- Email: [email protected]
Regression of unusual optic disk neovascularization after adalimumab in a case of juvenile idiopathic arthritis–related uveitis
Accepted Manuscript Regression of unusual optic disk neovascularization after adalimumab in a case of juvenile idiopathic arthritis–related uveitis Emanuela Interlandi, MD, PhD, Loredana Latanza, MD, Francesco Pellegrini, MD, Carlos Pavesio, MD PII:
S1091-8531(17)30571-2
DOI:
10.1016/j.jaapos.2017.05.028
Reference:
YMPA 2649
To appear in:
Journal of AAPOS
Received Date: 31 January 2016 Revised Date:
3 April 2017
Accepted Date: 8 May 2017
Please cite this article as: Interlandi E, Latanza L, Pellegrini F, Pavesio C, Regression of unusual optic disk neovascularization after adalimumab in a case of juvenile idiopathic arthritis–related uveitis, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2017.05.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Regression of unusual optic disk neovascularization after adalimumab in a case of juvenile idiopathic arthritis–related uveitis Emanuela Interlandi, MD, PhD,a,b Loredana Latanza, MDc Francesco Pellegrini, MD,a,b and Carlos Pavesio, MDd
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Author affiliations: aUveitis Service and bNeuro-Ophthalmology Service, Department of Ophthalmology, De Gironcoli Hospital, Conegliano, Italy; cUveitis Service, Department of Ophthalmology, A. Cardarelli Hospital, Naples, Italy, dUveitis Clinic, Moorfileds Eye Hospital, London, UK and BRC at the Institute of Ophthalmology, UCL
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Submitted January 31, 2016. Revision accepted April 7, 2017.
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Correspondence: Emanuela Interlandi, Via Cadore 6/c, 31015, Conegliano (TV), Italy (email: [email protected]).
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Word count: 983
ACCEPTED MANUSCRIPT
We report the case of a 9-year-old girl with a severe and uncommon presentation of juvenile idiopathic arthritis–related posterior uveitis, with neovessels at the optic disk associated with peripheral vasculitis. After two failed bevacizumab intravitreal injections,
RI PT
uveitis responded to systemic adalimumab administration, with a complete and long-term remission of ocular inflammation.
Uveitis related to juvenile idiopathic arthritis (JIA) is the most common cause of pediatric uveitis
SC
in the West, mostly associated with pauciarticular, antinuclear antibody–positive cases of
arthritis.1 Ocular inflammation mostly consists of bilateral nongranulomatous anterior uveitis
M AN U
with a typical chronic and relapsing course that may be complicated by sight-threatening conditions such as cataract, glaucoma, and band keratopathy but rarely involves the posterior segment of the eye.1 Case Report
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A 9-year-old girl with pauciarticular, antinuclear antibody–positive JIA was referred to the Uveitis Service of A. Cardarelli Hospital, Naples, for evaluation and treatment. She was diagnosed at 3 years of age. Six months after JIA onset she developed bilateral
EP
nongranulomatous anterior uveitis that responded to topical corticosteroids and mydriatics. Further episodes of anterior uveitis occurred over the following 3 years and always responded to
AC C
topical therapy, with preservation of good visual acuity (20/20) in both eyes. Oligoarthritis was successfully treated with systemic nonsteroidal anti-inflammatory drugs. At 13 years of age, the patient developed a relapse of ocular inflammation in the right eye
with concomitant reactivation of the arthritis in her right knee. Visual acuity in the right eye decreased to 20/65, and biomicroscopic examination disclosed nongranulomatous keratic precipitates associated with an intense anterior uveitis (flare 2+ and cells 3+). Fundus evaluation
ACCEPTED MANUSCRIPT
showed a swollen optic disk with neovessels (NVD) and signs of a mild peripheral retinal vasculitis. Fluorescein angiography disclosed intense leakage of dye at the optic disk edges and a lesser leakage in the areas affected by peripheral retinal vasculitis (Figure 1). No signs of retinal
RI PT
ischemia were detected. Indocyanine green angiography (ICG) and optic coherence tomography (OCT) were otherwise unremarkable. Corticosteroids were started promptly, and the patient underwent 2 successive intravitreal injections of bevacizumab (1.25 mg/0.05 ml) within 1 month.
