Juvenile Idiopathic Arthritis-Associated Uveitis: Evidence-Based Screening, Monitoring, and Treatment

Abstract

Juvenile idiopathic arthritis (JIA) is the most frequent chronic autoimmune rheumatic disease in children and adolescents. JIA-associated uveitis is its commonest extra-articular manifestation comprising usually a silent iridocyclitis. Due to this asymptomatic clinical presentation, it is estimated that one-third of JIA-associated uveitis may present with ocular complications by the time of diagnosis. Time-appropriate screening and monitoring are crucial for the prevention of sight-threatening ocular manifestations. Updated treatment is also essential for adequate management and, therefore, to guarantee the best long-term functional vision in these patients. The scope of this chapter involves: (a) JIA and JIA-uveitis introduction/background; (b) etiology, pathogenesis, and risk factors; (c) diagnosis, clinical presentation, and ocular complications; (d) monitoring and screening (including national/international screening guidelines); (e) management (treatment options and treatment monitoring); (f) disease burden; and (g) conclusion and take-home messages.

1. Introduction

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and adolescents. It comprehends a heterogeneous group of autoimmune arthritis with onset before 16 years of age and a duration of at least 6 weeks (Table 1) [1].

JIA category	Definition		Prevalence
			ACR	EULAR	ILAR
Oligoarthritis	Arthritis with 1–4 joints during the first 6 months of disease	Persistent: 1–4 joints	15.6%	17.6%	16.4%
		Extended: >4 joints after the first 6 months of disease
Polyarthritis	Arthritis with >4 joints during the first 6 months of disease	RF negative	6.2%	8.1%	4.2%
		RF positive on at least two occasions more than 3 months apart	1.9%	1.7%	0.6%
Psoriatic arthritis	Arthritis and psoriasis or arthritis and at least two of: dactylitis; nail pitting or onycholysis; psoriasis in a first-degree relative		4.1%	1.1%	1.1%
Enthesitis-related arthritis	Arthritis and enthesitis or arthritis or enthesitis with at least two of: presence or a history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain; presence of HLA-B27 onset of arthritis in a male older than 6 years of age; acute symptomatic anterior uveitis; history of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome or acute anterior uveitis in a first-degree relative		13.8%	1.5%	3.1%
Systemic	Arthritis with or preceded by daily fever of at least 2 weeks’ duration that is documented to be quotidian for at least 3 days and accompanied by one or more of: evanescent nonfixed erythematous rash; generalized lymph node enlargement; hepatomegaly and/or splenomegaly; serositis		6.4%	2.7%	2.4%
Undifferentiated	Arthritis that fulfills criteria in no category or in two or more of the above categories				2.7%

Table 1.

Table extracted from Neves et al. [6] with definitions of JIA categories and prevalence of uveitis for each JIA category defined by ACR, EULAR, and ILAR classification [7, 8].

ACR: American College for Rheumatology; EULAR: European League Against Rheumatism; ILAR: International League of Associations for Rheumatology.

Uveitis is the most frequent extra-articular manifestation of JIA, affecting up to one-third of patients within 7 years of the onset of arthritis, although the prevalence of uveitis can vary according to the disease group, being as high as 57% in the young oligoarticular onset subpopulation [2, 3]. JIA-associated uveitis is also the most common cause of uveitis in the pediatric population, representing around 20% of the cases [4, 5].

JIA-associated uveitis more commonly manifests itself presents as an asymptomatic chronic anterior uveitis without external evidence of inflammation, and a delayed diagnosis can result in sight-threatening complications, which can be seen in one-third of cases at presentation, and up to 67% of cases over all [9]. Ocular complications include band keratopathy, anterior and posterior synechia, glaucoma, cataract and macular edema, and scaring.

Differently, specific HLA B27-associated uveitis in children with spondyloarthritis typically presents as a symptomatic acute anterior uveitis which is often episodic and does not require systemic treatment [10].

The visual prognosis of children with JIA-associated uveitis can be very poor, with reports of severe sight loss and sight impairment varying from 9 to 22% [2, 11]. Early detection and appropriate treatment of uveitis are of utmost importance to avoid the development of sight-threatening irreversible complications and prevent permanent visual loss. International guidelines for JIA-affected children and young people have been developed as an attempt to reduce this burden.

In this chapter, we aim to revise this important cause of uveitis in the pediatric population, its clinical presentation, management, and the disease burden associated with it.

2. Epidemiology, pathogenesis, and risk-factors

2.1 Epidemiology

JIA incidence varies from 1.6 to 23/100,000 and JIA prevalence varies from 3.8 to 400/100,000 [8]. Oligoarthritis is its most frequent form. The pooled incidence and prevalence are higher for girls (10.0 [9.4–10.7]/100,000 and 19.4 [18.3–20.6]/100,000) than for boys (5.7 [5.3–6.2]/100,000 and 11.0 [10.2–11.9]/100,000) [8]. JIA-associated uveitis incidence is estimated in 1/100.000 [12].

