To develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts.
Modified Delphi process.
A survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement.
There was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies.
Consensus was achieved using a modified Delphi process to develop diagnostic criteria for nonparaneoplastic AIR. There is enough equipoise to justify randomized, placebo-controlled trials to determine whether patients with nonparaneoplastic AIR should be treated with long-term immunomodulatory therapy. Efforts to develop a standardized 2-tier assay system for the detection of antiretinal antibodies have been initiated as a result of this study.
Autoimmune retinopathies are a group of inflammatory-mediated diseases characterized by the presence of antiretinal antibodies, visual field deficits, and photoreceptor dysfunction in the setting of progressive, otherwise unexplained vision loss. Autoimmune retinopathies can be categorized as paraneoplastic AIR (pAIR) , which includes cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), or nonparaneoplastic autoimmune retinopathy in the absence of malignancy. As autoimmune retinopathy (AIR) is the preferred term for an acquired and presumed immune-mediated retinopathy due to antiretinal autoantibodies in the absence of a malignancy, we use AIR to indicate the nonparaneoplastic form of autoimmune retinopathy unless otherwise indicated.
Despite being described almost 20 years ago, AIR remains an ill-defined disease. The diagnosis of AIR is typically made based on the presence of antiretinal antibodies and a combination of certain clinical features, in the absence of another cause of symptoms. Although the prevalence of AIR is unknown, it is thought to be a rare entity. However, it is probable that AIR is more prevalent than thought and remains undiagnosed in many cases owing to the lack of standardized diagnostic criteria and its protean clinical features that overlap with other retinal degenerative diseases. Nonetheless, it is important to rule out malignant etiologies and treatable conditions when considering the diagnosis of AIR to prevent morbidity and treatable vision loss.
While clinical features may vary considerably, commonly recognized manifestations have been identified. The presence of circulating antiretinal antibodies is considered essential to the diagnosis of AIR. Although great strides have been made in the detection and measurement of antiretinal antibodies, there is no universally standardized assay for antiretinal antibody testing. Consequently, inconsistent diagnoses among institutions or physicians may result. One study compared the results of antiretinal antibody detection and measurement between 2 laboratories and found an overall concordance rate of any antiretinal antibodies detected to be 64% with a very poor interobserver agreement (kappa = −0.13). Further, the antiretinal antibody–specific concordance rate was a mere 36%. Currently, only 1 center in the United States provides antiretinal antibody testing commercially through a CLIA (clinical laboratory improvement amendments)-certified laboratory (Ocular Immunology Laboratory, Casey Eye Institute, Oregon Health & Science University). To establish diagnostic criteria, promote collaboration, and advance our understanding of AIR, the development of a standardized assay to detect antiretinal antibodies is essential.
Criteria have been proposed in the past ; however, efforts to establish comprehensive diagnostic criteria, including clinical criteria and a standardized assay system for antiretinal antibody detection, have not been documented until now. We believe the establishment of standardized diagnostic criteria and an assay system for antiretinal antibody detection is the first step toward understanding the pathogenesis of AIR. Ultimately, this will improve the management of patients with AIR. The purpose of this paper is to describe the consensus process and to report results of the consensus process among clinicians and researchers in establishing diagnostic criteria for AIR.
To develop consensus for the diagnosis of AIR, a modified Delphi process was used. The Delphi method is a structured communication method designed to elicit and collate the opinions of experts through anonymity, controlled feedback, statistical group response, and multiple iterations. The Delphi method was first developed by the RAND Corporation in the 1950s to forecast the impact of technology on warfare and has since been used throughout numerous healthcare fields including ophthalmology and in uveitis to build consensus among experts for the diagnosis and management of disease. In diseases where clinical evidence is lacking, this method is deemed suitable for the development of guidelines for diagnosis or management. The goal is to narrow the range of responses with each iteration to arrive at an expert consensus. Ultimately, the Delphi process allows experts to work together in a structured manner to gain a better understanding in areas where consensus is lacking.
The modified Delphi process used in this study consisted of multiple rounds of surveys and a face-to-face meeting, after which structured feedback was given for each round. Experts were then encouraged to reconsider their opinion in light of the cumulative responses of other experts. This allowed experts to remain anonymous while considering the responses and opinions of the group and clarifying their opinions for others. To develop consensus, a survey of uveitis specialists in the American Uveitis Society (AUS), a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of an expert panel survey were used ( Figure 1 ). This study was in adherence to the tenets of the Declaration of Helsinki.
