Current Knowledge of Biologics in Treatment of Noninfectious Uveitis

Abstract

The arena of uveitis deals with a number of entities, which can be infectious or immune mediated. Noninfectious uveitis (NIU) has been managed with corticosteroids and immunosuppressives. However, their prolonged use has side effects limiting clinical utility in the long run. Improved knowledge regarding pathogenesis of uveitis and associated systemic disease has led to a new epoch in the development of treatment strategies, of which biologics are the recent ones. Biologics revolutionized the management of NIU especially uveitis associated with spondyloarthropathy and refractory uveitis. They target inflammation at a molecular level with less side effects. The most widely used are tumor necrosis factor-alpha inhibitors (infliximab and adalimumab). Other drugs include anti-CD20 inhibitors (rituximab), interleukin-6R-inhibitor (tocilizumab), Interleukin-1R-inhibitor (anakinra), Iinterleukin-2-inhibitor (daclizumab), and the list is further increasing. New advances in biologics are the biosimilar molecules, which are biological products that are highly similar to the reference product, and they include Infimab (biosimilar of infliximab), Exemptia or Adfrar (biosimilar of adalimumab), and Intacept or Etacept (biosimilar of etanercept). Other group of biologics are Janus Associated Kinase inhibitors (JAK-inhibitors), which are long-term oral treatment options of rheumatoid arthritis. They inhibit JAKs, which cause activation of signal transducer and activator of transcription (STAT) proteins, and initiate transcription of inflammatory genes. Many inflammatory cytokines that are implicated in pathogenesis of ocular inflammation are known to utilize the JAK/STAT-signaling pathway, including interleukin-2 (IL-2) and IL-6. Thus, biologics are the future of uveitis treatment with promising results. This article aims to summarize the current knowledge on biologics and their clinical utility in the management of NIU.

Introduction

Uveitis embraces a group of intraocular inflammatory diseases, which accounts for ∼5%–20% of legal blindness in Western countries and 25% in the developing countries.¹ However, a larger population-based study from Northern California stated that the incidence of uveitis was much higher compared with that reported prior, and it was rising with the increasing age of the patients.² The noninfectious entity of uveitis are ocular immune-mediated inflammatory diseases, either isolated or a part of systemic diseases, such as HLA-B27-related spondyloarthropathies, Behcet's disease (BD), sarcoidosis, or juvenile-related arthritis (JIA).^3,4 Corticosteroids have been used as conventional first-line therapy outrightly for all cases of noninfectious uveitis (NIU), but these drugs have serious side effects.⁵ This led to the use of immunomodulatory drugs, of which biologics form a major part.^6,7

This article provides an updated comprehensive literature on the use and clinical studies of current biologics in treatment of recalcitrant NIU.

A stepladder approach is followed for treating NIU. Corticosteroids are the first-line drugs followed by conventional immunomodulators like methotrexate (MTx), mycophenolate mofetil, and azathioprine as second-line therapy.^8,9 However, in many cases patients are still not responsive and have side effects¹⁰ (Table 1). The next group are biologics, which are also known as biologic response modifiers target cellular receptors and cytokines in inflammatory cascade, such as TNF-α, Interleukins (IL), B and T-lymphocytes, and are increasingly being used in uveitis as depicted in Table 2.^11–13

Table 1.

Conventional Systemic Immunosuppressive Agents for Treatment of Noninfectious Uveitis (7)

Drug	Mechanism of action	Dose	Side-effects
Methotrexate	Inhibits dihydrofolate reductase	7.5–25 mg/week PO, SC or IM	GIT disturbance, hepatotoxic, alopecia, bone marrow suppression, pneumonitis, and infections
Azathioprine	Inhibits purine metabolism	1–4 mg/kg/day PO	GIT disturbance, hepatotoxic, alopecia, bone marrow suppression, hypersensitivity, and infections
Mycophenolate mofetil	Inhibits inosine monophosphate dehydrogenase	500–1,500 mg PO twice a day	GIT disturbance, bone marrow suppression, and infections
Cyclosporine	Inhibits T cell function	2.5–10 mg/kg/day PO twice a day	Nephrotoxic, hypertension, hirsutism, gingival hyperplasia, and infections
Tacrolimus	Inhibits T cell function	0.15–0.30 mg/kg/day PO	Nephrotoxic, hypertension, diabetes, and infections
Chlorambucil	Alkylates nucleic acid	0.1–0.2 mg/kg/day PO	Bone marrow suppression and infections
Cyclophosphamide	Alkylates nucleic acid	1–3 mg/kg/day PO	Bone marrow suppression and infections, hemorrhagic cystitis, alopecia, and sterility

PO, per oral; SC, subcutaneously; IM, intramuscularly.

Table 2.

