Elsevier

Autoimmunity Reviews

Volume 13, Issues 4–5, April–May 2014, Pages 351-354
Autoimmunity Reviews

Review
Cogan syndrome — Pathogenesis, clinical variants and treatment approaches

https://doi.org/10.1016/j.autrev.2014.01.002Get rights and content

Abstract

Non-syphilitic keratitis, coexisting with vestiboloauditory symptoms namely hearing loss and dizziness was first reported by Morgan and Baumgartner back in 1934. It was then ten years later when D.G. Cogan, an ophthalmologist (1908–1993) described 4 patients having the same symptoms but in addition, attacks of vertigo, tinnitus, hearing loss and ocular symptoms. This was published in Archives of Ophthalmology in 1945 and later named Cogan's syndrome (CS). Almost 20 years later on, bilateral recurrent episcleritis associated with vestiboloauditory symptoms were defined to be the atypical form of CS occurring in association with rheumatoid arthritis (RA). During the coming two decades the division of CS into typical (classical) and atypical variants, based mainly on the clinical presentation of this syndrome was accepted. Typical CS manifests primarily with interstitial keratitis and hearing loss, whereas atypical CS is usually presented with scleritis, chroiditis and more frequently with systemic inflammation. Approximately, 70% of these patients have systemic manifestations, of which vasculitis is considered the pathogenic mechanism and therefore carries a less favorable prognosis than typical CS. Since then, CS was considered by many to be autoimmune or immune mediated in origin, supported mainly by the beneficial response to corticosteroids. It was only later, using well developed assays such as western blotting and immunofluorescence (IF) when antibodies to inner ear antigens, anti neutrophil cytoplasmic antibodies (ANCA) and anti-endothelial antibodies were found and described to be associated with CS.

Introduction

The autoimmune theory in CS was finally confirmed in the 80s by the frequent finding of many autoantibodies against corneal, inner ear and endothelial antigens part of which are considered specific and of diagnostic value [1], [2], [3], [4]. Later, other autoantibodies such as ANCA, rheumatoid factor (RF) and others were also found to be present in association with CS though of less specificity, but further pointing to the autoimmune origin of CS. In acceptance with this is the early report on the histopathological nature of Cogan's. In this report the examination of corneal tissue and cochlea from patients with CS showed lymphocytic and plasma cell infiltration, strengthening the assumption that this disorder is of immune-mediated character [5].

Using the indirect IF technique, IgG and IgA antibodies against human cornea and IgG antibodies against human inner ear tissue were demonstrated in the serum of a patient with Cogan's syndrome. In contrast, sera of healthy individuals were free of such antibodies. This finding was the beginning of suggesting autoimmune mechanisms to be responsible for the development of CS [6]. In another study back then, antibodies against healthy inner ear tissue were found in the serum of 15 out of 21 patients suffering from idiopathic progressive sensorineural hearing loss. In 2 cases of CS, in addition to the above finding, it was also possible to demonstrate serum antibodies against epithelial structures of the cornea [7]. A decade later, aiming to establish the finding of autoantibodies to inner ear antigens and corneal structures, the serum of CS patients, namely IgM and IgG was analyzed for its ability to bind fresh cryosections of rat labyrinth and cornea. The predominant pattern of anti-corneal IgM was staining of the superficial cell layer of the non-keratinizing squamous epithelium. IgM against cornea was found in 3 patients, all of whom had bilateral inflammatory eye signs at the onset of the disease. During the first episode of CS in one patient, anti-corneal IgM became detectable one week after the onset of interstitial keratitis and 3 weeks after the onset of audiovestibular symptoms [8]. When humoral immune responses to inner ear proteins were studied in patients with sensorineural hearing loss (SNHL), antibodies to both heat shock protein 70 and the protein 68kDa extracted from bovine inner ear were found to identify subsets of autoimmune SNHL among which was also CS [9].

Further studies were later published aiming to establish the significance of autoantibodies to inner ear and endothelial autoantigens in CS. In one of these, pooled IgG immunoglobulins derived from 8 patients with CS was used in order to screen reactivity with relevant autoantigen peptides. Here, the authors identified an immunodominant peptide that showed similarity with antigens such as SSA/Ro and with the reovirus III major core protein lambda 1. The peptide sequence showed similarity also with the cell-density enhanced protein tyrosine phosphatase-1 (DEP-1/CD148), which is expressed on the sensory epithelia of the inner ear and on endothelial cells. IgG antibodies against the peptide, purified from patient's sera, recognized autoantigens and DEP-1/CD148 protein, bound human cochlea, and inhibited proliferation of cells expressing DEP-1/CD148. Furthermore, these antibodies were able to induce the features of Cogan disease in mice. These findings indicate that CS is indeed an autoimmune disease, characterized by the presence of these specific autoantibodies [10]. The above mentioned autoantibodies thought to be highly specific for the diagnosis of CS (therefore called anti-Cogan peptide antibodies). However, they were found later also to be existing in children diagnosed as having idiopathic SNHL. This study suggested these antibodies to become a marker for autoimmune SNHL a subset amenable for immune modulation therapy rather than being specific solely for CS [11].

The finding of other non-specific autoantibodies in patients with CS was also reported in many studies. Among these ANCA was reported in many cases of both typical and atypical CS. In some of these, it was in association with ANCA-related glomerulonephritis. Rheumatoid factor, anti-nuclear and anti-endothelial antibodies have also been reported in some patients with CS, suggesting again that autoimmunity is involved and therefore suggested that CS should be treated with steroids and cytotoxic therapies [12], [13].

Section snippets

Clinical variants of Cogan syndrome

Cogan syndrome has been reported in many case studies to be presented by typical oratypical clinical manifestations. In most of these, CS developed in young Caucasian adults, mostly during their first three decades of age, and with no gender-specific prevalence [14], [15], [16].

Therapeutic approaches

Medical treatment of CS depends on disease severity and on how extensive the disease is. In cases with mild eye involvement, the treatment of choice is the application of topical glucocorticoids and cycloplegiics, such as atropine eye drops. In a case report, topical cyclosporin A was used successfully in the treatment of severe anterior segment inflammation [27]. Systemic treatment is often reserved for patients with posterior involvement (retinal vasculitis and posterior uveitis). The

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