Management of Autoimmune Retinopathies with Immunosuppression

CLINICAL SCIENCES Management of Autoimmune Retinopathies With Immunosuppression

Henry A. Ferreyra, MD; Thiran Jayasundera, MD; Naheed W. Khan, PhD; Shirley He, PhD; Ying Lu, PhD; John R. Heckenlively, MD

Objective: To report the results of treating autoim- and 8 of 11 (73%) with npAIR/CME showed improve- mune retinopathy (AIR) with immunosuppression ment. Five of 21 patients (24%) had improvement in vi- therapy. sual acuity, 15 of 21 (71%) had expansion of visual field area, and 6 of 11 (55%) had resolution of CME. Twenty- Methods: Retrospective review of 30 consecutive pa- six of 30 patients exhibited diffuse retinal atrophy with- tients with AIR followed for 3 to 89 months (median, 17 out pigment deposits. An autoimmune family history was months) who were treated with immunosuppression (sys- common in all the groups: npAIR, 69% (9 of 13); npAIR/ temic or local). Subgroups were cancer-associated reti- CME, 64% (7 of 11); and CAR, 50% (3 of 6). nopathy (CAR), nonparaneoplastic AIR (npAIR), and npAIR with cystoid macular edema (npAIR/CME). Out- Conclusions: Long-term treatment with immunosup- come measures were improvement of Snellen visual acu- pression resulted in clinical improvement in all sub- ity by at least 2 lines, expansion of the visual field area groups of AIR. The most responsive subgroup was CAR; by more than 25%, and resolution of CME. the least was npAIR. These results challenge the com- monly held belief that AIR is untreatable. Results: Overall, 21 of 30 patients (70%) showed improvement. All 6 CAR patients, 7 of 13 (54%) with npAIR, Arch Ophthalmol. 2009;127(4):390-397

HE AUTOIMMUNE RETINOPA- (npAIR/CME) that appears to be a distin- thies (AIRs) are a group of guishing factor. Many npAIR patients are diseases characterized by referred with a diagnosis of simplex reti- acute or subacute progres- nitis pigmentosa (RP), and the 2 disor- sive vision loss, an abnor- ders have similar clinical features. The malT finding via electroretinogram (ERG) challenge is to identify cases of AIR, which (either rod-cone or cone-rod patterns), and can be treated. Complicating the issue is circulating antibodies directed against reti- that a few cases of hereditary RP may de- nal antigens. The AIRs encompass the bet- velop secondary AIR with rapid visual field ter-studied paraneoplastic syndromes, such loss and severe cystoid edema.5-7 as cancer-associated retinopathy (CAR) Cancer-associated retinopathy, MAR, npAIR, and npAIR/CME tend to have com- For editorial comment mon clinical features despite the fact that no uniform set of antiretinal antibodies see page 573 (ARAs) has been found to be circulating in these patients.8,9 Patients have a vari- and melanoma-associated retinopathy ety of antibody activity, often with 3 to 6 (MAR), and a larger group of AIRs that different ARAs found on Western blots, a have similar clinical and immunologic fea- laboratory technique that detects serum tures but that are not associated with an ARAs in patients.7 However, there is a com- Author Affiliations: underlying malignancy. We coined the monality in the presentation of patients Department of Ophthalmology, term nonparaneoplastic autoimmune reti- with AIR; frequently, without a history of Kellogg Eye Center, University nopathy (npAIR) to describe this latter visual problems or night blindness, the pa- of Michigan, Ann Arbor group, which has previously been called tient has rapid onset of photopsia, fol- (Drs Ferreyra, Jayasundera, recoverin-associated retinopathy,1 autoim- lowed by other symptoms, such as night Khan, He, Lu, and 2 Heckenlively); and Department mune retinopathy in the absence of cancer, blindness, scotomata, and visual field loss. 3,4 of Ophthalmology, Shiley Eye or, simply, autoimmune retinopathy. Some Some patients also develop diminished Center, University of California, npAIR patients have cystoid macular central vision. The presentation may be San Diego (Dr Ferreyra). edema (CME) as a prominent feature asymmetrical between the eyes. On first

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Strong Evidence Supportive Evidence Helpful Evidence Diffuse retinal atrophy Abnormal ERG findings in conjunction with typical Anti-arrestin antibody symptoms and no pigment deposits Negative waveform ERG findings Sudden onset with photopsias; vision normal prior to onset Anti–␣-enolase antibody Antirecoverin antibody Rapid progression by history or visual fields Negative family history of RP Response to trial of methylprednisolone (subtenons) Multiple antiretinal antibody bands on Western blot testing CME in panretinal degeneration Family history of autoimmune disease History of cancer (for CAR) History of autoimmune disease in 50% of immediate family

