Cutaneous and Ocular Toxicology
ISSN: 1556-9527 (Print) 1556-9535 (Online) Journal homepage: http://www.tandfonline.com/loi/icot20
Spectral domain-optical coherence tomographic findings in patients with ankylosing spondylitis under anti-tumor necrosis factor-alpha therapy Nilufer Ilhan, Nilgul Ustun, Esra Ayhan Tuzcu, Mesut Coskun, Abdullah Erman Yagiz, Ozgur Ilhan & Nihan Parlakfikirer To cite this article: Nilufer Ilhan, Nilgul Ustun, Esra Ayhan Tuzcu, Mesut Coskun, Abdullah Erman Yagiz, Ozgur Ilhan & Nihan Parlakfikirer (2015) Spectral domain-optical coherence tomographic findings in patients with ankylosing spondylitis under anti-tumor necrosis factor-alpha therapy, Cutaneous and Ocular Toxicology, 34:3, 222-226, DOI: 10.3109/15569527.2014.956178 To link to this article: http://dx.doi.org/10.3109/15569527.2014.956178
Published online: 03 Nov 2014.
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Date: 06 November 2015, At: 05:35
http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, 2015; 34(3): 222–226 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2014.956178
RESEARCH ARTICLE
Spectral domain-optical coherence tomographic findings in patients with ankylosing spondylitis under anti-tumor necrosis factor-alpha therapy
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Nilufer Ilhan1, Nilgul Ustun2, Esra Ayhan Tuzcu1, Mesut Coskun1, Abdullah Erman Yagiz2, Ozgur Ilhan1, and Nihan Parlakfikirer1 1
Department of Ophthalmology and 2Department of Physical Therapy and Rehabilitation, Medical Faculty of Mustafa Kemal University, Hatay, Turkey Abstract
Keywords
Objective: To evaluate the effect of tumor necrosis factor-alpha (TNF-a) blockade on the thickness of the peripapillary retinal nerve fiber layer (RNFL), the ganglion cell-inner plexiform layers (GCIPL), and the macula in ankylosing spondylitis (AS) patients under anti-TNF-a therapy. Materials and methods: Twenty-one patients with AS received etanercept, or adalimumab, or infliximab for at least 6 months. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores were measured before and 6 months after the beginning of the treatment. Peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), GCIPL, and macular thicknesses of the patients were analyzed by optical coherence tomography before the treatment, at 3 months and 6 months after the beginning of the treatment. Results: The mean BASDAI, ESR, and CRP values were 5.2 ± 1.5, 31.6 ± 21.7, and 15.7 ± 13.9, respectively, at the beginning of the treatment and 2.3 ± 1.7, 21.3 ± 15.1, and 10.1 ± 10.3, respectively, 6 months after the beginning of treatment. There were significant differences among the mean BASDAI, ESR, and CRP values at the beginning of treatment and 6 months later (p50.001, p ¼ 0.007, and p ¼ 0.009, respectively). There were no significant differences among peripapillary RNFL (p ¼ 0.24), four regional fields (p ¼ 0.98, p ¼ 0.23, p ¼ 0.09, p ¼ 0.47), GCIPL (p ¼ 0.25), or macular (p ¼ 0.33) thicknesses of the patients during anti-TNF-a treatment. In addition, the mean intraocular pressure levels throughout the follow-up did not show significant variation on repeated-measures ANOVA (p ¼ 0.77). Conclusions: TNF-a blockade does not seem to influence RNFL, GCIPL, or macular thickness of patients with AS in the short term.
Macula lutea, retinal ganglion cell, spondylarthropathies
Introduction Tumor necrosis factor alpha (TNF-a) is a cytokine produced by various types of cells, but generally monocyte-macrophages, neutrophils, T lymphocytes, and fibroblasts, as a result of infection or immunologic reaction. TNF-a promotes a wide range of cellular activity, including proinflammatory cytokine production and progression of the inflammatory immune response1. Elimination of TNF-a activity leads to deactivation of proinflammatory cytokine cascade, inhibition of cell migration from blood to the inflammation area, reduced angiogenesis produced by vascular endothelial growth factor, and variation in chemokines, acute phase proteins, and matrix metalloproteinases2,3. Ankylosing spondylitis (AS) is a chronic, progressive, inflammatory disease that affects the axial skeleton and can
History Received 25 June 2014 Revised 11 August 2014 Accepted 13 August 2014 Published online 30 October 2014
lead to structural and functional impairments4. Currently, anti TNF-a agents are commonly used in severe AS patients who are not sufficiently treated by non-steroidal anti-inflammatory drugs (NSAIDs) and sulfasalazine5. In recent years, noninvasive methods for the quantitative analysis of the retina have been developed. Optical coherence tomography (OCT) is beneficial in the determination of various retinal pathologies and glaucoma6. In the current study, AS patients receiving anti-TNF-a for the first time were followed up for at least 6 months with OCT. The aim of the present study was to evaluate the effect of TNF-a blockade on the thickness of the peripapillary retinal nerve fiber layer (RNFL), the ganglion cell-inner plexiform layers (GCIPL), and the macula of AS patients under anti-TNF-a therapy.
