Abstract
Background:
Autosomal dominant neovascular inflammatory vitreoretinopathy (NIV), formerly called “ADNIV”, is a rare autoinflammatory condition mainly of adulthood caused by mutations in calcium-activated calpain-5 protease (CAPN5). Our aim is to report the treatment and visual outcomes of children newly diagnosed with NIV after systemic treatment.
Methods:
We reviewed charts of patients ≤18 years old with CAPN5 gene mutation, ocular findings consistent with NIV, and treated with systemic immunosuppression for a minimum of 6 months. Treatment response was based on ophthalmic examination, ultra-widefield fluorescein-angiography (UWFFA), and optical coherence tomography (OCT).
Results:
Eight children (16 eyes) were diagnosed with NIV at a median age of 14 (Range [R] 9-16) years, with a median follow-up of 18 months (R6-20). At diagnosis, one patient had impaired visual acuity (VA>0.4), 8 had vascular leakage, 2 had neovascularization, and 3 had macular edema. All responded to oral or local glucocorticoids but was not sustained. Systemic immunosuppression was started in 7 patients with methotrexate and infliximab after a median time from diagnosis of 1.5 months (R0.5-2) and 3.2 months (R2.5-3.1) respectively. Infliximab was discontinued in all after a median time of 7 months (R3.5-10) for ineffectiveness, and 5/7 switched to tocilizumab and 1 to adalimumab. Five failed to respond (4 tocilizumab, 1 adalimumab) and 1 had a minimal response to tocilizumab.
Conclusions:
We report on the systemic treatment response of seven children with ADNIV treated with methotrexate, infliximab and tocilizumab. None were able to control disease. Further studies are needed to understand long-term outcomes and the utility of systemic immunosuppression.
Keywords: ADNIV, NIV, Autosomal dominant Neovascular inflammatory vitreoretinopathy, Autoinflammatory disease, uveitis, children, outcomes, therapy, infliximab, tocilizumab
Background:
Over the last two decades, the clinical spectrum of autoinflammatory diseases has expanded with the identification of new diseases and causative genes. Autoinflammatory diseases represent a class of immune-mediated disorders where pathogenic inflammation occurs in the absence of high-titer autoantibodies or self-reactive lymphocytes [1]. Typically, they are the consequence of a loss or gain of function mutation in specific genes which are crucial for the activation of the innate immune system.
Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (NIV) is a rare autoinflammatory disease localized to the eye and characterized by severe uveitis, retinal degeneration, neovascularization and intraocular fibrosis (OMIM reference number 602537) [2-5]. Since the first report in 1990 by Bennett et al, several studies have described the clinical characteristics and outcomes of adult patients with NIV [5-7] . In 2012, Mahajan et al identified calcium-activated calpain-5 protease (CAPN5) which is inherited in an autosomal dominant fashion [5]. Calpain 5 is a cysteine protease found in the cytoplasm and mitochondria of numerous cells such as photoreceptors and brain cells [8-14]. Calpain 5 is activated by increased levels of calcium due to endoplasmic reticulum stress or intercellular signaling. However, in patients with NIV, calpain 5 is activated at low concentrations of calcium, leading to the activation of necroptosis with the help of caspase 4. The overall mechanism remains poorly understood [4, 8, 12, 13, 15-20].
Historically, patients with NIV were asymptomatic and mostly undiagnosed until the third decade of life as symptoms typically occur in early adulthood when severe complications are already present. [7, 21]. Recently, cases of childhood onset NIV describe a more severe phenotype including hearing loss and development delay [7, 19, 22, 23]. As there is a high risk for poor vision outcomes, timely diagnosis and early treatment may prevent ocular complications. Further, as most patients are initially asymptomatic, novel use of multimodal imaging such as ultra-widefield fluorescein angiography (UWFFA) is an important modality for early diagnosis and disease monitoring[24]. Local steroid injections are standard first line therapy. Unfortunately, these treatments are not durable and repeated use can lead to the development of cataract and glaucoma [25-27]. . The utility of early treatment with systemic immunosuppression prior to severe eye disease is unknown. Prior literature has shown that NIV has been treated with many conventional uveitis therapies and surgery, but with poor response [7, 27]. Vitreous proteomic studies have provided some potential guidance on which drugs might work and which might not [19]. However, the number of patients studied thus far is limited and there has not been a focus on pediatric patients with early disease. Adult patients were reported to fail anti-TNF, and only one patient had been treated with anti-IL-6 to date, but at later stages of disease.
Our aim is to describe the clinical course of children with early NIV and their response to systemic immunosuppressive therapy using clinical examination and multimodal imaging.
Patients and methods:
Type of study and population.
This single center, retrospective study included patients with NIV from the same family who were followed at Cincinnati Children's Hospital Medical Center (CCHMC) and the Cincinnati Eye Institute (CEI) from December 2022 to May 2023. Patients were enrolled in a larger registry, “Pediatric Rheumatologic and Eye Disease Biorepository” (RED) Protocol, IRB approval number 2022-0137. The study was approved by the CCHMC Institutional Review Board and adheres to the tenets of the Declaration of Helsinki. Informed consent and assent were obtained from parents and children.
