Sarcoid Uveitis in Children

ABSTRACT

Sarcoidosis is a multi-system granulomatous disease that often presents with uveitis. Although sarcoidosis and sarcoid uveitis typically occur in adulthood, children also may be affected. There are two distinct clinical presentations of the pediatric disease, associated with younger and older age groups, and having different causations. “Early-onset sarcoidosis”, beginning at age 5 years or less, is an autosomal dominant genetic disease, caused by a mutation in the NOD2 gene. It is also known as sporadic Blau syndrome or Jabs syndrome. “Adult-type sarcoidosis”, usually beginning between the ages of 8 and 15 years, is believed to represent an excessive response to an environmental antigen. There is limited literature on the management of pediatric sarcoidosis, and treatment follows an approach applied to other forms of pediatric non-infectious uveitis. When systemic immunomodulatory therapy is indicated, methotrexate and/or adalimumab are often employed. The condition may persist into adulthood, and thus long-term follow-up is indicated.

KEYWORDS:

• Child
• sarcoidosis
• uveitis

Sarcoidosis is a multi-system granulomatous disease with diverse presentations, often having a chronic course and requiring treatment with corticosteroid drugs or immunomodulatory medications.¹ Between 30% and 60% of individuals with sarcoidosis develop eye disease, and this may be the major clinical manifestation and sometimes may develop without obvious systemic involvement.² Uveitis is most frequent form of eye involvement in sarcoidosis, affecting 20% to 50% of patients.³

Although sarcoidosis and sarcoid uveitis typically occur in adulthood, children also may be affected. In this article, we review the topic of pediatric sarcoid uveitis, summarizing what is known of its epidemiology, highlighting the differences in causation and presentation in younger versus older children, and discussing management considerations including diagnostic processes and treatment options.

Epidemiology

In their comprehensive review of pediatric uveitis, Maleki et al.⁴ summarized several studies to provide incidence and prevalence estimates for all childhood uveitis of 4.3 per 100,000 and 27.9 per 100,000, respectively. Although incidence and prevalence of pediatric sarcoid uveitis have not been documented specifically, when reviewed in the context of these figures, recent articles that report pediatric uveitis diagnoses indicate the condition must be exceedingly rare (Table 1).

Table 1. Quantitation of pediatric sarcoid uveitis in reported studies of pediatric uveitis diagnoses from different countries.

Country	Years of study	Children with uveitis (number)	Children with sarcoid uveitis (%)	First author, Year of publication^Reference
Egypt	2010–2017	413	12.8	E. Ab El Latif 2019^Citation5
Egypt	2017–2020	388	13.7	E. Ab El Latif, in press^Citation6
Finland	2008–2017	150	0	M. Siiskonen 2021^Citation7
France	2010–2017	147	6.1	G. Morelle 2019^Citation8
Greece	1996–2008	296	5.7	N.N. Markomichelakis, in press^Citation9
India	2005–2012	67	3.0	P. Kumar 2022^Citation10
Singapore	1989–2016	54	14.8	S. Waduthantri 2021^Citation11
South Korea	2005–2018	155	0	Y. Shin 2021^Citation12
Switzerland	2000–2019	317	1.6	F. Hoogewoud 2021^Citation13
Thailand	2010–2020	118	3.4	U. Seepongphun 2023^Citation14
Turkey	2010–2020	93	5.4	H. Eser-Ozturk 2021^Citation15
Turkey	2010–2020	102	0	E. Esen 2021^Citation16
United States	Up to 2005	527	2.7	J.A. Smith 2009^Citation17
United States	2005–2016	286	1.0	M. Ferrara 2019^Citation18

In a large multi-center study from the United States, of 527 children treated up to 2005 for uveitis, Smith et al.¹⁷ found 3% had sarcoidosis. Ferrara et al.¹⁸ reporting on 286 American children treated between 2005 and 2016 at the Massachusetts Eye Research and Surgery Institution for uveitis, observed just 1.0% had sarcoidosis.

Working at several French tertiary care centers from 2010 to 2017, Morelle et al.⁸ diagnosed 6.1% of 147 children with sarcoid uveitis. Hoogewoud et al.¹³ found sarcoidosis to be the cause of uveitis in 1.6% of 317 Swiss children managed at Jules-Gonin Eye Hospital between 2000 and 2019. Of 296 Greek children with uveitis seen at University General Hospital of Athens from 1996 to 2008, Markomichelakis et al.⁹ observed sarcoidosis in 5.7%. Siiskonen et al.⁷ did not diagnose a single case of sarcoidosis in 150 Finnish children treated for uveitis at Oulu University Hospital between 2008 and 2017.

