Use of corticosteroids in non-infectious uveitis – expert consensus in Taiwan

Abstract

Purpose

To offer consensus on the utilization of corticosteroids (CS) for treating non-infectious uveitis in the context of clinical practice in Taiwan. This entails examining the different administration methods, their advantages and disadvantages, and considering alternative treatments according to the prevailing evidence and health policies.

Methods

Ten ophthalmologists and one rheumatologist convened on December 11, 2022, to review and discuss literature on the topic. The databases explored were the Central Cochrane library, EMBASE, Medline, PUBMED, and Web of Science using relevant keywords. The search spanned from January 1996 to June 2023. After the initial results of the literature review were presented, open voting determined the final statements, with a statement being accepted if it secured more than 70% agreement. This consensus was then presented at significant meetings for further discussions before the final version was established.

Results

A flow chart and nine statements emerged from the deliberations. They address the importance of CS in uveitis management, guidelines for using topical CS, indications for both periocular or intravitreal and systemic therapies, and tapering and discontinuation methods for both topical and systemic CS.

Conclusion

While CS are a cornerstone for non-infectious uveitis treatment, their administration requires careful consideration, depending on the clinical situation and the specific type of uveitis. The consensus generated from this article provides a guideline for practitioners in Taiwan, taking into account local health policies and the latest research on the subject. It emphasizes the significance of strategic tapering, the potential for alternative therapies, and the importance of patient-centric care.

Keywords:

• Non-infectious uveitis
• regional corticosteroids
• systemic corticosteroids
• topical corticosteroids

Uveitis, a complex and potentially sight-threatening condition, refers to inflammation of the uveal tract, comprising the iris, ciliary body and choroid [1]. This ocular disorder is accountable for approximately 10% of cases of visual impairment in the developed world [2]. The aetiology of uveitis is diverse, encompassing infectious agents, autoimmune disorders and idiopathic causes [3]. Given the intricate nature of uveitis and its potential for severe complications, such as cataracts, glaucoma, and macular oedema, prompt and effective treatment is crucial [4].

Corticosteroids (CS) have long been the mainstay of therapy for non-infectious uveitis due to their potent anti-inflammatory and immunosuppressive properties [5]. Since their discovery in the 1940s, CS have been employed to manage various inflammatory conditions, including uveitis [6]. These drugs work by inhibiting the production of pro-inflammatory mediators, such as cytokines and chemokines, and by suppressing immune cell activation and proliferation [7]. Multiple routes of corticosteroid administration are available for the treatment of uveitis, including topical, systemic, periocular and intravitreal injections [8].

Topical CS, such as prednisolone acetate and dexamethasone, are commonly used for anterior uveitis, as they can rapidly penetrate the cornea and achieve therapeutic concentrations in the anterior chamber [9]. However, topical CS are less effective for intermediate, posterior, and panuveitis, as they have limited penetration into the posterior segment of the eye [10].

Oral CS, such as prednisone or prednisolone, are often prescribed for intermediate, posterior, and panuveitis, as they can achieve therapeutic levels throughout the eye [11]. Short-term intravenous CS offers a quick resolution of inflammation and sometimes be used in acute phase Vogt–Koyanagi–Harada disease. Nonetheless, systemic CS therapy can be associated with significant side effects, such as osteoporosis, hyperglycaemia and hypertension, particularly with long-term use [12].

Due to the special structure and blood ocular barrier, eye is the most attractive site for local treatment. Periocular and intravitreal CS injections have emerged as alternative routes of administration that enable targeted drug delivery to the inflamed tissues, thereby minimizing systemic side effects [13]. Triamcinolone acetonide is a commonly used CS for periocular and intravitreal injections, while dexamethasone intravitreal implants have also shown promising results [14]. These localized therapies have proven to be particularly beneficial for patients with contraindications to systemic CS or those experiencing side effects from systemic therapy [15].

Despite the widespread use of CS in managing uveitis via topical, periocular, intravitreal and systemic routes, concerns persist regarding their long-term safety and efficacy. Furthermore, a significant proportion of patients may experience corticosteroid refractoriness or develop side effects that necessitate discontinuation of therapy [16]. Consequently, novel therapeutic approaches, such as biologics and immunomodulatory agents, have been introduced to complement or replace CS therapy in selected cases [17].