Methods Address for correspondence: Dr Nilufer Ilhan, Department of Ophthal mology, Medical Faculty of the Mustafa Kemal University, Hatay, Turkey. E-mail: [email protected]
The study was conducted prospectively in the Department of Ophthalmology, School of Medicine, Mustafa Kemal University, and approved by the local Ethics Committee.
Anti-TNF- therapy and OCT
DOI: 10.3109/15569527.2014.956178
The study was conducted in accordance with the Declaration of Helsinki. Patients participating in the study were given detailed written and verbal information regarding the research. All the subjects signed informed consent forms.
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Subjects and ophthalmological examination Twenty-nine severe AS patients not controlled effectively with NSAIDs and sulfasalazine were enrolled at the Physical Therapy and Rehabilitation Clinic. Five patients with incomplete follow-up, one patient with infliximab-induced lupuslike syndrome, and two patients with infliximab-induced allergic reactions were excluded from the study. Other exclusion criteria were lens or other ocular media opacities, active uveitis, glaucoma, macular disease, diabetes mellitus, chronic heart disease, cardiovascular diseases, arterial hypertension, smoking, chronic inflammatory disorders including rheumatoid arthritis, psoriatic arthritis, Behcet’s disease, and inflammatory bowel disease. A detailed ophthalmological examination, including best-corrected visual acuity, intraocular pressure (IOP) measurement with Goldmann applanation tonometer, slit-lamp biomicroscopy, and fundus and OCT examinations, was performed on each patient before commencing the treatment and 3 and 6 months after the beginning of the treatment. The ophthalmological examination was done by the same ophthalmologist. Visual field test was performed on each patient at the beginning of the treatment. The study included 21 patients with 40.1 logMAR visual acuity (VA), IOP 21 mmHg, and no ophthalmological pathology or visual field defect. Scans of the macula (Macular Cube 512 1281024 protocol) and the optic discs (Optic Disc Cube 200 200 protocol) were performed using a Cirrus spectral domain (SD) OCT (Carl Zeiss Meditec, Dublin, CA), and only images with a signal power 47 were recorded. The measurements used for analysis included peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), and macular thickness. For the GCIPL analysis, the scan protocol of the macular cube was used to analyze mean CGIPL thickness. All scans were obtained by the same technician after dilating the pupils with 1% tropicamide. Active disease based on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and spinal mobility based on the Bath Ankylosing Spondylitis Metrology Index (BASMI) were evaluated by the same physical medicine and rehabilitation specialist. The patients were asked to rank their symptoms. The self-reported items are back pain, fatigue, peripheral joint pain and swelling, localized tenderness, and the duration and severity of morning stiffness. Each item was graded from 0 to 10 and the scores were averaged to determine a final score ranging from 0 (no disease activity) to 10 (maximal disease activity). BASDAI score 54 indicated low disease activity and BASDAI score 4 indicated moderate to high disease activity7. Patients with AS received etanercept, or adalimumab, or infliximab for at least 6 months. The regimens were 50 mg (subcutaneous injection) once weekly of etanercept (EnbrelÕ ; Immunex, Seattle, WA), 40 mg (subcutaneous injection) biweekly of adalimumab (HumiraÕ ; Abbott Laboratories, Abbott Park, IL), and 5 mg/kg (intravenous infusion) every
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8 weeks of infliximab (RemicadeÕ ; Schering-Plough, Welwyn Garden City, UK). The erythrocyte sedimentation rates (ESR), C-reactive protein (CRP) levels, and BASDAI scores were measured before the treatment and six months after the beginning of the treatment as part of the clinical care. Statistical analysis Statistical analyses were performed using SPSS for Windows (Statistical Package for Social Sciences 16.0; SPSS Inc., Chicago, IL). Data relating to the patients’ left eyes were used. The paired t test was used to compare ESR, CRP levels, and BASDAI scores between baseline and the sixth month of treatment. Variations in OCT parameters before commencing the treatment and 3 and 6 months later were evaluated using general linear models with repeated-measures ANOVA. p50.05 was considered to be statistically significant.
Results The mean age of the patients was 43.6 ± 7.9 years (31–60); 11 were male and 10 were female. The mean follow-up period was 8.1 ± 2.0 months and the mean duration of disease was 13.1 ± 8.6 years. The mean BASDAI, ESR, and CRP values were 5.2 ± 1.5, 31.6 ± 21.7, and 15.7 ± 13.9, respectively, at the beginning of the treatment and 2.3 ± 1.7, 21.3 ± 15.1, and 10.1 ± 10.3, respectively, 6 months after the beginning of the treatment. Demographic, clinical, and laboratory features of the patients are shown in Table 1. The mean IOP values of the patients were 16.6 ± 3.6 mmHg at the beginning, 17.1 ± 2.8 mmHg at 3 months, and 16.7 ± 2.7 mmHg at 6 months. The mean values of the peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), GCIPL, and macular thicknesses of the patients during anti-TNF-a therapy are shown in Table 2; no significant differences among those parameters were found. The mean IOP levels throughout the follow-up also showed no significant variation on repeated-measures ANOVA (p ¼ 0.77, Greenhouse–Geisser correction). There was significant difference among the mean BASDAI, ESR, and CRP values at the beginning of the treatment and 6 months after the beginning of the treatment (p50.001, p ¼ 0.007, p ¼ 0.009, respectively). In one 53-year-old patient, etanercept-induced acute uveitis developed in the right eye during the seventh month of treatment. Topical and periocular steroid agents and cycloplegic drops were administered, etanercept was stopped, and adalimumab treatment was started. The flares in the anterior chamber diminished, and IOP was 20 mmHg after 1 month.
