Aims International criteria for the diagnosis of ocular sarcoidosis (OS) was established by the first International Workshop on Ocular Sarcoidosis (IWOS) and validations studies revealed certain limitations of the criteria. To overcome the limitations, revised IWOS criteria was established in an international meeting. This manuscript was aimed at reporting the revised IWOS criteria.
Methods A consensus workshop was carried out to discuss and revise the IWOS criteria. The workshop was held on 27 April 2017, in Nusa Dua, Bali, Indonesia. Prior to the workshop, a questionnaire proposing revised criteria and consisting of one item for differential diagnosis, seven items for ocular clinical signs, 10 items for systemic investigations and three categories of diagnostic criteria was circulated to 30 uveitis specialists. Questionnaire items with over 75% support were taken as consensus agreement; items with below 50% support were taken as consensus disagreement and items with 50%–75% support were discussed at the workshop. Of the latter items, those supported by two-thirds majority in the workshop were taken as consensus agreement.
Results The survey and subsequent workshop reached consensus agreements of the revised criteria for the diagnosis of OS as follows: (1) other causes of granulomatous uveitis must be ruled out; (2) seven intraocular clinical signs suggestive of OS; (3) eight results of systemic investigations in suspected OS and (4) three categories of diagnostic criteria depending on biopsy results and combination of intraocular signs and results of systemic investigations.
Conclusions Revised IWOS criteria were proposed by a consensus workshop.
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Sarcoidosis is a systemic inflammatory disorder with unknown aetiology, affecting many organs including the eye and characterised by non-caseating granulomas.1–3 It causes a sight-threatening intraocular inflammatory condition, which is a major clinical type of uveitis around the world.4–11 Therefore, it is essential to make an accurate diagnosis and to initiate appropriate therapy for best management of patients with uveitis associated with sarcoidosis, that is, ocular sarcoidosis (OS). The gold standard for diagnosis of sarcoidosis is histopathological identification of non-caseating granulomas in biopsied tissue without demonstrable infectious agent. However, biopsy of intraocular tissue is rarely performed due to its potential risk for ocular damages. Therefore, a diagnosis of OS is based primarily on the combination of suggestive intraocular clinical signs and results of systemic investigations.
International criteria for the diagnosis of OS were not available until the first International Workshop on Ocular Sarcoidosis (IWOS) proposed international criteria in 2009.12 These criteria consist of seven intraocular clinical signs suggestive of OS and five non-invasive laboratory investigations in suspected OS and four categories of diagnosis (ie, definite OS, presumed OS, probable OS and possible OS) depending on biopsy results and a combination of intraocular clinical signs and findings of systemic investigations.
Several validation studies have been undertaken to assess the IWOS criteria, including one by a Japanese group13 and another by an international OS study group.14 The study conducted at a single institute in Japan found high diagnostic value of all IWOS criteria except abnormal liver enzyme tests,13 while the study with an international uveitis cohort raised more limitations of the criteria.14 One example is negative tuberculin test ‘in a BCG vaccinated patient or having had a positive purified protein derivative (PPD) skin test previously’. The conditions of the test were inapplicable to many patients of the international study because BCG vaccination was not performed in many countries and many patients had not received tuberculin test previously. The international study also suggested the need for more than five systemic investigations in suspected patients with OS. In addition, the international study revealed a low sensitivity of the category ‘possible OS’, as it did not increase the detection of patients with OS.
As well as the systemic investigations included in the IWOS criteria, many other tests have been reported to predict sarcoidosis and be useful for the diagnosis of the disease, and some of these are included in statements, guidelines or criteria for the diagnosis of systemic sarcoidosis.1 15 Results of additional systemic investigations that support a diagnosis of sarcoidosis include: abnormal label uptake on 67Ga scintigraphy or 18F-fluorodeoxyglucose positron emission tomography (PET)16 17, elevated serum soluble interleukin two receptor (sIL-2R)18 19, elevated serum Krebs von den Lungen-6 (KL-6)20 21, lymphopenia22 and elevated CD4/CD8 ratio in bronchoalveolar lavage fluid23–25 or in the vitreous.26 These systemic investigations are candidates for the systemic investigations in suspected OS.
