Cyclosporine for Conjunctival Sarcoidosis
2008; Elsevier BV; Volume: 115; Issue: 1 Linguagem: Inglês
10.1016/j.ophtha.2007.08.024
ISSN1549-4713
Autores Tópico(s)Ocular Infections and Treatments
ResumoWe report a patient with bilateral conjunctival nodules who was diagnosed with ocular sarcoidosis and apparently responded to topical cyclosporine 0.05% (Restasis, Allergan Inc., Irvine, CA).A 36-year-old male presented with bilateral red eyes refractory to treatment over 6 months with multiple medications, including 1% topical prednisolone acetate, 0.1% olopatadine hydrochloride, 0.5% levofloxacin, and preservative-free artificial tears. He had used the steroid eyedrops (prednisolone acetate 1% [Pred forte, Samil Pharm Co. Ltd., Seoul, Korea]) 4 times a day for 3 months, which partially improved signs and symptoms. The patient was a steroid responder; his intraocular pressures increased to 40 mmHg during treatment with 1% topical prednisolone acetate. Ocular and medical histories were unremarkable. Slit-lamp examination showed multiple, yellowish, elevated conjunctival nodules with hyperemia bilaterally in the bulbar conjunctiva (Fig 1 [all figures available at http://aaojournal.org]). There was no sign of intraocular inflammation. An incisional biopsy of the conjunctiva revealed scattered noncaseating granulomas that consisted of epithelioid histiocytes and multinucleated giant cells on hematoxylin–eosin section (Fig 2A, B) and abundant CD4+ T-lymphocyte infiltration on immunofluorescence staining using the monoclonal anti-CD4 antibody (Serotec, Oxford, United Kingdom; Fig 2C–E). Stains for acid-fast bacilli were negative, and there was no evidence of fungi or a foreign body. General medical evaluation was performed, including a chest x-ray, high-resolution computed tomography, pulmonary function tests, serum angiotensin-converting enzyme, serum and urinary calcium level analysis, and serology tests including antineutrophil cytoplasmic antibody. The results were normal. The patient was diagnosed with ocular sarcoidosis and treated with topical cyclosporine 0.05% (Restasis) 4 times a day. Four weeks later, complete resolution of conjunctival nodules was achieved (Fig 3). The patient remained free of symptoms during 6 months of follow-up with these eyedrops, once a day, for maintenance.Figure 2A, Histological examination with hematoxylin–eosin staining revealed the presence of noncaseating granulomas aggregated by numerous epithelioid macrophages and giant cells in the conjunctival stroma. B, Multinucleated giant cells were more discrete at a higher magnification. Immunofluorescence confocal images showed infiltration of CD4+ T-lymphocytes surrounding the granulomas after staining with monoclonal antibodies against CD4 (C, DAPI counterstaining for nuclei; D, CD4 staining; E, 2 images merged; original magnification, ×100 [A]; ×200 [B]; ×800 [C–E]). Arrows, positive-staining cells.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3The slit-lamp appearance of bulbar conjunctiva demonstrated complete resolution of the subconjunctival nodules in both eyes (A, right; B, left).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Sarcoidosis is a multisystem noncaseating granulomatous disease that is mediated by CD4+ Th1 lymphocytes.1Co D.O. Hogan L.H. Il-Kim S. Sandor M. T cell contributions to the different phases of granuloma formation.Immunol Lett. 2004; 92: 135-142Crossref PubMed Scopus (93) Google Scholar Conjunctival nodules are one of the most common findings (40%) among its ocular manifestations.2Jones N.P. Sarcoidosis.Curr Opin Ophthalmol. 2002; 13: 393-396Crossref PubMed Scopus (26) Google Scholar The diagnosis of sarcoidosis is supported by clinical and radiological findings and histological evidence of noncaseating granulomas, as well as exclusion of other diseases capable of producing a similar histological picture. Granulomatous inflammation may be present in a number of diseases; it serves as a protective response to chronic infections with persistent pathogens including Mycobacterium tuberculosis complex, Salmonella, Listeria, and many fungal organisms. Granulomas can be found around undigested foreign substances. Our patient had noncaseating conjunctival granulomas with no evidence of acid-fast organisms, fungi, or foreign bodies. The patient did not either live in or travel to endemic areas of histoplasmosis. Although the presence of noncaseating granulomas in a single organ is not pathognomonic for sarcoidosis, ocular sarcoidosis can be present without supporting systemic signs or symptoms, and in some cases, ocular involvement in systemic sarcoidosis can be observed years before lung and other organ involvement.3Dithmar S. Waring G.O. Goldblum T.A. Grossniklaus H.E. Conjunctival deposits as an initial manifestation of sarcoidosis.Am J Ophthalmol. 