The effect of ethnicity is unclear and JIA-associated uveitis seems to be more frequent in Caucasians than in Afro-American children and adolescents. Also, geographical differences show a higher JIA prevalence in Europe and North America than in Asia [7]. Nevertheless, this should be interpreted with caution as there is scarce epidemiological data in other areas such as Latin America and Africa.

2.2 Pathogenesis

The pathogenesis of JIA-uveitis is still not fully understood. What is currently known is its multifactorial immune-mediated background with complex genetic and environmental factors involving concealed infection, psychological stress, vitamin D deficiency, or use of specific vaccines [13].

Histocompatibility allele profiles have been widely assessed and human leukocyte antigen (HLA)-DRB*03, *08, *11, *12, *13, and *14 were associated with an increased risk of uveitis in JIA patients [13]. By contrast, the HLA-DR1 haplotype and HLA-DQA*0101 allele seem to be protective. HLA-B27, which is associated with enthesitis-related arthritis, confers an increased risk of acute anterior uveitis (AAU) [14].

Regarding genetic traits, there have been few reports of familial cases of JIA-uveitis, as there is a lack of a single-gene, mendelian trait of inheritance, suggesting also a complex genetic pathogenesis [15].

Interestingly, children with JIA-uveitis revealed higher levels of cytokines and chemokines (IL-2, IL-6, IL-13, IL-18, IFN-γ, TNF, soluble ICAM-1 (also known as CD54), C-C motif chemokine 5 (CCL5, also known as RANTES) and C-X-C motif chemokine 10 (CXCL10, also known as IP-10) in the aqueous humor than ones without uveitis [16].

2.3 Risk factors

It is well established that JIA-uveitis has several risk factors which are: age at arthritis onset, gender, JIA subtype, antinuclear antibody (ANA) positivity, human leukocytes antigen (HLA)-B27 positivity, and anti-histone antibodies (AHA) 15 U/mL [1, 9, 17].

These risk factors are different depending on the course (acute or chronic) of the uveitis. Chronic anterior uveitis (CAU) is associated with less than 6 years old at JIA onset, female gender, oligoarticular disease (four or fewer joints at disease onset), and ANA positivity, which occurs in 70–90% of JIA-uveitis cases [1, 9]. However, it seems that age-dependent risk of developing uveitis is related only for girls and not for boys [17, 18].

In contrast, AAU is associated with pre-teenaged and teenaged patients, male gender, enthesitis-related arthritis, and positive HLA-B27 [1, 7]. Uveitis can also be observed in patients with rheumatoid factor (RF)-negative polyarthritis, psoriatic arthritis, and, more rarely, in systemic-onset JIA [7]. In this regard, the polyarticular RF positivity subtype was revealed as protective for uveitis [9].

JIA-associated uveitis with risk of poor prognosis is associated with specific risk factors that should be mentioned, such as male sex, younger age at JIA-uveitis onset, short duration between onset of arthritis and uveitis (median 6 months), development of uveitis prior to arthritis, presence of synechiae, high anterior chamber cell grade (>2+), and poor visual acuity at uveitis diagnosis [19].

3. Diagnosis, clinical presentation, and ocular complications

Uveitis is the presenting complaint in 3–7% of patients with JIA, whereas in most cases arthritis precedes the uveitis by a mean of 4–5 months. Most patients that develop uveitis (73%) will do so in the first year after their arthritis diagnosis [20].

The most common manifestation of JIA-uveitis is as an asymptomatic, bilateral, non-granulomatous iridocyclitis [21]. Usually, its onset is insidious, its duration is persistent (lasts more than 3 months) and its course is chronic (relapse in less than 3 after discontinuing treatment) in up to 90% of cases [21]. In contrast, some subgroups can present with AAU (10–16.2% of cases), as those associated with HLA B27-related enthesitis. Panuveitis has rarely been described [21].

The diagnosis of JIA-uveitis is performed clinically during an ophthalmological examination mostly done at the slit-lamp, with the identification of signs of anterior chamber inflammation (cells and/or flare) or its complications. Smaller or uncooperative children may require the use of portable slit lamps or indirect ophthalmoscope for assessment.

As the CAU is typically asymptomatic with no external evidence of inflammation, one-third of patients will have ocular complications on diagnosis, and up to 67% of them will develop complication during the course of their disease [9]. Poor prognosis factors include severe disease at presentation, uveitis preceding arthritis and male gender [22, 23]. Anterior chamber flare is also considered an important marker of disease gravity in children, and its presence can be predictive of adverse events during the disease’s course [24].

Additionally, the fact that most children and young people will not notice changes in vision or symptoms until complications are present can lead to difficult treatment adhesion, especially in cases where the severity of the uveitis is more significant than the arthritis and guides their treatment.

3.1 Posterior synechiae

Posterior synechiae are adherences between the iris and lens which occur due to fibrin exudation in significant anterior chamber inflammatory processes [25]. They are a common complication (27–33%) that can collaborate with the increased intra-ocular pressure and accelerate cataract formation (see below) and have been independently associated with decreased vision [26].