Inclusion and Exclusion criteria.
Inclusion criteria were: 1) diagnosis of NIV in patients <18 years of age based on the presence of pathogenetic variants in CAPN5 gene and presence of ocular inflammation (mainly intermediate/posterior uveitis) confirmed by a uveitis-trained specialist (AS), 2) treatment with systemic immunosuppression for a minimum of 6 months, and 3) follow-up in rheumatology and ophthalmology clinics for at least 6 months. Exclusion criteria were: 1) incomplete medical records (i.e. medication history, ophthalmic examination) and 2) refusal or inability to participate.
Data Collection:
CCHMC and CEI medical records were reviewed from the time of first ophthalmic examination until May 2023. Demographic, clinical and medication data were collected (IM and AD) and entered into our REDCap database. Data included sex, race, ethnicity, age at diagnosis, ocular and systemic symptoms, clinical ocular examination, imaging results, and laboratory tests (e.g. ESR, CRP, ANA, angiotensin converting enzyme [ACE] and vitamin D level). Use of intraocular medications (including corticosteroids, methotrexate, anti-VEGF) and non-biologic and biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) including corticosteroids, methotrexate (MTX), adalimumab (ADA), infliximab (IFX) and tocilizumab (TCZ) (e.g. dose, frequency, route of administration and duration) were recorded. Imaging modalities included optical coherence tomography (OCT) (performed with Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany) and UWFFA (Optos, Inc, Marlborough, MA) which were recorded at the first and follow-up visits. Best corrected visual acuity (BCVA) was converted to logarithm of the minimum angle of resolution (logMAR) for statistical purposes. Ocular complications were recorded if they were present in terms of cataract, posterior synechiae, ocular hypertension or hypotension, band keratopathy, anterior segment neovascularization (NV) including NV of the iris or angle, peripheral retinal NV, vitreomacular traction (VMT), epiretinal membrane (ERM), macular edema, vitreous hemorrhage (VH), peripheral pigmentary changes, tractional retinal detachment (TRD), and/or rhegmatogenous retinal detachment (RRD) with or without macular involvement, optic disc swelling, or atrophy.
Genetic testing was performed using Invitae Inherited Retinal Disorders Panel (Invitae Corportation, San Francisco, CA) to detect the CAPN5 gene mutation.
Main outcomes.
The main outcome was treatment response based on ocular and imaging findings after 6 months of systemic treatment. All participants were examined every 3 months by clinical examination, UWFFA and OCT. Treatment response was defined as a decrease in 1) vitreous cells on clinical examination, 2) retinal vascular leakage on UWFFA, and/or 3) macular edema on OCT. Inadequate treatment response was defined as any or a combination of: 1) persistence of leakage on UWFFA and/or 2) worsening or new onset of ocular complications, or 3) requirement of glucocorticoids (intraocular, systemic or both).
As additional main outcome we considered was visual acuity that was stratified as normal if it was<0.4, impaired if >0.4 and <1, and blindness if > 1 logMAR [28].
Statistical analysis.
Summary statistics were performed using frequencies, means (standard deviations [SD], or medians [range]) where appropriate. Because of the small number of patients included, no further analyses were performed.
Results:
Initial disease characteristics and treatment (Table 1).
Table 1.
Characteristics of children with uveitis associated with Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (NIV) at diagnosis.
| n = 8 patients, 16 eyes n (%) unless otherwise stated |
|
|---|---|
| White | 8 (100) |
| Hispanic or Latino | 0 (0) |
| Female | 5 (62.5) |
| Age at NIV diagnosis, years, median (range) | 14 (9-16) |
| Duration of NIV, mos, median, (range) | 18 (6-20) |
| Asymptomatic at diagnosis | 3 (37.5) |
| Labs, in those who had them performed | |
| Earliest ESR, elevated n=8 | 0 (100) |
| Earliest Vitamin D, decreased, n = 7 | 3 (37.5) |
| ANA positive, n = 8 | 0 |
| ACE positive, n = 6 | 0 |
| Lysozyme positive, n = 3 | 0 |
| Initial ocular examination and imaging per patient (P) and eyes (E) | |
| Bilateral ocular involvement | 8 (100) |
| Visual acuity range, worse eye, median (range) in LogMar | 0.1 (0-0.7) |
| Patients with impaired visual acuity | 1 (12.5) |
| Anterior chamber cells present | 0 (0) |
| Vitreous cells present | 7 P (87.5), 13 E (81.2) |
| Macular edema on OCT | 3 P (37.5), 6 E (37.5) |
| Retinal leakage on UWFA | 8 P (100), 16 E (100) |
| Neovascularization on clinical exam/UWFA | 2 P (25), 4 E (25) |
| Cataract | 2 P (25), 4E (25) |
| Vitreous Hemorrhage | 1 P (12.5), 1 E (6.2) |
Abbreviations: NIV- Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy; OCT- Optical coherence tomography; UWFA- Ultra-widefield angiography, E= eyes, P=patients, ESR: Erythro-sedimentation rate, CRP: C reactive protein, ANA: antinuclear antibody, ACE: angiotensin converting enzyme, mos: months
Eight children, all part of the same family, were diagnosed with NIV (see Ebert et al for the representation of the family tree [24]). All shared the same variant in CAPN5 c.731T>C, p.L244P and had ophthalmic findings consistent with NIV. Of the 8 patients, 5 were female and all were non-Hispanic and White. Median age at diagnosis was 14 (range [R] 9-16) years, and a median follow-up of 18 months (R 6-20). Three children were asymptomatic, and the diagnosis was confirmed based on the ocular and genetic findings. Among patients who had ocular symptoms, the most commonly reported were decreased vision (2, 25%), floaters (2, 25%) and ocular pain (1, 12.5%). Concomitant systemic disorders included allergies (4, 50%), joint hypermobility (2, 25%), headache (2, 25%), developmental delay (1, 12.5%), autism (1, 12.5%) and pathological short stature (1, 12.5%). None of them showed hearing loss.
