PEER REVIEWED

Oral Mineralocorticoid Receptor Antagonists for the Treatment of CSC

Long-term CSC can be treated orally.

EHSAN RAHIMY, MD • JOHN D. PITCHER, III, MD • MITCHELL S. FINEMAN, MD • JASON HSU, MD

Central serous chorioretinopathy (CSC) is a relatively common cause of visual impairment in the working-age population, often characterized by the accumulation of subretinal fluid in the macula. Affected individuals typically present with a variety of symptoms, including relative central scotoma, metamorphopsia, dyschromatopsia, and micropsia.^1,2

Clinically, the characteristic funduscopic appearance is that of a posterior neurosensory retinal detachment, sometimes with a focal underlying retinal pigment epithelial detachment also visible.

While CSC primarily affects men between the ages of 20 to 50 years old, it can be seen in a wide patient demographic, and it has been associated with “type A” personality traits, corticosteroid exposure, use of phosphodiesterase 5 inhibitors, exogenous testosterone supplementation, obstructive sleep apnea, and an irregular sleep cycle.^3-9

CHRONIC CSC

Although CSC is typically self-limited with spontaneous resolution of subretinal fluid and restoration of visual acuity by three months, up to 20% of patients may have persistent serous macular detachment extending beyond six months, leading to damage to the RPE and ongoing visual impairment.^13,14

If the subretinal fluid has not fully resolved by three months, the patient is defined as having chronic CSC, and treatment is often considered at this time. Additionally, treatment for cases of acute CSC may be reserved for patients with specific occupational needs necessitating excellent VA as soon as possible (eg, airline pilots; Figure 1).

Figure 1. Acute central serous chorioretinopathy in a pilot. A 44-year-old commercial airline pilot presented with 2 days of blurry central vision, micropsia, and metamorphopsia in the right eye (visual acuity: 20/40) interfering with his ability to safely perform his occupation. Fluorescein angiography (A) revealed a focal area of leakage into the subretinal space with a neurosensory subfoveal detachment confirmed by optical coherence tomography (B) imaging. After reviewing risks, benefits, and alternatives of all available treatment options, including observation, he elected for a trial of oral eplerenone therapy, which was started at 25 mg once daily for the first week, and titrated up to 50 mg once daily for the ensuing 4 weeks. At his 1-month follow-up, the patient reported complete resolution of symptoms (visual acuity: 20/20), and OCT (C) obtained at this visit demonstrated no subretinal fluid.

A detailed review of the epidemiology, pathophysiology, diagnosis, and various treatment options for managing CSC is beyond the scope of this current article but was covered in a recent issue of this publication.¹⁰

However, the association of CSC with corticosteroids, both exogenous (ie, oral, topical, intranasal, inhaled, intravenous, and intramuscular) and increased endogenous levels (ie, hypercortisolism, pregnancy, and stress-related triggers), has led to increased interest recently in this pathway as a potential therapeutic target.^3,4,11,12

Several smaller case series have demonstrated a possible benefit from systemic corticosteroid antagonists in treating chronic CSC, including ketoconazole,^15,16 mifepristone,¹⁷ finasteride,¹⁸ and rifampin.^19,20

More recently, emerging evidence implicating the mineralocorticoid receptor (MR) pathway in the disease pathogenesis has sparked interest in the use of MR antagonists as a potentially viable treatment option for CSC (Figure 2).

Figure 2. Bullous central serous chorioretinopathy (CSCR) in a functionally monocular patient. A 49-year-old female with history of chronic CSCR secondary to chronic nasal steroid use presented with 1-month history of vision loss to 20/400 in her better seeing eye secondary to acute exacerbation of CSCR with a circumscribed exudative macular detachment on funduscopy (A), multifocal leakage on fluorescein angiography (B), and extensive subretinal fluid on OCT imaging (C). Oral eplerenone was initiated and after 1 month of therapy (50 mg daily), her visual acuity returned back to 20/20 with near complete resolution of subretinal fluid on OCT imaging (D). After 2 months, all of the fluid had resolved, and her vision remained 20/20. Case presented with permission from: Murtaza Adam, MD.

INTERPLAY OF GLUCOCORTICOIDS AND MINERALOCORTICOIDS

Glucocorticoids exert their physiologic effects by binding to the glucocorticoid receptor; however, these hormones may also bind to the MR with similar affinity as the receptor’s natural agonist, aldosterone.