Abbreviations: CAR, cancer-associated retinopathy; CME, cystoid macular edema; ERG, electroretinogram; NA, not applicable; RP, retinitis pigmentosa.

examination, there are frequently no obvious retinal nosuppression with oral or intravenous corticosteroids has changes on ophthalmoscopy, but a standardized ERG will shown mixed results.20 Generally, short courses of pred- show abnormal responses. Some cases have negative wave- nisone are ineffective, although the group that appears to forms, consisting of an a-wave that does not return to the have the best response with corticosteroids seems to be isoelectric point on dark-adapted bright flash ERG test- that with CAR, where a combination of chemotherapy and ing.10 Kinetic visual fields are better at measuring pe- milder immunosuppression variably gives some reversal ripheral losses or scotomata, blind spot enlargements, and of visual loss.21-23 Intravenous immunoglobulin has also pericentral losses. been used in patients with CAR and MAR.24,25 On questioning, most patients reveal that they have posi- The prevalence of AIR is unknown, although it is be- tive autoimmune family histories, with first-degree rela- lieved to be relatively uncommon. The rarity of AIRs, and tives who have lupus, rheumatoid arthritis, thyroid dis- the difficulty in firmly establishing the diagnosis, has lim- ease, and other autoimmune disorders. The diagnosis of ited investigations that evaluate treatment outcomes. A AIR is made by weighing the available evidence (Table 1) review of the literature shows that treatment results are and by finding ARAs on Western blot. Immunohistologic found primarily as case reports and a few small case se- staining of normal retinal tissue with the sera of patients ries. We report our clinical experience using immuno- is an additional technique that may pick up ARA activity. suppression to treat AIR in a series of 30 patients. The presence of antirecoverin or anti–␣-enolase antibodies is further confirmatory evidence.11-14 However, many patients who fit this clinical picture do not have antibod- METHODS ies against recoverin or ␣-enolase but have mixtures of antibodies directed against either other unidentified retinal Study participants were identified from a cohort of patients with antigens or ones whose pathogenicity is unknown.9 the diagnosis of AIR or CAR syndrome. The diagnostic criteria Finally, npAIR patients frequently have CME as a promi- are listed in Table 1. Except for 1 patient with early CAR, all the 6,14 patients underwent ARA Western blot testing. The sample in- nent feature. Many of these patients have been diag- cluded patients from the Jules Stein Eye Institute at the Univer- nosed by their ophthalmologist as having RP based on clini- sity of California, Los Angeles, but most were from the Kellogg cal findings, but they have no family history of RP. There Eye Center. The study was conducted with institutional review are also few patients with hereditary RP who develop AIR board approval from both institutions. Two of us (H.A.F. and as a secondary complication that manifests as CME.5-7,14 Pa- J.R.H.) reviewed the medical records to reconfirm that patients tients with RP and ARAs occasionally have visual field loss met the diagnostic criteria and to evaluate the response to the faster than usual; this last circumstance needs prospective treatment. There was no standard protocol, partly because no studies to objectively examine whether the presence of ARAs regimens have been established in the literature, and also be- worsens RP.15 Although optical coherence tomography dem- cause individual patients have different severity of disease and onstrates intraretinal cystic spaces or schisislike spaces, different tolerances to these medications, which tend to have adverse effects. many of these cases do not have leakage on fluorescein an- Western blot testing was performed by lysing normal hu- giography, and the AIR macular changes are really a form man, mouse, and bovine retinal tissue in a phosphate-buffered 7 of degenerative schisis. Prospective masked studies dem- saline, 1mM phenylmethylsulfonyl fluoride (PMSF), protease in- onstrated that 90% of patients with RP and cysts have cir- hibiter cocktail and sonicating the suspension. Thirty micro- culating ARAs by means of Western blot analysis com- grams of each lysate was heated for 10 minutes at 80°C in sample pared with 13% of patients with RP without macular cysts buffer with dithiothreitol, followed by sodium dodecyl sulfate– and 6% of controls.7 polyacrylamide gel electrophoresis. Proteins were transferred to Patients with RP cystoid “edema” may respond to car- nitrocellulose membrane and were incubated overnight with the bonic anhydrase inhibitor agents, such as acetazol- serum of the patient at 1:100 dilution. Membrane was washed amide and topical dorzolamide hydrochloride.16-18 Re- and incubated with anti–human IgG–tagged horseradish per- oxidase, and proteins were detected using a chemiluminescent bound failures are common, and immunosuppression detection kit (SuperSignal West Pico; Thermo Scientific Pierce, therapy may be more effective because the therapeutic Rockford, Illinois) and were exposed to film. 19 action is directed at the cause of the condition. Minimum follow-up for inclusion was 3 months on immu- No treatment regimens for the various autoimmune reti- nosuppression therapy, and median follow-up was 17 months. nopathies have emerged during the past decade.8 Immu- Outcome measures for improvement were at least 2 lines of