Discussion Ankylosing spondylitis is the prototype of immune-mediated inflammatory rheumatic diseases characterized by back pain and stiffness of joints with inflammation at the tendon insertions8. TNF-a plays an important role in the pathogenesis of AS; therefore, TNF-a blockers are widely used in refractory or severe AS. The anti-TNF-a agents most frequently used include infliximab (a chimeric human Ig G1
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Cutan Ocul Toxicol, 2015; 34(3): 222–226
Table 1. Demographic, clinical, and laboratory features of the study patients. BASDAI
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Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
ESR (mm/h)
CRP (mg/L)
Gender
Age
Duration of disease (years)
Anti TNF agent
Initial
6th month
Initial
6th month
Initial
6th month
F M M F F M M F M M F F M M M M F F F F M
35 44 45 53 49 42 30 58 48 36 47 35 38 32 43 41 53 33 44 36 53
8 20 8 10 5 23 7 40 10 20 6 5 5 8 20 12 20 9 8 10 21
ETN ETN ETN ADA ETN ADA ADA ADA ADA ETN ETN ADA INF ETN INF INF ETN ETN ADA INF ETN
6.5 3 6.2 3.6 5.4 4.6 4.2 7.2 4.8 8.6 4.8 4 6 3.6 2.6 5 6 7.6 5.8 3.8 6.8
4 2 0 2.6 5 0 1.8 4.6 0.4 0 0.6 2.6 4 0.6 0 1.6 4 4 4 3 4.6
69 27 35 20 34 37 9 17 25 32 48 9 53 5 5 6 32 68 59 8 66
27 10 20 32 42 2 2 15 21 24 15 10 34 5 4 9 37 53 47 12 28
39 9.6 7.9 43.5 12 29.9 3.3 3.3 32.8 33.4 10 13.9 33 4.3 0.6 3.3 3.3 6.17 13 3.3 26
26.3 3.3 4.5 24.5 13.5 3.4 3.3 3.3 9.27 24.9 4.9 4.2 40.6 3.3 3.3 3.3 3.3 7.28 10.7 3.3 12
TNF, tumor necrosis factor; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; ESR, erythrocyte sedimentation rates (0–20 mm/h); CRP, C-reactive protein (0–5 mg/L); F, female; M, male; ETN, etanercept; ADA, adalimumab; INF, infliximab.
Table 2. Mean peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), macular, and GCIPL thicknesses of patients with ankylosing spondylitis under anti-TNF-a therapy.
RNFL Peripapillary RNFL (mean ± SD, mm) Superior (mean ± SD, mm) Inferior (mean ± SD, mm) Nasal (mean ± SD, mm)) Temporal (mean ± SD, mm) GCIPL (mean ± SD, mm) Macula (mean ± SD, mm)
Initial
3th month
6th month
p value*
98.5 ± 10.7 126.5 ± 12.2 125.8 ± 24.0 74.3 ± 9.3 66.8 ± 10.8 84.9 ± 5.5 254.0 ± 31.3
100.1 ± 10.5 126.6 ± 12.2 130.1 ± 17.1 78.0 ± 11.3 67.3 ± 9.9 85.1 ± 5.7 250.3 ± 24.2
100.4 ± 10.6 126.7 ± 12.0 131.0 ± 17.7 76.7 ± 10.7 67.8 ± 11.1 85.4 ± 5.5 249.6 ± 24.0
0.24 0.98 0.23 0.09 0.47 0.25 0.33
RNFL, retinal nerve fiber layer thickness; SD, Standard deviation; GCIPL, ganglion cell-inner plexiform layers. *Repeated-measures ANOVA with the Greenhouse–Geisser correction.
