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07 May 2024: Review Articles  

Optimizing Behçet Uveitis Management: A Review of Personalized Immunosuppressive Strategies

Biao Li1ACEF, Kaiyao Chi1BDE, Haoran Li1BD, Jing Wang2BCF*, Yanlin Zheng12ABC

DOI: 10.12659/MSM.943240

Med Sci Monit 2024; 30:e943240

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Abstract

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ABSTRACT: Behçet uveitis poses significant management challenges, owing to its intricate pathogenesis and the severe prognosis it harbors, frequently culminating in irreversible visual impairment and an elevated risk of blindness. This review synthesizes contemporary insights into personalized immunosuppressive strategies for Behçet uveitis, emphasizing the necessity for a customized approach in recognition of the disease’s heterogeneity and the variable responsiveness to treatment. This discourse elaborates on the application, efficacy, and safety profiles of traditional immunosuppressants, highlighting a paradigm shift toward integrative combination therapies aimed at diminishing reliance on glucocorticoids and mitigating their associated adverse effects. This thorough evaluation seeks to enlighten clinical practices and spearhead future investigations aimed at refining the management of Behçet uveitis, championing a personalized, multidisciplinary strategy to amplify therapeutic efficacy and enhance patient quality of life.

Keywords: Behcet Syndrome, calcineurin inhibitors, Antimetabolites, Alkylating Agents, uveitis

Introduction

Behçet syndrome (BS) is a recurring immune-mediated condition characterized by pathological alterations of occlusive vasculitis and neutrophil hyperactivity [1,2]. Its quintessential manifestation comprises the triad of oral ulcers, genital ulcers, and non-infectious uveitis2. Additionally, it can involve multiple organs and systems, encompassing vascular, cutaneous, articular, pulmonary, gastrointestinal, and neurological systems [3]. BS exhibits global prevalence, with notably higher incidence and severity in regions along the ancient Silk Route, including the Middle East, the Mediterranean basin, and the Far East [4]. The condition’s prevalence varies significantly worldwide, with Istanbul, Turkey, reporting the highest prevalence of 420 cases per 100 000 inhabitants [5], in stark contrast to the United Kingdom’s estimated prevalence of 0.64 per 100 000 [6].

Behçet uveitis (BU), a prevalent manifestation of BS, is regarded as one of the most arduous uveitis types to manage [7–9]. The prognosis of BU is inferior than other common uveitis types, such as Vogt-Koyanagi-Harada disease, and is correlated with a heightened incidence of blindness [10–14]. The prevalence of BU in patients with BS fluctuates considerably across regions, with estimates ranging from 34.8% to 90% [2,4,15]. BU can afflict one or both eyes, and approximately 76.5% of patients with BU ultimately develop bilateral panuveitis [16,17]. Recurrent BU episodes frequently culminate in irreversible visual deterioration and a substantial risk of blindness, with a 6- to 10-year blindness rate varying from 13% to 74% among patients with BU [10,11,18], profoundly impacting patients’ quality of life.

The etiology and pathogenesis of BU remain unknown; nevertheless, it is widely postulated to arise from an autoimmune inflammatory reaction mediated by neutrophils and Th1 cells [19]. The pathological hallmarks of BU are non-granulomatous uveitis and retinal vasculitis [18,20]. Owing to the obscure etiology and pathogenesis of BS, formulating precise treatment guidelines proves arduous for clinicians, and a unified standard for BU management is currently lacking [21]. The primary therapeutic objective for BU is to induce and maintain ocular inflammation abatement by suppressing the immune response, thereby averting severe complications such as visual impairment [22–26]. The customary medications for managing BU are glucocorticoids (GCS), immunosuppressants, and biological agents. Since the first use of GCS for uveitis treatment in 1950, it has remained the first-line drug for acute BU management [27–30]; however, its long-term usage and associated adverse effects [31,32], coupled with its inability to modify the long-term prognosis [33,34], necessitate combining GCS with other immunosuppressants to diminish its dosage and adverse effects, decrease the recurrence rate, and ultimately achieve long-term inflammation relief [32,35,36].

At present, the principal immunosuppressive agents used to manage BU include alkylating agents (eg, chlorambucil, cyclophosphamide), antimetabolites (eg, azathioprine, mycophenolate mofetil, methotrexate), and calcium channel inhibitors (eg, cyclosporine A and FK506). These agents exhibit discrete indications and adverse effects, and their selection ought to be based on the patient’s overall condition, with vigilant monitoring conducted throughout the treatment course.