In parallel studies from different pediatric uveitis clinics in northern and southern Turkey, reporting across 2010 to 2020, Eser-Ozturk and Sullu¹⁵ treated 5.4% of 93 children for sarcoid uveitis, while Esen et al.¹⁶ saw no cases of sarcoidosis among 102 patients. Abd El Latif et al.^5,6 reported two consecutive series of childhood uveitis across multiple ophthalmology clinics in Egypt also spanning 2010 to 2020, consistently identifying 12.8% of 413 patients and 13.7% of 388 patients with sarcoidosis.

In describing a multi-ethnic Asian pediatric patient population treated at Singapore National Eye Centre up to 2016, Waduthantri and Chee¹¹ documented sarcoidosis in 14.8% of 54 patients. Seepongphun et al.¹⁴ found 3.4% of 118 Thai children had sarcoid uveitis at Songklanagarind Hospital in 2010 to 2020, while Shin et al.¹² did not identify sarcoidosis in 155 pediatric uveitis patients at the Yonsei University College of Medicine in 2005 to 2018. Managing pediatric uveitis at the Chandigarh Postgraduate Institute of Medical Education between 2005 and 2012, Kumar et al.¹⁰ saw 3.0% of 67 Indian children with sarcoid uveitis.

Both girls and boys develop sarcoid uveitis, and given the very low numbers, an accurate estimate of the sex ratio is challenging. One registry-based study with 53 patients recruited across North America, Europe, and Asia in the 1990s indicated a predominance of girls with sarcoidosis¹⁹; while a second registry-based study in Denmark with 48 patients enrolled from 1979 to 1994 indicated a predominance of boys.²⁰ In their University of Chicago-based clinical series from 1987 to 2008, Choi et al.²¹ reported 9 of 13 children with sarcoid uveitis were boys.

Disease subtypes

In the classic review of pediatric ocular sarcoidosis, published in Survey of Ophthalmology in 1986, Hoover et al.²² carefully distinguished two different presentations of pediatric sarcoidosis on the basis of age at the onset, although the reason behind this difference was not clarified until approximately 20 years later. These conditions are now referred to as “early-onset sarcoidosis”, also known as sporadic Blau syndrome or Jabs syndrome, beginning at age 5 years or less; and “adult-type sarcoidosis”, usually beginning between the ages of 8 and 15 years.

Early-onset sarcoidosis

Causation

Early-onset sarcoidosis is an autosomal dominant genetic disease caused by a mutation in NOD2, the gene encoding nucleotide binding oligomerization domain containing 2 (NOD2) or caspase recruitment domain-containing protein 15 (CARD15).²³ Involved in innate immunity, NOD2 is a member of the NOD-like receptor family of pattern recognition receptors, and it is activated by multiple pathogen-associated molecular patterns, including bacterial muramyl dipeptide.²⁴

In their thorough review of NOD2 mutations linked to early-onset sarcoidosis, Caso et al.²⁵ identified over one-half as missense mutations affecting the arginine residue at position 334 (i.e. R334W and R334Q). However, multiple other mutations were also implicated, all involving the central NACHT domain required for NOD2 oligomerization. These NOD2 protein variants may trigger excessive signaling via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), leading to transcription of multiple pro-inflammatory genes.²³ However, more recent work by Napier and Lee et al., focused on uveitis, suggests that hyper-pathogenic Th17 cells arise from dysfunctional NOD2.²⁶

Ocular involvement

Most reports of children with early-onset sarcoid uveitis provide little description of the specific features of the uveitis. The most detailed description of early-onset sarcoid uveitis is embedded in a multi-national report of “Blau syndrome-associated uveitis” that includes both familial and sporadic presentations (20 and 29 patients, respectively); both children aged under 18 years and adults (27 and 22 patients, respectively); and patients with and without ocular involvement (38 and 11 patients, respectively).²⁷

The data for children were not presented separately in this report,²⁷ but descriptions were largely consistent with information collected by Hoover et al.²² in their review of 26 cases of children under 5 years up to 1985.

Acknowledging this limitation, the study showed that early-onset sarcoid uveitis was bilateral in 97% of patients and included panuveitis (51% of eyes), anterior uveitis (29% of eyes) and combinations of anterior, intermediate and posterior (20% of eyes).²⁷ In addition to anterior chamber cell and flare, common anterior eye findings were keratic precipitates, band keratopathy, posterior synechiae, and cataract. In addition to vitreous haze, common posterior segment features were multifocal chorioretinal lesions, retinal vasculitis, optic nerve head changes including swelling or pallor, and peripapillary nodules. Glaucoma was also common, and macular oedema and retinal detachment were relatively infrequent.