A consensus meeting of international uveitis specialists was held in 2017 to review the diagnostic limitations of the IWOS criteria and to revise these criteria in that context. This article summarises the discussions and the conclusions of the meeting and reports revised international proposal for the diagnosis of OS.
A consensus workshop was held on 29 April 2017 at the sixth IWOS during the first Global Ocular Inflammation Workshops in Nusa Dua, Bali, Indonesia, to discuss and revise the IWOS criteria for the diagnosis of OS. Achieving consensus involved a two-step process.
A question-based survey. Prior to the workshop, a survey proposing revised IWOS diagnostic criteria was circulated to 36 uveitis specialists in 15 countries, including all 26 individuals who participated in the first IWOS to establish the criteria. This survey consisted of one item for differential diagnosis, seven items for intraocular clinical signs suggestive of OS, 10 items for results of systemic investigations in suspected OS and three categories of diagnosis (table 1 and online supplementary appendix 2). If specialists accepted the invitation, they were instructed to respond to the survey 1 month before the sixth IWOS.
Panel discussion. Before the survey results were reported at the sixth IWOS in Bali, agreement was reached on how to interpret the responses. Survey items with over 75% support in the survey were taken as IWOS consensus agreement, items with less than 50% support were taken as IWOS consensus disagreement and items with between 50% and 75% support were identified for panel discussion at the sixth IWOS in Bali. Items supported by a two-thirds majority at the IWOS panel discussion were taken as IWOS consensus agreement.
Of 36 uveitis specialists who were invited to participate in the questionnaire survey, two declined due to retirement and 30 completed the questionnaires (83.3% response rate). Eleven of the 30 participants were unable to attend the panel discussion in Bali. Eight additional uveitis specialists, including from three new countries, were invited to participate in the panel discussion in Bali. These 38 uveitis specialists from 18 countries are the members of IWOS Study Group (online supplementary file 1): 19 individuals participated both in the questionnaire survey and panel discussion; 11 individuals participated only in the questionnaire survey and seven individuals participated only in the panel discussion.
A summary of survey responses from the 30 panel members are shown in table 1. The first consideration in the diagnosis for OS was that other causes of granulomatous uveitis must be ruled out. This item had 83% support among survey respondents, and therefore it was accepted as IWOS consensus agreement.
Of seven intraocular clinical signs suggestive of OS, six items gained more than 75% support and were taken as IWOS consensus agreement. One additional item (ie, bilaterality, clinical or by imaging) was supported by 71% of survey respondents and thus was identified for panel discussion. Of 10 systemic investigations in suspected OS, six items (ie, bilateral hilar lymphadenopathy (BHL) by chest X-ray and/or chest CT, negative tuberculin test or interferon-gamma releasing assays (IGRA), elevated serum ACE, elevated serum lysozyme, elevated CD4/CD8 ratio (over 3.5) in bronchoalveolar lavage (BAL) fluid and abnormal 67Ga scintigraphy or 18F-fluorodeoxyglucose PET) achieved more than 75% agreement and were taken as IWOS consensus agreement. On the other hand, two items (ie, elevated serum gamma globulin and elevated serum Krebs von den Lungen (KL)-6) had less than 50% support in the survey, indicating consensus disagreement. Two items, that is, elevated serum sIL-2R and elevated serum calcium, obtained 50%–75% agreement and were listed for panel discussion.
Of the three categories of diagnosis, two categories (ie, definite OS, defined as a diagnosis supported by biopsy with compatible uveitis, and presumed OS, defined as a diagnosis not supported by biopsy, but BHL present with two intraocular clinical signs) had more than 75% support in the survey and were taken as IWOS consensus agreement. However, probable OS, defined as a diagnosis not supported by biopsy and BHL absent, but three intraocular clinical signs and two systemic investigations, reached 67% agreement in the survey and thus was identified for panel discussion.