Selected Biologic Drugs

Generic names	Specific target	Route	Dosage	Side effects	Monitoring
TNF-inhibitors					1. Complete systemic evaluation by a physician is important to rule out congestive heart failure, demyelinating diseases, malignancies, and infections. 2. Hematological analysis should be done before initiation of biologics and at the interval of 3 months while on biologics. 3. Liver and renal function tests, and glucose should be performed before starting therapy, and then every 3–6 months while on treatment. 4. TB skin test, QuantiFERON-TB gold or chest X-ray should be done annually in patients on biologic therapy 5. HIV and hepatitis B and C before starting the therapy 6. Patients on anti-TNF therapy should receive pneumococcal, influenza, and hepatitis B vaccines. However, it is contradicted to have live virus vaccines in patients started with anti-TNF therapy. 7. Monitoring of complete blood counts, comprehensive metabolic profiles are performed at all IFX or daclizumab infusions and antinuclear antibody is performed at IFX infusions. 8. For ADA, usually monitor laboratories monthly at the outset of therapy and as needed for concomitant drugs thereafter, or every 6 months.
Infliximab	TNF-α	IV	5–10 mg/kg at baseline, 2nd and 6th week and then every 4–8 weeks	Headache, abdominal pain, rash, pneumonia, urinary tract infections, and reactivation of latent tuberculosis
Adalimumab	TNF-α	SC	Initial dosage of 80 mg followed by 40 mg every 2 weeks	Localized allergic reactions and headache. Severe side effects include malignancy, thrombolytic events, and congestive heart failure, and reactivation of tuberculosis
Etanercept	TNF-α & β	SC	0.4 mg/kg twice a week	Worsens uveitis course or even induce inflammation as a paradoxical effect, Rashes, diarrhea, infection
Golimumab	TNF-α	SC	50 mg per month	ANA positivity, development of infections
Certolizumab	TNF-α	SC	400 mg every week	Nausea, infections
Anti-interleukin (IL) therapy
Anakinra	IL-1 receptor	SC	100 mg/day	Headache, vomiting Antibody development, allergic reactions, fever, nasopharyngitis
Tocilizumab	IL-6 receptor	IV	4 mg/kg every 4 weeks	Increased serum cholesterol, alanine, aminotransferase levels, injection site reaction
Lymphocyte inhibitors
Rituximab	B cells (CD20)	IV	375 mg/m² body surface per week for 8 weeks and then every 4 weeks for 4 months	Infusion reactions, GIT disturbance, hepatotoxic, myelosuppression, progressive multifocal leukoencephalopathy, Cardiovascular, fatigue, pruritis, nausea, urinary tract infections, antibody development, and pulmonary disease
Abatacept	T cells (CTLA-4)	IV	0.5–1 g at loading, 1.25 g at week 0, 2, and 4 and then every 4 weeks	Headache, nausea, Nasopharyngitis, infections
Basiliximab	T cells (IL-2Rα; CD25)	IV	40 mg IV at weeks 0, 2, 4, 8, and 12	GIT disturbance, infections, night sweats, flu-like illness, skin rashes
Daclizumab	T cells (IL-2Rα)	IV, SC	1–2 mg/kg every 2 or 4 weeks	GIT disturbance, infections, night sweats, flu-like illness, skin rashes
Specific receptor antagonist
Gevokinumab	IL-1β	IV, SC	60 mg every	GIT disturbance, hepatotoxic, alopecia, headache, infections, gastrointestinal complications, hypercholesterolemia, ANA positivity, infections, nasopharyngitis
Secukinumab	IL-17	IV	300 mg/kg
Ustekinumab	Anti-IL-12, Anti-IL-23	SC	45 mg at weeks 0 and 4 and every 12 weeks
Tocilizumab	IL-6R	IV	Initially 4 mg/kg once at every 4 weeks
Canakinumab	IL-1β	IV, SC	150 mg for 6 weeks
Alemtuzumab	Anti-CD52	IV	30 mg, thrice a week for 12 months
Efalizumab	Anti-CD11	SC	0.7 mg/kg followed by 1 mg/kg weekly
Sarilumab	IL-6R	SC	200 mg once every 2 weeks
Vedolizumab	Integrin α4β7	IV	300 mg
Interferons (IFN)	No specific target	SC	3–6 million units daily with slow taper	GIT disturbance, hepatotoxic, alopecia, myelosuppression, depression, abnormal thyroid function, and infections
Janus kinase inhibitors (JAK) Tofacitinib	JAK1–3	PO	10 mg/d	GIT disturbance, hepatotoxic, anemia, hypertension, thromboembolism
Intravenous immunoglobulins	—	IV	1.5–2.5 g/kg across 3 days	Fever, eczema, hypertension, thrombosis

IV, intravenously; R, receptor.

TNF-α inhibitors

TNF-α is produced by macrophages and neutrophils, which participate in the pathogenesis of autoimmune uveitis.^14–18 TNF-α comprises of FDA-approved drugs like infliximab (IFX), etanercept, adalimumab (ADA), certolizumab pegol (CZP), and golimumab (GLM).

IFX is a chimeric monoclonal IgG1 antibody that inhibits both membrane-bound and circulating soluble form of TNF-α, which disrupts its interaction with its receptor.^19,20 It is the most commonly used biologic agent for uveitis.^21–26 Kruh et al. established its efficacy for managing refractory-NIU (idiopathic, JIA, sarcoidosis, BD, birdshot chorioretinopathy, n = 88) where 82% patients achieved clinical remission and 58% patients required additional immunomodulators.²⁴ IFX treatment induces formation of autoantibodies in BD, which may have clinical significance in forecasting the recurrence of ocular attacks with long-term treatment.^27,28 Previous studies have shown that children with chronic NIU on high-dose IFX (10–20 mg/kg/dose) well tolerated the drug and there was rapid control of intraocular inflammation after second infusion.^26,29–34

ADA is a recombinant, fully humanized immunoglobulin against TNF-α. It acts against soluble form of TNF and neutralizes its biological function.³⁵ It was first FDA approved for RA in 2002. Later on, approved for JIA, CD, AS, ulcerative colitis (UC), plaque psoriasis, sarcoidosis, and associated uveitis.^36–38 The use of ADA in the treatment of JIA with chronic uveitis has been well established in children, even in patients who are nonresponsive to previous other anti-TNF therapy like IFX or Etanercept.^39–41 Two cases of severe idiopathic noninfectious pediatric panuveitis, unresponsive to traditional therapy, were effectively treated with ADA in the long term with no observed side effects.⁴²

Another prime case report was reported in a 41-year-old patient who initially presented as multifocal choroiditis but later found to have features compatible with acute zonal occult outer retinopathy resistant to standard immunosuppression. It responded well only to ADA therapy.⁴³ A multicenter study with JIA-uveitis called SYCAMORE trial was done to assess the effectiveness of ADA in combination with MTx, as described in Table 3.^44–46

Table 3.