Routine laboratory tests were normal, with the exception of a decreased vitamin D level in 3 patients.
At the time of diagnosis, ophthalmic examination showed a median BCVA in the worse eye of 0.1 LogMAR (R 0-0.7), 7 patients had vitreous cells (13 eyes), 1 patient had unilateral vitreous hemorrhage, 2 had bilateral cataracts, and 3 had pigmentary changes (5 eyes). UWFFA revealed retinal vascular leakage in all 8 patients (16/16 eyes), peripheral non-perfusion in 6 (11/16 eyes), and neovascularization in 2 (4/16 eyes). OCT demonstrated cystoid macular edema in 3 patients bilaterally (6/16 eyes) and an ERM/VMT in 2 patients (2/16 eyes). Median central subfield thickness (CST) on OCT was 334 μm (range 259-551 μm).
Initial treatment.
Five of the 8 children were initially treated with oral (n=5) and intravitreal corticosteroids (n=4) for inflammation and 2 with anti-VEGF therapy for neovascularization. All 4 patients who received intraocular corticosteroids (0.7mg Dexamethasone implant or triamcinolone acetonide 4mg/0.1mL) had rapid improvement of retinal vascular leakage (8/8 eyes) on UWFFA and resolution of cystoid macular edema (6/6 eyes) on OCT (Figure 1 and 2). However, vascular leakage relapsed after a median time of 7 weeks (range 6-8 weeks) in all patients. Administration of anti-VEGF in 2 patients led to a regression of neovascularization in 4/4 eyes (Figure 3). Three patients received additionally intraocular MTX (37.5%).
Figure 1:
Ultra-widefield fluorescein angiography (UWFFA) of an asymptomatic 10-year-old female with NIV demonstrating diffuse retinal vascular leakage (A) that improved following treatment with the dexamethasone intravitreal implant (B).
Figure 2:
Ultra-widefield fluorescein angiography (UWFFA) of the right eye of a 13-year-old male with NIV showing diffuse vascular leakage in addition to temporal vascular leakage consistent with peripheral neovascularization (A). Leakage improved with dexamethasone intravitreal implant and neovascularization regressed following intravitreal anti-VEGF treatment (B).
Figure 3:
Optical coherence tomography (OCT) of a 14 year-old Female with NIV showing cystoid macular edema with an attached posterior hyaloid in both eyes (A). There was marked improvement in cystoid macular edema two months following treatment with an intravitreal dexamethasone implant (B).
Non-biologic and biologic treatment (Table 2).
Table 2:
Local and systemic treatment administered to children with ADNIV
| Treatment administered | n = 7 patients, n (%) unless otherwise stated |
|---|---|
| Patients on treatment | 7 |
| Anti-VEGF | 2 (28.5) |
| Glucocorticoids | 6 (85.7) |
| Oral | 6 (85.7) |
| Intravitreal injection | 6 (85.7) |
| Time from NIV diagnosis to steroid, mos, median (IQR) | 0 (0-0.9) |
| Methotrexate intravitreal injection | 3 (42.8) |
| Methotrexate 25 mg/weekly SQ injection | 7 (100) |
| Time from NIV diagnosis to MTX, mos, median (R) | 1.5 (0.5-2) |
| Duration on methotrexate, mos, median (range) | 11 (6-14) |
| Infliximab/inflectra (10mg/kg/every 4 weeks IV) | 7 (100) |
| Time from NIV diagnosis to start IFX/, mos, median (IQR) | 3.1 (2.5-3.2) |
| Duration on IFX/inflectra, mos, median (R) | 7 (3.5-10) |
| Number of patients who responded to IFX | 0/7 |
| Number of patients who stopped IFX for inefficacy | 7 (100) |
| Tocilizumab (10-12 mg/kg/every 2 weeks IV) | 5 (71.4) |
| Time from NIV diagnosis to start TCZ, mos, median (R) | 9 (8-12) |
| Duration on TCZ, mos, median (R) | 8 (5-9) |
| Number of patients with ocular improvement on TCZ | 0/5 |
| Number of patients who stopped TCZ | 4/5 (80) |
| Adalimumab (40 mg/every other weeks SQ) | 1 (12.5) |
| Time from NIV diagnosis to start ADA, mos | 13 |
| Duration on ADA, mos | 6 |
| Number of patients who responded to ADA | 0/1 (0) |
| Number of patients who stopped ADA for inefficacy | 1 (12.5) |
List of abbreviation: NIV- Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy; VEGF- Vascular endothelial growth factor, E= eyes, P=patients, Anti-VEGF: anti Vascular endothelial growth factor, mos: months, MTX: methotrexate, IFX: infliximab, TCZ: tocilizumab, IQR interquartile range
Due to recurrence of vascular leakage seen on UWFFA, all patients were offered systemic immunomodulatory treatment, and 7/8 patients (87.5%) agreed to treatment. MTX (25 mg weekly subcutaneously) was initiated in all 7 patients after a median time from diagnosis of 1.5 months (R 0.5-2) for a median duration of 16 months (R6-18). Due to persistent leakage in all 7 patients, IFX (10 mg/kg/dose every 4 weeks intravenously) was added after a median time from diagnosis of 3.1 months (R 2.5-3.2). IFX was ineffective in all patients based on persistent leakage on UWFFA and was discontinued after a median time of 7 months (R 3.5-10). Five of the 7 patients were switched to TCZ (10-12 mg/kg/every 2-3 weeks intravenously), after a median time from diagnosis of 9 months (range 8-12) while one patient received ADA (40 mg every other week subcutaneously). One patient decided to hold on starting any systemic treatment including MTX while waiting for the outcomes of the other patients.
