Non-infectious uveitis: clinical guidelines

List of Abbreviations

ANCA — antineutrophil cytoplasmic antibodies

IOP — intraocular pressure

IBD — inflammatory bowel disease

AHF – aqueous humor of the anterior chamber

bDMARDs — biologic disease-modifying antirheumatic drugs

OD — optic disc

DNA – deoxyribonucleic acid

ICGA – indocyanine green angiography

IL — interleukin

IOL — intraocular lens

ICD-10 — International Classification of Diseases 10th Revision

MRI — magnetic resonance imaging

CT — computed tomography

NSAIDs — nonsteroidal anti-inflammatory drugs

OCT – optical coherence tomography

RF — rheumatoid factor

ESR — erythrocyte sedimentation rate

DED – dry eye disease

US – ultrasound examination

FA — fluorescein angiography

JIA — juvenile idiopathic arthritis

** — this symbol indicates a medicinal product used for indications according to its instructions for use

# — this symbol indicates a medicinal product used for indications not included in the instructions for use of the medicinal product.

Terms and Definitions

Hypopyon – an accumulation of white blood cells in the bottom of the anterior chamber of the eye.

Hyphaema – an accumulation of blood in the anterior chamber.

Posterior synechiae — adhesions between the iris and the anterior lens capsule.

Cataract – opacification of the lens.

Drug-induced remission – uveitis is in an inactive state while on pharmacotherapy for at least 3 consecutive months.

Inactive uveitis - absence of signs of inflammation in the anterior and posterior segments of the eye.

Oligoarthritis – arthritis affecting 1 to 4 joints within the first 6 months of the disease.

Polyarthritis – arthritis affecting 5 or more joints within the first 6 months of the disease.

Anterior synechiae – adhesions between the iris and the cornea.

Keratic precipitates — aggregates of inflammatory cells deposited on the corneal endothelium.

Remission – uveitis is in an inactive state for at least 3 consecutive months without anti-inflammatory treatment.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Uveitis is an inflammation of the uveal tract (iris, ciliary body, choroid), which can extend to the retina, its vessels, and the optic nerve [1-3].

Non-infectious uveitis is a heterogeneous group of autoimmune disorders in which a specific infectious agent triggering the inflammatory process in the uveal tract usually cannot be identified [4,5].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiopathogenesis of non-infectious uveitis is hypothesized to be driven primarily by immune mechanisms that may be initiated by various exogenous (common infections, toxins, medications, eyeball trauma, etc.) and endogenous (complement, etc.) stimuli [6]. Key components in the activation of immune-mediated inflammation in uveitis include genetic predisposition, molecular mimicry, environmental factors, and breakdown of the ocular immune privilege, ultimately leading to suppression of regulatory T-lymphocyte function, activation of T-helper cells (Th-1, Th-2, Th-17), and production of pro-inflammatory cytokines. It is suggested that the diversity of clinical forms of non-infectious uveitis and their specific courses are driven by the activation of various CD4+ (T-helper) subclasses and the synthesis of regulatory molecules: interleukins (IL): 1, 2, 4, 5, 6, 10, 13, 17, 23, etc., and tumor necrosis factor alpha (TNF-α), which should be taken into account when selecting therapeutic interventions [6-9]. As a result, there is a diffuse (in non-granulomatous types) or focal (in granulomatous types) infiltration of the inner coats of the eye by activated immune cells (macrophages, lymphocytes, and plasma cells), followed by tissue destruction and the eventual development of fibrosis, neoangiogenesis, and atrophy [10-11].

1.3 Epidemiology of the Disease or Condition

The incidence of adult uveitis ranges from 15 to 120 cases per 100,000 adult population, and for children, 3.5 to 14 per 100,000 pediatric population per year, with a prevalence of 3 to 717 and 28 to 106 per 100,000, respectively [12-20]. In the Russian Federation, large-scale epidemiological studies on uveitis have not been conducted. Currently, only isolated regional studies have been published. Specifically, over a 12-year period (2003–2014) in Perm, the prevalence of uveitis increased from 1.19 to 1.4 per 1,000, while the proportion of primary incidence rose from 0.45 to 0.53 per 1,000 [21,22].

The proportion of uveitis within the structure of ocular pathology is 5–15%. Uveitis most frequently debuts at a young age, with a mean age of 30.7 years [13, 15]. Anterior uveitis is the most common form (37–62%), followed by posterior uveitis (9–38%) and panuveitis (7–38%), while isolated intermediate uveitis is diagnosed less frequently, ranging from 4% to 17% [12-15, 17]. In children, intermediate uveitis is observed more frequently than in adults, accounting for up to 42% [23].

Non-infectious uveitis accounts for 50–87% of all uveitis cases and is more characteristic of developed countries [21, 23]. At the same time, the frequency and etiological structure of non-infectious uveitis vary significantly across different regions of the world, age groups, and ethnic groups [14, 15, 17]. From 25% to 50% of all uveitis cases are associated with systemic and syndromic diseases.

Uveitis can be associated with the following autoimmune diseases:

1. Spondyloarthritis

- ankylosing spondylitis (Bekhterew's disease)

- psoriatic arthritis

- reactive arthritis

- undifferentiated spondyloarthritis

2. Rheumatoid arthritis,

including adult-onset Still's disease

3. Vasculitis

- Behçet's disease

- ANCA-associated and non-associated vasculitis

- hepatitis B-, hepatitis C-, HIV-associated vasculitis

- malignancy-associated vasculitis

4. Other rheumatic diseases

- systemic lupus erythematosus

- systemic sclerosis

- dermatomyositis and others

* ulcerative colitis and Crohn's disease are included in the spondyloarthritis group.

In addition, non-infectious uveitis can develop as a result of trauma, hepatitis B, C, HIV infection, diabetes mellitus, or in the setting of intraocular tumor breakdown [2, 3, 24].

In children, the most frequent systemic association is juvenile idiopathic arthritis (JIA) [25-27]. The incidence of JIA-associated uveitis averages 1.5–2, and the prevalence is 8–11 per 100,000 pediatric population per year, respectively [28, 29]. Uveitis develops in 10–30% of patients with JIA, more frequently in children with oligoarthritis and rheumatoid factor-negative polyarthritis (Table 1), with early JIA manifestation (under 6 years of age), as well as concurrently or in the first 4–6 years following the onset of articular syndrome.

Table 1. Frequency of uveitis development across various JIA subtypes

Other potential systemic associations of uveitis in children include Blau syndrome (familial juvenile systemic granulomatosis), CINCA/NOMID syndrome, tubulointerstitial nephritis and uveitis (TINU) syndrome, Kawasaki disease; in both children and adults – Vogt-Koyanagi-Harada disease, Behçet's disease, sarcoidosis, inflammatory bowel disease (IBD), multiple sclerosis, scleroderma, systemic lupus erythematosus, granulomatosis with polyangiitis.