1999; 128: 361-362Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar The mainstay of therapy for ocular sarcoidosis has been corticosteroids. However, the long-term use of corticosteroids is often associated with side effects. From a pathogenic point of view, CD4+ Th1 cell–targeted treatment appears more reasonable for the treatment of sarcoidosis; this is because CD4+ T-cells, producing Th1-like cytokines such as interleukin 2, are the main contributors to granuloma formation.4Solbach W. Lange C.E. Rollinghoff M. Wagner H. Growth, interleukin-2 production, and responsiveness to IL-2 in T4-positive T Lymphocyte populations from malignant cutaneous T cell lymphoma (Sezary’s syndrome): the effect of cyclosporin A.Blood. 1984; 64: 1022-1027PubMed Google Scholar In this case, we used commercially available 0.05% topical cyclosporine, and complete resolution of the lesion was achieved in 4 weeks. Topical cyclosporine has been demonstrated to be effective in the treatment of chronic dry eye through its effects on subconjunctival and lacrimal gland inflammation.5Sall K. Stevenson O.D. Mundorf T.K. et al.Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease.Ophthalmology. 2000; 107: 631-639Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar The quick resolution of the sarcoid nodules in our case is notable when compared with topical cyclosporine treatment for dry eye, which may take months to show a benefit,5Sall K. Stevenson O.D. Mundorf T.K. et al.Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease.Ophthalmology. 2000; 107: 631-639Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar suggesting that cyclosporine can act quickly when the underlying cause of the condition is CD4+ T-lymphocyte proliferation.In summary, sarcoidosis should be considered in the differential diagnosis of conjunctival nodules; biopsy is needed for histological confirmation. Topical cyclosporine 0.05% in this patient appeared to be effective for the treatment of this disease. We report a patient with bilateral conjunctival nodules who was diagnosed with ocular sarcoidosis and apparently responded to topical cyclosporine 0.05% (Restasis, Allergan Inc., Irvine, CA). A 36-year-old male presented with bilateral red eyes refractory to treatment over 6 months with multiple medications, including 1% topical prednisolone acetate, 0.1% olopatadine hydrochloride, 0.5% levofloxacin, and preservative-free artificial tears. He had used the steroid eyedrops (prednisolone acetate 1% [Pred forte, Samil Pharm Co. Ltd., Seoul, Korea]) 4 times a day for 3 months, which partially improved signs and symptoms. The patient was a steroid responder; his intraocular pressures increased to 40 mmHg during treatment with 1% topical prednisolone acetate. Ocular and medical histories were unremarkable. Slit-lamp examination showed multiple, yellowish, elevated conjunctival nodules with hyperemia bilaterally in the bulbar conjunctiva (Fig 1 [all figures available at http://aaojournal.org]). There was no sign of intraocular inflammation. An incisional biopsy of the conjunctiva revealed scattered noncaseating granulomas that consisted of epithelioid histiocytes and multinucleated giant cells on hematoxylin–eosin section (Fig 2A, B) and abundant CD4+ T-lymphocyte infiltration on immunofluorescence staining using the monoclonal anti-CD4 antibody (Serotec, Oxford, United Kingdom; Fig 2C–E). Stains for acid-fast bacilli were negative, and there was no evidence of fungi or a foreign body. General medical evaluation was performed, including a chest x-ray, high-resolution computed tomography, pulmonary