TCZ was continued for a median time of 8 m (5-9). At final follow-up, persistent retinal vascular leakage was noted in all 5 patients. One patient was able to increase the interval of administration of intraocular corticosteroids, suggesting a partial leakage response to TCZ. This patient was continued on TCZ and was also given intravitreal fluocinolon acetonide 0.18mg implant in the right eye (Yutiq). Four patients discontinued TCZ for inefficacy and 2 were switched to tofacitinib, while the other 2 discontinued all systemic treatment.. The single patient discontinued ADA due to inefficacy. See supplementary Table 1 for a schematic presentation of the systemic treatment, intraocular treatment and visual outcomes across time.
Vision outcomes after systemic treatment.
Outcomes at the last available follow-up are reported in Table 3. After at least 6 months of follow up and systemic treatment (5 on tocilizumab and 1 on adalimumab), median visual acuity was 0.2 (range 0.1-1.2) with 3 (37.5%) patients with impaired visual acuity in at least one eye. One patient had macular edema in one eye, 5 showed vitreous cells bilaterally, 8 had diffused retinal leakage, and 5 (9 eyes) cataract (Table 3).
Table 3:
Clinical ocular examination and imaging findings at diagnosis and at the last available follow-up after treatment by patient (P) and eyes (E)
| Ocular outcomes | Onset, n (%) | Last Follow-up, n (%) |
|---|---|---|
| Visual acuity worse eye, LogMar median (range) | 0.1 (0-0.7) | 0.2 (0.1-1.2) |
| N° of patients with VA >0.3 | 1 (12.5) | 3 (37.5) |
| AC cells present | 0 (0) | 0 (0) |
| Vitreous cells present | 7 P (87.5) 13 E (81.2) |
5 P (62.5) 10E (62.5) |
| Macular edema on OCT | 3 P (37.5) 6E (37.5) |
1P (12.5) 1 E (6.2) |
| Retinal leakage on UWFA | 8 P (100) 16E (100) |
8 P (100) 16 E (100) |
| Neovascularization on clinical exam/UWFA | 2 P (25) 4 E (25) |
2 P (25) 4 E (25) |
| History of Vitreous Hemorrhage | 1P (12.5) 1 E (6.2) |
2 P (25) 3 E (18.7) |
| Cataract | 2 P (25) 4E (25) |
5P (62.5) 9 E (56.2) |
| Ocular Hypertension (>21 mmHg) | 0 | 4 P (50) 7 E (43.7) |
| Retinal pigmentation changes | 3 P (37.5) 5 (31.2) |
3 P (37.5) 5 (31.2) |
Abbreviations: NIV- Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy; OCT- Optical coherence tomography; UWFA- Ultra-widefield angiography; VEGF- Vascular endothelial growth factor, E= eyes, P=patients, VA visual acuity
During follow-up while being treated with systemic treatment and intraocular steroid injections, 4 patients (7 eyes) developed intraocular hypertension (intraocular pressure [IOP] > 21 mmHg) requiring topical antihypertensive drugs. Two patients received pan retinal photocoagulation for nevascular complications, and 1 patient had bilateral cataract surgery with intraocular lens implant for cataract.
Discussion:
Data regarding NIV are mostly derived from adult studies, as NIV is considered a disease with onset in the 2nd – 3rd decade of life [5-8, 19, 21, 22, 26, 29-39]. Previously, only six studies described a total of 12 children with this rare disease [7, 19, 22, 23, 29, 40]. In this study, we report the largest case series of pediatric patients with NIV treated with systemic immunosuppressive therapy and monitored by UWFFA, describing their ocular findings from diagnosis to follow-up, treatment and visual outcomes. Critically, our cohort of patients suggests that the first signs of ocular inflammation are present in childhood, even in completely asymptomatic or mildly symptomatic children. Such UWFFA findings in NIV have not been previously described by other authors and as demonstrated in this study, and in our previous already published study, provide foundational insights into the pathophysiologic mechanism occurring in early phases of the disease [24]. Moreover, we are the first to describe a pediatric onset with the Leu244Pro variant.