SC
After the second injection there was gradual resolution of the NVD, confirmed on fluorescein angiography (Figure 2A). Visual acuity was 20/20 in the right eye at this stage.
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Six months after the second injection, right eye visual acuity again decreased to 20/50 following reactivation of the papillitis and NVD, this time also associated with light macular leakage on angiography (Figure 2B-C). Adalimumab (40 mg subcutaneously every 2 weeks) was introduced in addition to systemic steroids. Thereafter, the patient achieved a progressive
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resolution of ocular inflammation and arthritis with complete resolution of the papillitis and neovessels (Figure 2D). Three months later, visual acuity in the right eye was 20/20; corticosteroids were gradually tapered. With 3 years’ follow-up, the patient is still on
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adalimumab. At the time of the last assessment she had visual acuity of 20/20 in the right eye and complete remission of the inflammatory disease, both articular and ocular.
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Discussion
NVD is a rare occurrence in JIA-related uveitis and, to our knowledge, its treatment with adalimumab has not been described before. Although NVD may occur with chronic uveitis in a setting of prolonged inflammation, in
most cases it is associated with conditions such as retinal ischemia, vitritis, or pars planitis. NVD in association with chronic uveitis has been described previously2-6; however, in only 2 reports
ACCEPTED MANUSCRIPT
was NVD as consequence of severe JIA-related uveitis.2,3 Semple and colleagues2 reported a case of NVD occurring in a 4-year-old boy with bilateral JIA-related uveitis, and Gray and colleagues3 described 2 cases of NVD in a 13-year-old girl and a 4 year-old-boy. In these cases,
RI PT
related to the particular subtype of JIA, NVD developed without other possible causes of
neovascularization; both cases were managed with periocular or oral corticosteroids, with prompt regression of NVD but poor visual recovery, since alternative treatment options were not
SC
available at that time. Similarly, our patient presented with NVD in the right eye with no evidence of retinal ischemia.
M AN U
Pathogenesis of NVD, when not induced by hypoxia, should be investigated according to the same inflammatory mechanisms involved in severe forms of uveitis where abnormal eye angiogenic factors release might be presumed. Based on these considerations, at first occurrence of NVD, we decided to treat our patient with intravitreal injection of bevacizumab in addition to
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oral steroids. This vascular endothelial growth factor (VEGF) antagonist extensively used in ophthalmology for the treatment of retinal and choroidal neovascularization, including NVD.7 However, our patient, after a transient improvement following the second injection, had a severe
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reactivation of NVD, forcing us to switch therapy to adalimumab, a tumor necrosis factor α (TNFα) blocker that has been used successfully in rheumatology for treatment of various
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autoimmune diseases, including JIA and JIA-related uveitis.8-9 In contrast with the above-cited reports,2-3 where patients received only steroidal therapy, treatment of our patient with adalimumab resulted in a complete and prolonged regression of NVD. In addition, there was full recovery of visual acuity and an excellent long-term control of ocular inflammation, attributable to the better efficacy of this agent in relation to autoimmune mechanisms and fewer side effects compared to high doses of steroids.
ACCEPTED MANUSCRIPT
At present, the role of TNFα in angiogenesis is quite controversial. The interesting study conducted in mice by Fajardo and colleagues10 suggests a bimodal, dose-dependent mechanism
RI PT
with diametrically opposite effects, where low doses of TNFα might induce angiogenesis, whereas high doses may inhibit it. A therapeutic response in our case suggests a role of TNFα citokines rather than VEGF in development of NVD, although further studies are necessary to elucidate it.
SC
Our results confirm that JIA may be associated with severe uveitis with posterior segment
M AN U
involvement and that NVD may be an exceptionally serious complication. Literature Search
PubMed was searched on April 3, 2017, for English-language results, excluding abstracts and meeting presentations, using the following terms: juvenile idiopathic arthritis, uveitis,
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EP
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adalimumab, and optic disc neovascularization.
ACCEPTED MANUSCRIPT
References Tugal-Tutkun I. Pediatric uveitis. J Ophthalmic Vis Res 2011;6:259-69.
2.
Semple HC, Landers MB 3rd, Morse LS. Optic disk neovascularization in juvenile rheumatoid arthritis. Am J Ophthalmol 1990;110:210-12.
3.
RI PT
1.