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Snellen visual acuity (VA), expansion of the visual field isop- of 30) in the combined AIR group. An autoimmune fam- ters on kinetic perimetry (Goldmann visual fields) by at least ily history was most common in the npAIR subgroup (69% 25%, and resolution of CME. Two patients had significant im- [9 of 13]), followed by the npAIR/CME (64% [7 of 11]) Ն provement in ERG amplitudes ( 50%). Medical records were and CAR (50% [3 of 6]) subgroups. When the patient’s reviewed for the following data: initial VA (at the start of treat- personal autoimmune history was examined, the preva- ment), final VA (at the last follow-up visit while on treatment), age at the onset of treatment, sex, the presence of CME, lence was 40% (12 of 30) for the combined AIR group. ERG amplitudes at the start of treatment (calculated as the per- When patient histories by subgroups were examined, the centage of the mean normal amplitude), the presence of nega- trends were similar: an autoimmune history was most tive waveforms on ERG, ARA activity on Western blot, a per- common in the npAIR group (46% [6 of 13]), followed sonal and family history of autoimmune disease (eg, systemic by the npAIR/CME (36% [4 of 11]) and CAR (33% [2 of lupus erythematosus, asthma, Crohn disease, idiopathic throm- 6]) groups. bocytopenic purpura, multiple sclerosis, psoriasis, rheumatoid arthritis, stiff man syndrome, and thyroid disease), immu- TREATMENT nosuppressive medications used, dosage, length of treatment, and adverse effects. A digital planimeter (Lasico, Los Angeles, Immunosuppression therapy was individualized to the pa- California) was used to measure the area in square centime- ters of the visual field (isopters IV-4-e and III-4-e). The per- tient. Triple therapy using cyclosporine, azathioprine, and centage change in visual field area was calculated for these isop- prednisone was given to patients with a classic severe pre- ters, and an increase in visual field size greater than 25% was sentation. The typical initial doses used were 100 mg/d for considered significant. The ERG findings were expressed as a cyclosporine, 20 to 40 mg/d for prednisone, and 100 mg/d percentage of the mean normal amplitude to show the differ- for azathioprine. In cases with a high clinical suspicion but ence from reference values. The AIRs in this study include CAR, without a classic presentation or available positive West- npAIR, and npAIR/CME. Although patients with MAR were ern blot information, treatment with 1 or 2 subtenon peri- evaluated during the medical record review, none were treated ocular injections of methylprednisolone acetate (40-60 mg) with immunosuppression and none were included in this study. was given to 1 eye as a clinical trial to evaluate for a treat- Data obtained were distributed nonparametrically and are ment effect. If there was clear improvement and ARAs were expressed using median values, interquartile ranges (IQRs), and ranges. subsequently found on Western blot, immunosuppression therapy was recommended to the patient. Twenty-nine of the 30 patients received at least 1 sys- RESULTS temic immunosuppressive medication during treatment (1 patient with CAR received subtenon methylpredniso- PATIENT CHARACTERISTICS lone acetate at multiple visits during 2 years). Of these 29 patients, 10 (35%) discontinued at least 1 of their sys- Thirty patients who were identified with a clinical diag- temic medications due to adverse effects (Table 2). Pa- nosis of CAR (n=6), npAIR (n=13), or npAIR/CME tients who were unable to tolerate any systemic immuno- (n=11) underwent treatment with immunosuppression suppression therapy or chose not to take systemic and met the inclusion criteria. For patients with CAR, medications were treated with periocular or intravitreal the distribution of carcinoma was 2 each with breast and corticosteroid injections. Some patients received sub- ovarian and 1 each with colon and prostate. tenon injections to the worse affected eye as supplemen- All but 4 of 30 patients exhibited diffuse retinal pig- tal therapy to the systemic medications. Of 23 patients ment epithelial atrophy without intraretinal bone spicule- treated with periocular methylprednisolone, 1 developed like pigment deposits, with only 1 patient with npAIR elevated intraocular pressure, which was controlled with (patient 16) and 3 with npAIR/CME (patients 22-24) hav- topical medications. Intravitreal triamcinolone acetate was ing pigment deposits. given to 4 patients with npAIR/CME without complica- Overall, the combined AIR group (CAR, npAIR, and tions. Overall, treatment ranged from 3 months to 89 npAIR/CME) was predominantly female (63% female [19 months (median, 17 months; IQR, 6-23.5 months). of 30] vs 37% male [11 of 30]) and had a median age of 51 years (range, 11-85 years; IQR, 35-70 years). Pa- RESPONSE TO TREATMENT tients 19 and 23, with npAIR/CME, have family histories of RP and may have genetic and autoimmune mecha- For the combined group (CAR, npAIR, and npAIR/ nisms that contribute to their retinopathy. The highest CME) the response to treatment was 70% (21 of 30). When female predominance was in the npAIR/CME subgroup examined by subgroup, the responses were 100% (6 of 6), (82% [9 of 11]), followed by the CAR subgroup (67% [4 54% (7 of 13), and 73% (8 of 11) for CAR, npAIR, and of 6]), whereas the npAIR subgroup showed no signifi- npAIR/CME, respectively. Responses to treatment con- cant sex difference (46% female [6 of 13]). The CAR sub- sisted of improvement in VA in 5 of 21 patients (24%) and group was the oldest (median age, 79 years; range, 71-85 expansion of the visual field area of at least 25% in 15 of years; IQR, 75-84 years), and the npAIR/CME group was 21 (71%). Of the 11 patients with CME, 6 (55%) had reso- the youngest (median age, 36 years; range, 11-66 years; lution or significant improvement of the CME. Although IQR, 16-51 years). The npAIR subgroup had a median not measured routinely, 2 patients (patients 13 and 27) age of 51 years (range, 28-78 years; IQR, 43-67 years). showed significant improvement in the ERG (increase in An autoimmune family history, defined as autoim- the rod-isolated or combined b-wave amplitude by Ͼ50%). mune diseases that affect the patient and at least 1 first- Examination of pretreatment and posttreatment Western degree relative, was present in 63% of the patients (19 blots (in 19 patients who were checked post-treatment)