3.2 Band keratopathy

Chronic degenerative condition is frequently associated with chronic ocular inflammation; it is characterized by the deposition of calcium in hydroxyapatite form into superficial layers of the cornea and is present in 15–29% of patients. These grayish-to-whitish opacities first appear peripherally in the corneal surface (3 h and 9 h), extending centrally to form coalescent dense plaques in the interpalpebral zone, affecting the visual axis and causing ocular discomfort (Figure 1) [27].

Figure 1.

Peripheral band keratopathy.

3.3 Cataract

Cataract formation is the most common ocular complication associated with visual impairment and occurs in about a third of the cases [25]. It is a consequence of chronic inflammation and topical and systemic corticosteroid use. The risk of cataract development with topical steroid use seems to be independent of the presence of active uveitis and posterior synechiae, and it increases as more drops are used over longer periods of time (especially if >3 drops daily) [28, 29].

Particular attention must be given to pre-school children with asymmetrical cataracts due to the risk of amblyopia.

3.4 Glaucoma or ocular hypertension

Ocular hypertension is defined as intra-ocular pressure of more than 21 mmHg in three consecutive measurements, or a single measurement of 30 mmHg or more [30]. It can be a result of a dysfunctional trabecular meshwork due to chronic anterior uveitis, a steroid response to topical (mainly) or systemic treatment with corticosteroids, or a combination of all. Its prevalence varies from 8 to 19% in JIA-associated uveitis. The presence of synechiae and pupillary seclusion can also compromise the aqueous humor outflow and collaborate to that. The use of 0.1% dexamethasone eye drops four times a day for more than 8 weeks can result in ocular hypertension in 60–70% of patients [29]. Secondary glaucoma occurs when there is optic glaucomatous nerve damage and visual field defects as a consequence of ocular hypertension.

3.5 Hypotony

Hypotony is defined by an intraocular pressure of less than 5 mmHg and results from severe ciliary body inflammation and/or atrophy. Although not as common as the previous complications (7.1–9.3%), it is associated with more severe uveitic disease, panuveitis, and the presence of posterior synechiae, and can lead to poor visual outcomes due to hypotony maculopathy and papillopathy and end-stage shrinking of the eye (phthisis bulbi) [31]. Early start of immunosupressive therapy seems to have a protective effect against the development of hypotony [31].

3.6 Macular edema

Macular edema is defined as an increase in central macular thickness, and can be related to inflammatory stress, microvascular changes, be a complication of cataract, other intra-ocular surgeries, or hypotony (Figure 2). Its prevalence is estimated in 6–25% of cases [32]. The duration of JIA-uveitis positively correlates with the development of macular edema [32]. The widespread use of optical coherence tomography (OCT) as part of the routine ocular exam has led to early detection of macular thickness changes, facilitating disease activity monitoring.

Figure 2.

Left chronic macular edema at OCT.

3.7 Papillitis

Often seen as a sign of inflammatory activity rather than a complication, it is often present in cases of severe anterior uveitis in children (12%), and is not necessarily associated with primarily intermediate or posterior uveitis, as in adults. It seems to be more present in boys than girls, and not independently related to worse visual acuity [33]. Clinically, optic nerve function tends to be preserved, with normal color vision and no red desaturation, and optic nerve imaging such as retinal nerve fiber layer thickness on OCT can be a useful monitoring tool.

4. Screening and monitoring

4.1 Screening

Ophthalmological screening is recommended when JIA is suspected or within the first 6 weeks of final diagnosis [34, 35] or, if symptomatic, within 1 week of referral [35]. Current literature has different recommendations regarding the frequency of ophthalmological screening after this first examination and they can be seen in Table 2.

	BSPAR/RCO	ACR/AF/SBOP			BSRP
First exam	Before 6 weeks of diagnosis; If symptomatic: within a week of referral	No recommendations (ACR/AF); When JIA is suspected or diagnosis within 6 weeks of diagnosis			At JIA diagnosis
Freq.	Every 2 m for 6 m; Followed by every 3–4 m for (see below):	Oligoarthritis, polyarthritis and negative RF, psoriatic arthritis and undifferentiated arthritis		Systemic JIA, polyarthritis and positive RF; Enthesitis-related arthritis	JIA age of onset ≤6 y, disease duration ≤4 y, oligo/poly and ANA positive; Every 3 m.
	Oligoarticular JIA, psoriatic arthritis and enthesitis-related arthritis despite ANA status onset under 11 y: < 3 y onset: 8 y; 3–4 y onset: 6 y; 5–8 y onset: 3 y; 9–10 y onset: 1y	PositiveANA, JIA age of onset <7 y and disease duration ≤4 y	NegativeANA, JIA age onset ≥7 y or disease duration >4 y		JIA age of onset ≤6 y, disease duration ≤4 y. Oligo/poly, negative ANA or JIA age of onset ≤6 y disease duration >4 y, oligo/polyarthritis, despite ANA status or JIA age of onset >6 y, disease duration ≤4 y, oligo/poly, despite ANA status; Every 6 m
	Polyarticular, positive ANA, JIA onset less than 10 y; < 6 y onset: 5 y; 6–9 y onset: 2 y
	Polyarticular, positive ANA JIA, JIA onset less than 7 y: 5 y	Every 3 m	Every 6–12 m		Systemic JIA, polyarthritis with positive RF, and enthesitis-related arthritis or JIA age of onset ≤6 y, duration of JIA ≥ 7 y oligo/polyarthritis, despite ANA status or JIA age of onset >6 y, duration of JIA > 4 y, oligo/polyarthritis, despite ANA status; Every 12 m.