Thus, the purpose of this article is to provide the consensus on the use of CS in non-infectious uveitis based on the circumstances of clinical practice in Taiwan. The panel proposed an algorithm regarding the use of corticosteroids in non-infectious uveitis treatment, focusing on the various administration routes, their benefits and limitations and emerging therapeutic alternatives based on the current evidence and health policy in Taiwan.

Methods

This study was performed with the approval of the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-20210015). A panel of 10 ophthalmologists from eight different referral centres with expertise in the management of uveitis and an experienced rheumatologist was held on December 11, 2022. Before the meeting, verbal informed consents for all participation in the study were obtained. A comprehensive literature review and discussion of general background, contraindications, indications, routes of administration and adverse effects of CS were performed. Databases including Central Cochrane library, EMBASE, Medline, PUBMED and Web of Science were searched with the keywords including corticosteroids, immune pharmacotherapy, immunosuppressives, intraocular inflammation, uveitides, uveitis. English language studies included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, review article and case series from January 1996 through June 2023 were reviewed. In the beginning of the meeting, results of literature review were summarized and reported by two experts (TEK and YCC). Personal opinions regarding healthcare situations, crucial precautions, or clinical experiences were then stated and discussed by each expert. Important issues to be included in the consensus were decided upon if more than half of the experts agreed. The initial statements were drafted after discussions, followed by open votes for each statement. A final statement was adopted only if more than 70% of the experts agreed and confirmed. Subsequently, the consensus was presented at the Taiwan Ocular Inflammation Society (TOIS) meeting and the Mid-year Scientific Joint Meeting of The Ophthalmological Society of Taiwan and the Taiwan Academy of Ophthalmology, which were opened to all members for further discussion. Eventually, the final version was accomplished.

Results

Following thorough deliberation, a total of nine statements were incorporated into the consensus. Among these statements, one pertained to the significance of CS in uveitis management, three were related to the utilization of topical CS, two addressed the implementation of periocular or intravitreal therapies, and the remaining three statements encompassed the use of systemic CS.

Statement 1: The Role of Corticosteroids in Uveitis

Corticosteroids, which exert a broad immune-suppressive effect through multiple mechanisms, constitute the cornerstone of noninfectious uveitis treatment. They can be administered topically, regionally, or systemically

Corticosteroids (CS), synthetic analogues of cortisol – a naturally occurring hormone produced by the adrenal cortex [7] – exert their immunosuppressive effects through various mechanisms:

1. Modulation of gene transcription: CS bind to intracellular glucocorticoid receptors, forming a complex that translocates to the nucleus [7]. This complex can upregulate the expression of anti-inflammatory genes, such as lipocortin-1, while downregulating pro-inflammatory genes, including cytokines like interleukin (IL)-1, IL-2 and tumour necrosis factor (TNF)-α [7].

2. Inhibition of immune cell functions: CS can suppress the function and proliferation of diverse immune cells, including T- and B-lymphocytes, macrophages, and neutrophils [7]. These effects collectively lead to reduced immune cell infiltration into inflamed tissues, diminished antigen presentation, and decreased cytokine production [7].

3. Stabilization of cell membranes and reduction of vascular permeability: By stabilizing the membranes of lysosomes and mast cells, CS prevent the release of histamine and other inflammatory mediators. Furthermore, they reduce vascular permeability, minimizing the infiltration of inflammatory cells into affected tissues [7].

Statement 2: Optimal Use of Topical Corticosteroids

Topical corticosteroid drops are predominantly indicated for managing inflammation of the anterior segment.

The administration route and CS dosage depend on the severity, location, and duration of uveitis, as well as the presence of other ocular or systemic comorbidities.

Topical CS drops are primarily recommended for addressing inflammation within the anterior segment. Anterior uveitis, which impacts structures like the iris and ciliary body, represents the most prevalent form of uveitis and is frequently managed through the application of topical CS. The different preparations of available steroid eye drops in Taiwan are outlined in Table 1. The utilization of topical CS presents a range of advantages:

Table 1. Common topical corticosteroid eye drops in Taiwan.

