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Assessment of CTLA-4 Deficiency–Related Autoimmune Choroidopathy Response to Abatacept

Assessment of CTLA-4 Deficiency–Related Autoimmune Choroidopathy Response to Abatacept Over the years, patients with recurrent infections and hypogammaglobulinemia generally have been classified as having common variable immune deficiency (CVID), without knowledge of the exact immune pathway defect. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a recently described protein that acts as a barrier to T-cell activation and is an important immune modulator.1-5 The loss of this protein in mice causes fatal autoimmune disease.4 Several investigators observed that CTLA-4 operates as an early checkpoint blockade of T-cell response to antigens and that this regulation is critical for prevention of autoimmunity.1-5 The presence of CTLA-4 averts immune targeting of host tissues, whereas a deficiency results in autoimmunity.2-5 Herein, we describe a patient with CVID who was later identified as having CTLA-4 deficiency and visually disabling autoimmune choroiditis that responded to abatacept, a CTLA-4 analogue. The requirement for approval of the study was waived by the Wills Eye Hospital Institutional Review Board, and the patient provided written consent to allow her data to be used in research. Report of a Case A woman of white race/ethnicity in her mid-20s with CVID for 11 years demonstrated frequent infectious disease and autoimmune disease, managed with antibiotics, corticosteroids, and immune globulin intravenous pentetate therapy. The dysregulated immunity led to autoimmune dermatitis, pancreatitis, colitis, cerebritis, and lung disease. In 2015, she was found to have specific CTLA-4 deficiency. For 3 weeks, she noted bilateral ocular pain and blurred vision. Visual acuity was 20/200 OD and 20/25 OS. The anterior segment, vitreous, and retina demonstrated no inflammation. On ophthalmoscopy, there were multifocal choroidal infiltrates in each eye (Figure 1). In the right eye, the infiltration measured 14 mm at the base, 3.9-mm thickness, and with overlying subretinal fluid plus additional tiny multifocal sites. In the left eye, multifocal small choroidal infiltrates of 0.5-mm diameter were noted. The differential diagnosis included choroidal infection, inflammation, or neoplasia. Figure 1. Autoimmune Choroidopathy From CTLA-4 Defiiciency View LargeDownload A-D, CTLA-4–deficient autoimmune choroidopathy is seen on ophthalmoscopy. E and F, Findings on optical coherence tomography are shown. Cytopathological examination of a transvitreous fine-needle aspiration biopsy specimen from the macular lesion in the right eye revealed scant lymphocytes and histiocytes, with no evidence of fungus, bacteria, or malignant cells. Microbiological studies of tumor aspirate, blood, and urine samples showed no infection. The patient began therapy with abatacept, a specific CTLA-4 synthetic analogue, and prompt resolution of the autoimmune infiltration and detachment was noted (Figure 2), achieving visual acuity of 20/70 OD and 20/20 OS at 6 months. Figure 2. Prompt Resolution of the Autoimmune Infiltration and Detachment With Abatacept View LargeDownload Shown are the findings after 3 months of abatacept therapy, a CTLA-4 therapy. A, Resolution of choroidal infiltration, with chorioretinal scar at site of needle biopsy in the right eye. B. Focal choroidal inflammatory sites were less apparent in the left eye. C. Resolution of subretinal fluid in the right eye with residual subretinal precipitates. D. Normal findings in the left eye. Discussion There are a series of immune checkpoints along the inflammatory cascade that identify pathogens and prevent autoimmunity. CTLA-4 operates as the earliest checkpoint and controls T-cell response to antigen.2 CTLA-4 has gained attention for its preeminent role in immunotherapy, particularly for cutaneous melanoma, because inhibition of CTLA-4 with ipilimumab can lead to endogenous attack on melanoma metastasis.2 The operation of B-lymphocytes and T-lymphocytes is complex and ranges from an intentional detection of pathogenic antigens to the unintentional attack against self-antigens, namely, autoimmunity. There are 2 T-cell receptors, CD28 and CTLA-4, which act as a positive and negative balance in recognition of antigens.2 Abatacept is a fusion protein of the extracellular domain of CTLA-4 and human IgG1. It binds to CD80/CD86 receptors on antigen-presenting cells, preventing binding to CD28 receptor on T-cell surfaces, thus blocking T-cell activation.6 Abatacept is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis in patients who have failed to respond to disease-modifying antirheumatic drugs and may have a role in the treatment of several autoimmune diseases. In 2011 and 2014, the findings of 2 independent studies3,4 identified that a heterozygous mutation in CTLA4 (OMIM 123890) led to T-cell immune dysregulation. Based on those reports, our patient was tested for CTLA4, and the mutation was found. After the occurrence of autoimmune choroidopathy, she began treatment with the targeted CTLA-4 synthetic analogue abatacept, and there was prompt response, resolving the inflammatory condition. We suggest that patients with CVID autoimmune ocular findings should consider reevaluation for newer receptors and targeted therapies. Back to top Article Information Corresponding Author: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Ste 1440, 840 Walnut St, Philadelphia, PA 19107 (carolshields@gmail.com). Published Online: May 12, 2016. doi:10.1001/jamaophthalmol.2016.1013. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported. Funding/Support: Support for this study was provided by the Eye Tumor Research Foundation (Drs C. L. Shields and J. A. Shields). Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, or approval of the manuscript. References 1. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56-61.PubMedGoogle ScholarCrossref 2. Sansom DM. Immunology: moving CTLA-4 from the trash to recycling. Science. 2015;349(6246):377-378.PubMedGoogle ScholarCrossref 3. Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11(12):852-863.PubMedGoogle ScholarCrossref 4. Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410-1416.PubMedGoogle ScholarCrossref 5. Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623-1627.PubMedGoogle ScholarCrossref 6. Vicente Rabaneda EF, Herrero-Beaumont G, Castañeda S. Update on the use of abatacept for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2013;9(7):599-621.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Ophthalmology American Medical Association