In this comprehensive review, we aimed to rigorously assess the application and efficacy of customized immunosuppressive strategies in the management of BU. Through a meticulous examination of the mechanisms, effectiveness, and safety profiles of diverse immunosuppressive agents, this study delves into optimizing patient outcomes via the identification of treatment methodologies that account for individual variances. Emphasizing the necessity for a personalized, interdisciplinary approach in light of the complexity of BU and the heterogeneity in treatment responses, our objective is to increase therapeutic efficacy and improve the quality of life for patients.

Alkylating Agents

CYCLOPHOSPHAMIDE:

It is crucial to acknowledge that CYC is frequently used as an anticancer drug for managing refractory non-infectious uveitis, encompassing BU and Vogt-Koyanagi-Harada disease [37,38].

CYC exhibits greater potency than chlorambucil, making it a viable alternative for BU patients unresponsive to chlorambucil therapy. The initial oral dose of CYC for BU treatment generally varies from 1 to 2 mg/kg/d, with a maintenance dose of 1 mg/kg/d [38]. For patients experiencing severe retinal vasculitis or hemorrhagic cystitis following oral CYC treatment, high-dose intravenous pulse therapy may be considered. This approach adopts a regimen analogous to conventional systemic vasculitis therapy, using a dose of 500 to 1000 mg/m2 body surface area every 3 to 4 weeks for a duration of 6 months. Intravenous administration offers a faster onset of action and reduced systemic toxicity than does oral administration, making it the preferred method [38].

Although some studies advocate the efficacy of CYC in treating BU, its effectiveness remains inconclusive. Kazokoglu et al investigated the long-term efficacy of CYC and colchicine in managing Behçet disease in 64 patients, divided into 2 groups from 1976 to 1989, to assess visual prognosis and attack frequency. The results of the study revealed no statistically significant improvement in visual acuity or reduction in attack frequency attributable to the treatments, when comparing the treatment period to the post-treatment period. The findings suggest that CYC and colchicine offer limited benefits in treating Behçet disease, highlighting the need for more effective therapeutic options [39]. One investigation administering CYC to 38 patients with BU unresponsive to traditional therapy reported that 68% of patients exhibited favorable responses after 2 months, with 55% achieving complete inflammation resolution and 41% discontinuing steroid therapy entirely [40]. Earlier research also corroborated the utility of CYC in BU management [41,42].

Nonetheless, a single-blind trial [43] comparing the effectiveness of CYC and cyclosporine showed visual acuity improvements in the cyclosporine cohort at 6 months, but not in the CYC group. Moreover, a systematic review [44] exposed insufficient evidence supporting CYC use for BU treatment. Consequently, the efficacy of CYC in addressing BU remains controversial.

CYC can be co-administered with other immunosuppressive agents possessing distinct mechanisms of action to minimize drug dosage and adverse effects. In clinical practice, CYC, azathioprine, and GCS are often used as first-line therapies for BU. In a study by Davatchi et al [45], the efficacy of combined treatment with CYC (1 mg/kg/d once a month for the initial 6 months, then every 2–3 months as needed), azathioprine (2–3 mg/kg/d), and prednisolone (initial dose of 0.5 mg/kg/d, progressively tapered after remission) for BU was assessed via a 10-year follow-up. The results illustrated that visual acuity enhanced in 44% of affected eyes, posterior uveitis subsided in 73% of affected eyes, retinal vasculitis alleviated in 70% of affected eyes, and the overall disease activity index improved in 72% of affected eyes.

CYC undergoes hepatic and renal metabolism, with acrolein, a metabolite, potentially inducing hemorrhagic cystitis and bladder tumors. Sufficient hydration can mitigate and avert these effects. Commonly observed adverse effects of CYC, such as leukopenia, liver damage, and fertility impairment, are dose-dependent and frequently manifest at BU treatment doses [46]. During CYC therapy, patients with BU should undergo routine blood and urine tests and adjust dosage based on drug response and leukopenia levels. If the white blood cell count falls below 2.5/L, CYC should be discontinued. Most adverse effects are reversible, and the incidence and severity of adverse effects can be diminished through intravenous administration [38].