Corticosteroid	Concentration	Brand Name	Relative Potency*
Prednisolone acetate suspension	1%	Econopred Plus (Alcon) Pred Forte (AbbVie)	High
Dexamethasone sodium phosphate suspension	0.1%	Maxidex (Alcon), Desalone (Aimedicine) Decason (Oasis)	Moderate
Betamethasone:	0.1%	Betame (Aimedicine) Fusone (Aimedicine)(Unit dose)	Moderate
Fluorometholone suspension	0.1%	FML (AbbVie) Flumetholone (Santen) Fluoron (Patron) Flucason (Synpac-Kingdom) Foxone (Winston)	Low
Loteprednol etabonate:	0.5%	Lotemax (Bausch & Lomb)	Low

*Mcghee CN, Dean S, Danesh-Meyer H. Locally administered ocular corticosteroids. Drug Saf. 2002;25(1):33–55.

1. Localized treatment: Topical CS afford targeted therapy to the inflamed anterior segment, thereby lessening the necessity for systemic CS administration and mitigating potential systemic side effects [5].

2. Ease of administration: Topical CS drops or ointments are relatively straightforward to apply, allowing patients to often self-administer the treatment [18].

3. Rapid onset of action: The quick onset of action associated with topical CS promptly alleviates inflammation and related symptoms [19].

However, it is important to acknowledge limitations and consider key factors related to the use of topical CS in clinical practice:

1. Penetration: In addition to difluprednate 0.05% (currently not available in Taiwan) which may penetrate to the vitreous [20], most topical CS may not effectively penetrate posterior segment inflammation, necessitating alternative administration routes such as periocular or intravitreal injections [21].

2. Adherence: Patient adherence to topical CS treatment significantly impacts achieving optimal outcomes. Clinicians must offer precise instructions regarding proper application and dosage, while also monitoring treatment adherence [19].

Statement 3: Guidelines for Topical Corticosteroid Application

In cases of intense and severe inflammation within the anterior segment, potent/fortified topical corticosteroids (e.g., prednisolone acetate 1%) may be administered at a frequency of one drop per hour, followed by a gradual tapering based on the patient's clinical progress

The utilization of CS for uveitis management has spurred considerable interest and debate within the medical community. In this discourse, our focus rests on two pivotal dimensions of CS use in uveitis—specifically, the application of topical CS in instances of severe anterior segment inflammation and the meticulous process of tapering and discontinuation of these medications.

In cases marked by active and severe anterior segment inflammation (i.e. 3+ or more cells or flares in the anterior chamber) [22], the preference frequently gravitates toward potent or fortified topical corticosteroids, exemplified by prednisolone acetate 1%. This preference arises due to their rapid onset of action and localized treatment effects [19]. The frequency of administration emerges as a critical determinant in achieving optimal therapeutic outcomes. During the acute phase of severe inflammation, the administration of a single drop of the corticosteroid can occur as often as every hour, effectively curbing inflammation. Nevertheless, it remains imperative to weigh the potential long-term side effects associated with topical corticosteroid use, encompassing ocular hypertension, glaucoma and cataract development [5]. To mitigate these risks while upholding adequate inflammation control, a gradual tapering of CS in accordance with clinical evolution is advisable.

Statement 4: Tapering and Discontinuation of Topical Corticosteroids

Tapering of topical corticosteroids could be initiated once there is observed improvement in anterior chamber cells. The treatment objective entails achieving either complete resolution of anterior chamber inflammation or achieving minimal inflammation without subsequent relapse, all while minimizing the frequency of topical steroid application.

The verdict to taper or cease topical CS should be guided by the patient’s clinical progression and the amelioration of anterior chamber cells – an indicator of inflammation reduction [19]. The treatment objective is twofold: either total eradication of anterior chamber inflammation or attaining minimal inflammation devoid of relapse while minimizing the frequency of topical CS administration [5]. Regular visits to an ophthalmologist are integral for monitoring treatment response, refining dosage and administration frequency, and assessing potential side effects [19]. The initiation of tapering follows observable improvement in anterior chamber cells. According to ‘The Standardization of Uveitis Nomenclature (Sun) Working Group’, improvement in the inflammation is defined as either a ‘two-step’ decrease in the level of inflammation (i.e. 3+ to 1+) or a decrease to ‘inactive’ (i.e. trace to 0) [22]. Then, we can entail a gradual reduction in administration frequency coupled with close vigilance over the patient’s clinical status. The treatment goal is usually to achieve complete resolution of anterior chamber inflammation. However, for patients with chronic anterior uveitis, a safer maintenance dose of 0.1% fluorometholone 1 drop twice a day is recommended to avoid CS-associated adverse effects [23].

