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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 13  |  Issue : 4  |  Page : 259-263

Use of biologic response modifiers for the management of ocular inflammatory conditions


1 Departments of Ophthalmology, Oregon Health and Science University, Portland, OR, USA
2 Department of Ophthalmology, Oregon Health and Science University, Portland, OR, USA; Singapore National Eye Centre, Singapore; Department of Laboratory of Immunology, National Institutes of Health, National Eye Institute, Bethesda, MD, USA
3 Department of Ophthalmology; Department of Medicine, Oregon Health and Science University; Uveitis Clinic, Legacy Devers Eye Institute, Portland, OR, USA

Date of Web Publication18-Nov-2018

Correspondence Address:
Dr. James T Rosenbaum
Oregon Health and Science University, 3181 SW Sam Jackson Pk Rd, L467Ad, Portland, OR 97239, USA.
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_83_18

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  Abstract 


Ocular inflammatory conditions can be challenging to manage due to their prolonged and complicated nature. While the mainstay treatment for most cases is oral or topical corticosteroids, it is very important that physicians know how other medications such as biologic response modifiers (biologics) could be used in certain cases. Through illustrative cases, we discuss how treatment with biologics can be helpful in the management of three challenging patients with ocular inflammatory conditions. We review and discuss, (1) a 60-year-old male with granulomatosis with polyangiitis and bilateral anterior scleritis who required rituximab; (2) a 25-year-old male with refractory, idiopathic, bilateral chronic panuveitis and retinal vasculitis, which was controlled with adalimumab after treatment failure with oral and topical corticosteroids, cyclosporine, and methotrexate; and (3) a 44-year-old female with unilateral blindness and juvenile psoriatic arthritis-related intermediate uveitis, who required adalimumab to control her complication of persistent macular edema. These cases highlight the considerations that are required when clinicians are faced with the need to commence biologic therapy for patients with refractory ocular inflammation.

Keywords: Biologics, scleritis, uveitis


How to cite this article:
Rivera-Grana E, Siak J, Rosenbaum JT. Use of biologic response modifiers for the management of ocular inflammatory conditions. Indian J Rheumatol 2018;13:259-63

How to cite this URL:
Rivera-Grana E, Siak J, Rosenbaum JT. Use of biologic response modifiers for the management of ocular inflammatory conditions. Indian J Rheumatol [serial online] 2018 [cited 2019 Jul 20];13:259-63. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/4/259/236717




  Introduction Top


Ocular inflammatory diseases which might confront rheumatologists include scleritis and uveitis. Scleritis is defined as inflammation of the white outer layer of the eye called the sclera. It is often acutely painful and associated with eye injection. The ocular morbidity can be significant due to complications including decreased vision, uveitis, glaucoma, and rarely, globe perforation.[1] It is associated with underlying systemic diseases in approximately 36%–57% of patients.[2] It can be classified as anterior or posterior, infectious or noninfectious, necrotizing or nonnecrotizing, and nodular or diffuse. Anterior, nonnecrotizing, and noninfectious are the most common.[3] For infectious scleritis, antibiotics should be promptly prescribed to avoid complications since the outcome of infectious scleritis is generally worse. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line agents for mild-to-moderate scleritis. Patients with severe disease are usually unresponsive to NSAIDs and are generally treated with systemic corticosteroids, often in combination with antimetabolites such as methotrexate (MTX), mycophenolate, or azathioprine.

Uveitis is inflammation of the uvea, the middle layer of the eye, composed of the iris, ciliary body, and choroid. Uveitis can be caused by different etiologies, which can be infectious (examples include herpes simplex or herpes zoster, syphilis, toxoplasmosis, and tuberculosis [TB]); noninfectious and immune-mediated (such as sarcoidosis, juvenile idiopathic arthritis, Behcet's syndrome, or multifocal choroiditis); adverse reactions to medications such as checkpoint inhibitors; trauma; and idiopathic (meaning that the pattern of inflammation does not fit easily into a diagnostic category). Many noninfectious examples of uveitis are confined to the eye and others are a component of a systemic syndrome. Classification is based in part on the anatomic location of inflammation, i.e., anterior, intermediate, posterior, and panuveitis.[4] Treatment depends in part on the underlying condition causing uveitis and type of uveitis, but topical, locally injected, or oral corticosteroids can be considered first-line medications for noninfectious uveitis.

