Cogan's syndrome: State of the art of systemic immunosuppressive treatment in adult and pediatric patients

Abstract

Objective

The aim of this study was to systematically evaluate the evidences for treatment of Cogan's syndrome (CS), with reference to adult and younger patients described in the literature.

Systematic review methodology: data sources

Studies reviewed were English language original articles ranging from 1990 to 2016 reporting data for subjects with CS (typical and atypical) undergoing any systemic treatment other than steroids alone. Medline/EMBASE, Cochrane Library were searched. The full text of articles meeting selection criteria was reviewed for: study type, diagnosis, number of subjects, treatment type and duration, clinical and/or functional outcomes, possible systemic manifestation or other autoimmune syndromes combined.

Results and conclusions

The authors identified 76 relevant reports: 4 prospective studies, 2 retrospective studies, 12 case series and 58 case reports. The studies included a total of 141 new patients: based on the available data, 46 men and 50 women with a mean age of 33 years (range 5–69). In the descriptive analysis adult patients (N = 87) were separated from pediatric patients (< 18 years old) (N = 17).

Concerning treatment strategies, except for a first-line approach to check for a rapid remission, or for a drug sensibility often supporting the diagnosis, a long-term steroidal monotherapy is no longer recommended in CS. As in other autoimmune and rheumatologic diseases, combined treatment with steroid-sparing immunosuppressant agents, also considering “biological” drugs, is nowadays preferred. However, the evidence of clearly effective or preferable treatment options for CS remains lacking, mostly due to the rarity of the disease and to the consequent difficulty in organizing high-quality prospective trials.

Introduction

Cogan's syndrome (CS) is named after the ophthalmologist David G. Cogan, who was the first to report “non-syphilitic interstitial keratitis and audiovestibular symptoms” [1]. The disease was probably present long before this formal identification, with Ludwig van Beethoven perhaps its most prominent sufferer [2]. CS is a rare autoimmune disease characterized by ocular inflammation and Ménière-like episodes including hearing loss, vertigo, and tinnitus. A number of possible related findings were described all with a pathogenetic mechanism of vasculitis. The ocular and audiovestibulary manifestations can develop within a few days to weeks from each other but can also progress several months apart. This clinical course makes the diagnosis challenging and often delayed. Possible combined systemic manifestations are mostly neurological, rheumatological, cardiovascular, and gastrointestinal; they can be very severe or potentially lethal [3], [4], [5], [6], [7], [8]. In 1980, Haynes et al. proposed a distinction between “typical” CS, as originally defined by Cogan, with the presence of iritis and conjunctival hemorrhage as possible additional features; and “atypical” CS (ACS), in which another significant inflammatory eye lesion such as chronic or recurrent conjunctivitis, scleritis, uveitis, optic disc edema, and retinal vasculitis is present in addition to or other than interstitial keratitis [8]. ACS is defined also in patients with audiovestibulary symptoms which occur more than 2 years before or after the onset of eye symptoms, or are not Menière-like. It is more common for patients with ACS than for those with typical CS to have systemic manifestations [3]. The etiology of CS is not clearly demonstrated but several evidences support an autoimmunity mechanism, particularly for the inner ear disease [9]. Infection was considered a trigger for the disease; the exposure to toxic substances or pollutants was also mentioned as possible involved agents. A third disorder, which may have an overlapping pathogenesis and manifestations, is autoimmune inner ear disease (AIED), defined as primary when the pathology is restricted to the ear and secondary when it occurs in the context of a systemic autoimmune disease [10], [11]. Since this form does not affect the ophthalmological competence we did not consider it in the present review.

Treatment of CS traditionally consisted of systemic corticosteroids, with the ocular symptoms being more responsive than the audiovestibulary symptoms. Since high doses of corticosteroids or prolonged treatment courses were required in many patients, immunosuppressive agents were increasingly combined. Finally, in cases with severe sensorineural hearing loss unresponsive to intensive and/or innovative immunosuppressive regimens cochlear implantation is still a valuable rescue surgical strategy for functional maintenance. As for all the autoimmune syndromes, however, also in CS surgery should be ideally postponed until a long-term medical control of the inflammatory manifestations is obtained.

In this review we considered all the English-written original articles describing systemic therapeutic approaches for CS other than steroidal monotherapy. Immunosuppressive drugs employed for treatment are discussed individually with reference to the pharmacological class, as proposed in a recent systematic review on treatments for AIED [12]. For the purpose of this review we considered without distinction both typical and atypical cases, since the published literature is not always unique concerning the definition of these terms and the clinical classification of the considered cases.