The four items that gained 50%–75% support on the survey were discussed and put to a vote to determine whether they should be included in the revised IWOS diagnostic criteria. In addition, three other investigation results were proposed by panel members during their discussion. These included lymphopenia, parenchymal lung changes consistent with sarcoidosis as determined by pulmonologists or radiologists and elevated CD4/CD8 ratio in the vitreous. These items were also reviewed as part of the IWOS panel discussion.
Results of the panel vote are presented in table 2. The following four items were supported by a two-thirds majority of panel members and taken as IWOS consensus agreement: (1) intraocular clinical signs suggestive of OS: bilaterality (clinical or by imaging), (2) systemic investigation results in suspected OS: lymphopenia, (3) systemic investigation results in suspected OS: parenchymal lung changes consistent with sarcoidosis as determined by pulmonologists or radiologists and (4) diagnostic criteria: probable OS, defined as a diagnosis not supported by biopsy and BHL absent, but three intraocular clinical signs and two systemic investigations. On the other hand, the following three items, that is, elevated serum sIL-2R, elevated serum calcium and elevated CD4/CD8 ratio in the vitreous, failed to gain the support of a two-thirds majority and were taken as IWOS consensus disagreement.
Revised IWOS criteria for the diagnosis of OS
Based on the question-based survey and panel discussion, revised IWOS criteria (2017) for the diagnosis of OS were established, as presented in (box 1).
Revised International Workshop on Ocular Sarcoidosis (IWOS) criteria for the diagnosis of ocular sarcoidosis (OS) (2017)
Other causes of granulomatous uveitis must be ruled out.
Intraocular clinical signs suggestive of OS.
Mutton-fat keratic precipitates (large and small) and/or iris nodules at pupillary margin (Koeppe) or in stroma (Busacca).
Trabecular meshwork nodules and/or tent-shaped peripheral anterior synechia.
Snowballs/string of pearls vitreous opacities.
Multiple chorioretinal peripheral lesions (active and atrophic).
Nodular and/or segmental periphlebitis (±candle wax drippings) and/or macroaneurysm in an inflamed eye.
Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule.
Bilaterality (assessed by ophthalmological examination including ocular imaging showing subclinical inflammation).
Systemic investigation results in suspected OS.
Bilateral hilar lymphadenopathy (BHL) by chest X-ray and/or chest computed CT scan.
Negative tuberculin test or interferon-gamma releasing assays.
Elevated serum ACE.
Elevated serum lysozyme.
Elevated CD4/CD8 ratio (>3.5) in bronchoalveolar lavage fluid.
Abnormal accumulation of gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography imaging.
Parenchymal lung changes consistent with sarcoidosis, as determined by pulmonologists or radiologists.
Definite OS: diagnosis supported by biopsy with compatible uveitis.
Presumed OS: diagnosis not supported by biopsy, but BHL present with two intraocular signs.
Probable OS: diagnosis not supported by biopsy and BHL absent, but three intraocular signs and two systemic investigations selected from two to eight are present.
The present work was undertaken in an effort to address limitations of the previous IWOS criteria, raised by two validation studies.13 14 A question-based survey and a consensus meeting were conducted to establish revised IWOS criteria for the diagnosis of OS. The revised criteria were achieved by consensus, and while there were some differences of opinion, this approach achieved a majority consensus among a large group of uveitis specialists.