with a mouse variable fragment with high TNF-a affinity), adalimumab (a fully humanized antibody against TNF-a), and etanercept (a recombinant dimeric protein of human TNF-a receptor linked to the fragment crystallizable portion of human IgG1)9. Although CRP and ESR sensitivity is controversial10, clinicians benefit from using these technically simple, inexpensive inflammatory markers for monitoring anti-TNF-a usage11,12. In the current study, CRP and ESR (as laboratory markers) and BASDAI (as a disease activity indicator) were used to predict the response to TNF-a blockers. We found a significant difference in mean BASDAI, ESR, and CRP values between the baseline and 6 months after the beginning of the treatment, indicating that patients with AS benefit from anti-TNF-a treatment. The relationship between TNF-a and glaucomatous changes has been demonstrated in human and animal studies, which have revealed elevated serum and intraocular TNF-a
levels13,14. TNF-a has been associated with retinal ganglion cell (RGC) death as a mediator in glaucomatous retina15, and Tezel and Wax reported that RGC apoptosis was decreased by a neutralizing antibody against TNF-a16. Nakazawa et al.17 found that blockade of TNF-a with a blocking antibody or deletion of the gene encoding TNF-a in genetically adapted mice directly prevents ocular hypertension (OH)-induced oligodendrocyte degeneration and the indirect loss of RGC. There is no published data regarding the effects of anti-TNF-a agents in eyes with normal IOPs. The current study did not include patients with OH or glaucoma, because our AS patient profile does not involve many OH or glaucoma cases. Although there were no significant differences in RNFL, GCIPL, or IOP between the baseline and 3 and 6 months after beginning of administration of the anti-TNF-a agents, these results cannot be supported by previous studies. A study including AS patients with OH or glaucoma might better to
Anti-TNF- therapy and OCT
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DOI: 10.3109/15569527.2014.956178
evaluate the effects of the TNF-a blockers on RNFL, GCIPL, and IOP. TNF-a blockers with anti-inflammatory features are considered an alternative for non-infectious ocular inflammation, particularly when more conventional glucocorticoid or antimetabolite treatments are ineffective to control the inflammation or unwanted clinical complications18. DiazLlopis et al. presented their results of anti-TNF-a treatment of 33 eyes with cystoid macular edema (CME) in 19 patients with severe autoimmune uveitis. After a year of administering adalimumab subcutaneously, 54.5% of the eyes with CME completely resolved, and 31% had an improvement in VA19. A non-comparative case series of infliximab in uveitic patients with chronic CME without clinically evident ocular inflammation suggested that infliximab reduced macular thickness and that VA improved20. Fukuda et al.21 reported the case of a patient with rheumatoid arthritis-associated panuveitis that was successfully treated with etanercept. In addition, preliminary studies have found a positive effect of intravenously administered infliximab on sight-threatening diabetic macular edema (DME) and neovascular age-related macular degeneration22,23. The particular nature of ocular diseases, in that they are restricted to ocular tissues, leads to the usage of intravitreal drug injections to achieve higher concentrations. Unfortunately, however, severe intraocular inflammatory reactions have been reported after intravitreal injection of infliximab24,25. Only the results of the same author’s study showed that intravitreal infliximab for refractory pseudophakic cystoid macular edema is beneficial in reducing macular edema and improving VA26. Based on these data, systemically administered anti-TNF-a agents might be considered beneficial to treat eyes with macular edema. In the current study, there was no macular edema in our patients; therefore, we did not observe a significant decrease in macular thickness. In addition, we did not include uveitic or diabetic patients. Therefore, we may conclude that TNF-a blockers have no effect on macular thickness in eyes with normal macular anatomy. There is a high margin of error when analyzing OCT segmentation in retinal morphologic pathologies; however, the segmentation error is very small in eyes with normal retinas27. Our study included only patients without retinal pathology. In addition, SD-OCT was used for the RNFL, GCIPL, and macula analyses in the current study; the Cirrus SD-OCT has excellent reliability of repeatability on RNFL measurements in healthy eyes28. Although biological therapies are widely used in rheumatological conditions, there are several side effects of antiTNF-a agents, such as infusion site reactions, infections, autoimmune diseases, drug-induced lupus erythematosus, liver function abnormalities, and malignancies29. Acute allergic reactions are seen in almost 5% of intravenous applications of infliximab30. In the current study, a patient receiving infliximab developed a lupus-like syndrome, and two patients were excluded because they developed infliximab-induced allergic reactions and had to switch to another TNF-a blocker within 6 months. Etanercept-induced acute uveitis developed in one patient; however, he was not excluded, as the uveitis occurred in the seventh month of the treatment. Although population-based studies of patients
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with AS have demonstrated that TNF-a blockers prevent uveitis, conversely, etanercept is deemed the main cause of uveitis according to anecdotal reports31–33.
Conclusions There are some limitations of the current study. First, the follow-up time was short and the sample size was small. Second, the TNF-a blockers were not uniform. Third, because we excluded patients with glaucoma or uveitis, we could not observe the effects of those agents on glaucomatous and uveitic eyes. The number of the patients was limited because of wide range of exclusion criteria, breakdowns during the follow-up, and drug-induced side effects. Despite these limitations, the study is important, because there is no published data investigating the effects of TNF-a inhibitors on retina of the AS patients without glaucoma and uveitis. We found that TNF-a blockade does not seem to affect RNFL, GCIPL, or macular thickness of patients with AS in the short term but further long-term and comprehensive studies are needed to determine the outcomes of these biological agents on the retina.
Declaration of interest The authors report that they have no declarations of interest.