CHLORAMBUCIL:

The mechanism of action of chlorambucil parallels that of CYC, but it exhibits relatively milder, longer-lasting efficacy and fewer severe adverse effects. Consequently, chlorambucil can effectively treat patients with BU who are unresponsive to CYC. Not only does chlorambucil control uveitis and extraocular symptoms, such as oral ulcers and skin lesions in patients with BU, but it is also particularly suitable for those with severe extraocular manifestations, including central nervous system involvement and thrombotic venous inflammation. In China, chlorambucil is typically the preferred drug for BU treatment, while international guidelines deem it a second-line drug [47].

The dosing regimen for chlorambucil in BU treatment remains unstandardized. In China, Zhong et al [48] suggest an initial dose of 0.1 mg/kg/d for continuous treatment lasting 3 to 6 months, adjusting the dose based on patient tolerance and adverse reactions. The maintenance dose is 2 mg/d, with a treatment duration of 8 months to 2 years, typically necessitating treatment for over a year. Godfrey et al [49] propose an initial dose of 2 mg/d for 1 week, followed by a weekly increase of 2 mg until satisfactory efficacy is achieved or the dose reaches 10 to 12 mg/d. However, Hemady et al [50] contend that the maximum dose should not surpass 18 mg/d. Tessler et al [51] recommend an initial dose of 2 mg/d for 1 week, followed by a weekly increase of 2 mg, until satisfactory efficacy is attained or the platelet count declines to 1011/L. During the mediation process, the total blood cell count should be examined weekly, and once the blood cell count stabilizes, assessments should occur every 4 weeks. Notably, chlorambucil takes longer to manifest its effects, often requiring over 2 months to exert its full influence. Thus, the absence of apparent efficacy in early treatment stages does not necessarily indicate drug inefficacy. Treatment should persist for at least 3 to 5 months to determine effectiveness.

A retrospective study by O’Duffy et al [52] showed that chlorambucil (0.1 mg/kg/d) was more effective than GCS in treating BS, with an average treatment period of 1.8 years. Miserocchi et al [53] reported the treatment outcomes of 28 patients with chronic non-infectious uveitis (BU and juvenile idiopathic arthritis-associated uveitis) who had poor responses to GCS and other immunosuppressive agents. After using chlorambucil (8 mg/d) for 3 months, 82% of patients had stable or improved vision, 68% successfully discontinued GCS, 50% had stable disease after discontinuation, and 25% discontinued treatment due to severe adverse effects. These results suggest that chlorambucil has notable anti-inflammatory effects in patients with BU who are unresponsive to GCS and other immunosuppressive agents. However, due to its potential severe adverse effects, chlorambucil is not recommended as a first-line therapy [51].

The adverse effects of chlorambucil are comparable to those of CYC, including bone marrow suppression, gonadal dysfunction, liver and kidney damage, and gastrointestinal symptoms. Long-term use of chlorambucil can result in a decrease in sperm count or even azoospermia in men (usually occurring after 4 months of treatment) and can induce menopause or amenorrhea in women over 35 years of age. Thus, BU patients with reproductive requirements should exercise caution when taking this medication [37,38].

Antimetabolites

AZATHIOPRINE:

Azathioprine (AZA) is a T-cell-specific antimetabolite derived from 6-mercaptopurine. As a first-line corticosteroid-sparing immunosuppressant, AZA is commonly used in the treatment of BU [37,47]. After being converted into a prodrug, 6-mercaptopurine ribonucleotide, by 6-mercaptopurine nucleotide transferase, AZA can interfere with DNA replication and transcription, causing coding errors and inhibiting dividing immune cells, thereby exerting its immunosuppressive effects. Although AZA has inhibitory effects on T and B cells, its inhibitory effect on T cells is more pronounced.

AZA is typically administered orally and is not effective when used alone. It is often used in combination with low-dose GCS or cyclosporine and can serve as an alternative treatment for cyclosporine [38].The European League Against Rheumatism recommends the routine use of AZA in combination with GCS as the initial treatment regimen for BU patients with posterior uveitis, and for severe BU patients with vision-threatening symptoms, AZA in combination with tumor necrosis factor alpha inhibitors is recommended as the initial treatment regimen [47]. The usual dose of AZA is 1–3 mg/kg/d, with Mat et al [54] recommending a dose of 2.5 mg/kg/d. Typically, a starting dose of 50 mg/d is used, and the target dose of 2.5 mg/kg/d is gradually increased over 24 weeks, based on patient tolerance. If possible, genetic testing should be performed before starting AZA to determine whether the patient has a thiopurine methyltransferase gene mutation. It should be noted that AZA takes about 3 months to take full effect when observing its therapeutic efficacy [54].