In the context of non-infectious uveitis, the apt and gradual deployment of potent topical corticosteroids remains paramount for addressing severe anterior segment inflammation. Clinicians are urged to thoughtfully contemplate administration frequency, optimal timing for tapering, and treatment objectives to optimize patient outcomes and limit potential side effects. Regular follow-up appointments and patient education regarding treatment adherence stand as pivotal constituents of a successful uveitis management paradigm.

Statement 5: Indications for Periocular or Intravitreal Therapy

Periocular or intravitreal steroid injections, administered via subconjunctival, transseptal, sub-tenon, intravitreal, or suprachoroidal routes, may be considered in the following clinical scenarios:

1. 1. As a supplement to systemic therapy, or when systemic therapy is contraindicated.

2. 2. In cases of inadequate adherence to topical or systemic treatment.

3. 3. For severe unilateral uveitis or instances of uveitis complicated by refractory cystoid macular edema (CME).

The decision to employ periocular or intravitreal therapy for the management of specific clinical conditions hinges on a multitude of factors. Periocular and intravitreal CS injections come into consideration when systemic therapy proves insufficient or is contraindicated. Moreover, these approaches find utility in scenarios marked by poor adherence to topical or systemic treatment, as well as in cases involving severe uveitis and uveitis that is complicated by refractory CME.

Periocular or intravitreal therapy assumes a complementary role alongside systemic therapy for select ocular conditions. Systemic therapy may be subject to limitations, encompassing inadequate delivery to the eye or the manifestation of systemic side effects. In such instances, periocular or intravitreal injections offer a targeted avenue, delivering medication directly to the affected region while curtailing systemic exposure. This strategy proves particularly advantageous when standalone systemic therapy proves insufficient or is contraindicated due to patient-specific factors or concurrent medical conditions [5].

In certain scenarios, patients may encounter challenges in adhering to prescribed regimens involving topical eye drops or systemic medications. Complex treatment protocols, inconvenience, or discomfort linked to specific drugs can contribute to suboptimal compliance. Periocular or intravitreal therapy presents an alternative channel for drug administration, potentially augmenting patient adherence and ensuring consistent medication delivery to the eye [14].

The sphere of severe uveitis, particularly unilateral involvement, characterized by pronounced intraocular inflammation, and uveitis complicated with refractory CME underscores the complexities of effective management. Periocular or intravitreal CS injections facilitate the targeted delivery of potent anti-inflammatory agents directly to affected tissues, effectively curbing inflammation and mitigating the risk of complications. The precision with which CS is administered via these routes engenders heightened local concentrations, offering the prospect of improved outcomes in the treatment of severe uveitis and refractory CME [3].

Crucially, the selection between periocular and intravitreal therapy is contingent upon the specific clinical milieu and the unique requisites of the individual patient. Parameters such as the scope and site of inflammation, the coexistence of concurrent ocular conditions, and the patient’s overall health must all be factored into the determination of the most suitable administration route.

Statement 6: Guidelines for Utilizing Periocular or Intravitreal Therapy

The selection of a delivery method is generally predicated on the patient's clinical condition, with each route presenting distinct merits and drawbacks. For short-term management (duration of less than 3 months) of intraocular inflammation, the potential consideration of betamethasone, dexamethasone, or triamcinolone acetonide via periocular or intravitreal routes arises. Conversely, for prolonged management (duration exceeding 3 months) of intraocular inflammation, contemplation of an intravitreal injection with a corticosteroid implant may be warranted.