Important Trials of Various Biologic Drugs

Drug	Trial/Study	Number of patients (n)	Disease	Method	Results
Adalimumab (ADA)	Sycamore trial	154	Active JIA-associated uveitis	Methotrexate was given for 12 weeks and in addition either ADA 20 mg/0.8 mL for patients <30 kg or 40/0.8 mL for 30 kg or more; or s/c injection every 2 weeks	Treatment failure occurred in 60% in the Methotrexate-only group and 27% in the ADA group at 18 months of follow-up
	Visual I	233	Active NIU	Intervention: ADA (40 mg every other week)Comparator:placeboConcomitant: oral pred 60 mg/d tapered to 0 mg by week 15 (100%) immunosuppressant (32%)	Time to treatment failure was 24 weeks for the patients treated with ADA and placebo;After 18 months, the ADA group had 50% reduction in the risk of treatment failure compared with placebo
	Visual II	229	Inactive NIU	Intervention: ADA (40 mg every other week)Comparator: placeboConcomitant: oral pred 10–35 mg/d tapered to 0 mg by week 19 (100%) immunosuppressant (47%)	Time to treatment for failure for the ADA group was 18 months, compared with 8.3 months for the placebo group, with 43% risk reduction of treatment failure at 18 months for ADA-treated patients.
	Visual III	Patients who completed Visual I and II	Both	Patients received adalimumab 40 mg every other week. Interim follow-up data were described from VISUAL III weeks 0 through 78	Patients with active uveitis at study entry who received adalimumab therapy were likely to achieve quiescence, improve visual acuity, and reduce their daily uveitis-related systemic corticosteroid use.Most patients with inactive uveitis at study entry sustained quiescence without a systemic corticosteroid dose increase.
Certolizumab pegol (CZP)	RAPID 1 and 2(Rheumatoid Arthritis Prevention of structural Damage)	982/619	RA	CZP versus placebo, plus methotrexate (MTX), in patients with active RA.RAPID1: subcutaneous CZP (400 mg at weeks 0, 2, and 4; followed by CZP 200 mg or 400 mg) plus methotrexate (MTX) every other week, or placebo plus MTXRAPID2: subcutaneous CZP (liquid formulation) 400 mg at weeks 0, 2, and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks.	CZP inhibits progression of structural damage with improvement in quality of life in patients with RA who failed treatment with MTx
	FAST4WARD	220	RA	Subcutaneous CZP 400 mg (n = 111) or placebo (n = 109) every 4 weeks.	Treatment with CZP 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing > or = 1 biologic compared with placebo, and demonstrated an acceptable safety profile.
	C-VIEW	89	active axSpA,human leukocyte antigen-B27 HLA-B27 positivity	Effect of CZP 400mg in AAUflares in patients with active axSpA with high risk of anterior uveitis	During 48 weeks' CZP treatment, 13 (15%) patients experienced15 AAU flares, representing an 87% reduction in acute anterior flare (AAU)incidence rate; significant reduction in the AAU flare rate during 48 weeks of CZP treatment
Tocilizumab (TCZ)	STOP-uveitis	37	Noninfectious intermediate uveitis, posterior uveitis, or panuveitis.	Group 1 received IV infusions of 4 mg/kg TCZ;Group 2 received IV infusions of 8 mg/kg TCZ.Infusions were given every 4 weeks in both groups until month 6 (primary endpoint)	Significant improvement in mean change in visual acuity, vitreous haze, and central macular thickness. Repeated IV administrations of TCZ are well tolerated. Both the doses 4 and 8 mg/kg were found to be effective
	Aptitude	21	Acute JIA	Patients weighing 30 kg or more were treated with 162 mg subcutaneous TCZ every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks.	Seven of 21 responded to treatment (P = 0.11).Safety results were consistent with the known safety profile of tocilizumab.

JIA, juvenile idiopathic arthritis; NIU, noninfectious uveitis; RA, rheumatoid arthritis.

The role of anti-TNF-α in managing HLA-B27-associated uveitis has been established in multiple studies,^47,48 but the literature in India is sparse. Lakra et al. presented the first case series from India, which retrospectively analyzed the efficacy of ADA and GLM in refractory cases of HLA-B27-associated uveitis.⁴⁹

TNF-α blockers also work in sarcoidosis having refractory posterior uveitis to steroid and/or MTx and found to have total resolution of cystoid macular edema and decrease in dosage of steroid.^50,51 Two randomized phase III trials, Visual I and Visual II, ended up in FDA approval for ADA in treatment of NIU with significant visual outcomes, as described in Table 3.^52–56 Recently few studies have compared the efficacy of ADA versus IFX and established similar efficacy of both in controlling uveitis relapses.^57–59 One of them showed ADA with better outcomes than IFX after 1 year of follow-up.⁵⁸ In contrast to this, another study showed IFX with more pronounced corticosteroid-sparing effect when compared with ADA.⁵⁹ However, ADA reflected better efficacy and safety profile than IFX for refractory JIA-associated uveitis at 2 years of follow-up.⁶⁰

Etanercept is a dimeric protein that is part-TNF-α receptor and part-Fc molecule of IgG. It prevents TNF from binding to cell-surface receptors. It is effective in RA, JIA, AS, and psoriasis with favorable outcomes in resistant uveitis.^61,62 However, its lower efficacy than IFX or ADA has been reported in some studies,^63,64 but it may rather have proinflammatory effect in triggering uveitis.^62,65–67 So, patients started on etanercept can be counseled for switching to IFX or ADA if possible.