Assessment of CTLA-4 Deficiency–Related Autoimmune Choroidopathy Response to Abatacept

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American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6165
eISSN
2168-6173
DOI
10.1001/jamaophthalmol.2016.1013
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Abstract

Over the years, patients with recurrent infections and hypogammaglobulinemia generally have been classified as having common variable immune deficiency (CVID), without knowledge of the exact immune pathway defect. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a recently described protein that acts as a barrier to T-cell activation and is an important immune modulator.1-5 The loss of this protein in mice causes fatal autoimmune disease.4 Several investigators observed that CTLA-4 operates as an early checkpoint blockade of T-cell response to antigens and that this regulation is critical for prevention of autoimmunity.1-5 The presence of CTLA-4 averts immune targeting of host tissues, whereas a deficiency results in autoimmunity.2-5 Herein, we describe a patient with CVID who was later identified as having CTLA-4 deficiency and visually disabling autoimmune choroiditis that responded to abatacept, a CTLA-4 analogue. The requirement for approval of the study was waived by the Wills Eye Hospital Institutional Review Board, and the patient provided written consent to allow her data to be used in research. Report of a Case A woman of white race/ethnicity in her mid-20s with CVID for 11 years demonstrated frequent infectious disease and autoimmune disease, managed with antibiotics, corticosteroids, and immune globulin intravenous pentetate therapy. The dysregulated immunity led to autoimmune dermatitis, pancreatitis, colitis, cerebritis, and lung disease. In 2015, she was found to have specific CTLA-4 deficiency. For 3 weeks, she noted bilateral ocular pain and blurred vision. Visual acuity was 20/200 OD and 20/25 OS. The anterior segment, vitreous, and retina demonstrated no inflammation. On ophthalmoscopy, there were multifocal choroidal infiltrates in each eye (Figure 1). In the right eye, the infiltration measured 14 mm at the base, 3.9-mm thickness, and with overlying subretinal fluid plus additional tiny multifocal sites. In the left eye, multifocal small choroidal infiltrates of 0.5-mm diameter were noted. The differential diagnosis included choroidal infection, inflammation, or neoplasia. Figure 1. Autoimmune Choroidopathy From CTLA-4 Defiiciency View LargeDownload A-D, CTLA-4–deficient autoimmune choroidopathy is seen on ophthalmoscopy. E and F, Findings on optical coherence tomography are shown. Cytopathological examination of a transvitreous fine-needle aspiration biopsy specimen from the macular lesion in the right eye revealed scant lymphocytes and histiocytes, with no evidence of fungus, bacteria, or malignant cells. Microbiological studies of tumor aspirate, blood, and urine samples showed no infection. The patient began therapy with abatacept, a specific CTLA-4 synthetic analogue, and prompt resolution of the autoimmune infiltration and detachment was noted (Figure 2), achieving visual acuity of 20/70 OD and 20/20 OS at 6 months. Figure 2. Prompt Resolution of the Autoimmune Infiltration and Detachment With Abatacept View LargeDownload Shown are the findings after 3 months of abatacept therapy, a CTLA-4 therapy. A, Resolution of choroidal infiltration, with chorioretinal scar at