The choice between periocular and intravitreal therapy hinges on the patient’s clinical condition, the distinct advantages and disadvantages associated with each route, and the intended duration of treatment. For short-term inflammation control, options include betamethasone, dexamethasone, or triamcinolone acetonide, which can be administered via periocular or intravitreal routes. Periocular injections including subconjunctival, transseptal, or sub-Tenon offer are less invasive than intravitreal injections [24]. However, periocular injections may exhibit a shorter duration of action and a heightened risk of periocular side effects like ptosis or subconjunctival haemorrhage [25]. Intravitreal injections have a more direct impact on the retina and vitreous and might provide longer-lasting effects compared to periocular injections [26]. According to the result from POINT trial, both intravitreal triamcinolone acetonide and the dexamethasone implant were superior to periocular triamcinolone acetonide for the treatment of uveitic macular oedema with modestly greater rates of mild intraocular pressure (IOP) elevation. The authors suggest that intravitreal therapy may be the preferred initial therapy for uveitic macular oedema [27]. Nevertheless, intravitreal injections carry a higher risk of intraocular complications, including vitreous haemorrhage, retinal detachment, endophthalmitis [28].

For prolonged inflammation control, consideration can be given to intravitreal CS implants. These implants ensure sustained drug release, reducing the need for repeated injections and enhancing patient adherence [29]. Implants like fluocinolone acetonide (Retisert) or dexamethasone (Ozurdex) have demonstrated effectiveness in managing inflammation and preserving visual acuity in uveitis patients [15]. Retisert provides longer effect but higher CS related complications, such as cataract and elevated IOP [26]. A lower dose long-acting injectable fluocinolone acetonide implants (Iluvien, Yutiq) were developed and reported to have an acceptable side-effect profile [30,31]. However, intravitreal implants may raise the risk of intraocular complications such as cataract formation, glaucoma, or infection, necessitating monitoring and management of these issues [32]. A summary of common CS preparations and their local delivery methods are presented in Table 2.

Table 2. Common steroid preparations for periocular or intravitreal therapy.

Corticosteroid	Brand name	Subconjunctival injection	Subtenon injection	Intravitreal injection
Triamcinolone Acetonide	Kenalog	20–40 mg/mL	20–40 mg/mL	2–4 mg/0.05–0.1 mL
Dexamethasone	Decadron	4–10 mg/mL	4–10 mg/mL
Betamethasone	Rinderon	3–9 mg/mL	3–9 mg/mL
Methylprednisolone Acetate	Solu-Medrol	20–40 mg/mL	20–40 mg/mL
Fluocinolone Acetonide Implant	Retisert			0.59 mg
	Iluvien*			0.19 mg
	Yutiq			0.18 mg
Dexamethasone Intravitreal Implant	Ozurdex			mg

*Approved for treatment of non-infectious posterior uveitis in several European countries, US FDA-approved to treat diabetic macular oedema, but not uveitis.

A relatively novel approach is suprachoroidal CS therapy, involving the direct injection of CS into the suprachoroidal space, the potential area between the choroid and sclera. This technique presents several advantages over traditional administration routes, such as periocular and intravitreal injections:

1. Targeted drug delivery: Suprachoroidal CS therapy delivers drugs more precisely to the choroid and retina, as the injected substance is placed directly adjacent to the uveitis-involved tissues [25]. This targeted delivery might result in higher drug concentrations at the inflammation site and potentially improved therapeutic outcomes [33].

2. Reduced systemic exposure and side effects: The targeted delivery of suprachoroidal CS therapy can lead to lower systemic exposure and fewer systemic side effects in comparison to other administration routes [34].

3. Lower risk of intraocular complications: Suprachoroidal CS therapy might carry a lower risk of intraocular complications like endophthalmitis, retinal detachment, or elevated IOP, which are more commonly associated with intravitreal injections [35].

Statement 7: Indications for Systemic Corticosteroid Therapy

Systemic corticosteroid therapy may be contemplated under the following circumstances:

1. 1. In instances of vision-threatening uveitis.

2. 2. When local corticosteroid therapy yields an inadequate response.

3. 3. In cases involving bilaterally or systemic involvement.