Median Snellen visual acuity at presentation and across 3 years of follow-up was 20/25 to 20/30, but over this period a mean 28% of patients recorded vision of 20/50 or worse and a mean 11% of patients had vision of 20/200 or worse.²⁷

Systemic manifestations

Early-onset sarcoidosis typically presents the triad of uveitis, dermatitis, and arthritis.^28,29 The characteristic rash is erythematous, scaly, and maculopapular, and there may be lichenoid papules or erythema nodosum. Joint disease often takes the form of polyarthritis with boggy synovial swelling. A review of 62 cases has identified additional systemic features, with persistent fever being relatively common, and a diverse range of other involvements reported, including hepatosplenomegaly, parotid swelling, pneumonitis and bronchial lesions, pericarditis and carditis, vasculitis, cranial neuropathies, and nephritis.²⁵

Diagnosis

The diagnosis of early-onset sarcoidosis is suspected when a child aged less than 5 years presents with uveitis in combination with joint and skin inflammation. The diagnosis is supported by detection of non-caseating granulomas, often on a skin biopsy, which is relatively non-invasive; it is confirmed by demonstrating a NOD2 mutation through sequencing all exon and exon-intron junctions of the gene.²⁵ For new mutations, increased NF-κB activity at baseline and in response to muramyl dipeptide can be identified in a reporter gene assay.³⁰

Adult-type sarcoidosis

Causation

In contrast to early-onset sarcoidosis, the pathogenic trigger of adult-type sarcoidosis remains unknown, and is likely different across individual patients. There is general consensus that the pathology represents a dysfunctional and ultimately excessive immune response to an environmental antigen.^1,31,32 A variety of potential inciting agents have been suggested, including microbes (e.g. Mycobacterium tuberculosis, Cutibacterium acnes) and inorganic materials (e.g. silicates). The basic structure of a granuloma involves epithelioid cells, macrophages, and lymphocytes, but diverse immune cell populations are involved in the disease pathogenesis.³² Genetic predisposition is often cited.³¹ An interesting study by Davoudi et al.³³ showed no difference in NOD2 common variant allele frequencies in patients with sarcoidosis and uveitis versus no uveitis.

Ocular involvement

Consistent with the findings of a recent large series of 143 Australian adult patients,³⁴ panuveitis was the most common presentation in a small series of 13 American children who presented with uveitis from age 5 upwards.²¹ Interestingly, anterior segment inflammation was non-granulomatous in most of the patients with panuveitis. While not developed for children specifically, the first report from the International Workshop on Ocular Sarcoidosis (IWOS) provides an excellent summary of the specific features of adult-type sarcoid uveitis, with illustrative color photographs, including mutton-fat keratic precipitates, iris and trabecular meshwork nodules, tent-shaped peripheral anterior synechiae, snowballs and string-of-pearls vitreous opacities, multifocal peripheral chorioretinal lesions, solitary choroidal nodules, nodular and/or segmental periphlebitis, and optic disc nodules.³⁵ Sarcoid uveitis is bilateral in the majority of patients.

Systemic manifestations

In their 2019 “primer” of sarcoidosis, Grunewald et al.¹ described the many potential systemic involvements of adult-type sarcoidosis, also emphasizing fatigue and other constitutional symptoms. One recent series of 27 children with pediatric sarcoidosis, with over 80% of adult-type, some common systemic involvements included hilar lymphadenopathy (40%) and parenchymal lung disease (26%), peripheral lymphadenopathy (30%), hepatosplenomegaly (30%), and arthritis (30%).³⁶ Almost one-half of the group suffered from fever.