Table 2.

Table extracted from Neves et al. [6] Screening criteria for ophthalmological examination in juvenile idiopathic arthritis by the British Society for Pediatric and Adolescent Rheumatology/Royal College of Ophthalmology (BSPAR/RCO), the American College of Rheumatology/Arthritis Foundation (ACR/AF), the Brazilian Society of Pediatric Ophthalmology (SBOP), and the Brazilian Society of Rheumatologic Pediatrician (BSRP) Guideline and [6, 35, 36, 37].

Freq.: frequency; JIA: juvenile idiopathic arthritis; m: months; y: years; ANA: antinuclear antibody; RF: rheumatoid factor.

Based on the British Society for Pediatric and Adolescent Rheumatology/Royal College of Ophthalmology (BSPAR/RCO) guidelines, the ophthalmological screening of uveitis frequency should be every 2 months for 6 months followed by every 3–4 months [35]. The duration of these examinations will be determined according to the patient’s age and to the type of JIA, as is described in Table 2.

Based on the American College of Rheumatology/Arthritis Foundation (ACR/AF) guidelines and also on the Brazilian Society of Pediatric Ophthalmology (SBOP) recommendations (Table 2 and Figure 3), patients with JIA are classified as high, moderate, and low risk for developing uveitis [36]. High-risk patients include those with oligoarthritis, polyarthritis with negative RF, psoriatic arthritis, and undifferentiated arthritis, those with positive ANA, younger than 7 years of age at JIA onset, and with a disease duration of less than 4 years [36]. Low to moderate-risk patients are those with JIA in the aforementioned categories but with negative ANA, older than 7 years at JIA onset or with more than 4 years of disease duration, and those with systemic JIA, positive RF-polyarthritis, and enthesitis-related arthritis [6, 36]. Based on this, high-risk uveitis patients should be screened every 3 months and low- to moderate-risk uveitis patients every 6–12 months (Table 2 and Figure 3) [36]. Follow-up should be until 11 years old or according to medical criteria [6].

Figure 3.

Figure extracted from Neves et al. [6]: Ophthalmological screening in juvenile idiopathic arthritis.

According to the Brazilian Medical Association (AMB) and the Brazilian Society of Rheumatology (SBR) guidelines, ocular screening should start at the time of JIA diagnosis [37]. Its frequency should be based on JIA subtype, age at the disease onset, disease duration, and positive ANA, as shown in Table 2.

Ophthalmological screening exams should include age-appropriate visual acuity tests, classification of the anterior chamber cell grade inflammation at the slit lamp by the Standardization of Uveitis Nomenclature Working Group (SUN) criteria and quantification of structural complications [38]. In addition, recording the duration of active inflammation and detailing the treatment response are also important for JIA-uveitis monitoring [39].

4.2 Monitoring

Therefore, ophthalmological screening is indicated in JIA patients without uveitis. For children and adolescents with uveitis-JIA, it is important to differentiate, at the examination, if the uveitis is controlled or uncontrolled.

Uncontrolled uveitis occurs when there is an increase of anterior chamber cells to grade 1+ or more, or new signs of inflammation/complications of inflammation [36]. Controlled uveitis is considered when there are no or grade < 1+ anterior chamber cells without new complications due to active inflammation; absence of optic disc, macular edema, and vitreous haze [36].

The frequency of ophthalmological monitoring in uncontrolled uveitis should be according to the anterior chamber degree of inflammation classification by SUN (Figure 4) [36, 40]:

Figure 4.

Figure extracted from Neves et al. [6]: Ophthalmological monitoring in juvenile idiopathic arthritis-related uveitis.

In grades 3+ or 4+: weekly until improvement.

In grades 1+ or 2+ (stable in two successive visits): every 2 weeks (or at least in less than 6 weeks).

In grade 0.5+ (stable in two successive visits): every 6 weeks (or at least in less than 3 months).

Naturally, this follow-up frequency is a suggestion and ophthalmological monitoring in uncontrolled uveitis should also be individualized based on clinical factors such as the frequency of topical glucocorticoid administration, the IOP, and the presence of ocular complications [36].

The recommendations for ophthalmological monitoring in children and adolescents with controlled JIA-uveitis can be divided into who is tapering/discontinuing therapy (topical or systemic) and who has stable therapy (Figure 4) [36]:

Tapering or discontinuing topical glucocorticoids: monitoring should be monthly. Also, the patient should be evaluated before each step of tapering.

Tapering or discontinuing systemic therapy: within 2 months. In the suspension of systemic or immunomodulatory therapy, monitoring should be performed every 2 months for 6 months.

Stable therapy, systemic or topical: every 3 months.

