Aims To investigate the hypothesis that lymphopenia is an independent predictor of sarcoidosis in new patients presenting with uveitis.
Patients and methods Retrospective case–control study of 112 patients with sarcoidosis-associated uveitis (SAU) against 398 controls with other forms of uveitis.
Results Of the patients with SAU, 30/112 (26.8%) had significant lymphopenia (<1.0×109/L), compared with 24/398 (6.0%) for other uveitis (p≤0.0001, OR 5.7 (95% CI 3.2 to 10.3)). The mean lymphocyte count for patients with SAU was 1.43 vs 2.04 for other uveitis (p≤0.0001). Logistic regression modelling using diagnosis of SAU as the independent variable identified age, ACE levels and lymphocyte count as independent predictors of SAU. A new patient with uveitis with significant lymphopenia has a risk of sarcoidosis (from this parameter alone) of 31.6%.
Conclusions Significant lymphopenia (<1.0×109/L) is an independent predictor of sarcoidosis in new patients presenting with uveitis. We recommend that diagnostic criteria for SAU should be modified to include this phenomenon.
- Diagnostic tests/Investigation
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Uveitis is a common manifestation of sarcoidosis.1 Patients may have multisystem inflammation, and in these, with supportive investigations including chest X-ray and ACE, diagnosis may be straightforward. Some patients may show no systemic involvement but may demonstrate ocular signs suggestive of sarcoidosis, including granulomatous anterior uveitis (GAU), intermediate uveitis, patchy retinal periphlebitis, multifocal choroiditis or punctate chorioretinal scarring, especially in the inferior fundus. Although more invasive investigation including high-resolution CT of the chest and bronchoalveolar lavage/biopsy are available, they are generally used only when diagnosis would change management. Biopsy confirmation of sarcoidosis for patients with uveitis is obtained in only a minority.
The possibility of a simple test supporting the diagnosis of sarcoidosis in new patients with uveitis is therefore appealing. In the Manchester Uveitis Clinic (MUC), some patients with uveitis diagnosed with sarcoidosis-associated uveitis (SAU) were noted to have significant lymphopenia (SL) at their first visit. This study was therefore undertaken to test the hypothesis that lymphopenia may be a predictor of SAU in patients presenting with uveitis.
Patients and methods
All new patients attending MUC are entered into a database, which includes a working diagnosis. Most new patients undergo a full blood count, and the results of all such tests since 2003 are available on the hospital intranet. For all such patients with a diagnosis of SAU, the total lymphocyte count was obtained and matched with data including age, racial background, ACE level, chest X-ray result and type of uveitis. Similar data were also extracted for the most recent patients within control groups with other forms of uveitis. Children often have higher lymphocyte counts than adults; therefore, patients <18 years at presentation were excluded. For all patients with SAU and an SL (<1.0×109/L) at presentation, clinical records were examined to exclude other causes including systemic disease and oral immunosuppression. Lymphocyte count was also analysed for each control group for direct comparison, and the possibility of spurious association with age, race, ACE level or chest X-ray abnormality was examined. A sample size calculator was used to identify a number of 111 to achieve a 99% confidence level with an error margin of 10%, for the population specified below. Statistical significance was tested using χ2 for comparison of percentages with SL, and Student's t test for comparison of means.
Since 2003 a total of 143 patients have been referred to MUC and have been diagnosed with biopsy-confirmed or presumed SAU. Of these, 21 were <18 years at presentation and were excluded, as were those without lymphocyte count at presentation. Control groups included Behçet's disease-associated uveitis (50 patients), Fuchs’ heterochromic uveitis (50), GAU not associated with sarcoidosis (50), human leucocyte antigen-B27 (HLA-B27)-associated uveitis (45), intermediate uveitis not associated with sarcoidosis (50), ocular toxoplasmosis (50), retinal vasculitis (REV) not associated with sarcoidosis (50), chronic panuveitis not associated with sarcoidosis (50) and tuberculosis-associated uveitis (50). There was some overlap in control groups; for example, some patients with tuberculosis were also within the REV group, and some with toxoplasmosis had GAU. In total there were 398 controls.