GLM is a novel fully humanized monoclonal antibody directed against TNF-α. It is approved for the treatment of moderate-to-severe active RA, AS, and psoriasis.⁶⁸ Little is known about the use of GLM for JIA, BD, HLA-B27-associated uveitis and idiopathic retinal vasculitis.^69–72 In a multicenter study of patients with ankylosing spondylitis-associated uveitis, reduction in the rate of uveitis recurrence and disease activity was noted with GLM. Notably, a study in 8 eyes with uveitis, treated with GLM, showed reduction in intraocular inflammation in 7/8 eyes at 12-months follow-up.⁷¹

CZP is an anti-TNF monoclonal antibody that contains Fab fragment, which is bound to polyethylene glycol. There are limited studies on the efficacy of certolizumab in uveitis. Favorable results have been noted in rheumatoid arthritis, spondyloarthropathies, and Crohn's disease 3.^73,74 In a case report, a 47-year-old woman with RA and scleritis who was not tolerating other TNF-α antagonists was administered CZP and helped in managing recalcitrant RA and scleritis.⁷⁵ Trials related to this drug are Rheumatoid Arthritis Prevention of structural Damage (RAPID 1 and 2) and the Efficacy and Safety of certolizumab pegol-4 Weekly dosage in Rheumatoid arthritis (FAST4WARD) and C-VIEW have been described in Table 3.⁷⁵ CZP is capable of causing improvement in visual function, even if previously treated with other anti-TNF-α.^76,77

Under side effects of TNF-α, one of the dire consequences of biologics is the reactivation or primary tuberculosis infection, therefore patients should be screened for infectious cause before starting on biologics.^78–82 The psoriasis-form skin conditions have been reported in psoriasis treated with TNF-α inhibitors. Malignancies were also reported, such as leukemia, lymphoma, and melanoma. Important side effects are listed in Table 2 with special mention to monitoring of drugs before and after commencement of biologics in a patient.

ESBA105 is a potent inhibitor of TNF-α made up of a single-chain antibody fragment. Due to its small size, it has better penetration through the corneal surface.⁸³ So, given topically it could achieve therapeutic intraocular levels with a favorable safety profile.^84,85 A phase II exploratory study has wrapped up the role of topical ESBA105 in acute anterior uveitis; however, the results have not been published yet (NCT00823173).⁸⁶

Anti-inflammatory cytokines

Anakinra (ANA) is a competitive inhibitor of IL-β1 receptor and inhibits IL-1-mediated inflammation. It has been approved for RA, BD, and chronic infantile neurological cutaneous articular (CINCA) syndrome.^87–93 The CINCA syndrome is associated with childhood chronic uveitis and papillitis due to mutation in CIAS1 gene (encodes cryopyrin) and result in IL-1 upregulation. ANA has shown successful results in posterior uveitis in CINCA syndrome, which responded poorly to steroids, MTx, and Etanercept.^90–93 Lately, in a case of HLA-B27 positive with multiple sclerosis-associated uveitis, ANA has shown a beneficial effect.⁹³

Tocilizumab (TCZ) is a monoclonal antibody directed against IL-6 Receptor and is approved for RA, vasculitis, and JIA, including refractory cases.^94,95 The outcomes of randomized clinical trial STOP-Uveitis were presented, which compared 2 doses of TCZ (4 and 8 g/kg monthly) and showed it a safe drug in treating NIU (Table 3).^96,97

Few clinical trials showed effectiveness of TCZ when switched route of administration from TCZ-intravenous (IV) to subcutaneous (SC).⁹⁷ In contrast to this, 4 patients with JIA-associated chronic uveitis reported sustained clinical response with TCZ-IV and experienced early flares after switching to TCZ-SC.⁹⁸ TCZ is efficient in reducing macular thickness in refractory cases.^99–106 In a retrospective case series of 25 patients, most patients had CME in both eyes and TCZ was used as monotherapy (n = 11) or combined with conventional immunosuppressive drugs.

Regardless of the underlying disease {JIA (n = 9), BD (n = 7), birdshot retinochoroidopathy (n = 4), idiopathic (n = 4), and sarcoidosis (n = 1)}, a statistically significant improvement in macular thickness (P = 0.00009), and visual acuity (P = 0.0002) was obtained, along with reduction in the daily dose of prednisone after 12 months.¹⁰² The results of the multicenter phase II APTITUDE study assessed the safety of TCZ in JIA-associated uveitis refractory to ADA and MTx. Despite negative primary outcome, the TCZ was found beneficial in few cases especially in those with baseline macular edema.^94,103,104 TCZ is an effective option for reduction of disease activity in children with refractory nonanterior uveitis.¹⁰⁵

Daclizumab is a monoclonal antibody against IL-2 receptor, which is expressed by T cells and thus, prevent their IL-2-dependent activation. In a long-term (>4 years) Phase I/II trial using intravenous daclizumab and a short-term Phase II study evaluating use of SC daclizumab for severe-uveitis established that long-term daclizumab therapy could be given in-lieu of standard immunosuppression for years in uveitis associated with JIA and refractory birdshot-retinochoroidopathy.^106–110 However, this drug failed to show positive results in BD-associated uveitis.¹¹¹ Considering its serious side effects like liver dysfunction and inflammatory brain disorders, the drug was withdrawn from the market worldwide in 2018.¹¹²