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ISSN: 1556-9527 (Print) 1556-9535 (Online) Journal homepage: http://www.tandfonline.com/loi/icot20
Spectral domain-optical coherence tomographic findings in patients with ankylosing spondylitis under anti-tumor necrosis factor-alpha therapy Nilufer Ilhan, Nilgul Ustun, Esra Ayhan Tuzcu, Mesut Coskun, Abdullah Erman Yagiz, Ozgur Ilhan & Nihan Parlakfikirer To cite this article: Nilufer Ilhan, Nilgul Ustun, Esra Ayhan Tuzcu, Mesut Coskun, Abdullah Erman Yagiz, Ozgur Ilhan & Nihan Parlakfikirer (2015) Spectral domain-optical coherence tomographic findings in patients with ankylosing spondylitis under anti-tumor necrosis factor-alpha therapy, Cutaneous and Ocular Toxicology, 34:3, 222-226, DOI: 10.3109/15569527.2014.956178 To link to this article: http://dx.doi.org/10.3109/15569527.2014.956178
Published online: 03 Nov 2014.
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Article views: 23
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icot20 Download by: [Washington University in St Louis]
Date: 06 November 2015, At: 05:35
http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, 2015; 34(3): 222–226 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2014.956178
RESEARCH ARTICLE
Spectral domain-optical coherence tomographic findings in patients with ankylosing spondylitis under anti-tumor necrosis factor-alpha therapy
Downloaded by [Washington University in St Louis] at 05:35 06 November 2015
Nilufer Ilhan1, Nilgul Ustun2, Esra Ayhan Tuzcu1, Mesut Coskun1, Abdullah Erman Yagiz2, Ozgur Ilhan1, and Nihan Parlakfikirer1 1
Department of Ophthalmology and 2Department of Physical Therapy and Rehabilitation, Medical Faculty of Mustafa Kemal University, Hatay, Turkey Abstract
Keywords
Objective: To evaluate the effect of tumor necrosis factor-alpha (TNF-a) blockade on the thickness of the peripapillary retinal nerve fiber layer (RNFL), the ganglion cell-inner plexiform layers (GCIPL), and the macula in ankylosing spondylitis (AS) patients under anti-TNF-a therapy. Materials and methods: Twenty-one patients with AS received etanercept, or adalimumab, or infliximab for at least 6 months. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores were measured before and 6 months after the beginning of the treatment. Peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), GCIPL, and macular thicknesses of the patients were analyzed by optical coherence tomography before the treatment, at 3 months and 6 months after the beginning of the treatment. Results: The mean BASDAI, ESR, and CRP values were 5.2 ± 1.5, 31.6 ± 21.7, and 15.7 ± 13.9, respectively, at the beginning of the treatment and 2.3 ± 1.7, 21.3 ± 15.1, and 10.1 ± 10.3, respectively, 6 months after the beginning of treatment. There were significant differences among the mean BASDAI, ESR, and CRP values at the beginning of treatment and 6 months later (p50.001, p ¼ 0.007, and p ¼ 0.009, respectively). There were no significant differences among peripapillary RNFL (p ¼ 0.24), four regional fields (p ¼ 0.98, p ¼ 0.23, p ¼ 0.09, p ¼ 0.47), GCIPL (p ¼ 0.25), or macular (p ¼ 0.33) thicknesses of the patients during anti-TNF-a treatment. In addition, the mean intraocular pressure levels throughout the follow-up did not show significant variation on repeated-measures ANOVA (p ¼ 0.77). Conclusions: TNF-a blockade does not seem to influence RNFL, GCIPL, or macular thickness of patients with AS in the short term.
Macula lutea, retinal ganglion cell, spondylarthropathies
Introduction Tumor necrosis factor alpha (TNF-a) is a cytokine produced by various types of cells, but generally monocyte-macrophages, neutrophils, T lymphocytes, and fibroblasts, as a result of infection or immunologic reaction. TNF-a promotes a wide range of cellular activity, including proinflammatory cytokine production and progression of the inflammatory immune response1. Elimination of TNF-a activity leads to deactivation of proinflammatory cytokine cascade, inhibition of cell migration from blood to the inflammation area, reduced angiogenesis produced by vascular endothelial growth factor, and variation in chemokines, acute phase proteins, and matrix metalloproteinases2,3. Ankylosing spondylitis (AS) is a chronic, progressive, inflammatory disease that affects the axial skeleton and can
History Received 25 June 2014 Revised 11 August 2014 Accepted 13 August 2014 Published online 30 October 2014
lead to structural and functional impairments4. Currently, anti TNF-a agents are commonly used in severe AS patients who are not sufficiently treated by non-steroidal anti-inflammatory drugs (NSAIDs) and sulfasalazine5. In recent years, noninvasive methods for the quantitative analysis of the retina have been developed. Optical coherence tomography (OCT) is beneficial in the determination of various retinal pathologies and glaucoma6. In the current study, AS patients receiving anti-TNF-a for the first time were followed up for at least 6 months with OCT. The aim of the present study was to evaluate the effect of TNF-a blockade on the thickness of the peripapillary retinal nerve fiber layer (RNFL), the ganglion cell-inner plexiform layers (GCIPL), and the macula of AS patients under anti-TNF-a therapy.