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Medications Stopped Patient No./ Because of Treatment, Sex/Age, y Diagnosis Improvementa Medications Adverse Effects mo Initial WB Bands AI/RP 1/F/61 npAIR No C, P, MP C, P 4 20, 22, 27, 42, 46, 48 Yes/no 2/F/67 npAIR No C, A A 8 42, 44, 48, 68 Yes/no 3/F/42 npAIR No MP, C, A, P, IVIG None 12 15, 28, 32, 35, 48, 70, Yes/no 75 4/M/63 npAIR No C, A, P, MP, M C 38 23, 26, 42, 46, 70 Yes/no Nonresponders 5/F/44 npAIR No IVIG, M, MP None 18 18, 28, 34, 52, 75 Yes/no 6/M/49 npAIR No C, A, P C, A, P 6 19, 50, 60, 70, 85 No/no 7/F/24 npAIR/CME No C, A, MP None 19 27, 32, 34, 62 No/no 8/F/51 npAIR/CME No C, A, P, T, IVIG C, A, P, IVIG 5 35, 40, 68 No/no 9/F/44 npAIR/CME No P, MP, I None 9 30, 48 Yes/no 10/M/36 npAIR Yes (VF) OS 60%↑, MP, P None 6 25, 28, 32, 34, 37, 50, No/no (VA) OD 2 lines↑ 62 11/M/27 npAIR Yes (VF) OD 60%↑, P, A, C A 37 26, 30, 32, 34, 44 Yes/no OS 144%↑ 12/F/51 npAIR Yes (VF) scotomata C, A, P None 18 15, 30, 37, 42, 46, 62 Yes/no reduction OU 13/M/70 npAIR Yes (ERG) scotopic BrFl P, C, A, MP None 29 34, 37, 46, 58 No/no amplitudeϾdouble 14/M/78 npAIR Yes (VF) OD 112% ↑, MP, C, P C, P 6 46, 120 (many weak Yes/no OS 43%↑ bands) 15/F/67 npAIR Yes (VF) OD 19%↑, MP, T None 17 19, 22, 30, 32, 62 Yes/no OS 87%↑ 16/M/48 npAIRb Yes (VF) OD 39%↑, MP, C, P None 3 17, 23, 26, 28, 38, 64, No/no OS had LP vision 68 17/F/16 npAIR/CME Yes (VF, CME) OD P, T None 24 34, 43, 57-64, 70 Yes/no 63%↑,OS62%↑ 18/M/11 npAIR/CME Yes (VF, CME) OS C, P, A, MP None 20 20, 26, 35, 44, 58 Yes/no 107%↑ 19/F/66 npAIR/CME Yes (VF, CME) OD MP, C, A, P C, P 22 22, 30, 33, 35, 44, 68 No/yesc 397%↑, OS 539%↑ 20/F/46 npAIR/CME Yes (VF) OD 35%↑, MP, M, C, P, I C 28 30, 32, 37, 70 Yes/no Responders OS 50%↑ 21/F/15 npAIR/CME Yes (VF) OD 68%↑, P, MP None 8 17, 20, 25, 28, 32, 60 Yes/no OS 150%↑ 22/F/63 npAIR/CMEb Yes (VA, CME) OD P, A, MP None 17 20, 37, 48, 68 No/no 2 lines↑ 23/M/21 npAIR/CMEb Yes (VA, CME) OU MP, P, C, A None 89 26, 34-37, 58, 65 Yes/yesc 8 lines↑ 24/F/36 npAIR/CMEb Yes (VF, CME) OD MP, T, A, P None 7 13, 22, 42, 46 Yes/no 124%↑,OS78%↑ 25/F/79 CAR (ovarian Yes (VF) recovery of VF P, MP None 27 26, 28, 30, 46, 48 No/no cancer) when not measurable 26/M/79 CAR (prostate Yes (VA,VF) OD 4 P, A, C, MPA None 4 32, 36, 46, 66 No/no cancer) lines↑, OD 284%↑, OS 124%↑ 27/F/71 CAR (ovarian Yes (ERG) rod P, C, A None 3 23, 25, 40, 46, 57, 65 Yes/no cancer) amplitude 60%↑ (case 23 is an antirecoverin antibody) 28/F/79 CAR (breast Yes (VF) OD 47%↑, MP, C, P None 20 22, 33, 43, 70 Yes/no cancer) OS 243%↑ 29/M/85 CAR (colon Yes (VA) HM to 20/200 P, MP None 7 36, 46, 48 (case 29 No/no cancer) OS, OD enucleated has antirecoverin painful glaucoma antibody on immunoblot testing) 30/F/83 CAR (breast Yes (VF) OD 124%↑, A, P, M, MP A, P, M 23 20, 50, 70, 100, Yes/no cancer) OS 220%↑ decreased