From an ocular perspective, our pediatric cohort showed similar spectrum of ocular findings as adult patients with NIV. Not only do children with NIV demonstrate mild uveitis, early cataract, retinal vasculitis or macular edema as previously reported, but we also identified signs of subsequent phases, that are usually seen later in the disease such as neovascularization as well as vitreous hemorrhage. Thus, a wide spectrum of disease with varied clinical stages is likely, even in children and adolescents.
The UWFFA findings showed that retinal vascular leakage is one of the predominant features in early stages of NIV, demonstrating retinal vascular leakage in 100% of our patients and peripheral non-perfusion in the vast majority of them. Our UWFFA findings of early occult vascular leakage and peripheral ischemia may represent a precursor for subsequent neovascular complications. Additionally, chronic retinal vascular leakage and subsequent ischemia are presumably responsible for the selective loss of b-wave amplitude on ERG seen in stage 1 disease, which can also be seen in other ocular inflammatory diseases like Birdshot Chorioretinopathy [41]. Moreover, another possible alternative hypothesis for the very early selective loss of the b-wave might be the consequence of the abnormal CAPN5 activity in the photoreceptor [16, 32].
More than 50% of our patients were already symptomatic at the time of diagnosis after a careful anamnesis. This contrasts with Boyce et al that reported primarily asymptomatic children [7], but similar to other reports that focused on children. Among the reported pediatric patients, the age at onset varied, and those 5 with an earlier onset (11 months-3 years old) had a more severe phenotype with associated systemic symptoms including hearing loss, development delay and gastrointestinal symptoms [19, 22, 23, 36]. To date, 12 specific mutations have been reported, which lead to a gain-of-function such that Calpain 5 is hyperactivated even with normal calcium levels. However, different variants disrupt varied critical regulatory motifs, such as regions regulating the opening of the active site (p.R243L, p.L244P, p.K250N, pG376S) [2, 3, 33], remotely regulating the catalytic domain (p.G267S) [8, 20], the catalytic domain itself (p.R289W/p.R289L, p.L73V) [19, 40], the autoinhibition domain (p.R408Q), the association with the cytoplasmatic membrane (p.L632I), or other regulatory functions (p.D72N, p.Q77R ) [5, 8, 22, 42]. Intriguingly, patients with very early onset disease (in the first 3 years of life) and systemic symptoms, showed specific mutations localized to the catalytic domains [19, 22, 23, 29, 40]. In contrast, others with isolated ocular involvement carry distinct mutations such as those affecting stability of the active site [22], including the variant displayed in our patients. Thus might explain partially why our pediatric patients did not show more systemic symptoms. Interestingly, even though our cohort of children shared the same variant, the severity of disease varied, possibly related to interactions with environmental factors, as highlighted in previous reports of two homozygous twin with different severity of the disease [30, 31, 39].
Considering the natural history of poor long-terms visual outcomes reported by Boyce et al [7], where the NIV populations showed a median VA of 1.48 at the last available follow-up, early diagnosis and treatment is critical. Thirty-seven percent of patients were asymptomatic, but imaging detected retinal vascular leakage and inflammation. Thus, early scheduled screening is likely necessary in patients with a family history of NIV.
We initiated immunomodulatory systemic therapy based on our experience treating adult and pediatric patients with other forms of non-infectious uveitis. First, we prescribed MTX and added IFX, which are standard first- and second-line treatment of uveitis. However, there was a complete absence of treatment response even though treatment was administered in the first stages of the disease and at high dose. This is not entirely surprisingly, based on the study in immunoassay of vitreous specimen conducted by the group of Velez, that did not show increased levels of TNF in the biospecimen of NIV patients at any stages [6, 20, 30]. Moreover the downregulation of Nr3c1, a glucocorticoid receptor, evaluated in these patients, might explain why our patients showed a limited clinical response to systemic and local glucocorticoids with very early relapse [3, 4]. Subsequent rescue therapy with anti-IL6 (tocilizumab) was based on studies on biospecimens and animal models where elevated IL-6 levels were found in the vitreous of patients [3]. We further tried to personalize treatment, using anti-VEGF to treat neovascularization showing optimal results in the short term for the management of this complication [30]. Regrettably, despite early initiation of systemic immunomodulatory treatment, we continued to observe inexorable progression of ocular disease, with persistent vascular leakage and deterioration of visual acuity. Moreover, several patients developed intraocular hypertension and cataract, probably as a consequence of persistent inflammation and intraocular corticosteroids. Unfortunately, our treatment outcomes are difficult to compare to other reports, due to variability in treatment prescribed and visual outcomes reported in these studies (11 systemic corticosteroids, 4 azathioprine, and 5 methotrexate, 1 tocilizumab, 1 infliximab, 1 mycophenolate), and most focused on surgeries performed or intraocular corticosteroid use [2, 7, 25, 26, 30, 32, 35, 37]. Additionally, in several studies, patients were typically further along in their disease course and not in the early stages as in our cohort of patients.