Yazici et al [55] conducted a double-blind, randomized controlled trial that included 73 male patients with BS who were treated with AZA [2.5 mg/kg/d] or placebo and followed up for 2 years. The results showed that, compared with the placebo group, the AZA group had a significantly lower rate of BU relapse and AZA could alleviate anterior chamber inflammation, protect vision, reduce the incidence of new ocular disease, and prevent disease onset in healthy eyes. Additionally, AZA reduced the incidence of oral ulcers, genital ulcers, and arthritis in patients with BS. A study by Hamuryud et al [56] included 57 patients from the same trial and found that after an 8-year follow-up, patients treated with AZA had better visual prognoses and a lower risk of new ocular disease, especially those who started using AZA within 2 years of disease onset. This study indicated that AZA could significantly improve the long-term prognosis of patients with BU and that early use is more effective. Moreover, some studies have demonstrated the effectiveness of AZA in combination with other immunosuppressants, such as CYC, GCS, and CSA for BU treatment [45,57,58]

Common adverse effects of AZA in BU treatment include gastrointestinal symptoms, which are the main reason for discontinuation. Additionally, bone marrow suppression, liver damage, hypersensitivity syndrome, secondary infections, tumors, hair loss, and interstitial pneumonia can occur [38]. When used with allopurinol, the AZA dose should be reduced by more than 25%, due to allopurinol’s ability to inhibit mercaptopurine metabolism and enhance its toxicity. Combination therapy with AZA and IFN-α is not recommended as it can significantly increase the risk of leukopenia [59].

MYCOPHENOLATE MOFETIL:

Mycophenolate mofetil (MMF) is a selective inhibitor of T-cell and B-cell activation and proliferation derived from mycophenolic acid. It suppresses the synthesis of nucleic acids and proteins by inhibiting inosine monophosphate dehydrogenase, ultimately inhibiting lymphocyte adhesion and chemotaxis [37,38]. For BU treatment, MMF is typically administered orally at a dose of 0.5–2 g/d or 10–30 mg/kg/d. The usual starting dose is 500 mg twice daily, which is gradually increased to the target dose of 1000–1500 mg twice daily based on the patient’s tolerance [60]. MMF is commonly used in combination with low-dose GCS or calcineurin inhibitors, such as cyclosporine and tacrolimus, and has shown good therapeutic efficacy. As MMF has a similar mechanism of action to AZA, it is not recommended to use them together [37].

Sobrin et al [57] conducted a retrospective study from 1998 to 2006 using MMF to treat 85 patients with uveitis or choroiditis who were unresponsive to methotrexate. Results showed that MMF achieved inflammation control in 47 patients (55%), thereby confirming its efficacy in treating non-infectious uveitis. Additionally, Teoh et al [61] retrospectively analyzed the medical records of 100 patients with non-infectious uveitis (including 14 cases of Behçet disease) treated with MMF between April 1, 2000, and August 1, 2006. Results showed that MMF was efficacious in controlling inflammation and reducing the use of corticosteroids, with good tolerability.

Moreover, MMF can induce gastrointestinal reactions, such as nausea, vomiting, diarrhea, and loss of appetite, which can be mitigated by administering MMF suspension. Furthermore, MMF can lead to infrequent adverse effects, such as liver and kidney toxicity, bone marrow suppression, and heightened risk of infections and tumors, necessitating close monitoring [38].

METHOTREXATE:

Methotrexate is a folate analog that inhibits dihydrofolate reductase, blocking tetrahydrofolate synthesis and interfering with nucleic acid and protein synthesis. It further restrains the proliferation of T and B lymphocytes and endothelial cells. Methotrexate can also prevent the synthesis of leukotrienes by neutrophils and the release of histamine by mast cells. The evidence supporting the use of methotrexate in treating BU is inadequate, and it is generally used as a less toxic option in milder cases.