Several major changes in the moving from the original to the revised IWOS criteria involve testing. The sensitivity of abnormal liver enzyme tests was reported to be extremely low in two validation studies,13 14 and thus this item has been excluded from the results of systemic investigations. Negative tuberculin test in a BCG vaccinated patient or having had a positive PPD skin test previously were also removed and replaced with the condition of a negative tuberculin test and/or IGRA. The tuberculin test and IGRAs are important tests to identify tuberculosis, particularly in endemic areas of the world. In fact, a previous report from India demonstrated that these tests are useful to differentiate ocular tuberculosis from OS.27 Therefore, a negative tuberculin test and/or IGRA is included in the systemic investigations of the revised IWOS criteria. It is possible that excluding cases with a positive IGRA may result in missing true cases of sarcoidosis because of well-recognised links between sarcoidosis and tuberculosis. In fact, associations between environmental microorganisms, such as Mycobacteria 28 or Propionibacteria,29 and sarcoidosis have been reported. In the revised criteria, negative tuberculin skin test and/or negative IGRA has been added as one of the eight systemic investigation results suggesting the diagnosis of OS, but not as an absolute requirement for the diagnosis. It is also noteworthy that while patients with sarcoidosis may be anergic to the tuberculin skin test, some of them might have a positive IGRA.30 31 The latter patients are likely to have latent tuberculosis and they may develop active tuberculosis during treatment with corticosteroid or other immunomodulatory drugs, as are indicated in the management of sarcoidosis. Taken together, careful attention to the interpretation of results of the tuberculin skin test and/or IGRA is necessary for the diagnosis of OS, as well as for its management. In the previous criteria, BHL by standard chest X-ray and BHL by CT scan were treated as two separate systemic investigation results, but in the revised criteria, the two tests are treated as one result, because both are imaging tests that detect the same chest pathology. In contrast, serum ACE and serum lysozyme have been included as two separate investigations in the revised criteria, because the two tests measure different enzymes. In addition, results of four new systemic investigations have been added in the revised criteria: (1) lymphopenia, (2) elevated CD4/CD8 ratio (>3.5) in BAL fluid, (3) parenchymal lung changes consistent with sarcoidosis as determined by pulmonologists or radiologists and (4) abnormal label uptake on 67Ga scintigraphy or 18F-fluorodeoxyglucose PET imaging. Taken together, the number of systemic investigation results has increased from five in the original criteria to eight in the revised criteria.
In the revised IWOS criteria, the classification of OS has become simpler, with only three categories (ie, definite OS, presumed OS and probable OS). The original criteria also included possible OS, which has been deleted in the revision. This change was made based on the following considerations on biopsy results. In previous criteria, biopsy results were classified into three groups: ‘biopsy supported’ in definite OS; ‘biopsy not performed’ in presumed OS and probable OS and ‘biopsy results negative’ in possible OS. However, some biopsies, such as the transbronchial lung biopsy, are performed without direct visualisation, and it is not possible to confirm with certainty that the pathological lesions have been sampled when results are negative. Therefore, in the current revised criteria, biopsy results are classified as only two groups: ‘diagnosis supported by biopsy’ in definite OS and ‘diagnosis not supported by biopsy’ in presumed OS and probable OS. In fact, the Japanese Society of Sarcoidosis and Other Granulomatous Disorders (JSSOG) uses such a classification of biopsy results in their Guidelines for the Diagnosis of Sarcoidosis.15
The most substantial changes to the revision of the IOWS criteria relate to new systemic investigations. Jones and his colleagues reported that lymphopenia below 1000 cells/μL was significantly higher in uveitis associated with sarcoidosis than in other forms of uveitis and predicted the presence of the disease.22 Measuring the peripheral lymphocyte count is a simple, non-invasive test that is readily performed in patients with uveitis. An elevated CD4/CD8 ratio in BAL fluid and abnormal label uptake on Ga-67 scintigraphy or 18F-fluorodeoxyglucose PET are widely used internationally to make the diagnosis of systemic sarcoidosis, and these tests are used as systemic investigations in the Guidelines for the Diagnosis of Sarcoidosis of JSSOG.15 Parenchymal lung changes are as important as BHL in the lung pathology of sarcoidosis. However, they were not referenced in the original IOWS criteria because of difficulty of interpreting parenchymal lung changes. Therefore, in the revised criteria, they are included with the condition, ‘as determined by pulmonologists or radiologists’.
