Relentless placoid chorioretinitis (RPC) is a rare, bilateral disease of the retinal pigment epithelium (RPE) and choroid, first described by Jones et al. (1). Due to the similarities of acute lesions with serpiginous choroiditis (SC) and acute posterior multifocal placoid pigment epitheliopathy (APMPPE), the diagnosis of RPC is often delayed due to disease overlap. The distinction of RPC consists of its atypical time course and retinal distribution. RPC is characterized by >50 bilateral chorioretinal lesions with involvement anterior and posterior to the equator. This is in contrast to SC, where, usually, only one eye contains active lesions at a time, consisting of subretinal infiltrates that spread centrifugally from the peripapillary region and result in a typical geographic scar (2). Similar to SC, however, the clinical course of RPC is prolonged and relapsing, with new lesions continuing to appear for 5–24 months without therapy (3). Patients may show recurrences for months to years after onset. Multimodal retinal imaging suggests that there is a common pathophysiology with APMPPE and SC, although the number of lesions (>50) and location suggest RPC (3).

Early in disease progression, RPC appears similar to APMPPE and SC on fundus autofluorescence (FAF) in that the lesions are hypoautofluorescent with hyperautofluorescent edges. In RPC, fluorescein angiography (FA) studies reveal hypofluorescence in the early phases of the angiogram. Later phases show staining of the lesions. Indocyanine green angiography (ICG) shows hypofluorescence in the areas corresponding to the clinical lesions that persist into the late phases. The hypofluorescence of RPC, like in APMPPE in the early phase of FA and throughout the ICGA sequence, suggests multifocal choroidal hypoperfusion. Both FA and ICG for RPC show a similarity to those for APMPPE and SC (3, 4). This suggests that it might be within the spectrum of inflammatory disease with primary involvement of the level of the choriocapillaris and secondary RPE damage as seen in APMPPE (5). Additionally, active lesions typically show focal areas of hyper-reflectivity developed in the outer retina, primarily localizing to the outer nuclear layer (ONL) but also being seen at the level of the outer plexiform layer on spectral-domain optical coherence tomography (SD-OCT). In lesions that fail to completely resolve, persistent disruption and/or irregularity of the RPE and associated retinal thinning are seen. An OCT-angiography (OCT-A) study has shown that the inner choroid is the primary site of disease pathogenesis in RPC, as well as in APMPPE (6).

No specific underlying etiology has been identified for RPC thus far; however, there may be infectious or autoimmune causes that lead to its presentation. Other systemic illnesses have been suggested to be associated with RPC, such as thyroiditis and cerebral vasculitis (7, 8). Viral or flu-like illnesses have been reported in approximately 33% of patients prior to ocular symptoms of APMPPE (9). During the COVID-19 pandemic, cases of choroiditis, APMPPE, SC, and RPC have been reported in patients infected with COVID-19, which may further support the theory that viral infections may play a role in triggering chorioretinal inflammation in susceptible individuals (10–14).

Multiple cases of RPC have been published in the literature; however, the shape of chorioretinal lesions, clinical course, and prognosis have varied. Early diagnosis is pivotal to ensure intervention before the further progression of the disease. However, no standard treatment for RPC exists; immunosuppressive drugs such as prednisolone, cyclosporine, intravitreal triamcinolone, adalimumab, infliximab, and mycophenolate mofetil (MMF) have been used to treat RPC (1, 8, 15–20). Other studies have also worked at using a combination of these medications (i.e., prednisolone/cyclosporine and adalimumab/infliximab) (1, 8, 15, 16, 19, 20).

The purpose of this paper is to compare the treatment outcomes in four cases of RPC, the largest series in pediatrics and young adults, to previously reported cases of RPC. Specifically, this paper discusses the efficacy of currently published treatments of RPC and the successful use of an anti-IL-6 agent (i.e., tocilizumab) for the first time, to our knowledge, to control the disease.

A literature search and subsequent screening of articles were conducted in December 2021 by one author (HAZ). Keywords relating to RPC were used to search the following electronic databases in the given order: Google Scholar, PubMed, and Web of Science. Keywords included relentless placoid chorioretinitis, ampiginous choroiditis, relentless placoid chorioretinitis and treatment, and ampiginous choroiditis and treatment. The retrieved articles were initially screened by title, and articles with the relevant titles were then screened by abstract using predefined inclusion and exclusion criteria. Inclusion criteria are as follows: (1) the paper must be in English and (2) the paper must discuss the presentation and management of RPC. Exclusion criteria are as follows: (1) the paper concerned patients only with other white dot syndromes, such as SC or APMPPE; (2) the paper did not clearly diagnose the patient with RPC; and (3) the citations were from gray literature. The full article was screened in cases where the relevance was unclear from the abstract. Relevant articles were ultimately compiled into a database, and duplicates were removed (Figure 1).