The balance of binding is regulated in part by the enzyme, 11-β hydroxysteroid dehydrogenase type II (HSD2), which is present in mineralocorticoid target tissues. Because there are significantly greater circulating levels of cortisol than aldosterone, HSD2 is able to prevent MR overstimulation by glucocorticoids and allow for selective mineralocorticoid action by catalyzing the deactivation of cortisol, the principal glucocorticoid, into cortisone.^21,22

In the human body, the kidney is the primary mineralocorticoid-sensitive organ. In the retina and choroid, expression of the glucocorticoid receptor, MR, and HSD2 have all been demonstrated.^21,23 Therefore, it has been hypothesized that glucocorticoid-induced effects in the retina and choroid may partly result from coactivation of the MR.^24,25

MINERALOCORTICOID RECEPTOR AND RETINAL DISEASE

Wilkinson-Berka and colleagues initially characterized the adverse effects of MR overactivation on the retinal microvasculature in a rat model of oxygen-induced retinopathy (OIR). In their study, angiogenesis in OIR was increased with aldosterone + salt (to potentiate the effects of aldosterone) but was reduced with the MR antagonist spironolactone.²⁶ In a follow-up study, the group again was able to attenuate neovascularization in OIR through aldosterone blockade, but this time using an aldosterone synthase inhibitor, FAD286.²⁷

With regard to CSC, Zhao et al demonstrated that mineralocorticoid activation in rat eyes via aldosterone or high-dose corticosterone induced choroidal vessel dilation and leakage, similar to that seen in humans with CSC.²⁵

Additionally, aldosterone-induced choroidal thickening was blunted in the presence of the MR antagonist canrenoate. Taken together, their findings suggested that inappropriate mineralocorticoid activation may play a role in the pathogenesis of CSC in humans.

PHARMACOLOGY OF EPLERENONE AND SPIRONOLACTONE

There are currently two MR antagonists commercially available in the United States: spironolactone and eplerenone (Inspra, Pfizer, New York, NY). Both agents have been shown to treat hypertension effectively and to improve morbidity and mortality in patients with advanced congestive heart failure (CHF).

Spironolactone, developed in the 1950s, is an older nonselective competitive antagonist of the aldosterone receptor. Due to its nonselectivity, administration of spironolactone additionally results in coantagonism of the androgen, glucocorticoid, and progesterone receptors.²⁸

Eplerenone is the first member in a new class of selective aldosterone antagonists originally approved in 2002 by the FDA for the treatment of hypertension and in 2003 for CHF after myocardial infarction. Derived from spironolactone, eplerenone was designed to enhance selective binding to the MR while minimizing binding to the other steroid receptors.²⁸

Significant differences exist in the pharmacodynamic and pharmacokinetic profiles of these medications. Most notably, eplerenone has a 10- to 20-fold lower binding affinity for the MR in vitro, compared to spironolactone.²⁸

However, in human studies, changes in blood pressure and hormone levels observed with the same daily dosage (100 mg) of spironolactone were greater than those with eplerenone, suggesting that, at least on a molecular weight basis, eplerenone is 50% to 75% as potent as spironolactone.²⁹

In addition, eplerenone has been demonstrated to bind with 100- to 1,000-fold lower affinity to the androgen, glucocorticoid, and progesterone receptors, compared to spironolactone.²⁸

Adverse Events

Adverse effects of both spironolactone and eplerenone include potentially life-threatening hyperkalemia, which can be potentiated by concurrent renal insufficiency, diabetes mellitus, advanced CHF, older patient age, and interactions with other drugs.^30,31

While both medications can produce dose-dependent rises in serum potassium concentrations, this effect appears to be greater with spironolactone when both are administered at the recommended dosages.^29,30

Additionally, due to its structural similarity to progesterone and its interaction with other steroid receptors, spironolactone is known to inhibit free testosterone from binding to androgen receptors, resulting in undesirable hormonal effects (gynecomastia, decreased libido, menstrual irregularities, and erectile dysfunction).^32,33 These sexual side effects are of particular concern, because patients are typically unwilling to tolerate them, and they are often a major reason for noncompliance with spironolactone.

Because of eplerenone’s selectivity for the MR, it does not cause these effects as frequently. For example, in the RALES trial, spironolactone caused gynecomastia and breast pain in 10% of CHF patients, compared to only 0.5% of CHF patients on eplerenone in the EPHESUS trial.^34,35

PROPOSED DOSING AND LABORATORY MONITORING FOR CSC

While there are no formal criteria for laboratory monitoring while patients are on MR antagonist therapy, several general guidelines have been proposed.^36,37 It is notable that these recommendations were made based on the initiating of treatment in patients with CHF and other vascular comorbidities that are likely to increase the risk of developing hyperkalemia.