Some comment on systemic investigations that were discussed by the panel and not taken as consensus agreement is appropriate. Elevated serum sIL-2R is reported to be sensitive and useful to identify sarcoidosis,18 19 and this test is included in the systemic investigations of the JSSOG Guidelines for the Diagnosis of Sarcoidosis.15 However, panel members considered the test was not used widely enough in uveitis clinics, and the group opinion did not achieve consensus agreement. Elevated serum KL-6, which is a mucin-like, high-molecular weight glycoprotein antigen, is reported to be a sensitive and specific indicator of interstitial pneumonia, and predictive of parenchymal infiltration in sarcoidosis.20 21 The majority of survey respondents considered serum KL-6 was used infrequently, and most had no experience with the test in relation to OS. These tests might be added in future iterations of the IWOS criteria, if new evidence suggests diagnostic value. Measurement of the vitreous CD4/CD8 ratio is a challenging investigation. Maruyama and his colleagues26 reported that CD4/CD8 ratio in the vitreous was significantly higher in uveitis associated with sarcoidosis vs other forms of uveitis. However, the majority of panel members considered the test to be too invasive to be performed solely for the purpose of diagnosing OS and voted not to include the test in the systemic investigations of the revised IWOS criteria.
Our work has certain limitations due to the nature of the study, that is, a question-based survey and a consensus meeting. Discussion and decision-making were based primarily on the personal experiences of panel members, which may cause some bias. To avoid this as much as possible, we invited uveitis specialists from many countries in different regions of the world. Furthermore, only items with greater than 75% agreement in the survey were taken as consensus agreement, while items with 50%–75% agreement were discussed by the panel and required a two-thirds majority of the panel to be taken as consensus agreement.
In summary, a question-based survey and consensus workshop were held to revise IWOS criteria for the diagnosis of OS. Based on the survey and panel discussion, revised IWOS criteria have been proposed (box 1). It will be important to validate these revised criteria in with large groups of patients in many different countries. Such studies to validate these revised criteria will provide scientific evidence that they are applicable internationally.
Collaborators Massimo Accorinti, Nisha R Acharya, Fatma Asyari, Kalpana Babu, Soumyava Basu, Jyotirmay Biswas, Bahram Bodaghi, Soon-Phaik Chee, Ramandeep Chhabra, Claude L. Cowan, Debra A Goldstein, Hiroshi Goto, Yih-Shiou Hwang, Mami Ishihara, Douglas A Jabs, Nicholas P Jones, Toshikatsu Kaburaki, Hidetoshi Kawashima, Moncef Khairallah, Phuc LeHoang, Kazuichi Maruyama, Peter McCluskey, Manabu Mochizuki, Philip I Murray, Kenichi, Namba, Nobuyuki Ohguro, Shigeaki Ohno, Annabelle A Okada, Narsing A Rao, Tsutomu Sakai, Shwu-Jiuan Sheu, Justine R Smith, Ko-hei Sonoda, Somsiri Sukavatcharin, Hiroshi Takase, Ilknur Tugal-Tutkun, Hyeong Gon Yu, Manfred Zierhut.
Contributors MM and JRS conceived the project; designed the study; collected the questionnaire survey; designed, conducted and moderated the sixth International Workshop on Ocular Sarcoidosis on 29 April 2017 in Nusa Dua, Bali, Indonesia, and drafted the manuscript. JRS, HT, TK, NRA and NAR reviewed and edited the manuscript draft. HT analysed the results of the questionnaire survey. MM, JRS, HT and TK built up questionnaire survey. NRA designed the study and reviewed the questionnaire survey. NAR made suggestions for the study. All authors and members of International Workshop on Ocular Sarcoidosis Study Group participated in the questionnaire survey and in the sixth International Workshop on Ocular Sarcoidosis on 29 April 2017 in Nusa Dua, Bali, Indonesia. All authors approved submission.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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