For the cases presented in this article, electronic medical records for relentless placoid chorioretinitis were reviewed for the initial presentation, imaging, laboratory studies and results, follow-up visit presentations, and medical management.

Due to the recurrence of bilateral lesions over 6–36 months (two patients) without or despite a steroid-sparing therapy, and/or because of the atypical location of the multiple lesions (>50) extending from the posterior pole to the equator and mid-peripheral retina (all four patients), we diagnosed these four patients as RPC to differentiate them from other commonly associated white dot syndromes, such as APMPPE and SC. This contrasts with APMPPE, which presents chorioretinitis lesions limited to the posterior pole. The lesions are smaller than those in APMPEE (<1/2 disc area) and are classically bilateral. In both entities, fresh lesions may develop, so lesions of different ages can be seen. Additionally, anterior uveitis and mild vitritis may be seen in both diseases. The duration of the disease and the persistent course were the key differences from APMPPE and SC. It is important that RPC is diagnosed early due to the increased threat of vision loss; however, even if diagnosed early, as represented in our four cases, RPC can have a poor visual recovery if an effective treatment has not been initiated. Guidelines for standard treatment for RPC still do not exist. Thus, this paper serves as an analysis of our cases and previously published cases of RPC as a means to contribute to the current knowledge and treatment options for RPC.

Clinically, two of our cases had initial symptoms of photopsias, scotomas, and persisting headaches. All four patients were initially started on high-dose oral or IV steroids and later transitioned to additional immunosuppressive agents or biologics for three of them and steroid tapering for all of them. The first case describes the use of oral prednisone, the inefficacy of conventional immunosuppressive therapy, MMF, and finally the efficacy of biologics, adalimumab, tocilizumab, and infliximab. The second case describes the use of IV solumedrol, oral prednisone, and the efficacy of SQ/2 weeks adalimumab started as early as during the first month of RPC presentation. The third case treatments were IV methylprednisolone, failure of IFN-alpha-2a, and finally the efficacy of IV infliximab with SQ/1 week adalimumab when the patient finally showed compliance to anti-TNF-alpha treatments. The fourth case received only oral and topical steroids with slow tapering over a course of 3 months without relapse.

Quiescence of the chorioretinitis lesions was obtained after 7 months (patient number 1), 1 month (patient numbers 2 and 4), and 36 months (patient number 3) but with problems of treatment compliance in patient number 3. Despite the response to treatment, the final visual acuity was affected in all four patients.

As regards previously published treatments for RPC (Table 3), systemic steroids are typically used as first-line treatments, as they assist in the healing of lesions and slowing progression. Despite this, combination immunosuppressive therapy is almost universally needed for the prevention of relapses, disease control, and systemic steroid tapering. Jones et al. (1) described the use of prednisone alone in one case where visual acuity remained impaired after cessation and more than 100 pigmented lesions were present 28 months after initial presentation. Similarly, Khalifa et al. (18) reported the use of oral prednisone (1 mg/kg/day) alone with successful tapering within 3 months without recurrence; however, due to extensive macular scarring, final visual acuity was impaired. This suggests that although the use of prednisone alone may prevent the initial recurrence of lesions, impaired visual acuity and future recurrences are still probable. Other immunosuppressants (i.e., cyclosporine and azathioprine) are typically added in combination with prednisolone due to relapse. We describe a different therapeutic approach for every patient based on ophthalmologists/rheumatologists and internal medicine preferences in our four different centers.

Uraki et al. (15) found that in their four reported cases of RPC, a combination of prednisolone 25–30 mg/day and cyclosporine 170–250 mg/day along with subtenon triamcinolone acetate injection in two of the patients resulted in no recurrence of lesions across each of the four cases for 8–48 months. Jones et al. (1) presented two cases where cyclosporine (100–150 mg/day) was added in combination with prednisolone with successful tapering of prednisolone without any recurrence of lesions. Two additional studies have found the effective use of prednisolone and MMF 1,000–2,000 mg/day with no recurrence of lesions for 15–18 months: Yeh et al. (8) reported that remission was achieved following 2 months of MMF treatment with successful tapering of oral prednisone (initial dose 20 mg/day), while Amer et al. (19) reported a case where a 3-day course of IV methylprednisolone (500 mg/day) with a tapering dose of prednisolone (1 mg/kg/day) and addition of MMF (500 mg × 2/day) for 1 month lead to no recurrence of lesions 15 months after the first presentation.