Methods Address for correspondence: Dr Nilufer Ilhan, Department of Ophthal mology, Medical Faculty of the Mustafa Kemal University, Hatay, Turkey. E-mail: [email protected]
The study was conducted prospectively in the Department of Ophthalmology, School of Medicine, Mustafa Kemal University, and approved by the local Ethics Committee.
Anti-TNF- therapy and OCT
DOI: 10.3109/15569527.2014.956178
The study was conducted in accordance with the Declaration of Helsinki. Patients participating in the study were given detailed written and verbal information regarding the research. All the subjects signed informed consent forms.
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Subjects and ophthalmological examination Twenty-nine severe AS patients not controlled effectively with NSAIDs and sulfasalazine were enrolled at the Physical Therapy and Rehabilitation Clinic. Five patients with incomplete follow-up, one patient with infliximab-induced lupuslike syndrome, and two patients with infliximab-induced allergic reactions were excluded from the study. Other exclusion criteria were lens or other ocular media opacities, active uveitis, glaucoma, macular disease, diabetes mellitus, chronic heart disease, cardiovascular diseases, arterial hypertension, smoking, chronic inflammatory disorders including rheumatoid arthritis, psoriatic arthritis, Behcet’s disease, and inflammatory bowel disease. A detailed ophthalmological examination, including best-corrected visual acuity, intraocular pressure (IOP) measurement with Goldmann applanation tonometer, slit-lamp biomicroscopy, and fundus and OCT examinations, was performed on each patient before commencing the treatment and 3 and 6 months after the beginning of the treatment. The ophthalmological examination was done by the same ophthalmologist. Visual field test was performed on each patient at the beginning of the treatment. The study included 21 patients with 40.1 logMAR visual acuity (VA), IOP 21 mmHg, and no ophthalmological pathology or visual field defect. Scans of the macula (Macular Cube 512 1281024 protocol) and the optic discs (Optic Disc Cube 200 200 protocol) were performed using a Cirrus spectral domain (SD) OCT (Carl Zeiss Meditec, Dublin, CA), and only images with a signal power 47 were recorded. The measurements used for analysis included peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), and macular thickness. For the GCIPL analysis, the scan protocol of the macular cube was used to analyze mean CGIPL thickness. All scans were obtained by the same technician after dilating the pupils with 1% tropicamide. Active disease based on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and spinal mobility based on the Bath Ankylosing Spondylitis Metrology Index (BASMI) were evaluated by the same physical medicine and rehabilitation specialist. The patients were asked to rank their symptoms. The self-reported items are back pain, fatigue, peripheral joint pain and swelling, localized tenderness, and the duration and severity of morning stiffness. Each item was graded from 0 to 10 and the scores were averaged to determine a final score ranging from 0 (no disease activity) to 10 (maximal disease activity). BASDAI score 54 indicated low disease activity and BASDAI score 4 indicated moderate to high disease activity7. Patients with AS received etanercept, or adalimumab, or infliximab for at least 6 months. The regimens were 50 mg (subcutaneous injection) once weekly of etanercept (EnbrelÕ ; Immunex, Seattle, WA), 40 mg (subcutaneous injection) biweekly of adalimumab (HumiraÕ ; Abbott Laboratories, Abbott Park, IL), and 5 mg/kg (intravenous infusion) every
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8 weeks of infliximab (RemicadeÕ ; Schering-Plough, Welwyn Garden City, UK). The erythrocyte sedimentation rates (ESR), C-reactive protein (CRP) levels, and BASDAI scores were measured before the treatment and six months after the beginning of the treatment as part of the clinical care. Statistical analysis Statistical analyses were performed using SPSS for Windows (Statistical Package for Social Sciences 16.0; SPSS Inc., Chicago, IL). Data relating to the patients’ left eyes were used. The paired t test was used to compare ESR, CRP levels, and BASDAI scores between baseline and the sixth month of treatment. Variations in OCT parameters before commencing the treatment and 3 and 6 months later were evaluated using general linear models with repeated-measures ANOVA. p50.05 was considered to be statistically significant.