A biologic therapy can be defined as a treatment produced using recombinant DNA technology and based on an understanding of the disease pathogenesis. Most biologic therapies can be classified as either monoclonal antibodies or soluble receptors. Biologics have been previously demonstrated to be successful as second-line agents in the management of ocular inflammatory conditions.[1],[2],[5],[6] In this case series, we will focus on adalimumab and rituximab. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for antitumor necrosis factor-alpha (TNF-α) and works by binding to TNF-α and blocking its interaction with TNF receptors. Rituximab is a chimeric monoclonal antibody against protein CD20 that is primarily found on the surface of immune system B cells. The main mechanism of action is depletion of B-cells and B-cell precursors.

Patients diagnosed with ocular inflammatory conditions can challenge most trained ophthalmologists. Compared to conditions such as cataract, glaucoma, or macular degeneration, uveitis is rare. Ophthalmologists receive minimal training in the appropriate use of immunosuppressives. Rheumatologists can play a very important role in the management and evaluation of these patients. Here, we describe three cases in which patients with ocular inflammatory conditions were treated successfully with biologic-modifying medications.


  Illustrative Cases Top


The cases were selected by us to illustrate the utility of biologic therapy in the management of patients with ocular inflammatory diseases. The Oregon Health and Science University (OHSU) Institutional Review Board has reviewed and approved documents for the purpose of publication of retrospective chart reviews of patients who are evaluated at the OHSU Ocular Inflammation Clinic.

Case 1

A 60-year-old Native American male presented to the ocular inflammation clinic with bilateral anterior scleritis, with painful red eyes which were tender to palpation for 2 months [Figure 1]. His comorbidities included recurrent sinusitis and epistaxis, bronchitis with intermittent hemoptysis, progressive hearing loss, hypertension, and a history of unprovoked subdural hematoma with diffuse dural thickening. His medications at presentation included an oral NSAID, difluprednate ophthalmic solution (a potent topical corticosteroid), and timolol ophthalmic solution for the control of his raised intraocular pressure (IOP). There was no family history of ocular or autoimmune disease. His visual acuity was 20/30 and 20/40 in his right and left eye, respectively, and his IOP was elevated at 23 and 29 mmHg in his right and left eye, respectively. His cytoplasmic antineutrophil antibody (C-ANCA) serology was positive with an elevated antiproteinase-3 level. The patient had a normal chest X-ray and no evidence of active renal disease. His condition was consistent with a diagnosis of limited granulomatosis with polyangiitis (GPA). Pachymeningitis is a well-described manifestation of GPA, and a subdural hematoma has been described as a rare association of GPA.[7] His scleritis was a clue that helped to explain the multisystem presentation.
Figure 1: Bilateral anterior scleritis – (a and b) Scleritis. Front view, right and left eyes, respectively. (c and d) Temporal sclera with scleritis, right and left eyes, respectively

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As the patient exhibited active ocular and systemic disease despite topical corticosteroids and oral NSAIDs, he was started on a daily dose of 80 mg (1 mg/kg body weight) oral prednisone. His scleritis improved significantly within a week, but he had persistent, mild hemoptysis and tinnitus with vertigo. Although we often elect to treat limited GPA with oral corticosteroids and MTX, in this case, an anti-B-cell biologic therapy was recommended to achieve a rapid control of his central nervous system disease. He received an induction regimen of two intravenous infusions of 1000 mg rituximab therapy with an interval of 2 weeks, and oral corticosteroids were gradually tapered off over a period of 3 months.

Three months after his rituximab induction therapy, he achieved remission of his ocular and systemic disease without a need for corticosteroids. His erythrocyte sedimentation rate, C-reactive protein, and ANCA tests had normalized. However, he noted intermittent tinnitus and vertigo, which could represent a low-grade active disease. He received two additional infusions of 500 mg rituximab, one 5 months after his induction treatment and a second 5 months after that.

Seven months after his last infusion, he reported no symptoms of active scleritis, no respiratory symptoms, and no vertigo or hearing loss. The patient reported that his eye and joint pains significantly improved after each rituximab infusion and he was able to taper completely off prednisone from 5 mg. Minor side effects included dry eyes, weight loss of >20 pounds, fatigue, and intermittent mild joint pain affecting his knees and shoulders.