Abbreviations: A, azathioprine; AI, autoimmune medical history or family history (first-degree relatives); AIR, autoimmune retinopathy; ARA, antiretinal antibodies; BrFl, bright flash dark-adapted electroretinogram; C, cyclosporine; CAR, cancer-associated retinopathy; CME, cystoid macular edema; ERG, electroretinogram; HM, hand movements; I, infliximab; IVIG, intravenous immunoglobulin; LP, light perception vision; M, mycophenolate mofetil; MPA, methylprednisolone acetate; MP, methylprednisolone (subtenon); NA, not available; npAIR, nonparaneoplastic autoimmune retinopathy; P, prednisone; RP, family history of retinitis pigmentosa; T, triamcinolone (intravitreals); VA, visual acuity; VF, visual field; and WB, Western blot. aHigh-quality optical coherence tomography was not available at the beginning of the study for quantification of CME. bWith intraretinal pigment deposits. cPatients had family history of RP. Patient 19 was from a family with autosomal dominant RP but clearly had signs of AIR, possibly secondary to RP degeneration. Patient 23 had a grandmother with RP but had classic signs of AIR with extensive cystic changes of the retina, which responded to immunosuppression therapy.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Figure 1. Patient 11, with nonparaneoplastic autoimmune retinopathy. A A 27-year-old man had a 3-year history of peripheral vision loss, nyctalopia, and a medical history of asthma but no family history of retinitis pigmentosa. His visual acuity was 20/20 OU. A, He had generalized retinal and retinal pigment epithelial atrophy, vascular attenuation, mild optic nerve pallor, and no pigment deposits. B, The electroretinogram was nonrecordable. C, Goldmann visual fields were severely contracted, but D, they were re-expanded moderately after treatment with systemic immunosuppressive agents: prednisone (20-40 mg/d), azathioprine (100 mg/d), and cyclosporine (100 mg/d). E, Comparison of baseline and treated sera shows a decrease in antiretinal antibodies on the Western blots. Both blots were run together (earlier serum was unfrozen, which has been shown to not affect activity) and then side by side on the same gel. Samples were heated at 80°C for 10 minutes. BR indicates bovine retina extract; HR, human donor retina extract; B Control OD OS kDa, kilodaltons; MR, mouse retina extract; OD, right eye; and OS, left eye.