Gray T, Kanski J, Lightman S. Steroid responsive disc neovascularisation in uveitis associated with juvenile chronic arthritis. Br J Ophthalmol 1998;82:327-8.
Shorb SR, Irvine AR, Kimura SJ. Optic disk neovascularization associate with chronic uveitis. Arch Ophthalmol 1976;82:175-8.
Kelly PJ, Weiter JJ. Resolution of optic disk neovascularization associated with
M AN U
5.
SC
4.
intraocular inflammation. Am J Ophtahlmol 1980;90:545-8. 6.
Pach JM, Herman DC, Garrity JA, Kalina PH. Disk neovascularization in chronic anterior uveitis. Am J Ophthalmol 1991;111:241-3.
Hoeh AE, Schaal KB, Ach T, Dithmar S. Treatment of peripapillary choroidal
TE D
7.
neovascularization with intravitreal bevacizumab. Eur J Ophthalmol. 2009;19:163-5. 8.
Zannin ME, Birolo C, Gerloni VM, et al. Safety and efficacy of infliximab and
EP
adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year follow-up data from the Italian Registry. J Rheumatol 2013;40:74-9. Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert
AC C
9.
panel recommendations for the use of anti-tumor necrosis factor biologic agents in
patients with ocular inflammatory disorders. Ophthalmology 2014;121:785-96.e3.
10.
Fajardo LF, Kwan HH, Kowalski J, Prionas SD, Allison AC. Dual role of tumor necrosis factor-alpha in angiogenesis. Am J Pathol 1992;140:539-44.
ACCEPTED MANUSCRIPT
Legends FIG 1. Fluorescein angiography (FA) of the right eye at baseline. A, Fluorescein leakage in
(NVD) leakage at 20 seconds (B), 1 minute (C), and 6 minutes (D).
RI PT
correspondence of peripheral retinal vasculitis. B-D, Sequential phases of neovessels of the disk
FIG 2. FA of the right eye after bevacizumab injections and adalimumab administration. A, Three months after second bevacizumab injection showing NVD and papillitis regression. B-C,
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Six months after second bevacizumab injection showing NVD and papillitis reactivation at 40
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months after adalimumab administration.
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seconds (B) and 2 minutes (C) of angiogram. D, Complete regression of NVD and papillitis 3
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TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
S1091-8531(17)30571-2
DOI:
10.1016/j.jaapos.2017.05.028
Reference:
YMPA 2649
To appear in:
Journal of AAPOS
Received Date: 31 January 2016 Revised Date:
3 April 2017
Accepted Date: 8 May 2017
Please cite this article as: Interlandi E, Latanza L, Pellegrini F, Pavesio C, Regression of unusual optic disk neovascularization after adalimumab in a case of juvenile idiopathic arthritis–related uveitis, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2017.05.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Regression of unusual optic disk neovascularization after adalimumab in a case of juvenile idiopathic arthritis–related uveitis Emanuela Interlandi, MD, PhD,a,b Loredana Latanza, MDc Francesco Pellegrini, MD,a,b and Carlos Pavesio, MDd
RI PT
Author affiliations: aUveitis Service and bNeuro-Ophthalmology Service, Department of Ophthalmology, De Gironcoli Hospital, Conegliano, Italy; cUveitis Service, Department of Ophthalmology, A. Cardarelli Hospital, Naples, Italy, dUveitis Clinic, Moorfileds Eye Hospital, London, UK and BRC at the Institute of Ophthalmology, UCL
SC
Submitted January 31, 2016. Revision accepted April 7, 2017.
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Correspondence: Emanuela Interlandi, Via Cadore 6/c, 31015, Conegliano (TV), Italy (email: [email protected]).
AC C
EP
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Word count: 983
ACCEPTED MANUSCRIPT
We report the case of a 9-year-old girl with a severe and uncommon presentation of juvenile idiopathic arthritis–related posterior uveitis, with neovessels at the optic disk associated with peripheral vasculitis. After two failed bevacizumab intravitreal injections,
RI PT
uveitis responded to systemic adalimumab administration, with a complete and long-term remission of ocular inflammation.