In summary, this case illustrates how the scleritis helped to identify the systemic disease and the benefit of rituximab therapy to achieve remission of his this disease. His long-term plan includes the use of MTX to stabilize his disease and the intermittent use of rituximab in addition to maintain this remission.

Case 2

A 23-year-old African American male presented to the ocular inflammation clinic with active bilateral chronic panuveitis of 6-month duration with neovascularization of the optic disk [Figure 2]. He had been treated with topical corticosteroids without resolution of his inflammation. His visual acuity was 20/30 and 20/25 in his right and left eye respectively, and his IOP was within normal range. His ophthalmic examination revealed diffuse granulomatous keratic precipitates (concretions of cells on the endothelium of the cornea) with anterior chamber and vitreous inflammation in both eyes and diffuse retinal vasculitis on fluorescein angiography in both eyes [Figure 3]. His prior investigations included a complete blood count, comprehensive metabolic panel, angiotensin-converting enzyme, antinuclear antibodies, rheumatoid factor, rapid plasma reagin, fluorescent treponemal antibody-absorption, and Lyme disease serology. These tests were unremarkable. Chest computed tomography scan was deferred due to his young age and the potential risk from radiation.
Figure 2: The right optic nerve shows evidence of neovascularization

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Figure 3: (a and b) Early fluorescein angiogram (c and d) late fluorescein angiogram. The white circle in the center of the images is the optic nerve. Retinal vessels are seen as thin white lines. Staining adjacent to the lines indicates that the dye is leaking. This is diagnostic of a retinal vasculitis, a definition of vasculitis which is far different from the vasculitis definition accepted by most rheumatologists. Some dye leakage is apparent in the early images (a and b); much more leakage is seen in the later images (c and d)

Click here to view


He was started on a course of oral prednisone at a daily dose of 40 mg. Due to a severe elevation of his IOP in response to oral corticosteroid treatment, he required topical ocular hypotensive medical treatment with four different topical medications and a more rapid reduction of his oral prednisone dose. Oral MTX was added at a dose of 15 mg weekly and that was subsequently switched to subcutaneous route for greater efficacy. As his uveitis worsened when oral prednisone was reduced to a daily dose of 20 mg, oral cyclosporine A (CsA) was added at a daily dose of 300 mg as a steroid-sparing agent.

Three months later, control of his intraocular inflammation was achieved with MTX, CsA, and a daily dose of 10 mg oral prednisone. However, his left visual acuity acutely decreased when he had a submacular hemorrhage from choroidal neovascularization, a known complication of panuveitis. He received an intravitreal injection of bevacizumab (an antivascular endothelial growth factor monoclonal antibody) with a successful resolution of the submacular hemorrhage and recovery of his left visual acuity.

He had a recurrence of anterior chamber inflammation in both eyes 8 months later while he was on subcutaneous MTX 25 mg weekly, oral CsA 150 mg every 12 h, and prednisone 3 mg daily. Topical 1% prednisolone acetate was added. Two months later, his retinal vasculitis recurred when oral prednisolone was decreased to 2 mg daily. We recommended switching to adalimumab therapy, but the patient initially declined due to financial considerations. Oral prednisone was increased to 10 mg daily, but his inflammation remained uncontrolled and he developed cushingoid side effects. He then started on adalimumab therapy (subcutaneous 40 mg fortnightly) and his panuveitis resolved rapidly. His last recorded visit was 1 year after starting adalimumab treatment. The patient was tolerating anti-TNF well with no sign of inflammation in either eye without oral prednisone or cyclosporine. No active retinal vasculitis was observed on fluorescein angiography. We planned to gradually reduce his subcutaneous MTX dose and to continue his adalimumab therapy for at least a few years.

In summary, this case illustrates the benefit of biologic therapy as a steroid-sparing agent for patients with severe ocular inflammatory disease. Although he had no evidence of systemic inflammation outside his eyes, his vision and general health were clearly precarious as a result of his cushingoid changes and ophthalmic complications of uncontrolled chronic panuveitis (choroidal neovascularization). He has responded very well to biologic therapy.