Ustekinumab targets the p40 subunit shared by both IL-23 and IL-12.¹¹³ Increased levels of IL-23 have been seen in the serum from patients with active Vogt–Koyanagi–Harada (VKH) and BD-associated uveitis when compared with patients with inactive uveitis; similar reports are seen in patients with spondyloarthropathy, psoriatic arthritis, and active sight-threatening uveitis.^113–118 Preliminary reports of a nonrandomized, uncontrolled open-label pilot study STELARA (ClinicalTrials.gov identifier: NCT02911116) evaluated ustekinumab in NIU and showed evidence of benefit with no significant adverse effects.¹¹⁹ A phase II clinical trial open-label study (STELABEC 1/2) is currently ongoing for patients with BD-associated uveitis (ClinicalTrials. gov Identifier: NCT02648581).⁸⁶ Another phase II trial is ongoing for those with severe NIU (USTEKINISU; NCT03847272).¹²⁰

Guselkumab is an anti-IL-23 drug. Phase III trials for tildrakizumab and guselkumab are successful in the treatment of psoriasis and showed significant benefit from switching to guselkumab.^121–123 There are currently no reports/ongoing clinical trials on the efficacy of this drug in uveitis, and moreover a case with poorly controlled sarcoidosis-related panuveitis showed worsening of uveitis with this drug.¹²⁴ Other anti-IL-23 drugs under study are brazikumab for CD (ClinicalTrials.gov NCT01714726)¹²⁵; risankizumab for psoriasis and CD ,^126,127 and ixekizumab for psoriatic arthritis.¹²⁸ Of late, anti–IL-23 studies have shown paradoxical worsening of symptoms in few odd cases.¹²⁹ Consequently, further studies are required to establish their safety.

Sarilumab is a human IgG1 monoclonal antibody, which binds to IL-6 receptor and inhibits IL-6-mediated inflammatory signals.¹³⁰ It has been FDA approved for RA in 2017. Sarilumab has shown superior clinical efficacy compared with MTx or ADA monotherapy in RA.^131–133 A multicenter Phase II Study was conducted to analyze efficacy of sarilumab in NIU (SARIL-NIU-SATURN) and suggested improvement in macular edema and vision especially in patients who reported worsening of symptoms, despite ongoing treatment with systemic corticosteroids or immunomodulatory therapy.¹³⁴ In contrast to the aforementioned positive results, this drug did not present as an effective treatment in patients with active AS.¹³⁵

Other Anti-IL-6 biologics are olokizumab and clazakizumab, which have been studied in clinical trials for RA refractory to MTx/anti-TNFs, showed significant improvements in disease activity, but the role in uveitis is yet to be explored.^136,137

Gevokizumab is a humanized monoclonal antibody that binds to IL-1β.¹³⁸ It has been granted status of an orphan drug by the FDA for refractory uveitis. Initial studies showed positive response in treating NIU secondary to BD without the need for high-dose corticosteroids.¹³⁹ Three phase III clinical trials were done to assess its role in patients with active NIU (EYEGUARD-A), BD (EYEGUARD-B), and controlled (EYEGUARD-C). The major outcomes included control in exacerbations, reduction in vitreous haze, and inflammation. While the EYEGUARD-B failed to meet its primary efficacy outcomes, data suggested some relevant effect in BD as gevokizumab preserved visual acuity, reduced uveitis severity, reduced macular edema, and showed corticosteroid-sparing effect.¹⁴⁰

Secukinumab is an anti-IL-17 antibody. Initial studies found it effective in uveitis secondary to RA, AS, plaque psoriasis and NIU with no adverse events.^141–143 Three multicenter, randomized, placebo-controlled phase III studies (SHIELD, INSURE, and ENDURE) investigated efficacy and safety of secukinumab in NIU. Of the 3 RCTs, only one was an enrolled patient with BD with posterior uveitis or pan uveitis (SHIELD study), whereas non-BD patients with active (INSURE study) or inactive NIU (ENDURE study) were included in the other 2. It was found that there were no significant differences in recurrence of uveitis (primary endpoint) between secukinumab group and placebo leading to early termination of each trial.

However, the secondary efficacy data from these trials suggested a beneficial effect of secukinumab in reducing the concomitant use of immunosuppressive agents.¹⁴⁴ Moreover, a report of 2 cases of AS treated with secukinumab showed exacerbation of BD in one and emergence of de novo BS in another.¹⁴⁵ In contrary to this, a study analyzing the pooled data from 3 phase III trials (MEASURE1–3) concluded that there was no increased incidence of uveitis in secukinumab-treated patients with active AS.¹⁴⁶

Brodalumab is another drug under anti-IL-17 therapies, which is approved for moderate-to-severe plaque psoriasis, but to date no report on the use of this agent in uveitis has been published.¹⁴⁷ A phase II randomized trial in cases with CD was terminated early in view of no benefit and worsening CD in active treatment groups with brodalumab.¹⁴⁸

Canakinumab is a fully human anti-IL-1β antibody. In a case with juvenile-BD with refractory eye disease and nonresponsive to ANA, the patient benefitted from canakinumab.¹⁴⁹ However, both the agents are IL-1 blockers, but act in different ways. While ANA locks IL-1α and 1β, canakinumab specifically targets IL-1β. Lately, multiple clinical trials proved the efficacy of these 2 IL-1 inhibitors in the management of refractory and long-lasting cases of BD-related uveitis.^{87,88,150,151}

