Microsoft Word - 5. Omar Rashid 132 Vol. 28, No. 3, Jul – Sep, 2012 Pakistan Journal of Ophthalmology Original Article Role of Subconjunctival Bevacizumab in Treatment of Pterygium Rashid Omar, Sarosh Rimsha, Raja Waseem, Rashid Arshad, Banday Shahid Shahzada, Sayed Iqbal Assif Pak J Ophthalmol 2012, Vol. 28 No. 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . See end of article for authors affiliations …..……………………….. Correspondence to: Omar Rashid 77, Osman abad Ashpeer Sopore -193201 J & K India …..……………………….. Purpose: To assess the efficacy and role of sub-conjunctival Bevacizumab in treatment of primary and recurrent pterygium. Material and Methods: This off-label, single-dose, interventional case series was conducted at Government Medical College Hospital in Srinagar from January 2011 to March 2011 in patients with primary pterygium. Twenty eyes of 20 patients with primary pterygium were selected and a single dose of sub- conjunctival injection of Bevacizumab (0.05 ml, 1.25mg) was given. Pterygium vascularity and thickness was graded. The size of the pterygium (measured by surface area in cm2) was recorded from baseline to 6 weeks, after injection. Treatment-related complications and adverse events were reported. The main outcome measurements were the change in size, vascularity and thickness. Results: There were 15 males (75%) and 5 females (25%) of 20 patients with a mean age of 45.5years (SD 11.68 years). There was a significant difference in the mean surface area of pterygium at different intervals (P < 0.05) and the size of pterygium were reduced. On comparison of the mean pterygium size, there was no significant difference between men and women (P >0.05). Conclusion: Sub-conjunctival bevacizumab injection is useful in management of patients with primary pterygium without local or systemic adverse effects. terygium is a triangular sheet of fibro vascular tissue that encroaches the cornea1,2. It occurs in the inter-palpebral fissure, more commonly on the nasal side of the eye and is often bilateral1,3. Recent studies have provided evidence implicating genetic components, anti-apoptotic mechanisms, cytokines, growth factors, extra cellular matrix remodeling, immunological mechanisms, and viral infections in the pathogenesis of the disease4-8. Vascular growth factors such as vascular endothelial growth factor (VEGF) have been detected in pterygium9-12. Jin and colleagues showed that pterygia contain decreased levels of pigment epithelium-derived factor, angiogenic inhibitor, and elevated VEGF levels12. The treatment of pterygium is myriad, with various treatments being advocated in the scientific literature13. Bevacizumab is a full-length, humanized, mono- clonal antibody against all types of VEGF. It binds to and neutralizes the biologic activity of all subtypes of human VEGF14. Bevacizumab is now an established modality in treatment of choroidal neovascularization due to age-related macular degeneration (ARMD), and diabetic macular edema. Bevacizumab, when administered intra-vitreally, is well tolerated and associated with improvement in visual acuity, decreased central retinal thickness, and reduction in angiographic leakage15-17. We conducted this study to asses the effects of Bevacizumab on ptregium, which has been shown to have VEGF in its matrix. MATERIAL AND METHODS This off-label, single-dosing, interventional case series was conducted at Government Medical College Hospital in Srinagar from January 2011 to March 2011 in patients with primary and recurrent pterygium. Pterygium measurement and grading was done according to Tan and coworkers grading scheme proposed in 199718. Grading is based on the visibility P ROLE OF SUBCONJUNCTIVAL BEVACIZUMAB IN TREATMENT OF PTERYGIUM Pakistan Journal of Ophthalmology Vol. 28, No. 3, Jul – Sep, 2012 133 of the underlying episcleral blood vessels. The pterygia were classified into grades I, II, or III based on slit lamp bio microscopy evaluation. Grade I (atrophic) had clearly visible episcleral vessels under the body of the pterygium. Grade II (intermediate) had partially visible episcleral vessels under the body of the pterygium. In grade III (fleshy) episcleral vessels were not visible under the body of the pterygium. On baseline examination, Grade II and grade III pterygium patients were included in the study. Exclusion criteria included grade I pterygium, any condition for which bevacizumab is contraindicated (hypertension, proteinuria, previous myocardial infarction or stroke). A complete eye evaluation was performed for each patient. This included visual acuity, applanation tonometry and slit lamp examination. The dimensions of the pterygium were determined by measuring its length in centimeters, from base (using the caruncle as landmark) to apex, and width in centimeters at the base and apical areas. 