Case 3

A 44-year-old female with psoriatic arthritis presented to our clinic with anterior and intermediate uveitis with a complaint of blurry vision in her right eye for 1 month. Her visual acuity was 20/150 in her right eye. She had left eye blindness with no light perception as a result of an episode of severe unilateral acute uveitis 1 year earlier, which was complicated by the development of intractable neovascular glaucoma. Her uveitis was refractory to topical, periocular, and oral corticosteroids which were prescribed by her other ophthalmologist.

Ophthalmic examination revealed anterior chamber and vitreous inflammation in both eyes with 360° of posterior synechiae (adhesion of the iris to the lens), iris neovascularization, and a dense white cataract in her left eye. The IOP was within the normal range for both eyes, but she had significant cystoid macular edema (CME) in the right eye [Figure 4], which was a complication of severe uveitis. Her systemic comorbidities included juvenile psoriatic arthritis since she was 15 years old and extensive thromboembolic disease with an intra-aortic clot and renal infarct. She was wheelchair bound and her arthropathy was not controlled with oral prednisone (10 mg daily) and leflunomide. MTX had caused photosensitivity.
Figure 4: (a) Optical coherence tomography OD at the first visit. White arrow shows subretinal fluid causing macular edema. (b) Optical coherence tomography OD at follow-up visit. The macular edema has resolved and the macula has a normal, concave appearance

Click here to view


Due to the severity of her uveitis and systemic disease and the failure and intolerance of two other immunosuppressive treatments, her oral prednisone dosage was increased from 10 to 30 mg daily and she started adalimumab treatment (40 mg subcutaneously fortnightly). Three months later, her right visual acuity improved with resolution of her CME and her arthropathy improved significantly. Her daily dose of oral prednisone was gradually decreased by 5 mg every 2 weeks. She developed a recurrence of her right eye uveitis and CME 3 months later and that resolved with a short course of 40 mg daily oral prednisolone, topical corticosteroid difluprednate, and an increase of her adalimumab treatment to 40 mg every 10 days. She subsequently underwent cataract surgery of the right eye after her uveitis had been inactive for 3 months. Two years after starting adalimumab therapy, she maintained good vision of 20/30 as measured with pinhole in her only seeing eye.


  Biologicals in Occular Inflammation Top


Aforementioned cases demonstrate the use of two biologic medications, adalimumab and rituximab in treating patients with ocular inflammatory conditions, two of whom had associated rheumatologic diseases. Corticosteroids have been used as the mainstay treatment of ocular inflammations. Long-term corticosteroid intake is associated with significant risk of undesired side effects which include cushingoid changes, weight gain, hypercholesterolemia, hyperglycemia, osteopenia, lowered resistance to infection, cutaneous atrophy, mood changes, and hypertension. Due to these potential side effects, an expert panel of the American Uveitis Society studied and supported the use of immunosuppressive drugs, including biologics, to be used in the management of selected patients.[5],[8] All of our patients were prescreened for latent TB with an interferon-gamma release assay test. If results were positive, patients were referred to a TB specialist for adequate management.

In our first case, rituximab was considered a good alternative due to the patient's systemic condition and the accepted inadequacy of corticosteroids alone as management for GPA. Rituximab has been shown to be noninferior to cyclophosphamide in the treatment of GPA and microscopic polyangiitis, and it has been approved by the United States Food and Drug Administration for that indication.[9] Suhler et al. found a positive therapeutic effect of rituximab in the treatment of patients with refractory scleritis, with 9 of 12 patients characterized as clinical responders after 24 weeks of therapy.[1] Another study retrospectively analyzed 15 patients with noninfectious scleritis treated with rituximab and demonstrated that 14 patients (93.3%) showed a clinical improvement, with 13 (86.6%) achieving a scleritis activity score of 0 at 6 months. The authors concluded that rituximab can be an effective treatment modality for recalcitrant noninfectious scleritis and in some, can result in long-term durable drug-free remission.[10]

In cases 2 and 3, we described two patients who were placed on adalimumab treatment for inflammation control and corticosteroid-sparing effect. Improvement of inflammation and steroid-sparing effect was achieved in both cases. Adalimumab can be used as a potential second-line treatment for conditions such as noninfectious intermediate, posterior uveitis, or panuveitis in patients requiring immunomodulation who have failed or who are not candidates for antimetabolite or calcineurin inhibitor modulation.[8] Being a humanized agent, it provides less risk for patients to develop antibodies against the medication compared to infliximab. Patients treated concomitantly with MTX have been shown to have a lower rate of antibody development compared to patients with anti-TNF-α monotherapy.[8] Two randomized controlled trials, each using time to treatment failure as the end point, established that adalimumab was effective for noninfectious intermediate, posterior, or panuveitis.[11],[12]