The use of the surgical fluocinolone acetonide implant 0.59mg (Retisert), a long-acting intraocular corticosteroid, was reported by several authors as Tlucek et al showed that this implant was able to control inflammation in 9 eyes of 5 patients with NIV. These patients however developed glaucoma and cataracts and progressive fibrosis of the anterior retina [25, 26].
Identifying the next therapeutic option after an inadequate response to standard therapy is critical given the visual morbidity of long-term intraocular corticosteroids. Evidence is currently scarce. Studies by Velez et al highlighted a possible key role of mTOR- PI3K signaling in the initial stage, as well as of IL-6 and IL-17F [8, 9, 27, 30]. However, only one of 5 patients treated with TCZ was able to increase the interval of administration of intraocular glucocorticoid. Not surprisingly this patient was one of those who received the drug for a longer period. Nonetheless, our results failed to achieve the ocular disease control although high dose of drug was administered over 6 months.
Another possibility was represented by inhibiting the Janus Kinase pathway with Janus Kinase inhibitors which are promising, considering their role as receptors of several cytokines and the high expression of the interferon-gamma pathway [30]. Two patients have started tofacitinib. Current promising studies in vitro, based on the pathogenetic mechanism, are trying to identify possible treatment able to block the activity of calpain 5 with gene silencing by short hairpin RNA interference or specific inhibitory intracellular antibodies, but further work is needed, before translating them to human [43-45].
There were several limitations to our study. First, the short duration of follow-up did not allow us to fully evaluate the long-term response to TCZ and its’ potential therapeutic role based on the underlying pathogenetic mechanism. However, the knowledge that standard treatment with IFX and MTX was unsuccessful may assist with future therapeutic decision making in other patients with NIV where other available medications may be considered as initial therapy based on the pathogenetic mechanism. Another limitation is the limited number of patients included, who are part of the same large pedigree and sharing the same CAPN5 variant. However, considering the rarity of the disease, we were able to report treatment and response of 8 pediatric patients in a standard and consistent manner.
Conclusions:
NIV is a rare hereditary autoinflammatory sight-threatening condition whose initial clinical manifestation of uveitis might be indistinguishable from typical pediatric non-infectious intermediate uveitis. We newly report active disease in asymptomatic children, thus early genetic testing and ophthalmic screening of at-risk patients with family history or an uveitis resistant to common immunosuppression, as anti-TNF or anti-IL6 may be critical to optimize vision outcomes. Pediatric ophthalmologists and rheumatologists should be aware of this novel rare autoinflammatory disease, and query about family history, in order to identify these patients early due to of the ineffectiveness of common immunosuppression. Further studies are needed to evaluate the potential role of a long-term local steroids, early immunomodulatory therapy targeting T cell signaling (mTOR and PI3K), IL17 or interferon-gamma pathway and the effect in clinical outcomes.
Supplementary Material
Supplementary Table 1: This table summarized the clinical features, and therapeutic modalities as well as initial and final visual acuities, and follow-up in each of the 8 different cases. This table would display more clearly the stepladder approach in each patient and the type and number of intravitreal corticosteroid injections in each eye
Footnotes
Disclosure statement: GSS: consulting fees from SOBI, research support from IpiNovyx, ABS: Carl Zeiss Meditec, Inc; Alimera Sciences, EyePoint Pharmaceuticals. The other authors do not declare any conflicting relationship regarding this paper.
Data availability statement:
The data will be available upon reasonable request emailing the corresponding author.
References
- 1.Nigrovic PA, Lee PY, Hoffman HM. Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach. The Journal of allergy and clinical immunology 2020;146(5):925–37. doi: 10.1016/j.jaci.2020.08.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bassuk AG, Yeh S, Wu S, et al. Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment. PloS one 2015;10(4):e0122352. doi: 10.1371/journal.pone.0122352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wert KJ, Bassuk AG, Wu W-H, et al. CAPN5 mutation in hereditary uveitis: the R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model. Human molecular genetics 2015;24(16):4584–98. doi: 10.1093/hmg/ddv189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wert KJ, Skeie JM, Bassuk AG, Olivier AK, Tsang SH, Mahajan VB. Functional validation of a human CAPN5 exome variant by lentiviral transduction into mouse retina. Human molecular genetics 2014;23(10):2665–77. doi: 10.1093/hmg/ddt661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Mahajan VB, Skeie JM, Bassuk AG, et al. Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration. PLoS genetics 2012;8(10):e1003001. doi: 10.1371/journal.pgen.1003001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Velez G, Yang J, Li AS, Tsang SH, Bassuk AG, Mahajan VB. Proteomic insight into the pathogenesis of CAPN5-vitreoretinopathy. Scientific reports 2019;9(1):7608. doi: 10.1038/s41598-019-44031-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Boyce TM, Whitmore SS, Varzavand K, et al. Long-Term Outcomes and Risk Factors for Severe Vision Loss in Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV). American journal of ophthalmology 2022;233:144–52. doi: 10.1016/j.ajo.2021.07.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Velez G, Sun YJ, Khan S, et al. Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants. Cell reports 2020;30(3):881–892.e5. doi: 10.1016/j.celrep.2019.12.077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Iwamoto T, Ishiyama E, Ishida K, Yamashita T, Tomita H, Ozaki T. Presence of calpain-5 in mitochondria. Biochemical and biophysical research communications 2018;504(2):454–59. doi: 10.1016/j.bbrc.2018.08.144. [DOI] [PubMed] [Google Scholar]
- 10.Franz T, Winckler L, Boehm T, Dear TN. Capn5 is expressed in a subset of T cells and is dispensable for development. Molecular and cellular biology 2004;24(4):1649–54. doi: 10.1128/MCB.24.4.1649-1654.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Coomer CE, Morris AC. Capn5 Expression in the Healthy and Regenerating Zebrafish Retina. Investigative ophthalmology & visual science 2018;59(8):3643–54. doi: 10.1167/iovs.18-24278. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Chukai Y, Ito G, Konno M, Sakata Y, Ozaki T. Mitochondrial calpain-5 truncates caspase-4 during endoplasmic reticulum stress. Biochemical and biophysical research communications 2022;608:156–62. doi: 10.1016/j.bbrc.2022.03.156. [DOI] [PubMed] [Google Scholar]
- 13.Chukai Y, Iwamoto T, Itoh K, Tomita H, Ozaki T. Characterization of mitochondrial calpain-5. Biochimica et biophysica acta. Molecular cell research 2021;1868(5):118989. doi: 10.1016/j.bbamcr.2021.118989. [DOI] [PubMed] [Google Scholar]
- 14.Harwood SM, Yaqoob MM, Allen DA. Caspase and calpain function in cell death: bridging the gap between apoptosis and necrosis. Annals of clinical biochemistry 2005;42(Pt 6):415–31. doi: 10.1258/000456305774538238. [DOI] [PubMed] [Google Scholar]
- 15.Shi J, Zhao Y, Wang Y, et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014;514(7521):187–92. doi: 10.1038/nature13683. [DOI] [PubMed] [Google Scholar]
- 16.Schaefer K, Mahajan M, Gore A, Tsang SH, Bassuk AG, Mahajan VB. Calpain-5 gene expression in the mouse eye and brain. BMC research notes 2017;10(1):602. doi: 10.1186/s13104-017-2927-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Schaefer KA, Toral MA, Velez G, et al. Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses. Investigative ophthalmology & visual science 2016;57(6):2509–21. doi: 10.1167/iovs.15-18680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lindblad A, Johansson C, Persson K, Demirel I. The role of caspase-1, caspase-4 and NLRP3 in regulating the host cell response evoked by uropathogenic Escherichia coli. Scientific reports 2022;12(1):2005. doi: 10.1038/s41598-022-06052-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Velez G, Bassuk AG, Schaefer KA, et al. A novel de novo CAPN5 mutation in a patient with inflammatory vitreoretinopathy, hearing loss, and developmental delay. Cold Spring Harbor molecular case studies 2018;4(3). doi: 10.1101/mcs.a002519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Velez G, Mahajan VB. Molecular Surgery: Proteomics of a Rare Genetic Disease Gives Insight into Common Causes of Blindness. iScience 2020;23(11):101667. doi: 10.1016/j.isci.2020.101667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Bennett SR, Folk JC, Kimura AE, Russell SR, Stone EM, Raphtis EM. Autosomal dominant neovascular inflammatory vitreoretinopathy. Ophthalmology 1990;97(9):1125–35; discussion 1135-6. doi: 10.1016/s0161-6420(90)32447-8. [DOI] [PubMed] [Google Scholar]
- 22.Li AS, Velez G, Darbro B, et al. Whole-Exome Sequencing of Patients With Posterior Segment Uveitis. American journal of ophthalmology 2021;221:246–59. doi: 10.1016/j.ajo.2020.07.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.O'Keefe G, Hanif AM, Mahajan VB, Jain N. Early Onset Neovascular Inflammatory Vitreoretinopathy Due to a De Novo CAPN5 Mutation: Report of a Case. Ocular immunology and inflammation 2019;27(5):706–08. doi: 10.1080/09273948.2019.1582783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ebert JJ, Maccora I, Sapp CC, et al. Ultrawidefield Fluorescein Angiography and OCT Findings in Children and Young Adults with Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy. Ophthalmology. Retina 2024. doi: 10.1016/j.oret.2024.05.010. [DOI] [PubMed] [Google Scholar]