5. Management (treatment options and monitoring)

5.1 Topical therapy

Topical glucocorticoids are the first-line treatment for JIA-uveitis, acute or chronic uveitis. Prednisolone acetate 1% eye drop is the topical glucocorticoid of choice due to its good corneal penetration and low risk of IOP elevation (Figure 5) [1, 36]. The frequency of the administration is based on the degree of anterior chamber inflammation. Topical and systemic nonsteroidal anti-inflammatory therapy should not be used as single therapy [41].

Figure 5.

Figure extracted from Neves et al. [6]: Treatment steps in juvenile idiopathic arthritis-related uveitis.

The cycloplegic eye drop, tropicamide 10 mg/ml, should also be given to prevent or treat posterior synechiae in active uveitis in a recommended frequency of one drop every 8 hours. Its adverse events include somnolence, reduced accommodation, and blurred vision.

Topical treatment should be maintained as long as there are ≥0.5+ cells in the anterior chamber. However, prolonged topical glucocorticoids therapy has potential ocular adverse effects. Therefore, in patients who are not on systemic therapy, but still require one to two drops of topical glucocorticoids daily for uveitis control over 3 months, it is recommended to add systemic therapy, described in the next item [1, 36] Eventually, in the absence of ocular complications, such as elevated IOP and cataract, and guaranteeing regular ocular follow-up, topical glucocorticoids at a dosage of one to two drops daily may be used as monotherapy [36].

Subtenon or orbital floor injection of glucocorticoids as a rescue therapy has been suggested in selected cases such as in unilateral or bilateral severe (3+ or 4+ AC cells) or refractory (after 2 weeks of topical and oral corticosteroids without clinical improvement) uveitis, especially in patients with sight-threatening risk factors [40, 41]. These risk factors include initial decreased visual acuity, massive anterior chamber inflammation, hypotony, glaucoma, cataract, dense vitreous opacities, or macular edema.

The injection dosage is 2–4 mg of dexamethasone phosphate or 20–40 mg of triamcinolone acetonide. The intravitreal injection dosage is 700 mg of a dexamethasone phosphate implant and 2–4 mg of triamcinolone acetonide. However, intraocular glucocorticoids are associated with cataract development and a risk of increased IOP, and IOP should be monitored weekly [40, 41].

5.2 Systemic therapy

Systemic treatment is usually indicated in JIA-uveitis in two scenarios: (a) when there is a failure of adequate control of inflammation after 3 months of topical treatment [1, 36] and (b) after 3 weeks without uveitis control in the presence of sight-threatening risk factors such as initial decreased visual acuity, massive anterior chamber inflammation, hypotony, glaucoma, cataract, dense vitreous opacities, or macular edema [40].

Systemic treatment options include glucocorticoid, disease-modifying anti-rheumatic drugs (DMARDs) (methotrexate, mycophenolate mofetil, cyclosporine A, and azathioprine), and biological agents (anti-tumor necrosis factor [anti-TNF] blockers: adalimumab, infliximab, golimumab, etanercept; CTLA4-Ig: abatacept; and anti-IL6: tocilizumab) (Table 3).

Drug name	Mechanism	Preferred dosage and route	Ocular and systemic side effects	Laboratory routine
Synthetic DMARDs
Methotrexate	Cellular adenosine release	10–15 mg/m^2 BS PO or SC weekly.; Adjust dose gradually to achieve an optimal response.	GI discomfort, nausea, diarrhea, photosensitivity, rash, increased AST or ALT, cytopenias.	Baseline: Complete blood and platelet count; Renal function; Liver function; Chest X-ray; Monitoring: Hemogram, renal and liver function tests every 1–3 month.
Mycophenolate mofetil	Inhibitor of inosine-5-monophosphate dehydrogenase	300 mg/m^2 bd, increasing to 600 mg/m^2 bd	GI discomfort, leukopenia, pure red cell aplasia, hair loss, lymphoma and malignancy (particularly of the skin)	Complete blood cell counts weekly during the first month, twice monthly for the second and third months and then monthly
Cyclosporine A	Calcineurin inhibitor blocking T-cell proliferation	2.5–5 mg/kg/day in 2 doses	GI disturbance, hypertension, renal and liver dysfunctions, lipid abnormalities, hirsutism, gum hypertrophy	Renal and liver functions, serum lipids, magnesium and potassium.; Cyclosporine blood concentration adjusted to 100 mcg/dl
Azathioprine	Purine nucleoside analogue, inhibits DNA replication	1–3 mg/kg/day	Myelotoxicity and hepatotoxicity.	Complete blood and platelet count, liver function tests every 1–3 months
Biological DMARDs
Adalimumab	Anti-TNF alfa/ human monoclonal antibody	Body weight 10–15 kg: 10 mg SC every other week; 15–30 kg: 20 mg SC every other week; ≥30 kg: 40 mg SC every other week	Opportunistic infections by Legionella, Listeria, tuberculosis, and invasive fungal infections. Hepatitis B virus reactivation.; Infusion reaction.; Hepatotoxicity (infliximab and tocilizumab).; Heart failure.; Hypersensitivity and anaphylaxis.; Risk of cancer (invasive cervical cancer, hepatosplenic T-cell lymphoma).; Cytopenias.; Lupus-like syndrome.; Demyelinating disease.; Gastrointestinal perforation (tocilizumab).; Vitreous hemorrhage (adalimumab and infliximab)	Check for latent infection.; Avoid live vaccines during treatment or offer live vaccines prior to treatment.; Complete blood count.; Hepatic function (infliximab and tocilizumab).
Infliximab	Anti-TNF alpha/chimeric (mouse-human monoclonal antibody)	Initially 6 mg/kg/dose IV; 3–10 mg/kg/dose IV at 2 weeks, then every 4–8 weeks, adjusted according to response
Tocilizumab	Anti-IL-6/humanized monoclonal antibody	Body weight < 30 kg: 10 mg/kg IV^6; body weight > 30 kg: 8 mg/kg IV^6 every 4 weeks
Abatacept	Inhibition of lymphocyte co-stimulation (CTLA4)/human fusion protein	10 mg/kg IV; At weeks 0, 2, 4, and every 4 weeks