Results The mean age of the patients was 43.6 ± 7.9 years (31–60); 11 were male and 10 were female. The mean follow-up period was 8.1 ± 2.0 months and the mean duration of disease was 13.1 ± 8.6 years. The mean BASDAI, ESR, and CRP values were 5.2 ± 1.5, 31.6 ± 21.7, and 15.7 ± 13.9, respectively, at the beginning of the treatment and 2.3 ± 1.7, 21.3 ± 15.1, and 10.1 ± 10.3, respectively, 6 months after the beginning of the treatment. Demographic, clinical, and laboratory features of the patients are shown in Table 1. The mean IOP values of the patients were 16.6 ± 3.6 mmHg at the beginning, 17.1 ± 2.8 mmHg at 3 months, and 16.7 ± 2.7 mmHg at 6 months. The mean values of the peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), GCIPL, and macular thicknesses of the patients during anti-TNF-a therapy are shown in Table 2; no significant differences among those parameters were found. The mean IOP levels throughout the follow-up also showed no significant variation on repeated-measures ANOVA (p ¼ 0.77, Greenhouse–Geisser correction). There was significant difference among the mean BASDAI, ESR, and CRP values at the beginning of the treatment and 6 months after the beginning of the treatment (p50.001, p ¼ 0.007, p ¼ 0.009, respectively). In one 53-year-old patient, etanercept-induced acute uveitis developed in the right eye during the seventh month of treatment. Topical and periocular steroid agents and cycloplegic drops were administered, etanercept was stopped, and adalimumab treatment was started. The flares in the anterior chamber diminished, and IOP was 20 mmHg after 1 month.
Discussion Ankylosing spondylitis is the prototype of immune-mediated inflammatory rheumatic diseases characterized by back pain and stiffness of joints with inflammation at the tendon insertions8. TNF-a plays an important role in the pathogenesis of AS; therefore, TNF-a blockers are widely used in refractory or severe AS. The anti-TNF-a agents most frequently used include infliximab (a chimeric human Ig G1
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Cutan Ocul Toxicol, 2015; 34(3): 222–226
Table 1. Demographic, clinical, and laboratory features of the study patients. BASDAI
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Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
ESR (mm/h)
CRP (mg/L)
Gender
Age
Duration of disease (years)
Anti TNF agent
Initial
6th month
Initial
6th month
Initial
6th month
F M M F F M M F M M F F M M M M F F F F M
35 44 45 53 49 42 30 58 48 36 47 35 38 32 43 41 53 33 44 36 53
8 20 8 10 5 23 7 40 10 20 6 5 5 8 20 12 20 9 8 10 21
ETN ETN ETN ADA ETN ADA ADA ADA ADA ETN ETN ADA INF ETN INF INF ETN ETN ADA INF ETN
6.5 3 6.2 3.6 5.4 4.6 4.2 7.2 4.8 8.6 4.8 4 6 3.6 2.6 5 6 7.6 5.8 3.8 6.8
4 2 0 2.6 5 0 1.8 4.6 0.4 0 0.6 2.6 4 0.6 0 1.6 4 4 4 3 4.6
69 27 35 20 34 37 9 17 25 32 48 9 53 5 5 6 32 68 59 8 66
27 10 20 32 42 2 2 15 21 24 15 10 34 5 4 9 37 53 47 12 28
39 9.6 7.9 43.5 12 29.9 3.3 3.3 32.8 33.4 10 13.9 33 4.3 0.6 3.3 3.3 6.17 13 3.3 26
26.3 3.3 4.5 24.5 13.5 3.4 3.3 3.3 9.27 24.9 4.9 4.2 40.6 3.3 3.3 3.3 3.3 7.28 10.7 3.3 12
TNF, tumor necrosis factor; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; ESR, erythrocyte sedimentation rates (0–20 mm/h); CRP, C-reactive protein (0–5 mg/L); F, female; M, male; ETN, etanercept; ADA, adalimumab; INF, infliximab.
Table 2. Mean peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), macular, and GCIPL thicknesses of patients with ankylosing spondylitis under anti-TNF-a therapy.
RNFL Peripapillary RNFL (mean ± SD, mm) Superior (mean ± SD, mm) Inferior (mean ± SD, mm) Nasal (mean ± SD, mm)) Temporal (mean ± SD, mm) GCIPL (mean ± SD, mm) Macula (mean ± SD, mm)
Initial
3th month
6th month
p value*
98.5 ± 10.7 126.5 ± 12.2 125.8 ± 24.0 74.3 ± 9.3 66.8 ± 10.8 84.9 ± 5.5 254.0 ± 31.3
100.1 ± 10.5 126.6 ± 12.2 130.1 ± 17.1 78.0 ± 11.3 67.3 ± 9.9 85.1 ± 5.7 250.3 ± 24.2
100.4 ± 10.6 126.7 ± 12.0 131.0 ± 17.7 76.7 ± 10.7 67.8 ± 11.1 85.4 ± 5.5 249.6 ± 24.0
0.24 0.98 0.23 0.09 0.47 0.25 0.33
RNFL, retinal nerve fiber layer thickness; SD, Standard deviation; GCIPL, ganglion cell-inner plexiform layers. *Repeated-measures ANOVA with the Greenhouse–Geisser correction.
