of inflammation, it is associated with significant morbidity and mortality. Long-term systemic CS use in the treatment of eye disease, rheumatological diseases, and organ transplantation has been shown to increase the risk of hypertension, hyperlipidemia, diabetes, and cardiovascular disease.¹ A large prospective trial of CS therapy in patients with rheumatoid arthritis (RA), stratified into no or limited steroid exposure, medium dose (> 7.5 mg/day) and long-term exposure, demonstrated that CS use is an independent risk factor for hypertension.² This important observation has been substantiated in several studies.^3,4 Several large population studies have also demonstrated an increase in cardiovascular disease in subjects treated with high-dose CS.^3,5 In one study, patients were stratified into groups based on CS dosages and route of administration as high (>7.5 mg/day), medium (<7.5 mg/day), or low (dosages lower than physiological range) and adjusted for variables such as diabetes, age, sex, and associated comorbidities. They reported a 2.5 times increased risk of cardiovascular events compared to controls.⁵

Despite widespread concern at the many complications of prolonged high-dose CS therapy, there have been no well-conducted prospective studies to provide guidelines for the appropriate dose and duration of systemic CS therapy to prevent cardiovascular and other complications. Recently, Ocon et al.,⁶ in a study of short-term dose and duration-dependent CS risk for cardiovascular events in CS-naïve patients with RA,⁶ have provided potential guidelines for minimizing the cardiovascular complications of systemic CS therapy. This well-designed observation study from the CorEvitas RA registry reported on 19,902 patients for a total of 66,436 patient-years and reported the incidence of cardiovascular events including cardiac death, acute coronary syndrome, stroke, hospitalization for hypertension, and peripheral vascular occlusions.⁶ Critically, the authors demonstrated that doses >5 mg after adjustment for potential confounders were associated with an increased risk of cardiovascular events HR 1.56 (95% CI 1.18–2.05). Cumulative doses of prednisolone of 750 or 1110 mg in a 6-month period were associated with an increasing risk HR 1.43 (95% 1.04–1.98) and HR 2.05 (1.42–2.94). Interestingly, a prednisolone dosage ≤ 4 mg per day and duration < 80 days was associated with fewer cardiovascular events. While there are notable differences between patients with RA and those who require systemic CS treatment for IED, this article highlights several important points. Patients with RA have systemic inflammation, which is hypothesized to accelerate atherosclerosis and subsequent cardiovascular events.⁷ In contrast, patients with IED most commonly have organ-specific ocular inflammation, which cannot be controlled with local or regional therapies, thus necessitating systemic medication. These patients may also have comorbidities that contribute to increased risk of cardiovascular disease, such as hypertension, hypercholesterolemia, and diabetes.

We previously conducted a review to evaluate the risk of CS therapy in patients with IEDs and could find no studies that addressed the risk of cardiovascular events in patients with IED.⁸ The largest population-based study in patients requiring systemic immunosuppression for uveitis, the Systemic Immunosuppressive Therapy for Eye Disease (SITE) cohort, did not comprehensively evaluate cardiovascular mortality or morbidity.⁹ The SITE study involved a retrospective study of patients treated with systemic CS and the development of hyperglycemia, a common complication and risk factor for vascular disease, within 12 months of the initiation of therapy. Initial CS dosages > 40 mg/day had a significantly increased risk of hyperglycemia requiring treatment, compared to subject treated with dosages < 40 mg/day (RR 3.21, 95% CI 1.06–9.77 and 5.54, 95% CI 2.00–15.3, respectively).¹⁰ However, this was not correlated with cardiovascular effects.

The early introduction of traditional disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs has resulted in improved safety and less drug side effects for patients with IED. Recent studies have demonstrated that uveitis specialists are increasingly prescribing these medications early in the disease course to lower the CS burden.^11–14 Similarly, In patients undergoing solid organ transplantation, there is significant evidence that avoiding high-dose CS, such as the use of alternative day CS therapy, early withdrawal of CS after transplantation, and steroid-free maintenance therapy results in lipid levels returning to pretreatment levels and hopefully reducing cardiovascular disease.¹⁵

Increasingly, it appears that there is no safe long-term CS dose. Clinicians should aim to reduce the dose of systemic CS as soon as possible after gaining disease control and to maintain their patients on less than or equal to 5 mg prednisolone (or equivalent) for as short a period as possible to minimize cardiovascular and other side effects. This is often best achieved by co-management with a physician (such as a rheumatologist or clinical immunologist) accustomed to the use of DMARDs as well as consultation with the patient’s primary care physician. If control cannot be maintained on maximal tolerated dose of a single DMARD, then either an additional conventional DMARD or a biologic should be added to limit the CS burden.

While cardiovascular risk factors and disease are not the only problems associated with high-dose and prolonged CS therapy, other complications, such as obesity, cushingoid features, metabolic changes, psychological effects, infections, and osteoporosis, would also benefit from decreasing the dose and duration of CS treatment.

Large real-world uveitis outcomes registries will help further address this important clinical question regarding the safety profile of CS dosage and duration, and the incidence of cardiovascular and other morbidities. The study by Ocan et al. adds compelling evidence that our aim in managing patients with IED who require systemic therapy should be a durable CS-free remission.