The ocular manifestations of relapsing polychondritis

Relapsing polychondritis (RPC) is a rare, multi-system, inflammatory disorder. Ocular disease is estimated to occur in 14–67% of patients with RPC, and any ocular structure can be affected. Published case reports and series of RPC were analysed to determine the frequency and nature of the ocular manifestations of RPC, including the age and gender distribution. A literature search of the MEDLINE database for case reports and series on RPC was conducted in October 2021 using search terms [relapsing polychondritis (MeSH Major Topic)] OR [relapsing polychondritis (Title/Abstract)]. Articles were included if the diagnosis of RPC was confirmed using established diagnostic criteria and if the paper described the clinical features of patients with RPC. 546 articles (454 case reports and 92 case series) described the clinical features in a total of 2414 patients with RPC. 49% of patients with RPC had ocular involvement, and this was a presenting feature in 21%. The most common ocular manifestations were scleritis (32%), episcleritis (31%) and uveitis (23%). Many patients with RPC will be seen by an ophthalmologist during the course of their disease. Knowledge and awareness of RPC and its ocular manifestations is therefore essential to enable the ophthalmologist to make the diagnosis.


Introduction
Relapsing polychondritis (RPC) is a rare, relapsing-remitting, multi-system, inflammatory disorder that affects multiple tissue types, including cartilaginous, hyaline, elastic and fibrous tissue [1]. The precise pathogenesis of the disease is unknown, but proposed mechanisms include infiltration by neutrophils and lymphocytes [2], macrophage activation [3], and immunoglobulin deposition and complement activation [4]. Both T cell-driven responses and humoral responses have been demonstrated, with serum antibodies against a number of targets including collagen II, IX and XI, matrilin-1 and cartilage oligomeric matrix proteins [5,6].

Diagnosing RPC
The non-specific and relapsing-remitting nature of the signs and symptoms of RPC can lead to a diagnostic delay of a number of years in many patients [7], particularly when features of the diagnostic criteria are not present simultaneously.
The diagnosis of RPC can be made using one of two sets of criteria by Michet [8] or McAdam [9] (later modified by Damiani and Levine [10]) (Fig. 1). The disease is characterised by a combination of chondritis at multiple sites (nose/ear/laryngotracheal), vestibulo-auditory dysfunction, a seronegative inflammatory arthritis and ocular inflammation.
When considering the diagnosis of RPC, the clinician should establish whether there are features (past or current) of the diagnostic criteria ( Fig. 1)-they should ask about episodes of ear pain/swelling/redness (classically, the earlobe, being non-cartilaginous, is not inflamed), nasal pain/deformity, breathing difficulties/stridor, joint inflammation, tinnitus/hearing loss (sensorineural).
In addition, there are a number of other extraocular manifestations of RPC that, while not part of the diagnostic criteria, are recognised associations included in the Relapsing Polychondritis Disease Activity Index (Fig. 2) [11]. The presence of these features may raise the index of suspicion for RPC. In a patient not meeting the diagnostic criteria on clinical grounds, if the index of suspicion was high, a biopsy may be considered to confirm the diagnosis.