CS play a pivotal role in managing uveitis, an inflammatory disorder affecting the uveal tract that holds the potential for vision impairment. While localized CS therapy often stands as the preferred method, specific contexts may necessitate the utilization of systemic CS therapy. The consideration for systemic CS arises in the following clinical scenarios:

1. Vision-threatening uveitis: Instances wherein uveitis jeopardizes vision, such as cases associated with retinal vasculitis, retinal detachment, choroidal neovascularization, poor visual acuity (corrected visual acuity ≤ 6/60), or an obscured fundus, may necessitate systemic CS to rapidly quell inflammation and avoid irreversible vision loss [36].

2. Poor response to local CS therapy: Some patients might not achieve satisfactory outcomes with local CS therapy, whether due to severe inflammation or refractory macular oedema. In such circumstances, systemic CS could be considered to attain more potent inflammation control [37].

3. Bilateral or systemic involvement: In patients with bilateral uveitis or systemic conditions linked to uveitis, such as sarcoidosis, Behcet’s disease, or Vogt-Koyanagi-Harada syndrome, usually require systemic CS therapy to manage both ocular and systemic inflammation [37].

The decision to employ systemic CS should be meticulously assessed against the backdrop of potential risks and benefits, with cautious monitoring of patients for adverse effects throughout treatment. Furthermore, systemic CS can be paired with other immunosuppressive agents or biologic therapies to reduce the requisite CS dosage and mitigate side effects [37]. This strategy, termed corticosteroid-sparing therapy, has demonstrated efficacy in inflammation control and vision preservation among uveitis patients [16].

The incorporation of systemic CS in uveitis management surfaces when local interventions prove inadequate or when particular clinical scenarios mandate their application. The potential side effects of systemic CS should be judiciously considered, and the adoption of a CS-sparing strategy may prove advantageous in limiting the risks linked to prolonged CS usage.

Statement 8: Guidelines for Administering Systemic Corticosteroids

Before initiation of systemic treatment, physicians should assess thorough medical history and to evaluate possible latent infectious diseases. Consultation of other specialists for monitoring or treating underlying diseases before administration if necessary. Treatment should consist of high dosage initially and then tapering according to clinical effect. In cases of severe uveitis, intravenous methylprednisolone (pulse therapy) might be considered. The judicious utilization of systemic corticosteroids encompasses meticulous assessment, prudent dosing, strategic tapering, and targeted considerations for severe uveitis cases.

Systemic CS play an indispensable role in the management of uveitis, especially when local therapies prove inadequate or specific clinical contexts necessitate their application. The effective utilization of systemic CS therapy requires careful consideration during both initiation and monitoring. The following steps are recommended when contemplating systemic CS therapy for uveitis:

1. Assessment of Medical History and Latent Infections: Before commencing systemic CS therapy, a comprehensive evaluation of the patient’s medical history such as hypersensitivity to any component of the formulation, osteoporosis, uncontrolled hyperglycaemia, uncontrolled hypertension, peptic ulcer disease and congestive heart failure is imperative [38]. This assessment should also encompass a meticulous review of potential underlying conditions and risk factors for latent infections [37]. Screening for diseases such as tuberculosis (TB), syphilis, and other infections that could exacerbate with systemic CS is essential [16].

2. Consultation with Other Specialists: When underlying diseases are suspected or present, collaboration with other specialists may be warranted. Such consultations facilitate appropriate monitoring and management prior to and during systemic CS treatment.

3. Treatment Initiation and Dosage: Systemic CS therapy usually commences with a high initial dose, followed by a tapering regimen in response to the patient’s clinical progress. Oral prednisone is commonly selected as the first-line therapy, with the starting dosage ranging from 0.5 to 1 mg/kg/day, contingent upon the severity of inflammation [39].

4. Pulse Therapy for Severe Uveitis: In cases marked by severe uveitis, the consideration of intravenous methylprednisolone (pulse therapy) is warranted. Pulse therapy entails administering high doses of intravenous CS, such as 500–1000 mg of methylprednisolone daily for three consecutive days, followed by a gradual reduction in oral CS dosages [39,40]. This approach is geared towards rapidly quelling inflammation and has demonstrated efficacy in severe uveitis instances, even those entailing vision-threatening complications [40].