Targeting T&B cells

Rituximab (RTX) is a monoclonal antibody directed against CD-20, which is a cell surface antigen on B cells. This causes apoptosis of B cells. It was first indicated in 1997 for treatment of non-Hodgkin's lymphoma and thenceforth it has been used for RA and polyangiitis nodosa with its beneficial effects in ocular inflammatory diseases.^152–156 Recently, successful long-term use and efficacy of RTX in JIA-associated uveitis and cases refractory to other biologic agents has been reported in retrospective case series.^157,158 RTX is a safe and effective agent for controlling scleritis and uveitis associated with granulomatosis with polyangiitis (GPA), with eventual progression toward steroid-sparing remission. Furhter extensive studies are required to adequately assess the safety profile of the drug in a milieu of uveitic diseases.^158–160

Abatacept (ABA) is a soluble fusion protein made up of human-IgG and the ligand-binding domain of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). It is a selective costimulatory, which binds to antigen-presenting cells and blocks T cell activation. It has been approved for RA, JIA, psoriatic arthritis, and in pediatric patients with idiopathic uveitis.^161–164 In a retrospective study on 21 patients with JIA with refractory uveitis, the uveitis inactivity was achieved in 11 patients, but recurred later in 8 of them, and remained active in another 10 cases.¹⁶² It may adequately control uveitis but not arthritis in few cases.¹⁶⁵ ABA is also useful in pediatric uveitis, which are unresponsive or had contraindication to other anti-TNF drugs.^165,166 However, its safety and efficacy profile need to be established by larger prospective studies.

Alemtuzumab is a cytolytic antibody directed against CD-52. Initial studies have shown some benefit in cases like RA and in refractory ocular inflammatory disease.^167,168 Nevertheless, it has proven to be effective in refractory and relapsing BD while maintaining an acceptable safety profile over a period of 20 years.¹⁶⁹ Recently, a case report has established its potential utility in multiple sclerosis-associated refractory uveitis.¹⁷⁰

Efalizumab, anti-CD11a antibody, has shown effective results in recalcitrant uveitis by improving visual function and reducing macular edema.^9,171 However, it was suspended from the market after occurrence of progressive multifocal leukoencephalopathy cases.¹⁷²

Vedolizumab (VDZ) specifically targets gastrointestinal tract. It binds to α4β7 integrin, which is expressed on activated gut-homing T-lymphocytes and blocks its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1).¹⁷³ It is efficacious in the treatment of UC and CD.^174,175 Anti-TNFs are beneficial for treating extraintestinal manifestations (EIM), such as arthralgia, skin diseases, small-vessel vasculitis in IBD, but they are not uniformly effective. So, VDZ may be an alternative for the management of EIMs, especially those that track closely with luminal disease.^176,177

In the contrary, a recent report stated a possible link with increased risk of developing EIM (especially skin and articular manifestations) after starting VDZ in patients with IBD. The gut-localized inflammation control of VDZ may potentially limit its clinical effect on preventing the development of systemic EIMs.^176–178

Sotrastaurin is a protein kinase-C inhibitor that prevents early T cell activation and β2-integrin-mediated T-lymphocyte endothelial cell adhesion.^179,180 A phase II, multicenter, open-label study of 13 patients with macular edema associated with posterior-segment NIU (NCT00615693) was done. Oral sotrastaurin was administered as 1,300 mg 2 times daily for 2 weeks, followed by 1,200 mg 2 times daily for 6 weeks. The outcomes include change in inflammation, BCVA, and macular edema. The results are not yet published.^181,182

Sirolimus (Rapamycin) is an immunosuppressant that blocks leukocyte activation, T and B cell proliferation/differentiation, and cytokines by inhibiting mammalian target of rapamycin (mTOR).¹⁸³ So, mTOR inhibition by sirolimus is an emerging bull's eye for T cell-mediated uveitis.^184–189 SAVE and SAKURA trials demonstrated efficacy of intravitreal injections for posterior segment-NIU.^188,190 A recent meta-analysis and systemic review on sirolimus for treating NIU concluded with promising results.¹⁹¹

Table 4 gives a summary of different phases and status of studies for biologic drugs in pipeline. The use of common biologics in various diseases has been depicted in Table 5.

Table 4.

Important Studies of Emerging Biologics with US Approval Status

Emerging therapy	US approval status
Sirolimus	Phase III of the SAKURA completed, phase III LUMINA study underway
Tocilizumab	PHASE II STOP-UVEITIS study approved for Rheumatoid arthritis
Sarilumab	Phase II SATURN, also in trials for Rheumatoid arthritis
Gevocizumab	Phase III Eyeguard
JAK inhibitors	NCT03580343 for NIU and scleritis & NCT03207815 for NIU phase II; results awaited
ACTH-gel	Ongoing Phase II ACTHAR clinical trial; NCT02931175
pEYS606 gene therapy	Phase II multicenter dose escalation study; NCT03308045
Fezakinumab	Phase I trial for psoriasis (NCT00563524) and a phase II trial for Rheumatoid arthritis (NCT00883896)

Table 5.

List of Drugs Commonly Used for Various Diseases

Disease	FDA-approved commonly used drug
Rheumatoid arthritis	IFX, ADA, Etanercept, Certolizumab, Golimumab, RTX, Abatacept, Anakinra
Plaque psoriasis	IFX, ADA, Etanercept, Efalizumab, Abatacept
Psoriatic arthritis	IFX, ADA, Etanercept, Golimumab
Crohn disease	IFX, ADA, Certolizumab
Ulcerative colitis	IFX
Ankylosing spondylitis	IFX, ADA, Etanercept, Golimumab
Juvenile idiopathic arthritis	ADA, Etanercept, Abatacept

IFX, infliximab; ADA, adalimumab; RTX, rituximab.