with a mouse variable fragment with high TNF-a affinity), adalimumab (a fully humanized antibody against TNF-a), and etanercept (a recombinant dimeric protein of human TNF-a receptor linked to the fragment crystallizable portion of human IgG1)9. Although CRP and ESR sensitivity is controversial10, clinicians benefit from using these technically simple, inexpensive inflammatory markers for monitoring anti-TNF-a usage11,12. In the current study, CRP and ESR (as laboratory markers) and BASDAI (as a disease activity indicator) were used to predict the response to TNF-a blockers. We found a significant difference in mean BASDAI, ESR, and CRP values between the baseline and 6 months after the beginning of the treatment, indicating that patients with AS benefit from anti-TNF-a treatment. The relationship between TNF-a and glaucomatous changes has been demonstrated in human and animal studies, which have revealed elevated serum and intraocular TNF-a
levels13,14. TNF-a has been associated with retinal ganglion cell (RGC) death as a mediator in glaucomatous retina15, and Tezel and Wax reported that RGC apoptosis was decreased by a neutralizing antibody against TNF-a16. Nakazawa et al.17 found that blockade of TNF-a with a blocking antibody or deletion of the gene encoding TNF-a in genetically adapted mice directly prevents ocular hypertension (OH)-induced oligodendrocyte degeneration and the indirect loss of RGC. There is no published data regarding the effects of anti-TNF-a agents in eyes with normal IOPs. The current study did not include patients with OH or glaucoma, because our AS patient profile does not involve many OH or glaucoma cases. Although there were no significant differences in RNFL, GCIPL, or IOP between the baseline and 3 and 6 months after beginning of administration of the anti-TNF-a agents, these results cannot be supported by previous studies. A study including AS patients with OH or glaucoma might better to
Anti-TNF- therapy and OCT
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DOI: 10.3109/15569527.2014.956178
evaluate the effects of the TNF-a blockers on RNFL, GCIPL, and IOP. TNF-a blockers with anti-inflammatory features are considered an alternative for non-infectious ocular inflammation, particularly when more conventional glucocorticoid or antimetabolite treatments are ineffective to control the inflammation or unwanted clinical complications18. DiazLlopis et al. presented their results of anti-TNF-a treatment of 33 eyes with cystoid macular edema (CME) in 19 patients with severe autoimmune uveitis. After a year of administering adalimumab subcutaneously, 54.5% of the eyes with CME completely resolved, and 31% had an improvement in VA19. A non-comparative case series of infliximab in uveitic patients with chronic CME without clinically evident ocular inflammation suggested that infliximab reduced macular thickness and that VA improved20. Fukuda et al.21 reported the case of a patient with rheumatoid arthritis-associated panuveitis that was successfully treated with etanercept. In addition, preliminary studies have found a positive effect of intravenously administered infliximab on sight-threatening diabetic macular edema (DME) and neovascular age-related macular degeneration22,23. The particular nature of ocular diseases, in that they are restricted to ocular tissues, leads to the usage of intravitreal drug injections to achieve higher concentrations. Unfortunately, however, severe intraocular inflammatory reactions have been reported after intravitreal injection of infliximab24,25. Only the results of the same author’s study showed that intravitreal infliximab for refractory pseudophakic cystoid macular edema is beneficial in reducing macular edema and improving VA26. Based on these data, systemically administered anti-TNF-a agents might be considered beneficial to treat eyes with macular edema. In the current study, there was no macular edema in our patients; therefore, we did not observe a significant decrease in macular thickness. In addition, we did not include uveitic or diabetic patients. Therefore, we may conclude that TNF-a blockers have no effect on macular thickness in eyes with normal macular anatomy. There is a high margin of error when analyzing OCT segmentation in retinal morphologic pathologies; however, the segmentation error is very small in eyes with normal retinas27. Our study included only patients without retinal pathology. In addition, SD-OCT was used for the RNFL, GCIPL, and macula analyses in the current study; the Cirrus SD-OCT has excellent reliability of repeatability on RNFL measurements in healthy eyes28. Although biological therapies are widely used in rheumatological conditions, there are several side effects of antiTNF-a agents, such as infusion site reactions, infections, autoimmune diseases, drug-induced lupus erythematosus, liver function abnormalities, and malignancies29. Acute allergic reactions are seen in almost 5% of intravenous applications of infliximab30. In the current study, a patient receiving infliximab developed a lupus-like syndrome, and two patients were excluded because they developed infliximab-induced allergic reactions and had to switch to another TNF-a blocker within 6 months. Etanercept-induced acute uveitis developed in one patient; however, he was not excluded, as the uveitis occurred in the seventh month of the treatment. Although population-based studies of patients
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with AS have demonstrated that TNF-a blockers prevent uveitis, conversely, etanercept is deemed the main cause of uveitis according to anecdotal reports31–33.
Conclusions There are some limitations of the current study. First, the follow-up time was short and the sample size was small. Second, the TNF-a blockers were not uniform. Third, because we excluded patients with glaucoma or uveitis, we could not observe the effects of those agents on glaucomatous and uveitic eyes. The number of the patients was limited because of wide range of exclusion criteria, breakdowns during the follow-up, and drug-induced side effects. Despite these limitations, the study is important, because there is no published data investigating the effects of TNF-a inhibitors on retina of the AS patients without glaucoma and uveitis. We found that TNF-a blockade does not seem to affect RNFL, GCIPL, or macular thickness of patients with AS in the short term but further long-term and comprehensive studies are needed to determine the outcomes of these biological agents on the retina.
Declaration of interest The authors report that they have no declarations of interest.
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