American Uveitis Society Member Survey
Consensus development began with a 10-question survey of AUS members to gauge the understanding of autoimmune retinopathies among uveitis specialists. The survey was developed electronically (Survey Monkey, Palo Alto, California, USA), and the survey link was posted in the AUS website forum. AUS is a subspecialty society for uveitis specialists with approximately 250 members. Only 1 response was allowed per computer in an effort to limit multiple responses from 1 respondent.
Autoimmune Retinopathy Workshop
Subsequently, a meeting of 40 clinicians and researchers in the field of uveitis and immunology was convened at the National Institutes of Health (NIH) on September 27, 2013. In the AIR Workshop meeting, the diagnosis, management, and pathophysiology of AIR were examined through presentations, expert panels, and group discussions. In addition, results of the initial AUS survey were reported. The most important questions in the field of AIR were identified through a group effort.
Based on discussions at the AIR Workshop meeting, 2 surveys—1 clinical and 1 basic laboratory—were developed to further collate opinions of experts and define consensus for the diagnosis and management of AIR. The expert surveys mostly consisted of statements with 5-point Likert scales (1, strongly disagree; 2, disagree; 3, neither agree nor disagree; 4, agree; 5, strongly agree). When appropriate, multiple-choice, ranking, and multiple-select questions were used in the modified Delphi process. For all items, experts were encouraged to provide comments and feedback. For the clinical survey, a summary of results from the initial AUS survey was included for experts to consider in the initial expert survey. In the subsequent expert surveys, a summary of results from the initial surveys was included for experts to consider as aligned with our modified Delphi process.
Supermajority consensus was used and defined as 75% of experts who selected either 4 (agree) or 5 (strongly agree) OR 2 (disagree) or 1 (strongly disagree) for items with Likert scales. For questions in which Likert scale was not used, supermajority consensus was defined as 75% of respondents who selected a given answer choice. Below in results, we use “consensus” to indicate supermajority consensus unless otherwise indicated. Because of the low number (n = 6) of experts to whom the basic laboratory survey was sent (experts with basic science and laboratory expertise in antiretinal antibody detection), we also report a simple majority consensus (>50%) and indicate when doing so.
In the subsequent iterations, only questions where at least 75% of responses fell within a range of 3 consecutive values (ie, 3, 4, 5) were included in order to obtain further consideration and consensus. Certain questions were reformulated and reiterated in the subsequent surveys based on comments and feedback from experts. Items reaching supermajority consensus were not reiterated. For example, when considering “response to treatment” as one of the Supportive Diagnostic Criteria in the diagnosis of AIR, 4 experts selected 3 (neither agree nor disagree), 3 experts selected 4 (agree), and 3 experts selected 5 (strongly agree). This item did not meet supermajority consensus, but because the response rate was ≥75% for consecutive values of 3, 4, 5, the item was reiterated to be considered as Supportive Diagnostic Criteria in the subsequent iteration.
To disseminate clinical and basic laboratory survey iterations and results, a password-protected site was developed using the NIH Clinical Trial Survey System (Bethesda, Maryland, USA). The clinical and basic laboratory surveys were developed using the NICHD/NIH Clinical Trials Database (Bethesda, Maryland, USA). Unique identifiers and passwords were distributed to experts via individual e-mails.
Definitions are as follows:
Essential Diagnostic Criteria: essential to the diagnosis of AIR and must be present to make the diagnosis of AIR.
Supportive Diagnostic Criteria: supports the diagnosis of AIR but is not necessary to make the diagnosis of AIR.
Core Diagnostic Test: essential to the diagnosis of AIR and should be performed at the initial or first diagnostic evaluation when AIR is suspected.
Fifty-four uveitis specialists participated in the initial AUS survey. Seventeen experts participated in the expert surveys (1 person had expertise in both clinical and basic fields). Twelve uveitis specialists participated in the initial clinical expert survey, and 11 participated in the subsequent expert survey. Six researchers participated in the initial and subsequent basic laboratory surveys. Here, we report the results of the final rounds of consensus development.
To gauge the experience of those surveyed in the final 2 iterations, experts (clinicians) were asked to approximate the number of patients with the diagnosis of paraneoplastic or nonparaneoplastic AIR seen in 1 year’s time: 7 see 3–7 patients, 3 see >7 patients, and 2 see 1–3 patients.