In a sizable adult population of 362 patients with sarcoid uveitis from the United Kingdom, Australia, and New Zealand, 77% of patients had diverse systemic involvements, most commonly pulmonary (56%), cutaneous (27%), arthropathy (16%), and neurological (14%).³⁷ In the series of 13 American children with sarcoid uveitis, 62% suffered pathology outside the eye, most often affecting the lungs (38%), but also the parotid gland, liver, and kidney.²¹

Diagnosis

The approach to making a diagnosis of adult-type sarcoid uveitis in children is no different to that used in adults. The International Workshop on Ocular Sarcoidosis (IWOS) proposed diagnostic criteria in 2009,³⁵ and these were revised in 2019 in response to limitations identified through validation studies.³⁸ Three criteria are applied, allowing the clinician to identify ocular sarcoidosis with three levels of certainty. Under Criteria I, other causes of granulomatous uveitis are excluded. Criteria II consists of seven intraocular clinical signs, and Criteria III includes eight findings by systemic investigation. The uveitis is judged to be: definite ocular sarcoidosis if a tissue biopsy shows non-caseating granulomas; presumed ocular sarcoidosis in the absence of a positive biopsy if chest radiology shows bilateral hilar lymphadenopathy and there are two intraocular clinical signs; and probable ocular sarcoidosis in the absence of a positive biopsy and chest radiology, if there are three intraocular clinical signs and two systemic findings. These criteria have already been implemented in approximately 50 clinical studies.

The Standardization of Uveitis Nomenclature (SUN) Working Group published classification criteria for sarcoidosis-associated uveitis in 2021, requiring one of the multiple defined compatible uveitis presentations, and a tissue biopsy showing non-caseating granulomas, or bilateral hilar lymphadenopathy on chest radiology. Similar to the IWOS Criteria I, exclusions are based on positive testing for syphilis and tuberculosis. As noted by the SUN Working Group, their classification criteria emphasize specificity and are intended for diagnosis in a research setting, rather than in the clinic.³⁹

Diagnostic challenge

The potential for the diagnosis of sarcoidosis to be missed or for disease to be misdiagnosed as sarcoidosis is well recognized in adults with uveitis.^40,41 In children, the same potential exists for sarcoidosis masquerade. For example, Sullu et al.⁴² reported the case of a 9-year-old girl whose presentation was consistent with birdshot chorioretinopathy. However, she did not carry the HLA-A29, and an axillary lymph node biopsy demonstrating non-caseating granuloma established the diagnosis of sarcoidosis. Eser-Ozturk et al.⁴³ reported a series of seven children who developed uveitis following COVID-19. Although the inflammation resembled sarcoidosis clinically, the diagnostic criteria were not meet and tubulointerstitial nephritis was diagnosed in several of the patients.

Sarcoid-type disease is a rare adverse reaction to tumor necrosis factor (TNF) blockade. While most cases have been reported in adults, there have also been descriptions of children with TNF blocker-induced sarcoidosis. Alhajri et al.⁴⁴ reported a 10-year-old boy who developed a sarcoid-like condition which included granulomatous skin rash and vitritis while being treated with etanercept for long-standing juvenile idiopathic arthritis (JIA). Hashkes and Shajrawi⁴⁵ reported a similar case of a 7-year-boy with JIA who developed acute panuveitis and a skin rash, with elevated ACE and non-caseating granulomas on liver biopsy, after treatment with the same drug.

Uveitis is a rare complication of decorative skin tattooing that has been reported in patients with sarcoidosis, as well as individuals without the systemic disease.⁴⁶ Tattoo-associated uveitis has diverse presentations, including some that are typical of sarcoidosis. In those without sarcoidosis, uveitis usually presents within 1 year of tattooing⁴⁶; however, it has been recommended that affected individuals remain under long-term surveillance.⁴⁷ While the condition is largely reported in adults, the possibility exists to occur children.

Management

Although the IWOS recently published expert recommendations for the management of ocular sarcoidosis, these guidelines were developed for sarcoid uveitis as it presents in adults.⁴⁸ Reports describing the management of pediatric sarcoidosis involve small cohorts, studied retrospectively, and do not distinguish patients with uveitis. Thus, pediatric sarcoid uveitis in childhood is usually approached similarly to other forms of non-infectious chronic uveitis in children, the most common of which is the uveitis that may complicate oligo- and poly-articular JIA.^49–51

Anterior uveitis is managed with corticosteroid eye drops – most commonly prednisolone acetate 1% – initially used intensively to control the inflammation, but reduced to no more than a two times daily frequency if needed for long-term treatment. This low frequency is associated with a reduced risk of cataract progression in children with JIA-related uveitis.⁵² Short-acting mydriatic eye drops are used in parallel to limit the formation of posterior synechiae, ideally given at night to limit any impact on vision that could promote amblyopia.