0.05 cc of bevacizumab (1.25 mg) was injected in sub-conjunctival area of pterygium body using an insulin syringe with 30- gauge needle and lid retractor at place. Patients were followed up after1, 3, and 8 weeks. A complete ophthalmologic evaluation was done for each follow- up. Any complications and adverse events were noted. Post injection complications such as ocular surface toxicity, corneal abrasion, persistent epithelial defect, sub-conjunctival hemorrhage, infection, were noted. RESULTS From Jan 2011 to March 2011, 20 patients (15 males 75% and 5 females 25%) were involved in the study. Patient age ranged from 24 to 62 years with mean of 43.5 years [standard deviation (SD) 10.58 years]. According to the results of table 1, average pterygium size reduction in the right eye (P=0.004), left eye (P=0.041) and both the eyes (P=0.002) during four stages of the study was significant. As seen from table 2 and 3, we had 12 cases of grade III and 8 cases of grade II pterygium selected for intervention. After a sub-conjunctival injection of Bevacizumab, 4 cases of grade III pterygium changed to grade II, and 3 changed to grade I. Also 4 cases of grade II pterygium changed to grade I after Bevacizumab injection. No ocular surface toxicity, persistent epithelial defects, corneal abrasion, infections, or uveitis were reported during the study. DISCUSSION Pterygium is a chronic, degenerative disorder described histologically as elastotic degeneration of conjunctival tissue. It has a stromal overgrowth of fibroblasts and blood vessels accompanied by an inflammatory cell infiltrate and abnormal extra cellular matrix accumulation composed of elastin and collagen4. Our study took into account the changes in the size and vascularity (grade) of pterygium after a sub– conjunctival injection of Bevacizumab. Comparing the size of pterygium, as seen in table 1 after an injection of Bevacizumab, we found a statistically significant reduction in length of pterygium as measured from caruncle (significant p-value using ANNOVA test). These results can be compared to a study done by Besharatiet al19. However, the dosage used by these workers was different. This encouraging result was supported by the changes seen in the vascularity or the grades of pterygium after our intervention. Eleven cases changed from a higher grade to a lower one, highlighting the decrease in the vascular component of the pterygia (significant p-value, using chi-square test). Over expression of VEGF in pterygium tissue20 and ocular inflammation21 together with the RASHID OMAR, et al 134 Vol. 28, No. 3, Jul – Sep, 2012 Pakistan Journal of Ophthalmology abundance of new vessels supported the role of angiogenesis in the formation of pterygias22-24. In a study done by Asergadoo25, it was found that if pterygium is going to recur, it usually grows back or shows signs of recurrence during the first three months. Our study observed effects maintenance of effects for at least 2 months. No local irritation, allergic reaction, or surface epitheliopathy was observed. This is in contrast with a 60% rate of spontaneous loss of epithelial integrity as recently reported by Kim et al where topical bevacizumab was used twice daily for a much longer period (3 months), and adverse effects generally appeared during the second month of treatment26. This suggests that the duration of treatment may well determine the safety of topical Bevacizumab. CONCLUSION This study showed that sub-conjunctival injection of bevacizumab is useful in treatment of patients with primary pterygium without local or systemic adverse effects. Author’s affiliation Dr. Rashid Omar Senior Resident Department of Ophthalmolgy HIMSR, Jamia Hamdard University, Hamdard Nagar Delhi-62 Dr. Sarosh Rimsha Resident Department of Ophthalmology Government Medical College Srinagar-190010 Dr. Raja Waseem Resident Department of Ophthalmology Government Medical College Srinagar-190010 Dr. Rashid Arshad Fellow, Minimal Access Surgery LokNayak Hospital Maulana Azad Medical College New Delhi-110002 Dr. Banday Shahid Shahzada Resident Department of General Surgery Government Medical College Srinagar-190010 Dr. Sayed Iqbal Assif Registrar Department of General Surgery Sher-e-Kashmir Institute of Medical Sciences Srinagar REFERENCE 1. Kanski JJ. Clinical Ophthalmology. 