Interferons (IFNs) are signaling proteins that activate immune cells. They possess antiproliferative, antiangiogenic, and apoptotic effects. IFN-α and IFN-β are type-I IFNs with strong immunomodulatory actions.¹⁹² IFN-α-2a and 2b are human recombinant IFNs affecting immune system. Initial studies recommend IFN-α in treating various uveitic entities.¹⁹³ Over a period of time, they are now useful in refractory cases and chronic macular edema.^194–197 In a retrospective cohort of 37 patients with postuveitic refractory macular edema, who were treated with SC IFN-α 2a injection for 8–24 months and followed up for up to 17 (10–38) months, showed significant reduction in central macular thickness for 12 months and improvement in BCVA.¹⁹⁷

Multiple studies have reported its role in treating refractory BD-associated uveitis not responding to conventional therapy.^198–203 When IFN was compared with IFX in patients with refractory BD-associated uveitis, both were effective in controlling inflammation and in decreasing relapses.²⁰⁴ Also, IFN-β was found to be superior to MTx in the management of intermediate uveitis with macular edema and in patients of MS with intraocular inflammation.^205,206

IFN can also be used in its pegylated form (alpha 2a and 2b). The pegylation process was developed in the 1970s by Abuchowski, which can increase the half-life and consequently reduce the number of injections required.²⁰⁷ A small series of 5 patients documented the potential value of pegylated IFN-α2a in treating uveitis associated with BD. Efficacy was evaluated in terms of fewer injections and hence, lesser side effects and better quality of life.²⁰⁸

While comparing peg-IFN-alpha-2b with IFN-alpha-2a in the treatment of refractory noninfectious inflammatory macular edema, it was found that IFN-alpha was rapidly effective despite a low-dosage regimen and there was no difference in efficacy and tolerance between IFN-alpha-2a and peg-IFN-alpha-2b.²⁰⁹ Seldom, IFN therapy-induced sarcoid-like disease has been reported with or without uveitis; however, further studies are required to underpin the observation.

Newer treatment tools in biologics

JAK inhibitors, also known as Jackinibs, are small molecules that inhibit Janus kinase family of receptors. JAK-mediated pathways are involved in pathogenesis of autoimmune diseases, such as RA, IBD, and psoriatic arthritis.^210–214 Tofacitinib is the first-generation drug that inhibits JAK-1, JAK-3, and to a lesser extent JAK-2 also. It is commercially approved for the treatment of RA.^212,215 It is currently being evaluated in a clinical trial (NCT03580343) for NIU and scleritis; results are awaited.²¹⁶ In 2018, a study of 2 cases (one with scleritis and another with anterior and intermediate uveitis) showed durable resolution of uveitis and scleritis when treated with tofacitinib after failure of multiple steroid-sparing and other biologic therapies.²¹⁷

Moreover, a prospective open-label trial to assess its efficacy in Birdshot chorioretinitis concluded it to be effective.²¹⁸ Filgotinib, a preferential JAK-1 inhibitor, is another orally administered JAK-inhibitor with long duration of action. It has shown decent preliminary efficacy in phase II studies in inflammatory diseases such as RA and CD.^219–221 Currently, it is under RCT phase II clinical trial to evaluate its efficacy in NIU and results will be out in 2023 (NCT03207815).²²² Very little is known about its role in the treatment of JIA-associated uveitis.^223–225

Repository corticotropin injection is an adrenocorticotropic hormone (ACTH) analog and belong to a group of molecules called melanocortins (MC) that exhibit their action by limiting transmigration of leukocytes, reduction of cytokines, and generation of local anti-inflammatory signals.²²⁶ It can be administered through SC/IM injection. Patients experienced a reduction in dose of uveitis medication.^227–229 The ongoing Phase II ACTHAR clinical trial to evaluate the efficacy of 2 different treatment regimens of ACTH-gel (80 U twice a week and thrice a week) in NIU patients, is yet to publish its results (NCT02931175).²³⁰

pEYS606 gene therapy is a plasmid DNA that encodes for a fusion protein of TNF-α and immunoglobulin-G. It is given by electrotransfection into ciliary muscle for sustained production of secreted therapeutic proteins into the eye. This nonviral gene transfer has shown significant reduction in ocular inflammation in 2 rat models of uveitis, the endotoxin-induced uveitis (EIU), and the experimental autoimmune uveitis (EAU).²³¹ In EAU, it also showed significant protection of photoreceptors. A phase I/II multicenter dose escalation study is going on to assess safety and clinical activity of gene therapy in 24 patients with NIU (NCT03308045) in UK and France.

Autologous Treg therapy are regulatory T cells (Treg) that maintain immune tolerance by inhibiting T-helper/T-cytotoxic cells, antibody production by B cells, and antigen-presenting cell maturation.^232,233 Initial studies found low levels of Treg in autoimmune diseases, including uveitis.^233–236 Few clinical trials studied Treg therapy refractory CD and type-I DM and supported its immunosuppressive mechanisms.²³⁷ Recently, a local ocular immunosuppressive activity of collagen type II-specific Treg was demonstrated in a mouse model of NIU.²³⁸ More robust clinical trials are needed to demonstrate its safety, efficacy, method of selection, and route of administration.²³⁹ It will significantly enlarge our therapeutic spectrum in managing refractory NIU; however, the challenge to obtain sufficient antigen-specific Treg to ensure efficacy still remains.