Despite the effectiveness of immunosuppressive agents, treatment can be further complicated in patients with risk factors for medication use. Roth et al. (17) reported a pregnant woman with RPC who was treated with intravitreal triamcinolone (IVTA) due to the risk of teratogenic effects of immunosuppressive agents. The patient was treated with 4 mg IVTA biannually for 3 years with preservation of vision at 20/25 at the 63-month follow-up from the initial presentation. IVTA improved the chorioretinitis lesions and visual acuity in this case; however, the patient developed a posterior subcapsular cataract and noninfectious endophthalmitis, likely caused by its use. Jyotirmay et al. (20) presented 26 eyes of 16 patients diagnosed with RPC. Of these, 13 patients were maintained on oral prednisolone (1.5 mg/kg/day) and azathioprine (1.5–2.0 mg/kg/day) and tapered until a minimum dose was reached without recurrence of lesions. In seven patients, 3 days of IV methylprednisolone pulse therapy (1 g/day) was given, followed by oral steroids and azathioprine due to macular involvement. Of the other cases, two eyes were treated with azathioprine alone, one eye was treated with prednisolone and posterior subtenon triamcinolone injection (STTA), and one eye was treated with steroid, azathioprine, and cyclosporine combination. Again, all of these cases reached a point of quiescence. Of all the cases presented in this report, 96.2% had favorable visual outcomes, with two patients showing no improvement in visual acuity despite IV methylprednisolone and maintained on oral steroids and azathioprine. Asano et al. (16) in a case series of two patients with RPC found effectiveness of the combination of prednisolone, cyclosporine, and adalimumab. In their first case, they present the use of oral prednisolone (15 mg/day), cyclosporine (200 mg/day), and adalimumab (40 mg/2 weeks) with successful tapering of corticosteroids after 1 year and immunomodulatory treatments after 3 months without any adverse effects or recurrence of lesions. In the second case, oral prednisolone (15 mg/day) and cyclosporine (150 mg/day) were initiated due to the recurrence of lesions, and after ocular inflammatory changes subsided, cyclosporine was subsequently terminated and adalimumab (40 mg/2 weeks) was started. Both cases reported by Asano et al. (16) are still treated with adalimumab at the time of the final visit; thus, the optimal duration of adalimumab treatment and tapering has yet to be determined.

Each of the four cases presented herein was treated with a combination of prednisolone and an anti-TNF or anti-IL-6 medication (i.e., adalimumab, infliximab, or tocilizumab). Two cases displayed a failure of MMF and interferon-alpha-2a in preventing flares of RPC. Other cases published in the literature have used adalimumab effectively, as discussed above; however, there have been no reports of treatment with infliximab. Previous papers have shown the efficacy of treatment with systemic steroids with slow tapering, with intravitreal steroids, and with subtenon steroid injections (Table 3). On the contrary, in our cases of RPC, we observed relapses when tapering oral steroids in three of the four cases but efficacy at obtaining the eye inflammation quiescence with slow steroid tapering over a course of 3 months in one patient. Due to the sight-threatening and chronic course of RPC, several reports have described the use of steroid-sparing agents to treat RPC. Several have also used efficient oral cyclosporine and oral azathioprine or MMF (Table 3). The first case here was unsuccessfully treated with MMF, and upon literature review, we have not encountered another report of IFN-alpha-2a being successfully used for RPC.

To our knowledge, this is the first study to present a case of RPC that responded to an anti-IL-6 agent (i.e., tocilizumab) for treating RPC. Our findings suggest that biologics, like anti-TNF-alpha agents (i.e., adalimumab and infliximab) and IL-6 agents, such as tocilizumab, may effectively prevent recurrences of RPC; however, MMF and IFN-alpha-2a should perhaps be avoided. However, we acknowledge the limitations of our study, given the small number of cases presented due to the rarity of RPC.

Here, we reviewed the diagnostic approach to early identification and treatment of RPC by distinguishing it from the similar counterpart APMPPE, which classically does not require treatment. Furthermore, we review treatment strategies for RPC and their anecdotal success in this case series of four patients and results from the current literature. This is the first study, to our knowledge, to report a case with the successful use of an anti-IL-6 agent (i.e., tocilizumab) for RPC. In our case series and upon literature review, we found that biologics like anti-TNF-alpha (adalimumab and infliximab) and anti-IL-6 (tocilizumab) may be more effective at RPC control, and MMF and IFN-alpha-2a may be insufficient to control RPC flares.