In contrast, the patient demographic afflicted with chronic CSC that retinal specialists are likely to prescribe MR antagonists for are more likely to be younger and otherwise healthy. Nevertheless, a conservative surveillance approach in managing these patients while on therapy is justified. In general, it is judicious to confer with the individual’s primary care physician prior to starting this class of medications.

Any use of potassium supplements should be avoided when using MR antagonists. Before starting either medication, patients must undergo baseline laboratory testing to establish normal serum potassium levels and renal function.

While the suggested cutoff levels for withholding treatment may vary, we generally recommend avoiding MR antagonists if the baseline serum potassium concentration is >5.5 mEq/L, the creatinine clearance is <50 mL/min, or the serum creatinine is >2 mg/dL in men and >1.8 mg/dL in women. We then obtain a follow-up basic metabolic panel one month after the initiation of treatment and every month while on treatment thereafter.

If a patient is on therapy for longer than three months with stable potassium levels and renal function, we reduce the frequency of subsequent testing to every three months. However, close collaboration with the PCP and/or specialist (eg, cardiologist) is very helpful for managing these patients.

Clinical examinations are initially conducted on an approximately monthly basis with serial optical coherence tomography imaging to assess for improvement/resolution of subretinal fluid. Patients should additionally be educated regarding potential hyperkalemic symptoms (malaise, muscle weakness, palpitations), and these symptoms should be assessed at each clinic visit.

Further Considerations

Concurrent use of MR antagonists together with other drugs that may exacerbate hyperkalemia, such as ACE inhibitors and NSAIDs, should prompt enhanced electrolyte surveillance during the treatment period.^38-40 Furthermore, unlike spironolactone, eplerenone is primarily metabolized by the cytochrome P450 (CYP) 3A4 system.⁴¹

Thus, we recommend avoiding eplerenone therapy altogether in patients who are already taking potent CYP3A4 inhibitors (amifostine, cyclosporine, fluconazole, itraconazole, ketoconazole, mifeprestone, posaconazole, clarithromycin, rituximab, tacrolimus, bactrim or voriconazole) because simultaneous use may significantly reduce eplerenone metabolism and markedly increase its circulating concentrations.⁴¹

Due to the overall decreased incidence of systemic side effects, we tend to prefer treatment first with eplerenone for chronic CSC in our practice. Therapy is generally started at 50 mg once daily. If a patient does not respond to therapy, and their laboratory indices are within a normal range, we consider doubling the daily dose to 50 mg twice per day.

Treatment Continuation and Termination

If, during subsequent testing, serum potassium levels rise to between 5.0 and 5.5 mEq/L, the physician may consider halving the dose to 25 mg daily or stopping the treatment altogether, depending on the input from the patient’s PCP and/or specialists. If serum potassium is >5.5 mEq/L (in a non-hemolyzed blood sample) at any point, then treatment is stopped. Similarly, if renal function parameters decline to the threshold levels indicated above, treatment should be discontinued.

As long as these markers remain in an acceptable range, treatment is continued. In most cases, a three-month course is initially prescribed, although it may be stopped sooner if there is complete resolution of subretinal fluid, or it may continue if there are signs of improvement on therapy but with residual exudation or concerns about recurrence.

Ghadiali and colleagues recently reported positive longer-term outcomes over 12 months of MR antagonist therapy in a cohort of 14 chronic CSC patients with minimal incidence of side effects.⁴² Treatment can be reinitiated in the future if the disease process reactivates (Figure 3).

Figure 3. Chronic recurrent central serous retinopathy responsive to eplerenone. Gradual improvement on OCT imaging from baseline (A) after 1 month (B) and 2 months (C) of oral eplerenone (50 mg daily) with resolution of subretinal fluid. One year after completion of therapy, the patient experienced disease reactivation (D) prompting reinitiation of eplerenone, which again resolved over the ensuing 2 months (E).

If spironolactone is prescribed, we would recommend starting with a dose of 25 mg daily and titrating up to 50 mg daily after the one-week mark as long as laboratory indices are in the range of acceptable as delineated above.

It is worth nothing that other groups with more experience using spironolactone for CSC have initiated therapy at 50 mg daily from the onset,^43,44 and some have prescribed doses of up to 100 mg daily.⁴⁵

For comparison, when used to treat primary hyperaldosteronism, the maximum daily dose of eplerenone is 200 mg and 400 mg for spironolactone. That said, the optimal dose or total duration of MR antagonist therapy required to treat CSC most effectively has not been fully elucidated and is the subject of ongoing investigations.