B27PD is an autoreactive CD4 T cells that recognize S-antigens in the eye and cause intraocular inflammation.²⁴⁰ It induces specific immune tolerance to S-antigen by a mechanism of molecular mimicry. A pilot study reported its long-term efficacy in 9 patients of chronic uveitis when treated with oral B27PD.²⁴¹

IL-10 is known by its ability to inhibit IFNŷ.²⁴² It is an anti-inflammatory, immunomodulatory cytokine, which regulates mucosal inflammation. When tested in animal studies, it showed a protective role in uveitis.^243,244 It has been tested for UC in several multicenter trials as a potential therapy, but found to be no more effective than placebo.^245–247 IL-22 is an essential homeostatic cytokine, which is mainly secreted by T cells and NK cells.^248–249 In humans, IL-22-producing Th clones have been isolated from the eyes of patients with BD and elevated levels have been identified in the serum of patients with uveitis and scleritis.^250–252 Also, serum levels of IL-22 decreased when patients with refractory uveitis were treated with ADA and these decreased levels corelated with the disease activity.^252–253

Fezakinumab is a human monoclonal antibody that works against IL-22. It was tested in a phase I trial for psoriasis (NCT00563524) and a phase II trial for RA (NCT00883896). The results of these studies have not yet been published. As of now, no studies are undertaken in patients with uveitis.²⁵⁴

Intravitreal (IVT) biologic drug administration for uveitis are effective in reducing ocular inflammation.²⁵⁵ The efficacy of IVT-IFX in uveitis has been documented in causing improvement in vision, anatomical outcomes, and reduction in inflammation with no reported systemic side effects.^256–258 Twenty patients with refractory posterior uveitis in BD were given 3 IFX injections in a row (1 mg/0.05 mL) and found to be safe and effective.²⁵⁸ However, these effects were short term, and reinjections were needed at intervals shorter than 6 weeks to achieve the best therapeutic goals. Similarly, IVT management with ADA in uveitis has shown favorable results in few studies.^259,260 A prospective study of patients on systemic ADA with breakthrough panuveitis in BD showed effective control of inflammation when given IVT ADA.^259–261

A randomized open-label clinical trial, Sirolimus as Therapeutic Approach for Uveitis (SAVE), was done to evaluate safety and efficacy of sirolimus administered as SC or IVT injections in patients with NIU.¹⁸⁸ Its local administration appeared to be safe and tolerable, irrespective of the route of administration. The IVT route, however, was better tolerated.²⁶²

The favorable outcome from the SAVE study was followed by conduct of the Sirolimus as a Therapeutic Approach for Uveitis: Protocol 2 (SAVE-2) study, which was a phase II randomized clinical trial evaluating 2 different doses of IVT sirolimus (440 μg given monthly and 880 μg given bimonthly) in patients with NIU.²⁶³ It demonstrated a significant reduction in vitreous haze in either of the 2 doses. However, SAVE-2 study did suggest that low-dose (440 μg) sirolimus administered monthly may be more efficacious in reducing macular edema compared with the group administered high dose (880 μg) every 2 months.

After the results of SAVE and SAVE-2 study, The Study Assessing Double-Masked Uveitis Treatment (SAKURA; ClinicalTrials.gov identifer: NCT01358266) was initiated consisting of 2 sequential phase III randomized trials (SAKURA 1&2) to evaluate efficacy and safety of IVT sirolimus at different doses (44, 440, and 880 μg) in the treatment of NIU of the posterior segment.^264–266

The end of primary endpoints of SAKURA-1 showed that the 440 μg dose obtained the most favorable outcome in the treatment of NIU-PS as measured by vitreous haze and SAKURA-2 showed equivocal results, however, the difference in them was not statistically significant. Hence, there was a further need to assess the efficacy of 440 μg dose.²⁶⁶ So, an extension phase III of the SAKURA programme, phase III LUMINA study, was launched and is currently under way (NCT03711929).

IVT tesidolumab/LFG316, a monoclonal antibody against C5, was studied in a recent phase II RCT (ClinicalTrials.gov identifer: NCT01526889) to evaluate its efficacy and safety in patients with NIU-PS; however, results are not available so far.²⁶⁷ IVT IFN-α-2b has been shown effective in treating EIU in animal models.²⁶⁸

The worldwide biologics market size was treasured as USD 276.6 billion in 2015. Furthermore, an increased understanding of the genetic and molecular basis of disease has opened up the development of a range of targeted treatments. Thus, the biologic agents have made the whole science luminous in the management of autoimmune uveitis by being extremely specific for one target molecule and hence blocking specific pathways and/or cell types.

Conclusion

With the accessibility of new data, biologics are “upcoming promising future” to meet “the unmet need.” Several biotherapies other than anti-TNF-α-like inhibitors of IL-6, IL-23, mTOR, ABA, and JAK-inhibitors still need to be confirmed in larger series. Other routes of drug delivery can be used as add-on treatments to treat acute flare-ups of the anterior segment (topical) and unilateral episodes of macular edema or posterior exacerbations of inflammation (IVT). So, we may not be surprised if biologic agents may be suggested as first-line therapy in the management of specific causes of uveitis in future.

Method of Literature Search

Desk research of literature was carried out using PubMed, MEDLINE, and CrossRef (Google) to gain broad understanding on biologics. We have reviewed the literature on the up-to-date knowledge about biologics and their use in uveitis. We have taken the literature material of last 15–20 years preferably. The criteria for including an article in our review were a broad description of the use of various biologics used in uveitis.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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