Isolated non-infectious uveitis includes phacogenic, sympathetic, HLA-B27-associated acute anterior uveitis without systemic manifestations, most intermediate and a number of posterior uveitides (birdshot chorioretinitis, acute zonal occult outer retinopathy, choriocapillaritis), etc.

In 35–65% of patients, despite a thorough workup, the cause of uveitis cannot be identified—these cases are classified as idiopathic uveitis [12, 14, 15, 17, 26–30].

Blindness due to uveitis and its complications is observed in 2–15% of patients in developed and up to 25% in developing countries, accounting for 2.8–10% of all cases of blindness [7, 15; 16, 25, 27].

1.4 Features of Coding the Disease or Condition

H20.0 – Iridocyclitis

H20.1 – Chronic iridocyclitis

H20.8 – Other iridocyclitis

H20.9 – Iridocyclitis, unspecified

H22.1 – Iridocyclitis in diseases classified elsewhere

H30 – Chorioretinal inflammation

H30.0 – Focal chorioretinal inflammation

H30.1 – Disseminated chorioretinal inflammation

H30.2 – Posterior cyclitis

H30.8 – Other chorioretinal inflammations

H30.9 – Chorioretinal inflammation, unspecified

H35.0 – Background retinopathy and retinal vascular changes (vasculitis)

H44.1 – Sympathetic uveitis

1.5 Classification of the disease or condition

Uveitis is classified by anatomical location, pathomorphology, and course type. Currently, the universally accepted classification is the one proposed by the SUN (Standardization of Uveitis Nomenclature) Working Group expert panel, 2005, presented in Table 2 [32, 33].

Table 2. Classification of uveitis

Non-infectious uveitis may be associated with systemic and syndromic diseases of the body or occur as an isolated intraocular inflammatory process (see Section 1.3).

1.6 Clinical presentation of the disease or condition

Clinical manifestations of uveitis depend on the location of inflammation, morphological characteristics, degree of activity, course, and the clinical form of the systemic disease [5].

Symptoms: patients with uveitis may complain of blurred or decreased vision, floating opacities in front of the eye. In acute anterior uveitis, panuveitis, sclerouveitis, keratouveitis, in addition, redness of the eye, photophobia, lacrimation, eye pain, changes in iris color, and pupil size and shape. In intermediate and posterior uveitis – flashes, loss of visual field fragments, micro- and macropsia, object distortion, and color perception disorders. Children with uveitis often have no complaints.

Clinical signs of anterior uveitis:

- pericorneal or mixed injection (may be absent, for example, in children or with a primarily chronic course type)

- endothelial "stippling"

- keratic precipitates on the posterior surface of the cornea: small (dust-like) in nongranulomatous inflammation; medium and large ("mutton fat" in a number of diseases) in granulomatous inflammation. As the inflammatory process subsides, the precipitates decrease in diameter, acquire clear borders, and undergo pigment deposition or resorption.

- exudative cellular effusion into the anterior chamber (AC), which is used to assess the activity and severity of the inflammatory process (Tables No. 3, 4) [32, 33].

Table 3. Criteria for assessing cellular reaction in the AC

Table 4. Criteria for assessing exudation in the anterior chamber

Laser Doppler flowmetry can be used for a more accurate and objective assessment of exudation in the anterior chamber [34 - 36].

- iris changes: stromal edema, dilatation of intrinsic vessels, possible development of new vessels. In granulomatous inflammation, Koeppe nodules (at the pupillary margin) and Busacca nodules (in the mid-zone of the iris and the anterior chamber angle) may form [30, 31, 34].

- formation of anterior and posterior synechiae (with the organization of fibrinous exudate), up to adhesion (to the anterior lens capsule) and pupillary seclusion with the formation of a pupillary membrane [29, 30, 34].

- possible change in intraocular pressure (IOP) from hypotony to hypertension.

- possible appearance of cellular and exudative reaction in the anterior vitreous body (in patients with iridocyclitis)

- with high inflammatory activity in the anterior segment, macular edema and/or papillitis may develop.

Anterior uveitis is observed in the majority of patients with JIA. Most JIA subtypes (oligoarthritis, rheumatoid factor-negative polyarthritis, systemic arthritis, psoriatic arthritis with preschool onset) are characterized by bilateral chronic anterior uveitis with an outwardly subtle onset and exacerbations of the inflammatory process; arthritis associated with enthesitis and psoriatic arthritis with school onset are characterized by acute unilateral anterior uveitis, usually associated with HLA-B27 and presenting with pronounced symptoms of ocular irritation. Anterior uveitis is also observed in sarcoidosis with disease manifestation before 5 - 6 years of age, HLA-B27-associated uveitis in adults, Fuchs heterochromic cyclitis, glaucomatocyclitic crises, scleroderma, Kawasaki disease, in the majority of patients with IBD, tubulointerstitial nephritis and uveitis syndrome, and rarely in Behçet's disease.

Clinical signs of intermediate (median, pars planitis, peripheral) uveitis:

- possible appearance of endothelial "beading", small precipitates; in children, endothelial "beading" is often localized paranalytically in the lower quadrant, and precipitates are small or medium-sized;

- inflammatory cells and exudate in the vitreous body, more pronounced in the peripheral regions. Intensity is assessed by counting the number of cells or by relative flare grading based on the haze of fundus visualization during indirect ophthalmoscopy with a 20-diopter lens (Table 5) [37].

Table 5. Criteria for assessing cellular inflammatory reaction in the vitreous body

Pars planitis is a subtype of intermediate uveitis characterized by the formation of exudative foci in the form of "snowballs", predominantly in the inferior vitreous and preretinally at the extreme periphery. Macular edema, papillitis, and peripheral retinovascularity (dilation and tortuosity of vessels, exudation along vessels, often with hemorrhages) may develop.

Peripheral uveitis in adults may be associated with sarcoidosis, multiple sclerosis, IBD; in children, rarely with JIA, but in most cases, both in adults and children, it is idiopathic in nature.

Clinical signs of posterior uveitis:

- preretinal exudation and cellular reaction in the vitreous body of varying intensity (may be absent in a number of choroiditis cases);

In choroiditis at the level of the outer retinal layers, retinal pigment epithelium, and choriocapillaris, yellowish foci are ophthalmoscopically visualized in most cases, the size and localization of which are determined by the clinical form of the disease. Upon resolution of inflammation, these foci can completely resorb or transform into zones of chorioretinal atrophy, often surrounded by hyperpigmentation [38 - 41].