Rod response Mixed response

200 µV 50 ms

Photopic A 32-Hz flicker

100 µV 50 ms

C 120 105 90 75 60 120 105 90 75 60 135 45 60 60 150 50 50 30 40 40 30 30 165 15 20 20 10 10 B 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 Control OD OS 10 10 20 20 195 345 30 30 Rod response 40 40 210 50 50 330 60 60 Mixed 200 µV 225 315 70 70 response 50 ms 240255 270 285 300 240255 270 285 300

Photopic D 120 105 90 75 60 120 105 90 75 60 135 45

60 60 100 µV 50 50 32-Hz 50 ms 150 30 40 40 flicker 30 30 165 15 20 20 10 10 C 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 10 10 20 20 2004 20/100 OD, 20/60 OS 195 345 30 30 Prednisone, 20 mg 40 40 210 50 50 330 Azathioprine, 100 mg 60 60 Cyclosporine, 100 mg 225 70 70 315 240255 270 285 300 240255 270 285 300 2005 20/40 OD, 20/40 OS Prednisone, 20 mg Prednisone, 20 mg Azathioprine, 100 mg Azathioprine, 100 mg Cyclosporine, 100 mg Cyclosporine, 100 mg

2007 20/25 OD, 20/30 OS E Prednisone, 10 mg HR MR BR HR MR BR Cyclosporine, 100 mg

150 150 Figure 2. Patient 23, with posterior pole cysts treated with 100 100 immunosuppression. A, A 21-year-old man with nonparaneoplastic autoimmune retinopathy with cystoid macular edema was initially seen with 75 diffuse cystic changes of the posterior pole. He had antiretinal antibodies 75 (Table 2) and, on initial examination in 1999, his visual acuity was 20/200

kDA OD and 20/300 OS, which improved to 20/25 OD and 20/30 OS by 2007 with 50 immunosuppression therapy. His electroretinogram (ERG) showed barely

kDA 50 recordable rod-isolated ERG, whereas the photopic b-wave amplitude was 37 50% of normal, with a suggestion of a negative wave in the right eye. B, The 37 bright flash dark-adapted ERG had negative waveforms and was diminished. 25 25 C, Optical coherence tomography showed reduction of the cystic changes in 20 the posterior pole to a thinner, but near normal appearance during 4 years of 20 immunosuppression therapy. Goldmann visual fields (not shown) showed 15 15 clearing of central scotomata. His grandmother had retinitis pigmentosa, but 10/20/04 4/9/08 he had no pigmentary changes in his retina and otherwise met the criteria for autoimmune retinopathy.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Figure 3. Patient 30. Treatment effect in cancer-associated retinopathy. A An 83-year-old woman had a 4-year history of central and peripheral vision loss, a medical history of breast cancer, and no family history of retinitis pigmentosa. She had antiretinal antibodies (Table 2). A, Her examination showed visual acuity of 20/300 OU, generalized retinal and retinal pigment epithelial atrophy with peripheral pigmentary deposits, and pale optic nerves. B, The electroretinogram showed rod and cone dysfunction, with a negative waveform. C, Goldmann visual fields showed constriction of all isopters. The patient was unable to tolerate azathioprine or mycophenolate mofetil therapy, and she stopped taking these drugs after 30 and 8 days, respectively; her condition has been maintained every 2 months with subtenon injections of methylprednisolone acetate (40 mg) in both eyes as an alternative to systemic immunosuppression therapy. D, She showed a better response (right eye [OD], 88%; left eye [OS], 163%; IV-4 isopter) on Goldmann visual fields from her base maintained by methylprednisolone acetate therapy after the brief period of treatment with mycophenolate mofetil. E, Pretreatment B Control OD OS and posttreatment Western blots show less immunoreactivity after treatment. Samples were heated at 80°C for 10 minutes. BR indicates bovine Rod response retina extract; HR, human retina extract; and MR, mouse retina extract. Mixed response

200 µV 50 ms showed that 13 blots were improved (less reaction), 4 were Photopic worse, and 2 were unchanged (Figures 1, 2, and 3). Sev- 32-Hz flicker eral patients showed improvement on their antibody immunoreactivity but did not show improvement clini- 100 µV 50 ms cally. However, it may be that their progression was slowed or halted.