Intermediate or posterior uveitis, or anterior uveitis that is not controlled with corticosteroid eye drops, is typically managed with systemic corticosteroid, including oral prednisolone or intravenous methylprednisolone. Corticosteroid treatment is transitioned within several months to a corticosteroid-sparing drug, due to adverse effects which are particularly significant in childhood. The most common corticosteroid-sparing conventional immunomodulatory drug is an antimetabolite, usually methotrexate orally or subcutaneously. Methotrexate has a long history of effectiveness and safety in childhood inflammatory diseases, and has been reported as a treatment for pediatric sarcoidosis.^36,53 The usual biologic immunomodulation approach in pediatric uveitis is TNF blockade, which is most often with adalimumab by subcutaneous injection in current medical practice.⁵⁴

In addition to case reports, small series have described treatment of pediatric sarcoid uveitis. In a series of children with non-JIA-associated uveitis, Sardar et al.⁵⁵ reported treating four French children with sarcoid uveitis, beginning treatment with corticosteroid and subsequently switching to methotrexate and/or infliximab to achieve control of the inflammation. In a series of Belgian children with uveitis described by Bazewicz et al.,⁵⁶ two patients with adult-type sarcoidosis were treated with corticosteroid and methotrexate plus/minus infliximab, and in a series of Brazilian children with early-onset sarcoidosis, two patients with uveitis were treated with methotrexate or infliximab along with corticosteroid by Cavalcanti et al.⁵⁷ Koay et al.⁵⁸ described pediatric sarcoid uveitis in their series of children with non-JIA-related uveitis who were followed by the British and Scottish Ophthalmological Surveillance Unit. They described topical and systemic corticosteroid, methotrexate, and adalimumab treatments, but did not clarify management of those patients with sarcoidosis individually.

A major report from across Japan that combined 32 patients with sporadic Blau syndrome and 18 with familial disease included 4 children aged 16 or less with early-onset sarcoidosis and uveitis. The authors described a preference for prednisolone, methotrexate, and adalimumab in various combinations and speculated that TNF blockade was protective of vision.³⁰ Another large multi-national report described 30 patients with sporadic Blau syndrome and 19 with familial disease, and included 27 children aged below 18 years, and 38 patients with eye involvement. The investigators also reported a preference for prednisolone, methotrexate, and adalimumab, commenting that efficacy was difficult to ascertain, but noting a high level of persistent uveitis at yearly visits.²⁷

Frequent review is essential when the uveitis is active, with visit intervals between weekly and monthly. Close co-management across ophthalmic disciplines is important, involving not only a uveitis specialist to manage the inflammation, but also the pediatric ophthalmologist to advise on avoidance of amblyopia, as well as cataract and glaucoma experts to manage these anterior segment complications. Systemic immunomodulatory drug selection needs to address all manifestations of sarcoidosis in the patient, and the ophthalmology team typically works alongside a team of pediatricians who prescribe and monitor these drugs, and treat the extra-ocular manifestations.

Long-term course

Understandably, a major question from the family of a child with sarcoid uveitis is the long-term outcome, and specifically whether the disease will continue into adulthood. Milman et al.⁵⁹ attempted to address this issue, using the Danish National Patient Registry to identify adults who had suffered sarcoidosis in childhood, including approximately 25% who had uveitis. Based on a questionnaire completed by a subset of the group, the complete recovery rate was 65%, with resolution occurring within a median of 1 year. The effect on uveitis was not detailed specially, however, and the work did not identify clinical factors associated with final disease status.

The French Sarcoidosis Group has addressed the issue broadly in a study of 52 adults with all forms of sarcoidosis beginning before the age of 16 years, with a follow-up of at least 3 years and a median follow-up of 11.5 years.⁶⁰ Fifty percent of these individuals had active disease requiring treatment into adulthood, and an additional 19% who enjoyed remission in childhood suffered recurrences during the adult years. Of those patients who experienced disease into adulthood, eye involvement continued in some, reported in 50% at the first pediatric evaluation and in 37% during adulthood. Despite diligently exploring multiple clinical factors, the authors were unable to identify prognostic predictors for persistence and severity in adulthood. They concluded that the severity and morbidity of this condition was significant and argued for life-long follow-up of patients.

Conclusion

Sarcoid uveitis is a rare disease in childhood, with different causation and clinical manifestations in younger versus older children. Although the literature on this disease is quite limited, treatment follows an approach used successfully for other forms of pediatric non-infectious uveitis, with methotrexate as a standard conventional drug and adalimumab as a standard biologic drug. A multidisciplinary approach is appropriate, and since the condition may persist into adulthood, long-term follow-up is indicated.

Acknowledgments

The authors wish to thank Ms. Janet Matthews for her administrative support in the preparation of this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.