As anticipated, there was unanimous agreement among all clinicians regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including CAR and MAR.
All 5 items considered as Essential Diagnostic Criteria in the diagnosis of AIR achieved consensus, including: (1) no apparent cause responsible for visual function abnormality such as malignancy, inflammation, infection, surgery, drug toxicity, trauma, or hereditary retinal degeneration; (2) electroretinogram (ERG) abnormality with or without visual field abnormality; (3) presence of serum antiretinal antibodies; (4) absence of fundus lesions and retinal degeneration or dystrophy that may explain visual function loss; (5) absence of overt intraocular inflammation ( Table 1 ).
|Diagnostic Criteria for AIR a|
|Essential Diagnostic Criteria||Supportive Diagnostic Criteria|
|No apparent cause responsible for visual function abnormality b||Symptoms: photopsias or scotomas or dychromatopsia or nyctalopia or photoaversion|
|ERG abnormality (with or without visual field abnormality)||Systemic autoimmune disease: personal or family history|
|Presence of serum antiretinal antibodies||Rapidity of onset of vision change e|
|Absence of fundus lesions and retinal degeneration or dystrophy that may explain visual function loss c|
|Absence of overt intraocular inflammation d|
|Core Diagnostic Tests f|
|Malignancy evaluation by appropriate physician||Fundus autofluorescence|
|Electroretinogram||Optical coherence tomography|
|Serum antiretinal antibody testing||Fluorescein angiogram|
c Absence of chorioretinal lesions (other than incidental/small peripheral benign degenerations such as pavingstone, lattice, etc, or old toxoplasmosis scar) or absence of retinal dystrophy, retinitis pigmentosa, or other hereditary retina vitreal disorders.
Absence of fundus lesions and retinal degeneration or dystrophy was defined through consensus as the absence of chorioretinal lesions (other than incidental or small peripheral benign degenerations such as pavingstone, lattice, etc, or old toxoplasmosis scar) and the absence of retinal dystrophy, retinitis pigmentosa, or other hereditary retina vitreal disorders. Absence of overt intraocular inflammation was defined through consensus as less than 1+ intraocular cells (anterior chamber or vitreous) or vitreous haze.
Supportive Diagnostic Criteria for the diagnosis of AIR reaching consensus included: (1) a personal or family history of systemic autoimmune disease; (2) the presence of photopsias, scotomas, nyctalopia or photoaversion, or dyschromatopsia; and (3) rapidity of onset of vision change ( Table 1 ). Though rapidity of onset of vision change reached consensus as supportive criteria, defining rapidity of onset of vision change failed to reach consensus: 6 of 11 clinician experts selected subacute (3–6 months) and 5 selected acute (0–3 months) to define rapidity of onset of vision change in the subsequent expert survey. Age and response to treatment did not reach consensus to be included as Supportive Diagnostic Criteria in the diagnosis of AIR.
Experts agreed that in order to make the diagnosis of AIR, all Essential Diagnostic Criteria needed to be present. The significance of supportive criteria in making the diagnosis was not explored.
Consensus was reached on the following Core Diagnostic Tests to be performed at the initial or first diagnostic examination: malignancy evaluation by an appropriate physician, serum antiretinal antibody testing, ERG, fluorescein angiogram, fundus autofluorescence, and optical coherence tomography (OCT) ( Table 1 ). Consensus could not be achieved for including the following as Core Diagnostic Tests: Goldmann visual field (GVF), Humphrey visual field (HVF), dark adaptation testing (DA), or color vision testing.
Treatment and Management
To assess preferred treatment practices among experts, the clinicians were surveyed regarding specific treatments in the management of AIR patients. Clinicians unanimously agreed that steroids (local or systemic) and conventional immunosuppressives (antimetabolites or T cell inhibitors) should be used as first- or second-line treatments in the management of AIR patients. Consensus was achieved for the following treatment types to be considered appropriate regardless of the stage of disease: steroids (local or systemic), conventional immunosuppressives (such as antimetabolites or T cell inhibitors), biologics (such as monoclonal antibodies), and intravenous immunoglobulin (IVIG) ( Table 2 ). Consensus was not reached for considering plasmapheresis in the management of AIR patients.