MR ANTAGONISTS IN CSC: “REAL-WORLD” CLINICAL EXPERIENCE

To date, 16 peer-reviewed publications have reported on the effects of MR antagonists on chronic CSC (>3 months duration) in a cumulative total of 282 eyes of 248 patients (average age: 54 years old).^25,42-56

Nine of these studies evaluated outcomes on eplerenone alone,^{25,46-51,54,55} three evaluated spironolactone alone,^43,44,56 and four evaluated both medications.^42,45,52,53 Three of these were prospective studies, which are reviewed below, while the remainder were retrospective case series with two being individual case reports.

Retrospective Case Series

In 2012, Zhao and colleagues published their initial experience using eplerenone (25 mg for one week, followed by 50 mg for the next four weeks) to successfully treat chronic nonresolving CSC in two patients.²⁵ They observed rapid resolution of subretinal fluid, reduced choroidal vasodilation, and improved VA in both individuals.

In 2013, the authors followed up with a prospective, nonrandomized pilot study to validate their proposed hypothesis of MR overactivation contributing to CSC development.⁴⁶ Thirteen consecutive patients (13 eyes) with chronic CSC of at least four months in duration were treated with eplerenone at the same doses (but with treatment up to three months). After three months, the authors observed objective improvements in all 13 cases, with statistically significant reductions in mean central macular thickness, subretinal fluid height, and increased VA.

Specifically, eight patients (61.5%) experienced complete resolution of subretinal fluid at the conclusion of the study period. The primary limitations of this study, however, were its small size and lack of a placebo-treated group.

Herold and colleagues reported on their own prospective, nonrandomized trial in 2014 evaluating spironolactone 25 mg two times daily for up to 12 weeks.⁴³ Eighteen consecutive patients (20 eyes) with chronic nonresolving CSC were enrolled in this study.

At the final three-month follow-up visit, the authors noted statistically significant improvements in central macular thickness, subretinal fluid, and VA. Notably, five (25%) of the eyes experienced complete resolution of subretinal fluid after treatment.

In 2015, Bousquet and colleagues published the only prospective, randomized, double-blind, and placebo-controlled study to date on the effects of MR antagonist therapy in treating CSC.⁴⁴ Using a crossover study design, 16 patients with chronic CSC were randomized to receive either spironolactone 50 mg daily or placebo once daily for the first 30 days. This stage was then followed by a one-week washout period with no treatment, and then the patients were switched over to the other treatment group for the ensuing 30 days.

A statistically significant reduction in subretinal fluid in eyes treated with spironolactone was measured, compared with the same eyes under placebo, supporting the investigators’ experimental hypothesis. Statistically significant reductions in subfoveal choroidal thickness were additionally observed, but no significant changes in VA were noted during the study.

Given the variability in study protocols, primary endpoints measured, and follow-up periods, drawing definitive conclusions from pooled data across all published studies is challenging. Nevertheless, 71.3% of treated eyes (201 of 282) experienced some form of objective improvement (VA, subretinal fluid, and/or central macular thickness measurements) after completing MR antagonist therapy.

Furthermore, when data were available, 46.5% of treated eyes (99 of 213) demonstrated complete resolution of subretinal fluid at the conclusion of their treatment regimen. While both agents appear to be efficacious options for chronic CSC, any differences between the two remain to be elucidated with future head-to-head comparisons using a larger cohort of patients.

Regarding safety, both drugs were relatively well-tolerated. Treatment-related side effects were observed in 7.8% (14 events) of eplerenone-treated patients, necessitating early treatment cessation in 10 cases. For those taking spironolactone, 21.8% (19 events) of patients experienced side effects, resulting in early termination in 12 instances.

The most common side effects experienced were dizziness, fatigue/malaise, weight loss, gastric/bowel discomfort, and blood pressure fluctuations. Notably, gynecomastia was reported in three cases (two on spironolactone, one on eplerenone), and hyperkalemia resulting in medication discontinuation was reported in two cases (both on eplerenone).

CONCLUSION

In summary, treatment of long-standing CSC with either eplerenone or spironolactone seems to be beneficial and well tolerated when carefully monitored. The class of MR antagonists offers a new potential oral medication in the retinal specialist’s armamentarium for treating a condition with no set gold-standard therapy.

A careful discussion with patients, weighing the potential risks, benefits, and alternatives of all potential treatment options, is warranted prior to initiating any of these off-label treatments. Further prospective, controlled studies in a larger population of patients are warranted and currently ongoing to evaluate the most appropriate doses and duration of oral MR-antagonist treatment in nonresolving CSC. RP

REFERENCES