C 120 105 90 75 60 120 105 90 75 60 135 45 COMMENT 60 60 150 50 50 30 40 40 30 30 165 15 The AIRs are diseases that besides their clinical and elec- 20 20 10 10 trophysiologic similarities all exhibit circulating antibod- 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 10 10 ies directed against retinal antigens. The spectrum of AIR 20 20 195 345 30 30 includes the paraneoplastic syndromes CAR and MAR and 40 40 210 50 50 330 npAIR. The few studies in the literature that have evalu- 60 60 225 70 70 315 ated treatment for AIR have reported conflicting results. 240255 270 285 300 240255 270 285 300 We retrospectively reviewed the use of immunosuppression to treat AIR in a group of 30 patients and found that it was effective in all subgroups, although there were dif- D 120 105 90 75 60 120 105 90 75 60 135 45 ferences in the response rates among subgroups. In hind- 60 60 150 50 50 30 sight, many patients are undertreated because we do not 40 40 30 30 have good markers to evaluate treatment effects. 165 15 20 20 10 10 The paraneoplastic retinopathies have been the most 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 extensively studied of the AIRs. Various investiga- 10 10 20 20 11,12 195 30 30 345 tions demonstrate the presence of circulating cross- 40 40 reactive antibodies that presumably bind to retinal anti- 210 50 50 330 60 60 gens and result in retinal degeneration by currently 225 70 70 315 240255 270 285 300 240255 270 285 300 unknown mechanisms. Several studies have shown that Mycophenolate mofetil, 1000 mg the tumors aberrantly express proteins normally exclu- sive to retinal tissue, leading to the production of antibodies directed against these retinal antigens. The most 26-29 E common antigen associated with CAR is recoverin, but HR MR BR HR MR BR other antigens have been identified, such as ␣-enolase,30 250 heat shock cognate protein 70,31,32 tubby-like protein 1,33 34 150 photoreceptor cell–specific nuclear receptor, and neu- 35 100 rofilament protein. Antibodies directed against retinal bi- Nonspecific 36 37 75 bands from polar cells, a 22-kDa neuronal antigen, and transdu- secondary cin have also been identified with MAR.38 antibody 50 Like CAR, npAIR was initially found to be associated kDA 1 37 with antibodies directed against recoverin. Since then, antibodies directed against the inner plexiform layer,2 the 25 inner retinal layer (described as the 35-kDa retinal Muller 20 cell-associated antigen),39 or other as-yet unidentified reti- 40 15 nal proteins have been described in npAIR patients. The October 2005 October 2007 pathogenicity of the various unknown ARAs must be de- termined by future research.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 The epidemiologic characteristics of AIR have not been effective in 70%. It was most effective in the CAR and well described in the literature. Adamus et al20 reported npAIR/CME subgroups (100% and 73%, respectively) com- the prevalence of ARAs in a group of 193 patients with pared with the npAIR group (54%). The least responsive symptoms resembling paraneoplastic retinopathy or AIR. subgroup (npAIR) had the highest autoimmune family his- They found that 58% were women and 42% were men. tory (69%). Likewise, there were differences noted be- The mean age of patients with paraneoplastic retinopa- tween the nonparaneoplastic subgroups: npAIR/CME pa- thy was 62.0 years compared with 55.9 years for npAIR tients responded significantly better than did those with patients. Chan8 reviewed the treatment outcomes of 55 npAIR (no CME). It may be that the mechanism respon- patients with CAR from the literature. Meta-analysis of sible for the development of CME in these patients is more these patients revealed that 51% were women, with a me- responsive to immunosuppression therapy. Nonre- dian age of 67 years. In the present series of 30 patients, sponders were also less likely to tolerate systemic immu- there was a greater overall female predominance: 63% for nosuppression; 56% of nonresponders (5 of 9) stopped the combined group, 67% for CAR, 46% for npAIR, and using at least 1 systemic immunosuppressive medication 82% for npAIR/CME. Likewise, we found a greater dif- owing to adverse effects compared with 25% of respond- ference in median ages: 79 years for CAR, 51 years for ers (5 of 20). Of the 6 npAIR patients who did not re- npAIR, and 36 years for npAIR/CME. spond, 4 (67%) discontinued taking at least 1 systemic im- Autoimmune diseases are regarded as having a multi- munosuppressive medication owing to adverse effects genic or a complex genetic basis, and this genetic template compared with 1 of 3 npAIR/CME patients (33%). We then variably affects