Biologic response modifiers are not free of side effects, most prominently serious infection. Therefore, precautions should be instilled at the moment of deciding to start treatment. The FOCUS Initiative group is an international expert-led consensus initiative that worked to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis. The FOCUS panel concluded that biologics may be introduced for the management of noninfectious uveitis to control persistent or severe inflammation or to prevent ocular structural complications that present a risk to visual function.[13]

Before electing to prescribe noncorticosteroid, systemic immunomodulatory medications, it is recommended that clinicians should determine baseline vital organ function and screen for infectious diseases that may be reactivated or exacerbated by immunosuppression.[13]


  Conclusion Top


Biologic medications should be used carefully for treatment of ocular inflammatory conditions. With proper use and precautions, patients can benefit from them either by being able to taper off corticosteroids and avoiding their side effects or obtaining better control of ocular inflammation. All patients placed on biologic medications should be followed closely although routine laboratory studies are usually obtained only every 6 months.

Further studies and guidelines like the ones stated in the FOCUS Initiative study [13] will help provide optimal management to patients with ocular inflammatory conditions across relevant specialties. As described here and in previous studies, there are significant data showing promising results in the use of biologics. It is of much importance that physicians involved in the care of these patients, such as ophthalmologists and rheumatologists, know all available options to better assess and treat these patients. Additional studies on existing medications and randomized controlled trials on additional targets will further refine this therapeutic option.

Financial support and sponsorship

This work was supported by the William and Mary Bauman Foundation, the Stan and Madelle Rosenfeld Family Trust, and Research to Prevent Blindness.

Conflicts of interest

Dr. Rosenbaum has consulted for Abbvie and Genentech/Roche.



 
  References Top

1.
Suhler EB, Lim LL, Beardsley RM, Giles TR, Pasadhika S, Lee ST, et al. Rituximab therapy for refractory scleritis: Results of a phase I/II dose-ranging, randomized, clinical trial. Ophthalmology 2014;121:1885-91.  Back to cited text no. 1
    
2.
Beardsley RM, Suhler EB, Rosenbaum JT, Lin P. Pharmacotherapy of scleritis: Current paradigms and future directions. Expert Opin Pharmacother 2013;14:411-24.  Back to cited text no. 2
    
3.
Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: Clinical features and treatment results. Am J Ophthalmol 2000;130:469-76.  Back to cited text no. 3
    
4.
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol 2005;140:509-16.  Back to cited text no. 4
    
5.
Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: Recommendations of an expert panel. Am J Ophthalmol 2000;130:492-513.  Back to cited text no. 5
    
6.
Martel JN, Esterberg E, Nagpal A, Acharya NR. Infliximab and adalimumab for uveitis. Ocul Immunol Inflamm 2012;20:18-26.  Back to cited text no. 6
    
7.
Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. Neurological involvement in Wegener's granulomatosis: An analysis of 324 consecutive patients at the mayo clinic. Ann Neurol 1993;33:4-9.  Back to cited text no. 7
    
8.
Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN, et al. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 2014;121:785-96.e3.  Back to cited text no. 8
    
9.
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.  Back to cited text no. 9
    
10.
Cao JH, Oray M, Cocho L, Foster CS. Rituximab in the treatment of refractory noninfectious scleritis. Am J Ophthalmol 2016;164:22-8.  Back to cited text no. 10
    
11.
Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med 2016;375:932-43.  Back to cited text no. 11
    
12.
Nguyen QD, Merrill PT, Jaffe GJ, Dick AD, Kurup SK, Sheppard J, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): A multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet 2016;388:1183-92.  Back to cited text no. 12
    
13.
Dick AD, Rosenbaum JT, Al-Dhibi HA, Belfort R Jr., Brézin AP, Chee SP, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals of care for uveitiS (FOCUS) initiative. Ophthalmology 2018;125:757-73.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


This article has been cited by
1 Prednisone/rituximab
Reactions Weekly. 2018; 1733(1): 278
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