Table 3.

T extracted from Neves et al. [6]: Drug names; mechanism of action; preferred dosage and route; ocular and systemic side effects; adverse events; and laboratory routine of synthetic and biological disease-modifying anti-rheumatic drugs (DMARDs) for juvenile idiopathic arthritis-associated uveitis [1, 41].

PO: by mouth; SC: subcutaneous; GI: gastro intestinal; Bd: twice daily; Anti-TNF: anti-tumor necrosis factor; IV: intravenous; IL: interleukin; CTLA4: cytotoxic T-lymphocyte-associated protein 4.

Methotrexate (MTX) is the first-line systemic treatment either oral or parenteral (subcutaneous, preferably, or intramuscular routes) [1, 36]. Laboratory routine with transaminases should be performed every 1–3 months. If transaminases increase up to 1 fold the upper limits, MTX dose should be reversed; if transaminases increase more than 2 fold the upper limits, MTX should be suspended for 2–4 weeks and then restarted. Under normal transaminases status, treatment should be resumed otherwise it is recommended its withdrawal (Table 3).

Briefly, Figure 5 summarizes the steps to achieve optimal uveitis control under systemic therapy. Systemic therapy is initiated with MTX. Systemic glucocorticoids may be used as bridge therapy in patients with sight-threatening risk factors until a DAMARD effect can is achieved5 In addition, patients with sight-threatening complications, should initiate treatment with MTX combined with a monoclonal TNF inhibitor [36] (Table 3).

If no control of uveitis is observed or the disease worsens after 3–4 months on MTX initial therapy, it is recommended to associate a biological agent [1]. The ACR recommends monoclonal anti-TNF drugs, preferably adalimumab, infliximab, or golimumab [36] (Table 3).

If the patient is under one monoclonal anti-TNF at a standard dose and still has active CAU, the recommendation is to escalate the dose and/or frequency to above the standard before switching to another monoclonal anti-TNF [36]. In children and adolescents with active CAU who have failed the first monoclonal anti-TNF with proper dosage and/or frequency, changing to another monoclonal TNF inhibitor is recommended over switching to another biologic category [36] (Table 3).

If the patient still has active CAU, despite the use of MTX combined with monoclonal anti-TNF at a higher dosage/frequency, it is recommended to switch to another biological agent of different mechanism of action (abatacept or tocilizumab) or associate with immunomodulatory synthetic agents (mycophenolate, leflunomide, or cyclosporine) [36] (Table 3).

Both ophthalmologist and pediatric rheumatologist follow-ups are fundamental for appropriate management of JIA-associated uveitis. Regarding this, vaccination should be completed preferably within 4 weeks before treatment [41]. Tuberculosis and latent tuberculosis infection screening should also be done before initiation of anti-TNF biologics. Drug adherence, contraception for adolescents, and rigorous monitoring for infections and malignancy should also be routinely evaluated [41] (Table 3).

Table 3 comprises drug names; mechanism of action; preferred dosage and route; ocular and systemic side effects; adverse events; and laboratory routine of synthetic and biological DMARDs for JIA-associated uveitis [1, 41].

6. Disease burden

JIA and JIA-associated uveitis have a huge impact on the children affected by it. This impact extends not only to the patients, but also to their caregivers and other family members, and imposes a significant burden on different spheres of their lives, even after they reach adulthood. This includes, but is not limited to, their health-related quality of life, physical function, visual outcomes, school attendance, psychological and emotional development as well as the costs involved with long-term treatments and multiple hospital appointments [42]. A study from Germany looked into the direct costs (healthcare and non-healthcare costs) and indirect costs (productivity loss due to sick leave and work disability) for patients with JIA over a 17 year follow-up, and the results showed an estimated mean total cost of €3500 per patient/year [43]. The large majority of the costs (90%) were related to patients with persistently active disease (55%), as well as functional disabilities and certain JIA subgroups, and could reach up to €17,000 a year. Although most healthcare-related costs will vary between countries with different healthcare systems, it is valid to assume that a similar financial burden will fall upon JIA patients worldwide.

Additionally, as these children reach adolescence and young adulthood, the impacts of having a chronic illness and possible disabilities may negatively influence their ability to develop their own identity and independence, as they may need to rely more on their caregivers for financial support and morbidities management than other young people [44].