- 25.Tlucek PS, Folk JC, Sobol WM, Mahajan VB. Surgical management of fibrotic encapsulation of the fluocinolone acetonide implant in CAPN5-associated proliferative vitreoretinopathy. Clinical ophthalmology (Auckland, N.Z.) 2013;7:1093–98. doi: 10.2147/OPTH.S43939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Tlucek PS, Folk JC, Orien JA, Stone EM, Mahajan VB. Inhibition of neovascularization but not fibrosis with the fluocinolone acetonide implant in autosomal dominant neovascular inflammatory vitreoretinopathy. Archives of ophthalmology (Chicago, Ill. 1960) 2012;130(11):1395–401. doi: 10.1001/archophthalmol.2012.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Roybal CN, Velez G, Toral MA, Tsang SH, Bassuk AG, Mahajan VB. Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target. American journal of ophthalmology 2018;186:152–63. doi: 10.1016/j.ajo.2017.11.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. American journal of ophthalmology 2005;140(3):509–16. doi: 10.1016/j.ajo.2005.03.057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Wang Y, Li H, Zang S, et al. Photoreceptor Cell-Derived CAPN5 Regulates Retinal Pigment Epithelium Cell Proliferation Through Direct Regulation of SLIT2 Cleavage. Investigative ophthalmology & visual science 2018;59(5):1810–21. doi: 10.1167/iovs.17-22689. [DOI] [PubMed] [Google Scholar]
- 30.Velez G, Bassuk AG, Colgan D, Tsang SH, Mahajan VB. Therapeutic drug repositioning using personalized proteomics of liquid biopsies. JCI insight 2017;2(24). doi: 10.1172/jci.insight.97818. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Tang PH, Chemudupati T, Wert KJ, et al. Phenotypic variance in Calpain-5 retinal degeneration. American journal of ophthalmology case reports 2020;18:100627. doi: 10.1016/j.ajoc.2020.100627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Tang PH, Kinnick TR, Folk JC, et al. PROGRESSION OF SCOTOPIC SINGLE-FLASH ELECTRORETINOGRAPHY IN THE STAGES OF CAPN5 VITREORETINOPATHY. Retinal cases & brief reports 2021;15(4):473–78. doi: 10.1097/ICB.0000000000000828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Randazzo NM, Shanks ME, Clouston P, MacLaren RE. Two Novel CAPN5 Variants Associated with Mild and Severe Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Phenotypes. Ocular immunology and inflammation 2019;27(5):693–98. doi: 10.1080/09273948.2017.1370651. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Mahajan VB, Vallone JG, Lin JH, et al. T-cell infiltration in autosomal dominant neovascular inflammatory vitreoretinopathy. Molecular vision 2010;16:1034–40. [PMC free article] [PubMed] [Google Scholar]
- 35.Mahajan VB, Lin JH. Lymphocyte infiltration in CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy. Clinical ophthalmology (Auckland, N.Z.) 2013;7:1339–45. doi: 10.2147/OPTH.S46450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Han IC, Critser DB, Folk JC. Multilaminated Vitreomacular Traction in Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy. Ophthalmology. Retina 2019;3(7):588. doi: 10.1016/j.oret.2019.04.004. [DOI] [PubMed] [Google Scholar]
- 37.Cham A, Bansal M, Banda HK, et al. Secondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy. Clinical ophthalmology (Auckland, N.Z.) 2016;10:1187–97. doi: 10.2147/OPTH.S103324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Stone EM, Kimura AE, Folk JC, et al. Genetic linkage of autosomal dominant neovascular inflammatory vitreoretinopathy to chromosome 11q13. Human molecular genetics 1992;1(9):685–89. doi: 10.1093/hmg/1.9.685. [DOI] [PubMed] [Google Scholar]
- 39.Rowell HA, Bassuk AG, Mahajan VB. Monozygotic twins with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy. Clinical ophthalmology (Auckland, N.Z.) 2012;6:2037–44. doi: 10.2147/OPTH.S40086. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Xia F-J, Lyu J, Zhang X, Fei P, Zhao P-Q. Early-onset Neovascular Inflammatory Vitreoretinopathy Due to Two de Novo CAPN5 Mutations in Chinese Patients: A Case Series. Ocular immunology and inflammation 2022:1–8. doi: 10.1080/09273948.2022.2110901. [DOI] [PubMed] [Google Scholar]
- 41.Tzekov R, Madow B. Visual Electrodiagnostic Testing in Birdshot Chorioretinopathy. Journal of ophthalmology 2015;2015:680215. doi: 10.1155/2015/680215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Gakhar L, Bassuk AG, Velez G, et al. Small-angle X-ray scattering of calpain-5 reveals a highly open conformation among calpains. Journal of structural biology 2016;196(3):309–18. doi: 10.1016/j.jsb.2016.07.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Wert KJ, Koch SF, Velez G, et al. CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials. Human mutation 2019;40(12):2377–92. doi: 10.1002/humu.23894. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Wang Y, Zhang X, Song Z, Gu F. An anti-CAPN5 intracellular antibody acts as an inhibitor of CAPN5-mediated neuronal degeneration. Oncotarget 2017;8(59):100312–25. doi: 10.18632/oncotarget.22221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Nelson NG, Skeie JM, Muradov H, Rowell HA, Seo S, Mahajan VB. CAPN5 gene silencing by short hairpin RNA interference. BMC research notes 2014;7:642. doi: 10.1186/1756-0500-7-642. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1: This table summarized the clinical features, and therapeutic modalities as well as initial and final visual acuities, and follow-up in each of the 8 different cases. This table would display more clearly the stepladder approach in each patient and the type and number of intravitreal corticosteroid injections in each eye
Data Availability Statement
The data will be available upon reasonable request emailing the corresponding author.