Methotrexate can be administered via different routes, including oral, intramuscular, intravenous, and intravitreal injection. Oral administration of methotrexate is characterized by easy absorption, and peak blood concentrations typically occur within 1 to 4 h. In contrast, peak blood concentrations after intramuscular administration generally occur within 0.5 to 2 h. When taken orally, more than 35% of the drug is metabolized by intestinal bacteria, while non-intestinal routes of administration can result in 100% absorption of the drug.

The methotrexate dosage for BU treatment follows the same oral regimen as that for rheumatoid arthritis. Typically, methotrexate treatment starts at 15 mg/week, gradually increasing to a target dose of 25 mg/week, based on patient tolerance. After the disease stabilizes, the maintenance dose is lowered to 15 mg/week. Some researchers have recommended an initial dose of 40 mg of methotrexate administered intravenously per week, followed by a switch to oral administration of 15 mg/week once the disease stabilizes. Several intravitreal methotrexate injection regimens are available for BU treatment, with the standard protocol involving twice-weekly injections of 400 mg (0.1 mL) for 4 weeks, once-weekly injections for 8 weeks, or monthly injections for 9 months.

Davatchi et al [62] conducted a 15-year follow-up study of 682 patients with BU and found that the combination therapy of methotrexate (7.5–15 mg/week) and prednisolone (0.5 mg/kg/d) was effective in treating uveitis. The improvement rates for visual acuity score, posterior uveitis, retinal vasculitis, and overall disease activity index were 47%, 75%, 54%, and 69%, respectively. Notably, posterior uveitis showed more significant improvement than did retinal vasculitis. Although the improvement in vision was slight, it was mainly due to secondary cataracts. Furthermore, several small studies have demonstrated the efficacy of low-dose oral methotrexate in the treatment of BU [34,63].

Studies on intravitreal methotrexate for BU treatment are limited, and its efficacy and safety require further evaluation, as potential adverse reactions like corneal endothelial damage and decompensation need to be closely monitored [64,65]. In a study by Taylor et al [66], 15 patients with non-infectious uveitis were treated with intravitreal injection of methotrexate 400 ug/mg (0.1 mg) with or without cystoid macular edema. After 3 to 6 months of treatment, the mean visual acuity improved by 4 to 5 lines compared to pre-treatment (P<0.05), with no significant difference in visual improvement compared to the previous use of GCS or IVTA. These findings suggest that this therapy can improve visual acuity and reduce cystoid macular edema, thereby decreasing the need for GCS. The median time to BU recurrence was four months, but repeated injections of methotrexate can achieve similar efficacy. In a study by Khalil et al in 2016 [67], the efficacy of intravitreal methotrexate injection was compared with posterior sub-Tenon injection of triamcinolone acetonide in controlling uveitis and inducing remission in patients with BU. The results showed that intravitreal methotrexate injection had better therapeutic effects and could maintain inflammation remission for a longer duration than could triamcinolone acetonide injection.

The adverse reactions of methotrexate are generally milder than that of other immunosuppressants and GCS. Common adverse reactions include bone marrow suppression, hepatotoxicity, pulmonary toxicity, gastrointestinal reactions, alopecia, and dermatitis. During methotrexate treatment, supplementing folic acid (1 mg/d) or folinic acid and regularly monitoring of blood routine and liver function is important to prevent hematological diseases and other complications. Additionally, the effect of methotrexate on the reproductive system should be monitored. Methotrexate can decrease sperm count in men, and it generally takes more than 3 months to return to normal after discontinuation of the drug. Due to the teratogenicity of methotrexate, pregnant and lactating women should not use it.

Calcineurin Inhibitors

CYCLOSPORINE A:

Cyclosporine A CSA, an 11-amino acid lipophilic cyclic peptide derived from fungi, is a macrolide antibiotic exhibiting specific immunosuppressive properties. Frequently used in the treatment of BS, CSA surpasses other cytotoxic drugs and GCSs in immunosuppressive efficacy, without compromising fertility or inducing bone marrow suppression [68]. Upon administration, CSA forms a complex with cyclophilin, inhibiting calcineurin activity and interfering with T-cell nuclear factors, subsequently obstructing mRNA formation and impeding antigen-induced T-cell activation signal transduction. Consequently, T-cell activation is inhibited, along with the expression of cytokines, such as IL-2 and IFN-α, and anti-apoptotic proteins [69]. Widely used in the prevention and treatment of immune rejection responses following organ or bone marrow transplantation, CSA has demonstrated effectiveness in managing severe BS patients with recurrent attacks, particularly those intolerant to the reproductive toxicity of other immunosuppressive agents. CSA has also proven efficacious in treating BS-associated ocular manifestations, including oral ulcers, genital ulcers, and skin lesions [70–72].