In acute retinitis (rare in non-infectious uveitis), retinal infiltrates are ophthalmoscopically visualized as whitish areas with blurred margins. The number and size of infiltrates (foci) may vary and depend on the clinical form of uveitis. Upon resolution of inflammation, these foci can completely resorb or transform into zones of retinal atrophy.

When inflammation is active in the posterior segment of the eye, the following may be detected:

- macular retinal edema;

- retinovascularitis with the appearance of retinal edema, "soft" exudate, and less frequently - hemorrhages along the vessels;

- papillitis or optic neuritis;

- exudative retinal detachment

Posterior uveitis includes acute retinal pigment epitheliitis, multiple evanescent white dot syndrome, acute zonal occult outer retinopathy, birdshot retinochoroidopathy, most cases of acute posterior multifocal placoid pigment epitheliopathy and serpiginous choroiditis [34, 39, 41, 42]. Posterior uveitis can be observed in Behçet's disease, Vogt-Koyanagi-Harada disease, IBD, sarcoidosis; retinovascularitis - in systemic lupus erythematosus, giant cell arteritis, anti-C1q vasculitis, polyarteritis nodosa, Cogan syndrome, etc. [29, 34, 40, 43-46].

In panuveitis (generalized uveitis), symptoms described for anterior, intermediate, and posterior uveitis are combined, although their manifestation intensity may vary. Uveitis presents as generalized in Vogt-Koyanagi-Harada disease, Behçet's disease, Blau syndrome, sympathetic ophthalmia, and rarely in tubulointerstitial nephritis and uveitis syndrome, and granulomatosis with polyangiitis [29, 34, 40, 44-46].

Complications of non-infectious uveitis.

The frequency and pattern of uveitis complications depend on the localization of the inflammatory process, etiological form, duration and severity of the uveitis course, and the adequacy of diagnosis and treatment.

Possible complications of uveitis include:

• scleral perforation (in sclerouveitis);

• corneal ulcer (perforation) (in keratouveitis);

• secondary corneal dystrophies;

• formation of anterior synechiae;

• formation of posterior synechiae up to pupillary seclusion;

• formation of prepiriform/prelenticular membranes up to pupillary occlusion;

• rubeosis (neovascularization) of the iris, hyphema;

• secondary ocular hypertension and glaucoma (with pre-angular, angular, pupillary, or malignant block), neovascular glaucoma;

• complicated cataract;

• vitreous fibrosis;

• hemophthalmus;

• retinal vessel occlusion

• retinal and/or optic disc neovascularization;

• retinal detachment (rhegmatogenous, tractional, exudative)

• choroidal neovascularization

• optic disc atrophy (partial, complete)

• macular edema;

• epiretinal membrane,

• macular hole

• ischaemic maculopathy,

• retinoschisis;

• retinal/subretinal fibrosis;

• ocular hypotony and subatrophy.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing non-infectious uveitis include:

- analysis of complaints and medical history;

- ophthalmological examination data;

- results of laboratory diagnostic tests;

- results of instrumental diagnostic examinations;

- other diagnostic examinations performed during differential diagnosis (infectious nature of uveitis excluded; "masquerade syndromes" excluded).

2.1 Complaints and Anamnesis

Comments: 1. Ocular symptoms may include: redness, photophobia, pain, decreased and/or blurred vision, floaters, flashes of light, metamorphopsia, altered color vision, visual field defects, changes in iris color, pupil size and shape. Children with uveitis are often asymptomatic.

2. The interview should focus on back pain combined with morning stiffness lasting over 30 minutes, joint pain and/or swelling, morning joint stiffness, myalgia, skin rashes (including plaques), nail lesions (psoriasis-like), oral and/or genital ulcers, finger numbness and/or tingling sensations, headaches and their characteristics, tinnitus, hearing loss, cough (not caused by smoking or colds), premature graying and hair loss, vitiligo, nocturia, proteinuria, low-grade fever, thrombophlebitis, paresthesias and ataxia, cystitis, vaginitis and urethritis, diarrhea, blood in stool, enterocolitis and other gastrointestinal symptoms, hepatosplenomegaly, cerebrovascular disorders, miscarriage.

3. History of ocular surgeries and trauma (presence/absence).

4. The presence of general medical conditions diagnosed by specialists should be clarified.

2.2 Physical Examination

Physical examination is not used for diagnosing non-infectious uveitis.

Comments: the choice of a specialist profile is determined based on the patient's suspected or confirmed systemic or syndromic disease and the risk of systemic complications.

2.3 Laboratory Diagnostics

Additional laboratory tests are prescribed to clarify the diagnosis and identify systemic and syndromic diseases associated with uveitis, which is important for further treatment strategy. The decision on selecting and prescribing additional laboratory and instrumental examinations is made based on the results of the baseline examination by an ophthalmologist and/or other specialists (rheumatologist, neurologist, dermatologist, pulmonologist, cardiologist, hematologist, otorhinolaryngologist, urologist, obstetrician-gynecologist, gastroenterologist).

Comments: In agreement with relevant specialists, additional laboratory and instrumental examinations may be prescribed:

1. Determination of antibodies to cyclic citrullinated peptide (anti-CCP) in the blood, determination of native DNA antibodies, determination of antinuclear antibodies to Sm antigen (nucleosomes), determination of anticardiolipin antibodies in the blood, determination of beta-2 glycoprotein antibodies in the blood, determination of antibodies to cell nucleus antigens and DNA, determination of antineutrophil cytoplasmic antibodies (ANCA) in the blood, determination of phospholipid antibodies in the blood, assessment of angiotensin-converting enzyme level in the blood.

2. Urine beta-2-microglobulin analysis, determination of albumin in urine.

3. Magnetic resonance imaging (MRI) of bone tissue (one region), radiography of the lumbar and sacral spine, computed tomography (CT) of the pelvic bones.

4. Brain MRI.

5. Targeted chest radiography, MRI or spiral CT of the lungs.

6. Ultrasound examination of the abdominal organs (comprehensive), MRI of the abdominal organs.

7. Colonoscopy

8. Spinal puncture, etc.

2.4 Instrumental Diagnostics

At the diagnostic stage and during follow-up examinations:

Comments: it is important to remember that the depth of the anterior chamber must be assessed before pharmacological pupillary dilation.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: perimetry can be performed in children starting from 7 years of age.