In patients with JIA, having uveitis has been associated with a worse quality of live. Among JIA-uveitis patients, additional factors that negatively influenced the quality of life were bilateral uveitis, visual impairment and posterior involvement [45]. Other studies looking into the quality of life of pediatric patients with chronic uveitis have shown that the visual loss and fear of blindness are not the only stressors for the patients and their families, as the frequency of eye examinations, treatment regimens and side effects also play an important role. Both the disease and its treatment can interfere with transition to autonomy in adulthood, as reported for other chronic conditions, and problems with treatment adherence are frequent [46]. The development of unified multidisciplinary teams, with joint clinics for all healthcare team involved in their management, seem to have a positive impact on patients and family members [47].

Understanding the impact of the disease and its treatment on a child’s or young person’s life is of utmost important to allow us to provide better care and support for young patients, and more studies are required to find ways to reduce the disease burden following an hollistic approach [48].

7. Differential diagnosis

Pediatric uveitis represents less than 10% of all uveitis and have a broad etiologic spectrum. It can be classified as idiopathic (majority), infectious (viral, bacterial, parasitic, and less commonly, fungal), non-infectious diseases (mainly autoimmune), and masquerade syndromes (tumoral, non-autoimmune inflammation, retinal dystrophies) [49, 50]. Age, geographic location, and socioeconomic status appear to affect the prevalence of each disease, but it is beyond the scope of this chapter.

It is important to briefly describe the main differential diagnosis of JIA-associated uveitis, as some of the anterior ocular findings may be similar among them. Table 4 shows the main diseases and their similarities and differences with JIA-uveitis [49, 50].

JIA-uveitis differential diagnosis	Type of uveitis	Systemic findings	Ocular similarities	Ocular differences
Non-infectious uveitis
Idiopathic anterior uveitis	Anterior uveitis (acute or chronic)	Nothing; Exclusion diagnosis	Chronic anterior uveitis	Age of onset 7–12 years, acute anterior uveitis
Enthesis-related arthritis	Acute unilateral anterior uveitis	Enthesitis	Anterior chamber inflammation, complications such as band keratopathy, cataracts, and ocular hypertension	Pain, redness, HLA-B27 positivity
Sporadic early-onset sarcoidosis (onset before age 5)	Acute bilateral anterior uveitis	Multisystemic granulomatous inflammatory disorder. While older children may present with pulmonary involvement, young children typically present with a triad of arthritis, skin (follicular or nodular rash) lesions and uveitis	Anterior chamber inflammation, complications such as band keratopathy (rare), cataracts, and ocular hypertension Lately, chronic anterior uveitis	Pain, anterior chamber granulomatous features (granulomatous keratic precipitates, iris nodules), peripheral and broad-based posterior synechiae, granulomatous optic neuropathy, choroidal involvement (multifocal choroiditis, choroidal granulomas).
Tubulointersticial nephritis uveitis syndrome	Acute bilateral anterior uveitis	Fever, malaise and weight loss. Tubulointerstitial nephritis evidenced by increasing urea and creatinine levels, proteinuria, microhematuria, glycosuria and elevated urinary beta-2-acroglobulin level.	Anterior chamber inflammation	Median age of onset 15 years old, pain, photophobia, there may be anterior chamber granulomatous features, retinal periphlebitis, disc edema, multifocal choroiditis
Pars planitis	Intermediate uveitis	Idiopathic	Mild to moderate anterior segment inflammation, Complications: Band keratopathy, peripheral corneal endotheliopathy, posterior synechiae, less commonly cystoid macular edema.	Age of onset 7–12 years., diffuse vitreous cells and haze, snowballs and snowbanks located inferiorly. Complications such as optic disc edema, neovascularization of the optic disc, inferior peripheral retinoschisis.
Familial autosomal dominant hereditary Blau Syndrome	Chronic bilateral granulomatous panuveitis with multifocal chorioretinal lesions	Granulomatous polyarthritis + dermatitis+ uveitis; CARD15/NOD2 gene on chromosome 16q12; autosomal dominant pattern	Anterior chamber inflammation and complications	Granulomatous panuveitis with multifocal chorioretinal lesions
Behçet Disease	Panuveitis with retinal vasculitis, retinitis and vascular occlusion.	Recurrent, painful, oropharyngeal and genital ulceration, systemic vasculitis, acne, folliculitis, epididymitis, arthralgia, erythema nodosum, gastrointestinal inflammation.	Mild to moderate non-granulomatous anterior chamber inflammation. Complications such as cataract, intraocular pressure elevation, macular edema or maculopathy, and optic atrophy are the most common complications	Panuveitis with retinal vasculitis and retinitis. Mean onset of 11 years old, HLA B51 positivity
Vogt-Koyanagi-Harada syndrome	Bilateral panuveitis.	Acute meningoencephalitis, vitiligo, poliosis and dysacusia.	Anterior chamber inflammation	Pain, anterior chamber granulomatous features, serous retinal detachment, thick choroids
Infectious uveitis
Toxoplasmosis	Unifocal and unilateral retinalchoroiditis	Primary infection: mononucleosis-like systemic symptoms	Mild to moderate anterior chamber inflammation	Granulomatous features, retinitis, choriorretinal scar
Syphilis	Usually posterior uveitis but can be anterior, intermediate and panuveitis	Congenital or acquired (sexual abuse)	Mild to moderate anterior chamber inflammation	If congenital, intersticial keratitis. If acquired, diverse presentation
Herpes	Anterior uveitis	Measles-like symptoms	Non-granoloumatous anterior uveitis, although can be granulomatous	Unilateral, pain, dendritic keratitis, cornea hypoesthesia, intersticial keratitis, posterior uveitis with retinitis
Masquerade syndromes
Retinoblastoma	Leukocoria, strabismus and uveitis	Family history	Anterior uveitis in 0.5–3%	Leukocoria, strabismus, anterior uveitis with pseudohypopyon, neovascular glaucoma, posterior retinal lesions or vitreous seeding
Leukemia	Anterior or posterior uveitis, chloroma	Weight loss, fever, tiredness, easy bleeding/bruising	Anterior chamber inflammation	Multiple flame retinal hemorrhages (often with white centers) and retinal infiltrates.