Uveitis related to juvenile idiopathic arthritis (JIA) is the most common cause of pediatric uveitis
SC
in the West, mostly associated with pauciarticular, antinuclear antibody–positive cases of
arthritis.1 Ocular inflammation mostly consists of bilateral nongranulomatous anterior uveitis
M AN U
with a typical chronic and relapsing course that may be complicated by sight-threatening conditions such as cataract, glaucoma, and band keratopathy but rarely involves the posterior segment of the eye.1 Case Report
TE D
A 9-year-old girl with pauciarticular, antinuclear antibody–positive JIA was referred to the Uveitis Service of A. Cardarelli Hospital, Naples, for evaluation and treatment. She was diagnosed at 3 years of age. Six months after JIA onset she developed bilateral
EP
nongranulomatous anterior uveitis that responded to topical corticosteroids and mydriatics. Further episodes of anterior uveitis occurred over the following 3 years and always responded to
AC C
topical therapy, with preservation of good visual acuity (20/20) in both eyes. Oligoarthritis was successfully treated with systemic nonsteroidal anti-inflammatory drugs. At 13 years of age, the patient developed a relapse of ocular inflammation in the right eye
with concomitant reactivation of the arthritis in her right knee. Visual acuity in the right eye decreased to 20/65, and biomicroscopic examination disclosed nongranulomatous keratic precipitates associated with an intense anterior uveitis (flare 2+ and cells 3+). Fundus evaluation
ACCEPTED MANUSCRIPT
showed a swollen optic disk with neovessels (NVD) and signs of a mild peripheral retinal vasculitis. Fluorescein angiography disclosed intense leakage of dye at the optic disk edges and a lesser leakage in the areas affected by peripheral retinal vasculitis (Figure 1). No signs of retinal
RI PT
ischemia were detected. Indocyanine green angiography (ICG) and optic coherence tomography (OCT) were otherwise unremarkable. Corticosteroids were started promptly, and the patient underwent 2 successive intravitreal injections of bevacizumab (1.25 mg/0.05 ml) within 1 month.
SC
After the second injection there was gradual resolution of the NVD, confirmed on fluorescein angiography (Figure 2A). Visual acuity was 20/20 in the right eye at this stage.
M AN U
Six months after the second injection, right eye visual acuity again decreased to 20/50 following reactivation of the papillitis and NVD, this time also associated with light macular leakage on angiography (Figure 2B-C). Adalimumab (40 mg subcutaneously every 2 weeks) was introduced in addition to systemic steroids. Thereafter, the patient achieved a progressive
TE D
resolution of ocular inflammation and arthritis with complete resolution of the papillitis and neovessels (Figure 2D). Three months later, visual acuity in the right eye was 20/20; corticosteroids were gradually tapered. With 3 years’ follow-up, the patient is still on
EP
adalimumab. At the time of the last assessment she had visual acuity of 20/20 in the right eye and complete remission of the inflammatory disease, both articular and ocular.
AC C
Discussion
NVD is a rare occurrence in JIA-related uveitis and, to our knowledge, its treatment with adalimumab has not been described before. Although NVD may occur with chronic uveitis in a setting of prolonged inflammation, in
most cases it is associated with conditions such as retinal ischemia, vitritis, or pars planitis. NVD in association with chronic uveitis has been described previously2-6; however, in only 2 reports
ACCEPTED MANUSCRIPT
was NVD as consequence of severe JIA-related uveitis.2,3 Semple and colleagues2 reported a case of NVD occurring in a 4-year-old boy with bilateral JIA-related uveitis, and Gray and colleagues3 described 2 cases of NVD in a 13-year-old girl and a 4 year-old-boy. In these cases,
RI PT
related to the particular subtype of JIA, NVD developed without other possible causes of
neovascularization; both cases were managed with periocular or oral corticosteroids, with prompt regression of NVD but poor visual recovery, since alternative treatment options were not
SC
available at that time. Similarly, our patient presented with NVD in the right eye with no evidence of retinal ischemia.