Treatment of RPC
There are no evidence-based guidelines for the therapeutic management of RPC.
Various treatment strategies and agents have been employed, based on disease severity and organ involvement. Historically, glucocorticoids and dapsone have been the mainstay of treatment, with a positive response to these agents reflected in the diagnostic criteria for RPC. For mild disease affecting the nasal or auricular cartilage, non-steroidal antiinflammatories (NSAIDs) or colchicine may be used. Glucocorticoids are commonly used for acute inflammatory episodes. Various conventional second-line immunosuppressive agents (e.g. methotrexate, azathioprine, ciclosporin, mycophenolate mofetil, hydroxychloroquine, sulfasalazine) may be used in cases of severe disease or as steroid-sparing agents for refractory disease.
In cases of life-threatening disease (e.g. laryngotracheo-broncheal disease) or in severe ocular inflammation such as necrotising scleritis or peripheral ulcerative keratitis (PUK), high dose oral or intravenous glucocorticoids in addition to cyclophosphamide may be given.
RPC is rare, with an estimated prevalence of 9 per million and incidence of 0.7 per million [20]. The incidence is higher in certain patient populations. In patients with scleritis for example, the incidence of RPC has been reported between 0.24 and 6.4%. [21,22]. Ocular disease is a common feature of RPC, with an estimated frequency of 14-67% [23][24][25][26][27]. Previous reports estimate that 20% of patients with RPC may have ocular inflammation as a presenting feature [27]. The aim of this article was to determine the frequency and nature of the ocular manifestations of RPC by reviewing published case reports and series. This will improve our understanding of the ophthalmic features of RPC and will enable the ophthalmologist to recognise this disorder at an earlier stage and prevent diagnostic delay. was limited to articles on human subjects and those published in English. Figure 3 shows the literature review flow diagram.

Method
For inclusion into the analysis, the RPC diagnosis must have been made according to the McAdam or Michet criteria; this could either be stated to be true in the paper or inferred based on the clinical detail in the report.
Data were analysed using Microsoft Excel with StatPlus. Data on age at presentation were compared using an independent t-test. A Chi-square test was used to analyse the frequency of ocular involvement by gender.

Results
546 articles were analysed (454 case reports and 92 case series) (see supplementary file 1). Publication dates ranged from 1960 to 2021. The articles described the clinical features of a total of 2414 patients with RPC.
The mean age at presentation was 46.6 +/− 15.4 years.

Ocular manifestations
In 698 cases, a specific description of the ocular disease was given ( Table 1).

Uveitis
23.2% of patients with RPC and eye disease had uveitis. Anterior uveitis was more frequently reported than posterior uveitis (12.3% vs. 2.6% respectively).

Conjunctivitis
Conjunctivitis (independent of other ocular inflammation) was reported in 17% of cases of RPC with ocular involvement.
There was one case of pseudomembranous conjunctivitis (who went on to develop anterior scleritis) [33] and a case of chronic conjunctivitis where a biopsy showed a granulomatous obliterative microangiopathy [34].

Keratitis
Keratitis was reported in 10.5% of patients.
The most common description of corneal disease was keratoconjunctivitis (2%). Where the corneal stroma was involved, peripheral disease was most common [corneal infiltration or peripheral ulcerative keratitis (PUK)]. PUK was reported in five cases. Four of these five cases had co-existent scleritis, and one had episcleritis. Another case was possibly PUK that was described as a marginal keratitis that failed to respond to topical antibiotics and subsequently perforated. This was in a 10-year-old child with features of RPC and Behcet's disease, known as MAGIC syndrome (Mouth and Genital ulcers with Inflamed Cartilage) [35]. Central corneal disease in RPC is rare and has been reported in only three patients, one with a central non-healing epithelial defect [36] and two with discrete stromal infiltrates without an epithelial defect, affecting the peripheral and central cornea [37,38].

Retinal manifestations and serous retinal detachment
Retinopathy was reported in 8.2% of cases with ocular involvement. In the majority of cases, this was associated with either uveitis or scleritis. Retinal presentations that have been described include cotton wool spots [39], embolic branch retinal artery occlusion [40], branch retinal vein occlusion secondary to occlusive vasculitis [29], retinal haemorrhages, and cystoid macular oedema [30,41]. A retinopathy resembling Coats' disease has been described in two patients with RPC [31,39]. 1% of cases (n = 7) had a serous retinal detachment. In the majority of cases (6/7), the serous detachment was in association with scleritis or uveitis.

Optic nerve manifestations
Optic nerve involvement was reported in 3% of patients with ocular disease. Optic neuritis [42] and ischaemic optic neuropathy have been reported. One patient developed an ischaemic optic neuropathy secondary to a retinal and optic nerve vasculitis [30] Optic perineuritis is a rare manifestation of RPC with only three reported cases [43][44][45] and may be considered as the ocular analogue of meningitis +/− encephalitis that has been well documented in RPC [46,47].