2.5 Other Procedures

Comments: when performing a differential diagnosis, one should carefully evaluate the clinical signs of the intraocular process, its predominant localization, granulomatous or non-granulomatous type, unilateral or bilateral involvement, nature of the course, and concomitant systemic manifestations. For a number of systemic diseases presenting with uveitis (Behçet's disease, sarcoidosis, Vogt-Koyanagi-Harada disease), diagnostic criteria have been developed, which, however, are not universally accepted [57-59].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

The goal of treatment is the relief of active inflammation through local and systemic drug administration, the achievement of long-term, preferably non-pharmacological remission, and the preservation of visual functions.

Treatment tactics are determined by the localization and severity of the inflammatory process in the eye, whether the process is unilateral or bilateral, the presence and risk of uveitis complications and vision loss, as well as the presence of associated systemic and syndromic pathology and concomitant diseases.

Treatment of non-infectious uveitis is carried out by an ophthalmologist; if an associated systemic or syndromic disease is present, it is done in close collaboration with relevant specialists (rheumatologist, dermatologist, neurologist, pulmonologist, etc.).

In cases where there is no systemic disease, the ophthalmologist performs local therapy, determines indications for prescribing and adjusting systemic treatment, prescribes systemic immunosuppressive therapy provided they have appropriate experience (in patients with systemic or syndromic diseases, in cooperation with relevant specialists), monitors the development of potential local and systemic treatment complications, and provides medical and surgical treatment for post-uveitic complications.

General practitioners, in accordance with established etiological causes, conduct therapy in accordance with the Federal Clinical Guidelines for the treatment of the underlying disease, monitor the somatic status of patients and adverse events of systemic therapy.

Due to the relative rarity and clinical variability of non-infectious uveitis, drugs are rarely developed specifically for the treatment of ocular inflammatory diseases. Most systemically administered drugs were originally created for transplant medicine, the treatment of rheumatic diseases, psoriasis, etc., and are used in ophthalmology without approved indications (off-label). The prescription of medications (systemic and local) not approved for the indication "treatment of non-infectious uveitis" is carried out by decision of the medical commission of the medical organization, adhering to a multidisciplinary approach to treatment.

Patients (or patients' parents) must be informed about the benefits and potential side effects of therapy.

Comments: Instillations (dexamethasone 0.1%) are prescribed for inflammatory processes in the anterior segment of the eye. The frequency of instillations varies depending on the severity of inflammation: from 3–5 times a day down to 2 times a day.

Comments: Symptoms of severe inflammation include cells in the anterior chamber at ≥ 2+, fibrinous exudate, hypopyon, and synechia formation; subconjunctival injections of corticosteroids (dexamethasone**) are indicated. Instillations do not provide a therapeutic concentration of corticosteroids in the vitreous body and the posterior segment of the eye; therefore, in active intermediate uveitis, posterior uveitis, panuveitis, or in the presence of macular edema or papillitis, corticosteroids (dexamethasone**, #betamethasone, #triamcinolone) are administered as parabulbar or subtenon injections as additional local therapy [5, 65, 67, 68, 69].

#Betamethasone dipropionate* combined with disodium phosphate 1.0 ml or triamcinolone hydrochloride 1.0 ml is injected into the subtenon space in adults 1-2 times every 14 days until complete resolution of inflammation [5].

#Triamcinolone hydrochloride is administered at a dose of 40 mg (1 ml) into the subtenon space as a single injection; repeat administration is possible after 14 days. The use of triamcinolone is contraindicated under the age of 18 years. Smoking has been noted as a factor reducing the efficacy of subtenon triamcinolone administration. [69]

The frequency of subconjunctival injections is determined by the severity of inflammation and ranges from daily to 1-2 times a week.

It is advisable to administer sustained-action corticosteroids via para- and retrobulbar injections at intervals of 10-14 days for a total of 3-5 injections.

When periocular injections are insufficiently effective in intermediate uveitis, posterior uveitis, and panuveitis, especially in cases of unilateral or asymmetrical involvement, as an alternative or in the presence of contraindications to systemic therapy, as well as in addition to ongoing systemic therapy, intravitreal administration of the medicinal product—#dexamethasone** implant—is indicated. The effect of the drug reaches its maximum by 1.5 - 2 months after implantation and remains significant for up to 6 months. Repeated administration of the implant is possible if indicated [1, 72-82].

2. Treatment is carried out until the complete resolution of active inflammation symptoms in the anterior and posterior segments of the eye. After achieving inactive uveitis, periocular glucocorticosteroid injections are discontinued, and the frequency of instillations is gradually tapered (1 drop every 1-2 weeks) under the control of biomicroscopy of the eye and, when indicated, OCT of the central retinal zone and contrast imaging methods (FA, ICGA). Complete discontinuation of topically applied glucocorticosteroids is desirable. If discontinuation is not possible, the frequency of local glucocorticosteroid use should be reduced until drug-induced remission is achieved [5, 65, 66].

3. The leading adverse effects of local glucocorticosteroid therapy are increased IOP and the development / progression of cataract [47, 48, 64, 67].

4. Glucocorticosteroid treatment requires careful monitoring of potential adverse events, which include: increased IOP, development or progression of cataract, rarely reactivation of ocular herpes, allergic reactions (mainly to preservatives contained in the drugs); during periocular injections – eyeball perforation, orbital fat fibrosis, optic nerve and extraocular muscle damage, upper eyelid ptosis, strabismus; during intravitreal administration – lens damage, hemophthalmus, retinal detachment, endophthalmitis. In addition, prolonged and intensive local use of glucocorticosteroids may lead to systemic adverse events characteristic of this group of drugs [24, 62, 64]. If glucocorticosteroid-induced IOP elevation occurs, they should not be discontinued immediately, but reduced to the minimum effective dose and hypotensive therapy should be added. The development of complications from uveitis glucocorticosteroid therapy (increased IOP, cataract) is an indication for the early initiation of systemic immunosuppressive therapy.

5. Anti-inflammatory therapy is not prescribed for mild intermediate uveitis in adults, acute retinal pigment epitheliitis, the first episode of multiple evanescent white dot syndrome due to a favorable course, and in Fuchs iridocyclitis due to the ineffectiveness of glucocorticosteroids [8, 41].

Comments: local NSAID therapy is not recommended in isolation for the treatment of non-infectious uveitis due to their weak anti-inflammatory activity.

Information on the method of administration, dose, and duration of #diclofenac** 0.1%: 1-2 drops 4 times/day. The course of treatment may last from 1 to 2 weeks [5, 85].

Information on the method of administration, dose, and duration of #indometacin 0.1%: 1-2 drops 4 times a day depending on the severity of the condition. The course of treatment may last from 1 to 2 weeks.

Information on the method of administration, dose, and duration of #nepafenac 0.1%: instillation of 0.1% solution, 1 drop 3 times a day for 1 month [5, 85].