function tests, serum angiotensin-converting enzyme, serum and urinary calcium level analysis, and serology tests including antineutrophil cytoplasmic antibody. The results were normal. The patient was diagnosed with ocular sarcoidosis and treated with topical cyclosporine 0.05% (Restasis) 4 times a day. Four weeks later, complete resolution of conjunctival nodules was achieved (Fig 3). The patient remained free of symptoms during 6 months of follow-up with these eyedrops, once a day, for maintenance. Sarcoidosis is a multisystem noncaseating granulomatous disease that is mediated by CD4+ Th1 lymphocytes.1Co D.O. Hogan L.H. Il-Kim S. Sandor M. T cell contributions to the different phases of granuloma formation.Immunol Lett. 2004; 92: 135-142Crossref PubMed Scopus (93) Google Scholar Conjunctival nodules are one of the most common findings (40%) among its ocular manifestations.2Jones N.P. Sarcoidosis.Curr Opin Ophthalmol. 2002; 13: 393-396Crossref PubMed Scopus (26) Google Scholar The diagnosis of sarcoidosis is supported by clinical and radiological findings and histological evidence of noncaseating granulomas, as well as exclusion of other diseases capable of producing a similar histological picture. Granulomatous inflammation may be present in a number of diseases; it serves as a protective response to chronic infections with persistent pathogens including Mycobacterium tuberculosis complex, Salmonella, Listeria, and many fungal organisms. Granulomas can be found around undigested foreign substances. Our patient had noncaseating conjunctival granulomas with no evidence of acid-fast organisms, fungi, or foreign bodies. The patient did not either live in or travel to endemic areas of histoplasmosis. Although the presence of noncaseating granulomas in a single organ is not pathognomonic for sarcoidosis, ocular sarcoidosis can be present without supporting systemic signs or symptoms, and in some cases, ocular involvement in systemic sarcoidosis can be observed years before lung and other organ involvement.3Dithmar S. Waring G.O. Goldblum T.A. Grossniklaus H.E. Conjunctival deposits as an initial manifestation of sarcoidosis.Am J Ophthalmol. 1999; 128: 361-362Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar The mainstay of therapy for ocular sarcoidosis has been corticosteroids. However, the long-term use of corticosteroids is often associated with side effects. From a pathogenic point of view, CD4+ Th1 cell–targeted treatment appears more reasonable for the treatment of sarcoidosis; this is because CD4+ T-cells, producing Th1-like cytokines such as interleukin 2, are the main contributors to granuloma formation.4Solbach W. Lange C.E. Rollinghoff M. Wagner H. Growth, interleukin-2 production, and responsiveness to IL-2 in T4-positive T Lymphocyte populations from malignant cutaneous T cell lymphoma (Sezary’s syndrome): the effect of cyclosporin A.Blood. 1984; 64: 1022-1027PubMed Google Scholar In this case, we used commercially available 0.05% topical cyclosporine, and complete resolution of the lesion was achieved in 4 weeks. Topical cyclosporine has been demonstrated to be effective in the treatment of chronic dry eye through its effects on subconjunctival and lacrimal gland inflammation.5Sall K. Stevenson O.D. Mundorf T.K. et al.Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease.Ophthalmology. 2000; 107: 631-639Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar The quick resolution of the sarcoid nodules in our case is notable when compared with topical cyclosporine treatment for dry eye, which may take months to show a benefit,5Sall K. Stevenson O.D. Mundorf T.K. et al.Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease.Ophthalmology. 2000; 107: 631-639Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar suggesting that cyclosporine can act quickly when the underlying cause of the condition is CD4+ T-lymphocyte proliferation. In summary, sarcoidosis should be considered in the differential diagnosis of conjunctival nodules; biopsy is needed for histological confirmation. Topical cyclosporine 0.05% in this patient appeared to be effective for the treatment of this disease.
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