Statement 9: Guidelines for Tapering and Discontinuation of Systemic Corticosteroids

Tapering of systemic corticosteroids should be in accordance with achieving the goal of inflammation control and corticosteroids associated side effects, and should be done with continuously smaller decrements to lessen the risk of relapse. If uveitis/intraocular inflammation has been controlled for a certain time (according to different disease entity), the maintenance dose of corticosteroids may be discontinued. If the safety maintenance dose of corticosteroids cannot be achieved, the addition of immunosuppressives or biologics should be considered.

The judicious tapering and discontinuation of CS usage hold paramount importance to avert potential side effects and prevent the recurrence of inflammation. Tapering systemic CS should be guided by the dual goals of achieving inflammation control and addressing corticosteroid-associated side effects. The tapering process should involve progressively waning decrements in the CS dose (Table 3) to minimize the risk of inflammation relapse [5,37].

Table 3. Recommended tapering schedules for oral prednisone.

Dosage (mg/day)	Decrement (mg/day)	Interval
Over 40	10	1–2 weeks
40–15	5	1–2 weeks
15–7.5	2.5	1–2 weeks
Less than 7.5	2.5	Weekly to monthly

Supplemental therapy: calcium 1,500 mg/day, vitamin D 800 IU/day, oestrogen and antiresorptive agents as needed.

Close monitoring of the patient’s condition during the tapering phase is of utmost significance to ensure sustained inflammation control and effective management of side effects. For patients who need long-term use of systemic CS, the safer maintenance dose is 7.5 mg per day [37]. The discontinuation of the maintenance dose of CS may be considered once uveitis or intraocular inflammation has been effectively controlled for a specific timeframe, which varies in accordance with the particular disease entity. However, a cautious and gradual approach is advised to avert abrupt inflammation flare-ups [16]. To mitigate this risk, a gradual tapering of the CS dose over weeks or months is recommended, considering individual patient response and disease severity.

In cases where achieving a safe maintenance dose of CS is challenging, the inclusion of immunosuppressive agents or biologic therapies warrants consideration [5,37]. Immunosuppressive medications like methotrexate, azathioprine, or mycophenolate mofetil can serve as CS-sparing agents, diminishing the necessary CS dosage and thereby reducing potential side effects [40]. Biologic therapies, including tumour necrosis factor (TNF) inhibitors, may be contemplated when conventional immunosuppressive treatments are inadequate or poorly tolerated [5,37].

The careful tapering and discontinuation of systemic CS in uveitis management are pivotal to achieving sustained inflammation control, minimizing adverse effects, and averting relapses [41]. By tailoring the tapering process to individual patient needs and diligently monitoring their response, healthcare professionals can optimize treatment outcomes. In cases where maintaining a safe CS dose proves challenging, the incorporation of immunosuppressive agents or biologic therapies offers a promising avenue to support patients’ treatment plans and enhance long-term prognosis. Staying current with evolving research and recommendations in uveitis management is essential for clinicians to deliver optimal patient care.

Contraindications for corticosteroids in uveitis management

Topical CS are a standard therapeutic approach for managing anterior uveitis; however, certain situations warrant cautious consideration:

1. Ocular Infections: The use of topical CS is contraindicated in individuals with corneal infections, including viral infections like herpes simplex keratitis, bacterial infections such as bacterial keratitis, and fungal infections like fungal keratitis [5]. CS can suppress the local immune response, potentially exacerbating the underlying infection and leading to severe complications that endanger vision [4].

2. History of steroid-induced glaucoma or uncontrollable IOP: Patients with a history of steroid-induced ocular hypertension or primary open-angle glaucoma should avoid topical CS [42]. Prolonged CS use may elevate IOP, which can result in optic nerve damage and irreversible vision loss [43].

3. Corneal Thinning or Perforation: Individuals with a history of corneal thinning or perforation should steer clear of topical CS, as these agents might worsen the condition and heighten the risk of further corneal damage [44].

4. Hypersensitivity: Patients with a known hypersensitivity to CS or any component of the formulation should not be prescribed topical CS, as this can induce allergic reactions [40].

Systemic CS is a valuable tool in uveitis treatment; however, several contraindications should be carefully considered:

1. Active Infections: Systemic CS pose an increased infection risk and can mask infection symptoms. Consequently, they are contraindicated in patients with active bacterial, fungal, or viral infections [33]. This includes individuals with TB, as CS may reactivate latent TB [45]. Nonetheless, TB uveitis can be treated with oral steroid after starting adequate anti-TB therapy [46,47].