Information on the method of administration, dose, and duration of #bromfenac 0.09%: instillation of 1 drop 2 times a day for 1 to 2 weeks.

Comments: Information on the method of administration, dose, and duration of atropine**: instillations of 1% solution in patients over 7 years of age are performed as 1-2 drops 2 times with an interval of 8-12 hours for 2 to 10 days.

Information on the method of administration, dose, and duration of #phenylephrine**: #phenylephrine** is used in iridocyclitis to prevent the development and rupture of already formed posterior synechiae and to reduce exudation into the anterior chamber of the eye in the form of instillations of 1 drop 2-3 times a day.

If eye drop instillations are insufficiently effective, a subconjunctival injection of a mixture of 0.2 ml of 0.1% adrenaline solution and 0.1% atropine solution is administered, preferably perilimbally in the projection of posterior synechiae zones.

Comments: local therapy is prescribed as monotherapy or, if insufficiently effective, as combinations of drugs. Drugs of choice are carbonic anhydrase inhibitors (brinzolamide 1%, dorzolamide** 2%), beta-blockers (timolol** 0.25%, 0.5%, #betaxolol 0.5%), sympathomimetics for glaucoma treatment (brimonidine 0.15%, 0.2%); in the absence of uveitis activity, prostaglandin analogues may be prescribed (latanoprost 0.005%, travoprost 0.004%, tafluprost 0.0015%**). Travoprost, tafluprost, and betaxolol are not used under 18 years of age.

Parasympathomimetics (pilocarpine**) are not recommended for patients with active uveitis due to the risk of increased exudation into the anterior chamber and the formation of posterior synechiae. Systemic hypotensive therapy with carbonic anhydrase inhibitors (#acetazolamide) is performed in the absence of IOP normalization during maximum tolerated local treatment, for a duration of no more than 1-2 months.

Information on the method of administration, dose, and duration of #betaxolol 0.5%: in patients over 18 years of age at a dose of 250 mg per day 1-4 times a day, duration no more than 1-2 months.

Level of evidence C (level of reliability of evidence – 4)

Comments: 1. Systemic immunosuppressive therapy is prescribed: if local treatment is ineffective within 3–4 months to achieve inactive uveitis; earlier - in case of severe uveitis, the occurrence of new complications caused by the inflammatory process, as well as adverse events of local glucocorticosteroids (S01BA Corticosteroids) immediately after the detection of retinovascultis in patients with Behcet's disease [1, 44, 64]. Early initiation of systemic immunosuppressive therapy promotes more frequent achievement of stable remission and reduces the frequency of uveitis complications [100].

2. Systemic glucocorticosteroid therapy plays a key role in the acute phase of inflammation due to its rapid and pronounced anti-inflammatory effect; systemic corticosteroid use as maintenance therapy is limited due to side effects.

The standard dose is 0.5-1 mg/kg (calculated as predniso(l)one**) per day, which is used until a positive effect is achieved (preferably no more than 4-8 weeks) and then gradually tapered or, if complete withdrawal is impossible, reduced to the minimum effective maintenance dose, which should not exceed 7.5 mg per day calculated as predniso(l)one** in adults and 0.1 mg/kg in children [1, 5, 67, 94].

In case of severe inflammatory process, exudative retinal detachment, or optic nerve involvement, pulse therapy may be performed (#methylprednisolone** intravenous drip administration 250-1000 mg daily or every other day, total not exceeding 3 grams, in children – 20–30 mg/kg) until the process stabilizes, followed by transition to oral administration [67, 99, 101].

The duration of administration and tapering schedule of systemic glucocorticosteroid therapy are determined individually for each patient. However, rapid tapering carries a risk of uveitis relapse, and use for more than 3 months at a dose of more than 7.5 mg per day of predniso(l)one** in adults and 0.1 mg/kg in children carries a risk of side effects. An approximate glucocorticoid dose reduction schedule is presented in Table 6.

Table 6. Systemic corticosteroid dose reduction schedule

If signs of active inflammation appear while tapering the drug dose, it is possible to return to a higher dosage or additionally administer local corticosteroids (as instillation and injections) [5, 67, 94, 102-104].

Patients receiving systemic corticosteroid therapy require careful monitoring for potential side effects.

Ocular complications may include the development of cataract and glaucoma.

Systemic complications include: endocrine (obesity, hirsutism, Cushing's syndrome, diabetes, menstrual irregularities), metabolic (hypokalemia, fluid retention, hyperosmolar coma), musculoskeletal (systemic osteoporosis, myopathies), gastrointestinal (nausea, gastric and intestinal ulceration, pancreatitis), cardiovascular (arterial hypertension, myocardial dystrophy), neurological (headache, seizures, hyper-excitability, insomnia, depression), and a number of others. Monitoring for their occurrence and management is carried out with the participation of relevant specialists. In children, the risk of adverse events from systemic corticosteroid use is higher than in adults, therefore their prescription should be restricted as much as possible [102-104].

During corticosteroid treatment, patients are advised to limit alcohol consumption, and women of childbearing potential should avoid pregnancy [105,106].

Indications for prescribing other immunosuppressive drugs:

- Lack of uveitis remission at a prednisolone dose of **7.5 mg (0.1 mg/kg)

- Activation of uveitis upon tapering the corticosteroid dose;

- Intolerable side effects during glucocorticosteroid therapy [1-6, 10, 24, 101].

2. #Cyclosporine** — specifically and reversibly inhibits the G0 and G1 phases of the cell cycle of immunocompetent lymphocytes, especially T-helper cells, suppresses the production and release of interleukin-2 (IL-2) and its binding to specific receptors.

In uveitis, cyclosporine is prescribed orally at a dose of 3–5 mg/kg per day in 2 divided doses; in children, also 3–5 mg/kg per day in 2 divided doses. The efficacy of cyclosporine** monotherapy ranges from 24 to 57%. In cases of insufficient response to cyclosporine** monotherapy within 3 months, combination with antimetabolites is possible [2, 5, 107-112].

The most frequent adverse effects of cyclosporine** are: arterial hypertension, hypertrichosis, gingivitis, renal dysfunction, elevated serum creatinine, liver dysfunction, anemia, hyperuricemia, fatigue, headache, paresthesia/hyperesthesia.