Table 4.

JIA-uveitis Differential Diagnosis regarding type of uveitis, systemic findings, ocular similarities and ocular differences.

In the presence of anterior chamber inflammation, it is important to exclude ocular infections such as toxoplasmosis, especially in endemic areas, syphilis, and herpes. Usually, the first two manifest as posterior uveitis with mild to moderate granulomatous anterior uveitis. Herpes simplex infection commonly presents as keratitits or keratouveitis, but more rarely presents as a unilateral painful non-granulomatous anterior uveitis with cornea hypoesthesia, high intra-ocular pressure, and iris atrophy.

Painless CAU can be found not only in JIA, but also in idiopathic causes and familial autosomal dominant hereditary Blau syndrome. In the first case, the anterior uveitis is not associated with any systemic findings, whereas in the second it presents with arthritis, granulomatous ocular signs, chorioretinal lesions, and a family history of similar features, which can mimic ocular sarcoidosis.

Painful AAU is typical of enthesis-related arthritis, sporadic early onset sarcoidosis and tubulointersticial nephritis uveitis syndrome. Each of them has specific systemic findings described in Table 4. Less commonly, Behçet disease and Vogt-Koyanagi-Harada syndrome, two causes of panuveitis, should also be remembered as differential diagnosis, although the first one has ocular signs of vasculitis and retinitis and the second one has typical systemic signs of vitiligo, poliosis, dysacusia, as well as typical choroidal involvement.

Less commonly but crucial to point out are the masquerades syndromes, such as retinoblastoma and leukemia, that can manifest as anterior uveitis. Clinical history and complete ophthalmological examination with fundoscopy are essential to their diagnosis.

8. Future directions

Recent efforts have been made to review the currently used JIA classifications to include a more evidence-based approach, that allows the division of the multiple heterogeneous autoimmune arthritis groups in children, into more homogenous clinical groups, based not only on clinical presentation but also routine laboratory tests, and better differentiates these groups from adults presentations [51]. One of the subgroups that require better classification is that of early JIA onset (before 6 years of age) with specific features of female prevalence, symmetric arthritis, anterior uveitis, ANA, and HLA-DR8 positivity. It is expected that a better classification will facilitate research and clinical practice normalization, ultimately allowing for better treatment planning and treatment response predictions [52].

In addition, with up-to-date evidence pointing toward better survival and better visual outcomes with early treatment of JIA and JIA-uveitis, there is a worldwide tendency toward starting immunosuppressive therapy sooner rather than later. On the other hand, long-term data on potential side effects and complications of reasonably new medications, as biologics, will help us better understand the long-term impact of these, so we can provide young people and their family with more accurate information on what to expect.

Children and young people with arthritis and uveitis are increasingly seen as capable of being involved in their treatment decisions, and the mental health impacts of a chronic condition in their growth and personal development is fortunately being taken into account more frequently. The importance of multidisciplinary teams and a holistic approach on healthcare is progressively valued.

9. Conclusion and take-home messages

JIA is the most common rheumatic disease in children and adolescents. JIA-associated uveitis is, not only its most frequent extra-articular manifestation, but also the most common cause of uveitis in the pediatric population.

JIA-associated uveitis is responsible for significant personal, familiar, and economic burdens as it is usually an asymptomatic uveitis, what delays its diagnosis and, therefore, treatment. This results in an incidence of ocular complications as high as 67% in affected children. Also, unfortunately, one-third of the patients present with sight-threatening complications at the time of diagnosis.

Timely screening in children and adolescents who have suspected or recently diagnosed JIA is crucial for avoiding vision impairment and improving the health-related quality of life of JIA patients. Screening frequency is based on clinical and laboratorial risk factors for developing uveitis.

If the patient has already JIA-associated uveitis, appropriate monitoring is essential to determine the type of treatment necessary and for uveitis control. Monitoring frequency is based on the degree of AC inflammation, the response to treatment and the presence of ocular complication.

Conflict of interest

The authors declare no conflict of interest.