For BU treatment, CSA is typically administered orally at a lower dose than that used for immunological rejection prevention after organ transplantation. The standard initial dose is 3 to 5 mg/kg/d, which can be gradually decreased to a maintenance dose of 2 mg/kg/d once disease stabilization is achieved. Abrupt withdrawal should be avoided to prevent rebound phenomena. Treatment duration generally exceeds 8 months, as short-term therapy is often ineffective, and unanticipated treatment interruptions can render uveitis difficult to control [60,73]. Low-dose CSA combined with low-dose GCSs (0.2–0.4 mg/kg) constitutes the preferred treatment for BS uveitis, exhibiting increased efficacy and reduced nephrotoxicity, compared with CSA monotherapy [74]. Potassium supplementation is usually unnecessary when combined with GCSs, given the potassium-sparing properties of CSA, and potassium-containing medications or potassium-retaining diuretics should be avoided. In cases of suboptimal therapeutic response, the addition of alkylating agents (chlorambucil, CYC) or AZA can be considered [43,44,75–78]. CSA and colchicine are often used concomitantly for retinitis and retinal vasculitis resulting from BS, but caution is warranted due to their potent neurotoxicity. CSA and FK506 share similar mechanisms of action, and their concurrent use can substantially elevate adverse effects; thus, they should not be administered together.

The body of research concerning CSA monotherapy for BU remains limited. In a 3-year randomized, double-blind trial, Benezra et al [75] compared conventional treatments (GCS or chlorambucil) with CSA treatment in 40 patients with BU, discovering that CSA proved more effective in managing ocular lesions but less effective in addressing joint, skin, and mucosal lesions. Two randomized, single-blind trials conducted by Zyazgan in 2002 [79] and Akman [80] in 2008, respectively, determined that CSA exhibited greater efficacy in reducing intraocular inflammation and enhancing vision in patients with BU, compared with CYC, during a 6-month follow-up period [43,80]. Furthermore, multiple studies have demonstrated the superiority of CSA in treating recurrent BU over colchicine, GCS, and chlorambucil [81,82].

Two studies [71,83] have established that combining CSA with GCS elicits a robust anti-inflammatory effect, leading to improved visual acuity and reduced frequency and severity of relapses. This combination therapy has demonstrated greater efficacy and lower renal toxicity than CSA monotherapy, with the protective effect on vision lasting for over 4 years [74]. In recent years, as biologics have gained prominence in BU treatment [76], studies have indicated that combining CSA with infliximab can achieve superior efficacy than can infliximab monotherapy [84].

CSA, a prevalent immunosuppressant for BU treatment, has proven effective in controlling ocular inflammation and improving visual acuity. The combination of CSA and GCS delivers a more potent anti-inflammatory effect and superior efficacy with reduced renal toxicity than does CSA alone. However, the extensive use of CSA is limited by its severe adverse effects, including renal function impairmen [78], which is typically reversible in early stages but can cause irreversible glomerular damage over time [37,38]. Consequently, regular blood tests and kidney function monitoring are advised during treatment [38,85].

Another frequent adverse effect of CSA is hypertension, which is usually reversible and dose-dependent. Approximately 15% to 27% of patients experience hypertension with doses below 5 mg/kg/d [71,86]. When combined with steroids, CSA is more likely to induce hypertension. Neurotoxicity is also common, complicating the distinction from neurological Behçet disease and potentially increasing the incidence of neurological disorders [80,87–89]; thus, patients with pre-existing neurological diseases should avoid CSA [90]. Other adverse effects encompass gastrointestinal reactions, anemia, abnormal limb sensations, hair growth, and gum hyperplasia. Concurrent NSAID use can elevate the risk of secondary infections and lymphoproliferative disorders.

Prior to CSA administration, complete blood cell counts, blood urea nitrogen, serum creatinine, creatinine clearance, liver function tests, and baseline blood pressure measurements are essential. During treatment, regular follow-up visits are recommended for timely dosage adjustments or medication discontinuation if severe adverse effects occur. No significant correlation between CSA and mortality has been identified in patients with BU [91].