M AN U
Pathogenesis of NVD, when not induced by hypoxia, should be investigated according to the same inflammatory mechanisms involved in severe forms of uveitis where abnormal eye angiogenic factors release might be presumed. Based on these considerations, at first occurrence of NVD, we decided to treat our patient with intravitreal injection of bevacizumab in addition to
TE D
oral steroids. This vascular endothelial growth factor (VEGF) antagonist extensively used in ophthalmology for the treatment of retinal and choroidal neovascularization, including NVD.7 However, our patient, after a transient improvement following the second injection, had a severe
EP
reactivation of NVD, forcing us to switch therapy to adalimumab, a tumor necrosis factor α (TNFα) blocker that has been used successfully in rheumatology for treatment of various
AC C
autoimmune diseases, including JIA and JIA-related uveitis.8-9 In contrast with the above-cited reports,2-3 where patients received only steroidal therapy, treatment of our patient with adalimumab resulted in a complete and prolonged regression of NVD. In addition, there was full recovery of visual acuity and an excellent long-term control of ocular inflammation, attributable to the better efficacy of this agent in relation to autoimmune mechanisms and fewer side effects compared to high doses of steroids.
ACCEPTED MANUSCRIPT
At present, the role of TNFα in angiogenesis is quite controversial. The interesting study conducted in mice by Fajardo and colleagues10 suggests a bimodal, dose-dependent mechanism
RI PT
with diametrically opposite effects, where low doses of TNFα might induce angiogenesis, whereas high doses may inhibit it. A therapeutic response in our case suggests a role of TNFα citokines rather than VEGF in development of NVD, although further studies are necessary to elucidate it.
SC
Our results confirm that JIA may be associated with severe uveitis with posterior segment
M AN U
involvement and that NVD may be an exceptionally serious complication. Literature Search
PubMed was searched on April 3, 2017, for English-language results, excluding abstracts and meeting presentations, using the following terms: juvenile idiopathic arthritis, uveitis,
AC C
EP
TE D
adalimumab, and optic disc neovascularization.
ACCEPTED MANUSCRIPT
References Tugal-Tutkun I. Pediatric uveitis. J Ophthalmic Vis Res 2011;6:259-69.
2.
Semple HC, Landers MB 3rd, Morse LS. Optic disk neovascularization in juvenile rheumatoid arthritis. Am J Ophthalmol 1990;110:210-12.
3.
RI PT
1.
Gray T, Kanski J, Lightman S. Steroid responsive disc neovascularisation in uveitis associated with juvenile chronic arthritis. Br J Ophthalmol 1998;82:327-8.
Shorb SR, Irvine AR, Kimura SJ. Optic disk neovascularization associate with chronic uveitis. Arch Ophthalmol 1976;82:175-8.
Kelly PJ, Weiter JJ. Resolution of optic disk neovascularization associated with
M AN U
5.
SC
4.
intraocular inflammation. Am J Ophtahlmol 1980;90:545-8. 6.
Pach JM, Herman DC, Garrity JA, Kalina PH. Disk neovascularization in chronic anterior uveitis. Am J Ophthalmol 1991;111:241-3.
Hoeh AE, Schaal KB, Ach T, Dithmar S. Treatment of peripapillary choroidal
TE D
7.
neovascularization with intravitreal bevacizumab. Eur J Ophthalmol. 2009;19:163-5. 8.
Zannin ME, Birolo C, Gerloni VM, et al. Safety and efficacy of infliximab and
EP
adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year follow-up data from the Italian Registry. J Rheumatol 2013;40:74-9. Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert
AC C
9.
panel recommendations for the use of anti-tumor necrosis factor biologic agents in
patients with ocular inflammatory disorders. Ophthalmology 2014;121:785-96.e3.
10.
Fajardo LF, Kwan HH, Kowalski J, Prionas SD, Allison AC. Dual role of tumor necrosis factor-alpha in angiogenesis. Am J Pathol 1992;140:539-44.
ACCEPTED MANUSCRIPT
Legends FIG 1. Fluorescein angiography (FA) of the right eye at baseline. A, Fluorescein leakage in
(NVD) leakage at 20 seconds (B), 1 minute (C), and 6 minutes (D).
RI PT
correspondence of peripheral retinal vasculitis. B-D, Sequential phases of neovessels of the disk
FIG 2. FA of the right eye after bevacizumab injections and adalimumab administration. A, Three months after second bevacizumab injection showing NVD and papillitis regression. B-C,
SC
Six months after second bevacizumab injection showing NVD and papillitis reactivation at 40
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EP
TE D
months after adalimumab administration.
M AN U
seconds (B) and 2 minutes (C) of angiogram. D, Complete regression of NVD and papillitis 3
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EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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