4thed. Pterygium. Butterworth-Heinemann Ltd Publisher. 1994; 96. 2. Duke-Elders. Systems of Ophthalmology. Diseases of the outer eye.Conjunctivaldiseases: degenerative and pigmentary changes. London. Henry Kipton Publisher. 1977; 7: 568. 3. Pinkerton OD, Hokman Y, Shigemura LA. Immunologic basis for the pathogenesis of pterygium. Am J Ophthalmol. 1984; 98: 2256. 4. Di Girolamo N, Chui J, Coroneo MT, et al. Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metallo- proteinases. Prog Retin Eye Res. 2004; 23: 195-228. 5. Di Girolamo N, Coroneo MT, Wakefield D. Active matrilysin (MMP-7) in human pterygia: potential role in angiogenesis. Invest Ophthalmol Vis Sci. 2001; 42: 1963-8. 6. Vansetten G, Aspiotis M, Blalock TD, et al. Connective tissue growth factor in pterygium: simultaneous presence with vascular endothelial growth factor-possible contributing factor to conjunctival scarring. Graefes Arch Clin Exp Ophthalmol. 2003; 241: 135-9. 7. Solomon A, Grueterich M, Li DQ, et al. Overexpression of insulin-like growth factor binding protein-2 in pterygium body fibroblasts. Invest Ophthalmol Vis Sci. 2003; 44: 573-80. 8. Maini R, Collison DJ, Maidment JM, et al. Pterygiaderived fibroblasts express functionally active histamine and epidermal growth factor receptors. Exp Eye Res. 2002; 74: 237-44. 9. Marcovich AL, Morad Y, Sandbank J, et al. Angiogenesis in pterygium: morphometric and immune histochemical study. Curr Eye Res. 2002; 25: 17-22. 10. Lee DH, Cho HJ, Kim JT, et al. Expression of vascular endothelial growth factor and inducible nitric oxide synthase in pterygia. Cornea 2001; 20: 738-42. 11. Gebhardt M, Mentlein R, Schaudig U, et al. Differential expression of vascular endothelial growth factor implies limbal origin of pterygia. Ophthalmology. 2005; 112: 1023-30. 12. Jin J, Guan M, Sima J, et al. Decreased pigment epithelium derived factor and increased vascular endothelial growth factor levels in pterygia. Cornea 2003; 22: 473-7. 13. Hirst LW. The treatment of pterygium. Surv Ophthalmol 2003; 48: 145–80. 14. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350: 2335-42. 15. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005; 112: 1035-47. 16. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age related macular degeneration. Ophthalmic Surg Laser Imaging. 2005; 36: 331-5. 17. Avery RL, Pieramici DJ, Rabena MD. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006; 113: 363-72. 18. Tan DTH, Chee SP, Dear KBG, et al. Effect of pterygium ROLE OF SUBCONJUNCTIVAL BEVACIZUMAB IN TREATMENT OF PTERYGIUM Pakistan Journal of Ophthalmology Vol. 28, No. 3, Jul – Sep, 2012 135 morphology on pterygium recurrence in a controlled trial comparing conjunctival autografting with bare sclera excision. Arch Ophthalmol. 1997; 115: 1235-40. 19. Besharati MR, Manaviat MR, Souzani A. Sub- conjunctival Bevacizumab Injection in Treatment of Pterygium. Acta MedicaIranica. 2011; 49: 179-83. 20. Hosseini H, Nejabat M, Khalili MR. Bevacizumab (Avastin) as a potential novel adjunct in the management of pterygia. Med Hypotheses. 2007; 69: 925–7. 21. Nagy JA, Dvorak AM, Dvorak HF. VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2007; 2: 251-75. 22. Hosseini H, Nejabat M, Mehryar M, et al. Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis. Clin Experiment Ophthalmol. 2007; 35: 745-8. 23. Bock F, Onderka J, Dietrich T, et al. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphan- giogenesis. Invest Ophthalmol Vis Sci. 2007; 48: 2545-52. 24. Bahar I, Kaiserman I, McAllum P, et al. Sub-conjunctival bevacizumab injection for corneal neovascularization in recurrent pterygium. Curr Eye Res 2008; 33: 23-8. 25. Asregadoo ER. Surgery, Thio-TEPA and corticosteroid in the treatment of pterygium. Am J Ophthalmol. 1972; 74: 960. 26. Kim SW, Ha BJ, Kim EK, et al. The effect of topical bevacizumab on corneal neovascularization. Ophthalmology 2008; 115: 33-8