3. #Methotrexate** is a folic acid analogue that disrupts its synthesis and, consequently, DNA and RNA metabolism. The drug is prescribed orally or parenterally at a dose of 7.5-12.5 mg/week; if well tolerated, the dose is gradually increased up to 20 mg/week. In children, #methotrexate is prescribed at a dose of 10–15 mg/m² of body surface area once a week. Calculation of body surface area: S = (4m+7) / (m+90), where m is the child's body weight. Due to the disruption of folic acid metabolism by #methotrexate**, #folic acid** is prescribed at a dosage of about 1/3 of the #methotrexate** dosage: 1 mg daily except on the day of #methotrexate** administration [113-126]. The efficacy of #methotrexate** in patients with non-infectious uveitis is 50–86%. #Azathioprine or #mycophenolate mofetil may be used as alternatives to #methotrexate** [127-135].

#Azathioprine** is a structural analogue (antimetabolite) of adenine, hypoxanthine, and guanine, which are components of nucleic acids, and disrupts their biosynthesis. The drug is used orally at a dose of 2.4-2.5 mg/kg per day; efficacy is 61.5-81% [99, 127-130].

The action of #mycophenolate mofetil** is based on the inhibition of inosine monophosphate dehydrogenase and the suppression of de novo guanosine nucleotide synthesis. The drug is used orally at a dose of 500–1000 mg twice daily in adults, and 600 mg/m² twice daily in children. Control of the inflammatory process is achieved in 24–73% of cases [131-139].

The effect of antimetabolites develops relatively slowly (within 1–2 months), and 3–4 months are required to evaluate their efficacy.

The most frequent side effects of antimetabolites are: hepatotoxicity, hematological disorders (leukopenia, thrombocytopenia), increased incidence of infections, gastrointestinal disturbances, fatigue, headache, myalgia. However, with appropriate use and monitoring, the incidence of adverse events associated with antimetabolites is relatively low.

4. Monoclonal antibodies and immunosuppressants containing monoclonal antibodies are prescribed for non-infectious intermediate, posterior, and severe-to-moderate panuveitis in adults, and for anterior uveitis in children in cases of insufficient efficacy of conventional immunosuppressive therapy [59-60, 63-66, 101]. They represent the first line of immunosuppressive therapy for uveitis associated with Behçet's disease. #Adalimumab** is a tumor necrosis factor alpha (TNF-alpha) inhibitor. The drug contains monoclonal antibodies to TNF-α identical to human IgG1. It is administered subcutaneously, starting with a dose of 80 mg in adults, followed by 40 mg every 2 weeks; in children, at a dose of 24 mg/m², but not exceeding 40 mg every 2 weeks. The efficacy of uveitis treatment is 60–82%. In case of insufficient efficacy of the standard dose for uveitis treatment, weekly administration or doubling the dose is possible [140-156].

#Infliximab** is a chimeric (murine/human) antibody against TNF-alpha. Standard administration schedule: intravenous drug administration of 3–10 mg/kg at weeks 0, 2, and 6, then every 8 weeks. The efficacy of uveitis treatment is 43–95%. In children, 5 mg/kg, then 2 weeks and 6 weeks after the first dose, and then every 8 weeks as maintenance therapy. A disadvantage of infliximab** is the high frequency of infusion reactions, as well as a higher incidence of secondary resistance compared to other biologic DMARDs due to the chimeric structure of the drug [157-167].

Alternative 2nd-choice drugs are #golimumab** and #certolizumab pegol**. #Golimumab** is an anti-TNF-alpha antibody drug identical to human IgG1. Standard dosing regimen: subcutaneous drug administration of 50 mg once every 4 weeks in patients weighing ≥40 kg, or 30 mg/m² in patients weighing <40 kg. The efficacy in treating non-infectious uveitis reaches 71% [168-172].

#Certolizumab pegol** is a Fab' fragment of humanized monoclonal antibodies against TNF-alpha conjugated with a PEG fragment at the Fc fragment attachment site. The drug is used only in adults. The initial dose for adults is 400 mg, followed by 200 mg every 2 weeks via subcutaneous drug administration [172, 173]. The drug is contraindicated in patients under 18 years of age.

In the absence of efficacy or in case of secondary resistance to TNF-alpha inhibitors, biologic DMARDs with a different mechanism of action may be prescribed.

#Tocilizumab** is a recombinant humanized monoclonal antibody drug targeting the human interleukin-6 (IL-6) receptor, belonging to the IgG1 immunoglobulin subclass. It is prescribed as an intravenous drug administration of 8 mg/kg every 4 weeks or a subcutaneous drug administration of 162 mg once a week. It is effective in 59–79% of patients with non-infectious uveitis [174-182].

#Rituximab** is a chimeric monoclonal antibody drug that binds to the CD20 transmembrane antigen on B lymphocytes (intravenous drug administration of 375 mg/m², maximum 1 gram, at weeks 0 and 2, then every 6 months) [183-185].

#Abatacept** is a selective immunosuppressant that blocks the co-stimulatory activation signal of T lymphocytes expressing CD28; it is prescribed as an intravenous drug administration of 10 mg/kg every 4 weeks. Efficacy is 34–86% [186-187].

Possible adverse effects of bDMARDs include: injection-site and allergic reactions; infections, including activation of latent tuberculosis (especially during TNF-alpha inhibitor therapy); hematologic abnormalities (anemia, pancytopenia); autoantibody production and autoimmune reactions; risk of demyelinating diseases; worsening of heart failure symptoms; and potential oncogenic effects. Prior to prescribing the drug, it is necessary to perform a complete blood count (CBC), general clinical blood biochemistry, blood glucose test, blood sodium test, blood potassium test, blood chloride test, blood urea test, blood creatinine test, determination of blood aspartate aminotransferase activity, determination of blood alanine aminotransferase activity, serum C-reactive protein test, and determination of hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) in the blood. Determination of hepatitis C virus (Hepatitis C virus) antibodies in the blood. Testing for human immunodeficiency virus HIV-1/2 antibodies (classes M and G, IgM/IgG) and p24 antigen (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood, and screening for tuberculosis infection. bDMARD therapy is contraindicated in the presence of malignant neoplasms, decompensated heart failure, and this treatment should be avoided in the presence of or risk factors for demyelinating diseases of the nervous system.

Comments: #diclofenac** 2–3 mg/kg/day, #ibuprofen** 20–40 mg/kg/day, #naproxen 10 mg/kg/day, #nimesulide 3–5 mg/kg/day, or #meloxicam 7.5–15 mg/day [5].

Patients receiving NSAIDs require monitoring for potential adverse events: gastrointestinal tract lesions, nephrotoxicity, allergic reactions, hepatotoxicity, hematotoxicity, and others.

3.2 Surgical Treatment

Comments: 1. The efficacy of the dexamethasone** intravitreal implant for intermediate and posterior uveitis peaks by 2 months after implantation and remains significant for up to 3 months [77, 80].