site of needle biopsy in the right eye. B. Focal choroidal inflammatory sites were less apparent in the left eye. C. Resolution of subretinal fluid in the right eye with residual subretinal precipitates. D. Normal findings in the left eye. Discussion There are a series of immune checkpoints along the inflammatory cascade that identify pathogens and prevent autoimmunity. CTLA-4 operates as the earliest checkpoint and controls T-cell response to antigen.2 CTLA-4 has gained attention for its preeminent role in immunotherapy, particularly for cutaneous melanoma, because inhibition of CTLA-4 with ipilimumab can lead to endogenous attack on melanoma metastasis.2 The operation of B-lymphocytes and T-lymphocytes is complex and ranges from an intentional detection of pathogenic antigens to the unintentional attack against self-antigens, namely, autoimmunity. There are 2 T-cell receptors, CD28 and CTLA-4, which act as a positive and negative balance in recognition of antigens.2 Abatacept is a fusion protein of the extracellular domain of CTLA-4 and human IgG1. It binds to CD80/CD86 receptors on antigen-presenting cells, preventing binding to CD28 receptor on T-cell surfaces, thus blocking T-cell activation.6 Abatacept is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis in patients who have failed to respond to disease-modifying antirheumatic drugs and may have a role in the treatment of several autoimmune diseases. In 2011 and 2014, the findings of 2 independent studies3,4 identified that a heterozygous mutation in CTLA4 (OMIM 123890) led to T-cell immune dysregulation. Based on those reports, our patient was tested for CTLA4, and the mutation was found. After the occurrence of autoimmune choroidopathy, she began treatment with the targeted CTLA-4 synthetic analogue abatacept, and there was prompt response, resolving the inflammatory condition. We suggest that patients with CVID autoimmune ocular findings should consider reevaluation for newer receptors and targeted therapies. Back to top Article Information Corresponding Author: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Ste 1440, 840 Walnut St, Philadelphia, PA 19107 (carolshields@gmail.com). Published Online: May 12, 2016. doi:10.1001/jamaophthalmol.2016.1013. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported. Funding/Support: Support for this study was provided by the Eye Tumor Research Foundation (Drs C. L. Shields and J. A. Shields). Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, or approval of the manuscript. References 1. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56-61.PubMedGoogle ScholarCrossref 2. Sansom DM. Immunology: moving CTLA-4 from the trash to recycling. Science. 2015;349(6246):377-378.PubMedGoogle ScholarCrossref 3. Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11(12):852-863.PubMedGoogle ScholarCrossref 4. Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410-1416.PubMedGoogle ScholarCrossref 5. Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623-1627.PubMedGoogle ScholarCrossref 6. Vicente Rabaneda EF, Herrero-Beaumont G, Castañeda S. Update on the use of abatacept for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2013;9(7):599-621.PubMedGoogle ScholarCrossref

Journal

JAMA OphthalmologyAmerican Medical Association

Published: Jul 1, 2016

Keywords: drug response,autoimmunity,choroid diseases,cytotoxic t-lymphocyte antigen 4,abatacept,choroiditis,common variable hypogammaglobulinemia

References