All patients presented de novo with uveitis, but at presentation may also have exhibited symptoms or signs of sarcoid involvement at other sites. These included first, pulmonary/hilar symptoms or signs (dyspnoea, dry cough, pleuritic pain or chest X-ray showing hilar/mediastinal nodes or parenchymal involvement) in 47% of those with SL and 32% without SL; second, arthropathy in 13% with and 13% without SL; third, skin lesions consistent with sarcoidosis (but not necessarily biopsied) in 17% with SL and 15% without SL; fourth, neurological signs (including facial palsy or optic neuropathy) consistent with sarcoidosis in 3% with SL and 5% without SL; and lastly, constitutional symptoms including fevers, night sweats and weight loss in 30% with SL and 19% without SL.
In total, 112 patients with SAU were included, of whom 61 (55%) were male. Twenty-two (19.6%) were biopsy-confirmed and 90 (80.4%) were presumed. In the SAU group, the mean age was 46.0 years (SD 13.78, range 19–81) compared with 42.4 years (SD 14.08, range 19–91) for controls. In the SAU group, 18 were Asian (19.1%), 73 Caucasian (65%) and 21 Afro-Caribbean (19%). This is compared with 76 Asian (19.1%), 281 Caucasian (70.6%) and 38 Afro-Caribbean (9.5%) in the control group (missing data=3). The mean lymphocyte count was 1.43×109/L (SD 0.62, range 0.33–3.17) in the SAU group and 2.04 (SD 0.77, range 0.41–6.75) in the control group.
In the SAU group, 30 patients (26.8%) had SL at presentation, compared with 6.0% of controls (χ2; p≤0.0001, OR 5.7 (95% CI 3.2 to 10.3)). The highest percentage with SL for any control group was 10% (5/50 each for REV and GAU, from each of which patients diagnosed with SAU were excluded). The results for all groups are shown in table 1. Patients with SAU are subdivided into biopsy-confirmed and presumed; these are defined in table 2.
Compared with controls, those with SAU were older (46.0 vs 42.4 years; p=0.017), were twice as likely to be Afro-Caribbean (19% vs 9.5%; p=0.14) and showed a higher ACE level (mean 94.3 vs 42.6; p≤0.0001) and a lower lymphocyte count (mean 1.43 vs 2.04; p≤0.0001).
For those with SAU and SL, 68% were male and the mean age was 43.7 years (SD 9.2); for those with SAU without SL, mean was 46.5 years (SD 14.1; p=0.31). For SAU, the chest X-ray results were compared with lymphocyte count: for those with SL, 17% had normal chest X-ray, 61% had hilar lymphadenopathy and 22% had parenchymal disease with or without lymphadenopathy with 83% overall having an abnormal X-ray. For those without SL the figures were 32%, 55%, 13% and 68%, respectively. Although those with SL were more likely to have an abnormal chest X-ray, this was not statistically significant (p=0.31). Again for patients with SAU, lymphopenia was tabulated against racial background (table 3) and against ACE level (figure 1) showing no correlation.
A (stepwise) logistic regression model (table 4) was constructed using the diagnosis of SAU as the dependent variable and the following as independent variables: age, race, ACE levels and lymphocyte count; age (p=0.0389), ACE levels (p=0.0001) and lymphocyte count (p=0.0001) were identified as independent predictors of SAU. Ethnicity did not contribute significantly to the model.
Clinical records were retrieved for the 30 patients with SAU and SL. No patients were using oral steroids at the time of blood testing; four were using an ACE inhibitor for systemic hypertension (ACE levels 7, 68, 84, 139); no patients were using oral immunosuppressives; one patient had been diagnosed with common variable immune deficiency (lymphocytes 0.53, ACE 76); no further iatrogenic or natural causes of lymphopenia were identified. However, HIV testing was not performed.
The most commonly used lower limit of normal for absolute lymphocyte count is 1.5×109/L (which permits a significant minority of normal outliers), whereas a level lower than 0.5×109/L is described as ‘severe’.2 We have chosen a level of 1.0×109/L to represent ‘significant lymphopenia’ as this level excludes the great majority of minor abnormalities and is used commonly as a cut-off.3
Lymphopenia is recognised as a feature in some patients with sarcoidosis and was first assumed to reflect extravascular migration to sites of immune reaction.4 Unsurprisingly, therefore, lymphopenia may predict disease severity5 ,6 and may be an early marker of disease chronicity.7 It has also been postulated as a partial cause of the anergy seen in sarcoidosis.8 Lymphopenia appears to affect all subsets.5 However, the usefulness of lymphopenia as a predictor of sarcoidosis has not been investigated for ocular disease. If lymphopenia is merely an indicator of disease extent and severity, then other better-recognised markers (including ACE level) are already used. If this is correct, it is counterintuitive to suggest that lymphopenia may be a marker of sarcoidosis for apparently well patients presenting with uveitis.