2. In accordance with the instructions, the use of the dexamethasone** implant is not recommended in patients with infectious uveitis, aphakia, presence of anterior chamber IOL, iris-clip intraocular lenses, fixed posterior chamber IOL with a posterior capsule defect, advanced glaucoma, hypersensitivity to the drug components, and in individuals under 18 years of age. Repeated administration of the implant is possible no earlier than 6 months from the date of the first injection.

3. Potential complications of intravitreal dexamethasone** implant administration include: subconjunctival hemorrhage, elevated intraocular pressure, cataract, migration of the implant into the anterior chamber, reactivation of ocular herpes, vitreous hemorrhage, retinal detachment, and endophthalmitis.

Comments: to remove extensive dense band-shaped corneal dystrophy, scarification and cauterization of corneal inflammatory foci or phototherapeutic keratectomy may be performed [65, 192].

Level of evidence C (level of data reliability – 5)

For adults – Level of evidence C (level of data reliability – 2)

For children – Level of evidence C (level of reliability of evidence – 4)

Comments: 1. Currently, hydrophobic acrylic IOLs are preferred.

2. IOL implantation is not indicated in subatrophy or marked hypotony of the eyeball, extensive anterior synechiae with the development of corneal endothelial changes, or a combination of cataract and malignant glaucoma.

Comments: 1. In glaucoma caused by pupillary block, urgent laser or surgical iridectomy is performed; in malignant glaucoma in pseudophakic or aphakic eyes, urgent laser hyaloidotomy is performed; in phakic eyes, lensvitrectomy or pars plana vitrectomy combined with hyaloidotomy and iridectomy is indicated.

2. In glaucoma with an open anterior chamber angle or the presence of goniosynechiae, surgical treatment is performed when the glaucoma process cannot be compensated for with the maximum hypotensive regimen. Currently, the operations of choice are trabeculectomy (sinustrabeculectomy) or other penetrating antiglaucoma surgeries (with a drainage device).

- vitreous opacities significantly reducing visual acuity,

- retinal tractions with a high risk of or developing retinal detachment,

- vitreous hemorrhage unresponsive to medical therapy for 4 weeks,

- tractional cystoid macular edema,

- dense epimacular membranes, macular hole,

- cyclitic membranes and persistent hypotony in order to improve or preserve visual functions [192, 201, 202].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments:1. Depending on the clinical situation, vitrectomy, local episcleral buckling, circular episcleral buckling, or a combined intervention is performed. In case of a local peripheral retinal detachment, barrier laser photocoagulation may be performed. During microinvasive vitrectomy or vitreoschwartrectomy, when indicated, membrane peeling, retinotomy, endolaser photocoagulation, endodiathermocoagulation, tamponade of the vitreous cavity with ophthalmic gas, perfluorocarbon liquid, silicone oil, and other manipulations can be performed.

Comments: the duration of vitreous cavity endotamponade with silicone oil is determined by the physician based on the results of patient dynamic monitoring. The decision on the need for repeat vitreous cavity endotamponade is made by the physician based on the assessment of the patient's eye condition, the risk of recurrent hemorrhage, retinal detachment, etc.

Comments: ranibizumab** is the drug of choice; its use in children under 18 years of age is contraindicated. Intravitreal administration of the medicinal product ** is carried out at a dose of 0.5 mg, with additional injections as needed.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments:1. Treatment is carried out 2 times a year under the control of the inflammatory process activity.

2. Medications affecting peripheral circulation and improving microcirculation are used – peripheral vasodilators, other psychostimulants and nootropic drugs (nootropic combinations), vitamins, general tonic preparations (antihypoxants and antioxidants) [205-210].

3. Physiotherapy procedures (drug electrophoresis for eye diseases, magnetophoresis) with neurotrophic and vasodilating drugs, and optic nerve electrical stimulation may be prescribed.

4. Patients with ametropia undergo appropriate correction, and special correction as indicated.

Comments: 1. Spa treatment is carried out during the remission stage of the disease; for chronic iridocyclitis, no earlier than 3 months after achieving an inactive disease state.

2. If the patient has iridocyclitis of rheumatic etiology, climate therapy is indicated at the resorts of Pyatigorsk, Sochi - Matsesta, Saki, and Staraya Russa during the summer-autumn season. For chronic iridocyclitis of non-rheumatic etiology, visiting resorts such as Essentuki, Pyatigorsk, Zheleznovodsk, Staraya Russa, etc., as well as local resorts, is recommended.

3. Dry-air baths are prescribed according to the mild cold load regimen (gentle regimen) and are performed only at comfortable equivalent-effective temperatures of at least 21 degrees. The first procedures start at 8–15 minutes and the exposure time is increased every 3 procedures.

Heliotherapy is prescribed according to two regimens: a) mild exposure (starting with 1/8 of a biodose) and bringing it up to 1 biodose by the end of the treatment course; b) moderate exposure—also starting with 1/8 of a biodose and increasing it to 1.5 biodoses by the end of the treatment.

4. Spa treatment is contraindicated in the presence of abundant mucopurulent discharge, corneal erosion, elevated IOP, pronounced ocular hypotonia, gross fibroplastic changes of the vitreous body, retinal detachment, threat of retinal detachment, recurrent ocular hemorrhages, and neoplasms of the eye and its adnexa.

5. Prevention and Dispensary Observation

Comments: 1. When determining the frequency of examinations in patients with JIA, the age of onset, disease subtype, and potential nature of uveitis progression are taken into account (Table 7). Screening criteria for eye involvement in other systemic diseases have not been established. An ophthalmological examination of the child is performed upon establishing the diagnosis of the systemic disease and then annually in the absence of pathology.

Table 7. Ophthalmologist follow-up schedule for a child with juvenile idiopathic arthritis

Comments: 1. The frequency of examinations depends on the etiology, severity, and potential course of uveitis (symptomatic or asymptomatic), presence and risk of complications, as well as ongoing treatment. After achieving inactive uveitis, ophthalmologic examination is performed once a month for 3 months, then, if stable, once every 3 months for a year, and subsequently every 6 months. Following discontinuation of systemic therapy, monitoring should be performed at least once every 3 months for at least 3 years, as most uveitis relapses occur during this period [30, 31].

2. During dispensary follow-up, pharmacotherapy is adjusted, and exacerbations and new complications of uveitis are identified

6. Organization of Medical Care

Routine medical care is provided in outpatient and inpatient settings.

Stages of Medical Care Delivery

1. First medical aid

2. Outpatient

3. Inpatient

Medical indications for hospitalization in a medical organization

Emergency medical care is provided to patients with non-infectious uveitis in the following cases:

· hypopyon uveitis

· uveitis complicated by ocular hypertension,

· sharp decrease in visual acuity due to severe, generalized, including complicated, uveitis.