Orbit and adnexa
Periorbital oedema was the most common adnexal manifestation of RPC (3.9%). There was only one case of dacrocystitis reported [27].
Orbital inflammation was reported in 3% of patients with the type and severity of orbital involvement varying significantly. Cases ranged from mild proptosis only with normal radiological investigations [48] to a Tolosa-Hunt-like syndrome with inflammation involving the orbital apex, cavernous sinus and pachymeninges [49], to an invasive sclerosing orbitopathy resembling IgG4 disease [50]. In two patients, thyroid-associated orbitopathy was the likely cause of orbital signs [40,51]. In one case with proptosis [52], biopsy of a retrobulbar mass surrounding the optic nerve showed B cell lymphoma. In another patient [17], orbital inflammation occurred 2 weeks after commencing abatacept, raising the possibility of a paradoxical drug reaction as the cause.

Neurological disease with ocular manifestations
Patients with RPC may also develop non-inflammatory ocular manifestations. Nystagmus was described in < 1% of patients (n = 6) and has been reported as horizontal, pendular, vertical and rotatory [53][54][55][56]. Horner's syndrome was reported in two cases, one as part of a lateral medullary syndrome [55] and one in conjunction with a sixth nerve palsy and cranial arteritis [57].

Discussion
This analysis of 546 articles describing 2414 cases provides the most comprehensive account to date of the nature and frequency of the ocular manifestations of RPC.
Ocular inflammation in RPC was found to be significantly more common in males than females (58% vs. 50%). This finding has not been described previously, and the reason for this difference is uncertain. While autoimmune disease is more common in females generally, autoimmune diseases where there is a male preponderance (e.g. ankylosing spondylitis, myocarditis) are characterised by a Th-1-type helper T cell response. Th-1 responses tend to be more predominant in males, whereas females tend towards a Th-2 response and it is suggested that androgens promote Th-1 responses [58].
There is evidence that RPC is a Th-1-mediated disease, with a higher correlation between disease activity and levels of Th-1 cytokines compared with Th-2 cytokines [5]. Similarly, in patients with uveitis and in experimental models of autoimmune uveitis, there is a predominant Th-1 response [59, 60]. This tendency towards a stronger Th-1 immune response in males may explain the higher proportion of inflammatory eye disease in males in the context of RPC.
The current study is limited to MEDLINE-indexed articles only, and it is possible that some relevant literature may have been overlooked. However, given the number of articles included, it is unlikely that any omitted literature would significantly affect the figures reported herein. In addition, there is the possibility of inconsistencies/bias in the reporting of ocular disease in the literature, particularly in cases where there were no ophthalmologists in the authorship group. In many cases, it is unclear whether the patient had a formal ophthalmology review and therefore there may be a degree of diagnostic uncertainty with regard to their ophthalmic disease. In 41% of cases with ocular involvement, the nature of the ocular disease was not documented. The estimates on the frequency of specific ocular manifestations in RPC are based on the 59% of cases (n = 698) where this information was available. It is possible that patients with milder ophthalmic disease (e.g. mild episcleritis or conjunctivitis) did not receive a formal ophthalmology review and hence did not receive a specific diagnosis. Thus, these 698 cases with a specific diagnosis may represent the more severe end of the spectrum of ocular disease, i.e. those with disease severe enough to warrant an ophthalmology review.
This analysis shows that approximately half of patients with RPC will be seen by an ophthalmologist during the course of their disease and that in approximately 20% the initial presentation will be to an ophthalmologist. Although RPC is a rare disease, the 5-year mortality has been reported to be between 6 and 30% [20]. Therefore it is important that RPC is considered on the differential diagnosis in patients with inflammatory disease of the eye and adnexa. An increased awareness and understanding of the ocular manifestations of RPC can aid the ophthalmologist in making the diagnosis.