Lymphopenia has previously been reported in association with REV;9 although that association was not replicated in this study, non-SAU REV and non-SAU GAU were the two control groups with the highest rate of SL at 10% each. Since we have demonstrated a much higher proportion of SL in patients with SAU, and since both REV and GAU are accepted manifestations of this disease, there are two potential explanations for this; either lymphopenia is associated with the clinical expression of both REV and GAU whatever the cause; or some of these ‘non-SAU’ patients actually have sarcoidosis but remain undiagnosed.
The behaviour of lymphocyte subsets has been well reported for several forms of uveitis; for instance, a T-lymphopenia was associated with acute anterior uveitis.10 However, global lymphopenia has not been reported as a consistent feature of SAU. This is a retrospective study, but lymphocyte count is measured in automated fashion and is not subject to observer bias. We have demonstrated for the first time a highly significant association between lymphopenia and SAU, possibly independent of systemic involvement.
We have attempted to test the association between lymphopenia and SAU to destruction, by identifying spurious correlation with other parameters used for diagnosis. Lymphopenia appears to be independent of ACE level and race. A weak correlation with chest X-ray abnormality did not reach statistical significance. We have compared control groups showing clinical signs, which can also occur in sarcoidosis; two of these subgroups (GAU and REV) exhibit the highest rate of SL within the controls (10% each). Nevertheless, there remains a substantial difference between the incidence of SL in these groups, and for those with SAU (26.8%). The GAU and REV groups may show an ‘intermediate’ level of SL for one of two reasons: first, lymphopenia may be intrinsically linked to these clinical manifestations; or second, there may be some within these groups with ‘missed’ sarcoidosis, a hypothesis worth further study.
The lymphocyte count may slowly decrease with age in adults, but evidence is conflicting, and although the sample difference is not significant, in fact those with SL were younger, not older. There is therefore no evidence in this study that SL is age-related. We have shown more males with SL in SAU, but the data on sex differences in lymphocyte count in normal adults are weak and the validity of this finding is unknown. We have identified no correlations with traditional diagnostic markers and conclude that lymphopenia is an independent predictor of sarcoidosis.
Our patients with SAU have been divided into ‘biopsy-confirmed’ and ‘presumed’, the latter according to previously published criteria11 and defined in table 2. There is no evidence that SL is more common in those with biopsy-confirmed compared with presumed SAU (27.3% and 26.7%, respectively). This, together with a lack of correlation between lymphocyte count and ACE levels, suggests that lymphopenia is not a granuloma mass effect, nor does it seem to reflect the degree of systemic involvement. Further study, possibly including fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning, may be interesting.12
There is no evidence here that race affects the proportion with SAU and SL. Lower white cell counts in healthy black adults are well accepted,13 ,14 whereas lymphocyte counts tend to be significantly higher in blacks,15 so that a different reference range has been suggested.16 The proportion of black patients with SL in this study is similar to that for white Caucasians. Since no agreed normal reference range exists, it is not possible to use a correction factor.
Of the SAU group, 55% were male (and 68% of those with SL). Sarcoidosis is normally considered more common in females.17 We found that of all 296 patients with SAU on the MUC database, 152 (51.3%) were male. The test sample is therefore reasonably representative. Lymphocyte count is higher in females than males,18 ,19 but racial groups may show different ratios and the relationship is complex. This study does not have the power to suggest a greater likelihood of SL in male patients with SAU.
Our patients with SAU have a 26.8% rate of SL, compared with 6.3% of controls. Although the absolute prevalence of lymphopenia in the SAU group is not in itself very high, there is a highly significant difference between this and the control group. A previous study20 has shown that SAU is diagnosed in 9.7% of patients in MUC. This means that 7.9% of new patients with uveitis would have SL, and their chance of being diagnosed with SAU using this parameter alone is 31.6%, with a relative risk of 4.46. In 2009 the International Workshop on Ocular Sarcoidosis met to formulate diagnostic criteria.21 Lymphopenia was not discussed. We conclude that SL (<1.0×109/L) is an independent predictor of SAU in patients presenting with uveitis, and recommend that diagnostic criteria be modified to reflect this.
Contributors NPJ conceived and designed the study, analysed much data and wrote most of the paper; LT collected most data and created the database; NP undertook statistical analysis and contributed to paper writing.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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