individuals in families, depending on found that most AIR patients need immunosuppression their individual gene makeup. We specifically took fam- therapy for extended periods, with monitoring of visual ily histories for autoimmune diseases to get an indication functions regularly. of the autoimmune tendencies in these patients. This se- Although these results are limited by the limitations ries of patients had a high prevalence of an autoimmune inherent in any retrospective series, they demonstrate the history: 67% for the overall group, 50% for CAR, 69% for potential benefits of using immunosuppression to treat npAIR, and 64% for npAIR/CME. The highest preva- AIR. Patients with earlier disease were more responsive lence of autoimmune history was found in the npAIR and than were severely affected patients (at the time of ini- npAIR/CME groups compared with the CAR group. In tial visit). This series of 30 patients represents the larg- some npAIR/CME patients, we hypothesize that develop- est case series evaluating the treatment of AIR, and the ment of the AIR/CME component in RP may be a response positive results highlight the need for prospective trials to retinal antigens released during the degeneration, and to further evaluate which medications are most effec- these are recognized in the more antigenically sensitive pa- tive in the treatment of AIR. tients, who have a template of autoimmune genes. Some Finally, until there are specific diagnostic tests to iden- cases may also represent primary idiopathic AIR; histories tify AIR, so that AIR can be clearly distinguished from of head or ocular trauma are occasionally obtained and may RP, some cases may be difficult to identify when ini- represent moments of retinal antigen release. tially encountered in the clinic. Table 1 gives the cur- We found a higher prevalence of patients with an au- rent criteria for identifying AIR patients. The most help- toimmune family history who were less responsive to im- ful features are the rapid onset and course of photopsia munosuppression therapy. This trend was most evident and visual field loss compared with slower losses in typi- in the npAIR subgroup, which had the highest preva- cal RP, positive family history of autoimmune disease, lence of an autoimmune family history vs the other sub- lack of pigment deposits in most patients, abnormal ERG groups. In the npAIR subgroup, the prevalence of an findings and visual fields in the face of a relatively quiet autoimmune family history was 83% (5 of 6) in nonre- fundus appearance, and negative waveforms on ERG (if sponders vs 57% (4 of 7) in responders. This finding sug- present). Clinical trials of immunosuppression therapy gests that patients with stronger autoimmune tendencies in uncertain cases for at least 2 to 3 months are usually may need more intensive immunosuppression therapy. justified in patients who meet most of the criteria listed Immunosuppression has previously been used to treat in Table 1 and in all patients with severe CME. AIR with mixed results. Sawyer et al41 treated 1 of the original 3 patients with CAR with prednisone but saw Submitted for Publication: August 27, 2008; final revi- no improvement. Keltner et al42 reported the first pa- sion received December 7, 2008; accepted December 15, tient with CAR responsive to corticosteroid therapy. Since 2008. then, there have been numerous case reports in the lit- Correspondence: John R. Heckenlively, MD, 1000 Wall erature using short-course high-dose intravenous meth- St, Ann Arbor, MI 48105 ([email protected]). ylprednisolone or oral prednisone that report mild to mod- Author Contributions: Dr Heckenlively had full access to erate improvement in VA and visual fields. Plasmapheresis, all of the data in the study and takes responsibility for the when used alone, led to no improvement43; when used integrity of the data and the accuracy of the data analysis. with prednisone, vision improved in 1 patient.44 Guy and Financial Disclosure: None reported. Aptsiauri24 reported improvement in 2 of 3 patients treated Funding/Support: This work was supported in part by with intravenous immunoglobulin and stabilization in Foundation Fighting Blindness. the third. Espandar et al45 recently reported stabiliza- Additional Contributions: Jennifer Burkheiser assisted tion of CAR with alemtuzumab therapy. with illustrations, Kari Branham, MS, obtained family his- In the present series of 30 patients using an ad hoc long- tories, Richard Hackel, MA, provided fundus photogra- term therapeutic method, immunosuppression therapy was phy, and Jill Oversier, BS, coordinated patients.

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