TACROLIMUS:

Tacrolimus (FK506), an immunosuppressive agent derived from Streptomyces tsukubaensis, is used to treat autoimmune diseases and organ transplant rejection. It has also demonstrated effectiveness in treating refractory BU, particularly for extraocular and gastrointestinal symptoms [92]. The drug’s immunosuppressive effect is achieved through competitive calcineurin binding, inhibiting T-cell activation and cytokine production by forming a complex with the intracellular protein FKBP12. The mechanism of action of FK506 is akin to that of CSA, but FK506 is more potent and possesses superior safety, with a binding strength 10 to 100 times greater than that of CSA [93].

In contrast to the intravenous administration used in post-transplantation immune rejection therapy, oral administration is generally favored for BU management with FK506. The recommended dosage typically spans from 0.05 to 0.15 mg/kg/d, which can be divided into 2 doses, or alternatively, begins with an initial dose of 2 mg/d and incrementally increases until the blood drug concentration reaches 5 to 10 μg/L, then that dose is maintained. After the stabilization of the patient’s condition, dosage reduction can be gradually initiated. Figueroa et al [94] conducted a prospective study of 11 patients (21 eyes) with autoimmune uveitis, including 2 with BU, administering FK506 (with a blood drug concentration of 7–10 ng/mL). The mean follow-up period was 45 months. Results revealed a significant decrease in the annual frequency of relapses (from 3.2 to 1.29, P=0.021) and complete control of inflammation in 6 eyes (54.5%), without the necessity of other medications. Furthermore, 16 eyes (76%) maintained stable vision, while 1 eye (5%) improved, and 4 eyes (19%) displayed decreased vision. No severe adverse effects requiring drug cessation were observed. This study suggests that FK506 is efficacious and well-tolerated in controlling autoimmune uveitis.

Although FK506 exhibits more potent pharmacological effects than does CSA, it is associated with fewer adverse effects. A randomized trial comparing CSA and FK506, conducted by Murphy et al [95], demonstrated similar efficacy between the 2 drugs, with CSA presenting more frequent adverse reactions. Common adverse reactions linked to the use of FK506 encompass liver and kidney function impairment, neurotoxicity, hypertension, hyperlipidemia, and hyperglycemia [38].

Future Directions

Despite the progress made in understanding the pathogenesis of BU and the development of novel immunosuppressive agents, current research primarily relies on case reports and small sample cohort studies. To decisively enhance the evidence base regarding the efficacy and safety of current and emerging immunosuppressive agents for BU, it is imperative to conduct large-scale, double-blind, randomized controlled trials. Such rigorous scientific inquiry will solidify our understanding and provide robust evidence to support therapeutic decisions.

Furthermore, investigating the molecular mechanisms underlying BU pathogenesis is vital for the identification of novel therapeutic targets. This exploration is expected to lead to the development of treatments that are more effective and safer, thereby revolutionizing patient care.

Central to advancing BU management is the adoption of a personalized medicine approach. Tailoring treatment protocols to align with the unique disease manifestations, genetic predispositions, and therapeutic responses of each individual holds the promise of significantly enhancing therapeutic efficacy. Concurrently, this approach aims to minimize adverse effects, culminating in an improved prognosis and heightened quality of life for those with BU [96].

Moreover, future investigations should consider the synergistic potential of integrating conventional immunosuppressive drugs with biological agents, especially the role of interferon-alpha and anti-tumor necrosis factor alpha therapies. This innovative strategy aspires to refine therapeutic outcomes by reducing the incidence of adverse effects [97].The ultimate objective is to elevate patient well-being through treatments that are not only more effective and safer but are also meticulously customized.

Lastly, the fortification of interdisciplinary collaboration stands as a cornerstone for optimizing therapeutic outcomes. By fostering a holistic, patient-centered care model, this cooperative approach ensures that treatment strategies are comprehensive, encompassing the full spectrum of patient needs to enhance overall well-being.

Conclusions

In conclusion, the management of BU necessitates a personalized and multidisciplinary strategy, reflecting the disease’s complexity and the variability in treatment responses. This review highlights the critical importance of customized immunosuppressive strategies in improving therapeutic outcomes and the quality of life for patients with BU. It underscores the necessity of selecting appropriate immunosuppressive agents tailored to individual patient factors, in conjunction with a collaborative effort among specialists, to optimize efficacy while minimizing adverse effects.

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