2. Uncontrolled Diabetes: Poorly controlled diabetes can be exacerbated by systemic CS, making it a contraindication for individuals with unregulated diabetes [48].

3. Gastrointestinal (GI) Ulcers: Systemic CS heighten the likelihood of GI bleeding and perforation, thus being contraindicated in patients with a history of peptic ulcers or significant GI pathology [49].

4. Osteoporosis: Systemic CS can decrease bone density, elevating fracture risk in osteoporosis patients [50]. Alternative treatment options should be explored in such cases.

5. Glaucoma: Systemic CS can raise IOP, potentially worsening pre-existing glaucoma or inducing steroid-induced glaucoma [51]. Caution is warranted when contemplating CS therapy in these patients.

6. Growth Suppression in Children: Systemic CS may impede growth in children. Therefore, the decision to employ systemic CS in paediatric uveitis cases should be weighed meticulously, considering the condition’s severity, potential growth impact, and alternative treatments’ availability [52].

7. Pregnancy: Although CS are considered relatively safe during pregnancy, they should be used with caution and only when the potential benefits outweigh the risks [53]. Studies have shown an increased risk of oral clefts in infants when CS are used during the first trimester [54]. Moreover, prolonged use of CS during pregnancy has been associated with an increased risk of preterm birth and low birth weight [55].

Upholding a comprehensive understanding of these contraindications is pivotal for safeguarding patient well-being and achieving favourable uveitis management outcomes.

Conclusion

In summary, CS play a crucial role in addressing uveitis, an inflammatory disorder impacting the uveal tract that can result in vision impairment if left untreated. Our comprehensive discussion has yielded consensus statements that underscore the significance of CS in diverse uveitis treatment modalities. A flowchart regarding the proper use of CS in non-infectious uveitis is shown in Figure 1.

Figure 1. General flow for the use of corticosteroids in noninfectious uveitis.

*BID: bis in die (twice daily); IMT: Immunomodulatory Therapy; IV: intravenous; kg: kilogram; ME: macular oedema; mg: milligram; Q1H: quaque 1 hora (every one hour).

Topical CS provide a focused remedy for anterior segment inflammation, curbing systemic side effects while rapidly alleviating symptoms. However, for posterior segment inflammation, alternative administration paths like periocular or intravitreal injections might be necessary due to limited penetration. Potent topical CS are often preferred for severe anterior segment inflammation, necessitating careful tapering to manage potential adverse effects.

In specific clinical scenarios, such as vision-threatening uveitis or poor local therapy response, systemic CS could be warranted. Vigilant monitoring and consideration of CS-sparing therapies are indispensable to minimize associated risks. Additionally, emerging approaches like suprachoroidal CS therapy hold promise in delivering targeted treatment and diminishing systemic exposure. Nevertheless, further research is essential to establish its effectiveness and safety in uveitis care.

The decision-making process regarding CS application should meticulously account for contraindications, notably in cases of active infections, uncontrolled diabetes, glaucoma, and other conditions that might interact adversely with CS. Overall, judicious CS utilization and tapering, be it through topical, systemic, or novel methods, are pivotal in achieving efficacious uveitis management. Collaborative efforts among clinicians, vigilant patient monitoring, and staying up-to-date of evolving research will continue advancing treatment outcomes and safeguarding visual health in individuals afflicted by uveitis.

Authors contributions

Conceptualization: S.J.S. and C.P.L. Methodology: Y.C.C., T.E.K., C.L.C. and D.K.H. Validation: Y.S.H., C.J.L. and W.C.C. Writing–original draft preparation: Y.C.C., T.E.K. and C.L.C. Writing–review and editing: Y.C.L, S.J.S. and S.N.C. Funding acquisition: Y.C.C. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

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

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article. Upon reasonable request, the corresponding author will provide the dataset.

Additional information

Funding

This study was supported by grants KMTTH-110-002 from Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan and KMHK-111-08 from Kaohsiung Municipal Siaogang Hospital, Taiwan.