Elective hospitalization is performed for the management of uveitis complications.

Criteria for discharge of a patient from a medical organization: recovery or improvement of ophthalmological status.

7. Additional Information

Currently, thanks to early detection and modern methods of medical and surgical treatment, the prognosis of non-infectious uveitis is favorable in the majority of patients. The prognosis is largely determined by the etiopathogenetic form of the disease. Predictors of a good functional prognosis include a mild course of the inflammatory process in the eye, as well as timely initiation of local and systemic therapy.

Predictors of a poor functional prognosis include: severe course or persistent activity and development of uveitis complications, resistance to ongoing therapy, and long-term disease duration.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Astakhov Yu.S., MD, PhD, Professor, Professor at the Department of Ophthalmology with Clinic, Academician I.P. Pavlov First St. Petersburg State Medical University, Vice-President of the Association of Ophthalmologists.

2. Brovkina A.F., MD, PhD, Professor, Academician of the RAMS, Academician of the RAS, Professor at the Department of Ophthalmology with a Course in Pediatric Ophthalmology and a Course in Ocular Oncology and Orbital Pathology, Russian State Medical Academy of Postgraduate Education, Presidium Member of the Association of Ophthalmologists, Presidium Member of the Russian Ophthalmological Society.

3. Davydova G.A., PhD in Medicine, Researcher at the Helmholtz National Medical Research Center of Eye Diseases of the Ministry of Health of the Russian Federation (Moscow), Member of the Association of Ophthalmologists, Member of the Russian Ophthalmological Society.

4. Denisova E.V., PhD in Medicine, Researcher at the Helmholtz National Medical Research Center of Eye Diseases of the Ministry of Health of the Russian Federation (Moscow), Member of the Association of Ophthalmologists, Member of the Russian Ophthalmological Society.

5. Drozdova E.A., MD, PhD, Associate Professor, Professor at the Department of Eye Diseases, South Ural State Medical University of the Ministry of Health of Russia, Member of the Association of Ophthalmologists, Member of the Russian Ophthalmological Society.

6. Kuznetsova T.I., Ophthalmologist at the Department of the Ophthalmology Clinic with Department, Academician I.P. Pavlov First St. Petersburg State Medical University, Member of the Association of Ophthalmologists.

7. Nikitin M.V., MD, PhD, Professor, Chief freelance specialist of the Russian Ministry of Health on sanatorium-resort treatment, Director of the Vulan Sanatorium-Resort Complex, Scientific and Clinical Branch of the National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation, Association of Physicians of Restorative Medicine.

8. Panova I.E., MD, PhD, Professor, Deputy Director for Science, St. Petersburg Branch of the S.N. Fyodorov National Medical Research Center "Eye Microsurgery" of the Ministry of Health of the Russian Federation, Member of the Association of Ophthalmologists, Member of the Russian Ophthalmological Society.

9. Fesyun A.D., MD, PhD, Acting Director of the National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation, Association of Physicians of Restorative Medicine.

10. Yurova O.V., MD, PhD, Professor, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation, Association of Physicians of Restorative Medicine.

11. Yakovlev M.Yu., PhD in Medicine, Head of the Scientific Department, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation, Association of Physicians of Restorative Medicine

12. Ankudinova S.V., PhD in Medicine, Methodologist and Ophthalmologist at the St. Petersburg Branch of the S.N. Fyodorov National Medical Research Center "Eye Microsurgery" of the Ministry of Health of the Russian Federation, Associate Professor at the Department of Ophthalmology, North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of the Russian Federation, Member of the Russian Ophthalmological Society.

Conflict of interest: none

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Ophthalmologists;

• General practitioners (family physicians)

Methods used for evidence collection/selection: search in electronic databases, analysis of modern scientific developments on the problem of non-infectious uveitis in Russia and abroad; synthesis of practical experience of Russian and foreign specialists; library resources. Description of methods used for evidence collection/selection: the evidence base for the guidelines includes publications included in the Cochrane Library, EMBASE and MEDLINE databases, as well as monographs and articles in leading specialized peer-reviewed domestic medical journals on this topic. The search depth was 10 years. Methods used to assess the quality and strength of evidence: expert consensus, significance assessment in accordance with the rating scheme.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Current package leaflets for the drugs mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru

International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). World Health Organization.

Nomenclature of Medical Services. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, its Adnexa, and Orbit. Order of the Ministry of Health of the Russian Federation No. 902n dated November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, its Adnexa, and Orbit."

List of Vital and Essential Drugs for Medical Use for 2020. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on April 26, 2020), "On Approval of the List of Vital and Essential Drugs for 2020, as well as Lists of Drugs for Medical Use and the Minimum Assortment of Drugs Required for the Provision of Medical Care."

Table 3. Criteria for assessing cellular reaction in the anterior chamber

Table 4. Criteria for assessing exudation in the anterior chamber

Table 5. Criteria for assessing cellular inflammatory reaction in the vitreous body

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Uveitis—inflammation of the vascular tunic of the eye—if not diagnosed and treated in a timely manner, can lead to low vision, blindness, and visual disability.

Non-infectious uveitis is a polymorphic group of diseases that can affect eye structures in isolation or be a manifestation of a systemic disease.

A patient with a diagnosed systemic disease and a risk of developing uveitis should be examined at least once a year, even in the absence of visual symptoms.

The patient should be informed about the possible symptoms of uveitis and its complications, and the need to urgently consult an ophthalmologist if they appear. Immediate consultation with an ophthalmologist is necessary if any of the following symptoms occur: eye redness, photophobia, pain, decreased and/or blurred vision, floaters, flashes of light, lightning streaks, distortion of lines, visual field loss, impaired color perception, change in iris color, or change in pupil size and shape.

Strict adherence to all prescriptions by the ophthalmologist and related specialists (rheumatologist, dermatologist, general practitioner, pediatrician, etc.) is required.

It is necessary to strictly follow the recommended frequency of examinations by an ophthalmologist and, if a systemic disease is present, by related specialists. Even in the absence of visual symptoms, a patient with non-infectious uveitis should be examined by an ophthalmologist at least twice a year.

The patient must be aware of the potential side effects of therapy and the need to seek immediate medical attention from an ophthalmologist (or related specialists) if they develop.

In cases of irreversible blindness or low vision, the patient must be fully informed about the opportunities for vocational, social, and psychological rehabilitation.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Criteria for assessing cellular reaction in the anterior chamber, criteria for assessing exudation in the anterior chamber, and criteria for assessing cellular inflammatory reaction in the vitreous body are given in Appendix A3.