Kathy Sivils and colleagues report results of a large-scale association study of Sjögren's syndrome, a common autoimmune disease. They confirm strong associations with the HLA region and establish genome-wide significant associations at several non-HLA loci implicated in both innate and adaptive immunity. Sjögren's syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10−114), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10−19), STAT4 (Pmeta = 6.80 × 10−15), IL12A (Pmeta = 1.17 × 10−10), FAM167A-BLK (Pmeta = 4.97 × 10−10), DDX6-CXCR5 (Pmeta = 1.10 × 10−8) and TNIP1 (Pmeta = 3.30 × 10−8). We also observed suggestive associations (Pmeta < 5 × 10−5) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.

AIMS To map the thickness, elevation (anterior and posterior corneal surface), and axial curvature of the cornea in normal eyes with the Orbscan corneal topography system. METHODS 94 eyes of 51 normal subjects were investigated using the Orbscan corneal topography system. The anterior and posterior corneal elevation maps were classified into regular ridge, irregular ridge, incomplete ridge, island, and unclassified patterns, and the axial power maps were grouped into round, oval, symmetric bow tie, asymmetric bow tie, and irregular patterns. The pachymetry patterns were designated as round, oval, decentred round, and decentred oval. RESULTS The thinnest point on the cornea was located at an average of 0.90 (SD 0.51) mm from visual axis and had an average thickness of 0.55 (0.03) mm. In 69.57% of eyes, this point was located in the inferotemporal quadrant, followed by the superotemporal quadrant in 23.91%, the inferonasal quadrant in 4.35%, and the superonasal quadrant in 2.17%. Among the nine regions of the cornea evaluated (central, superotemporal, temporal, inferotemporal, inferior, inferonasal, nasal, superonasal, and superior) the central cornea had the lowest average thickness (0.56 (0.03) mm) and the superior cornea had the greatest average thickness (0.64 (0.03) mm). The mean simulated keratometry (SimK) was 44.24 (1.61)/43.31 (1.66) dioptres (D) and the mean astigmatism was 0.90 (0.41) D. Island (71.74%) was the most common elevation pattern observed in the anterior corneal surface, followed by incomplete ridge (19.57%), regular ridge (4.34%), irregular ridge (2.17%), and unclassified (2.17%). Island (32.61%) was the most common topographic pattern in the posterior corneal surface, following by regular ridge (30.43%), incomplete ridge (23.91%), and irregular ridge (13.04%) patterns. Symmetric bow tie was the most common axial power pattern in the anterior cornea (39.13%), followed by oval (26.07%), asymmetric bow tie (23.91%), round (6.52%), and irregular (4.53%) patterns. In the pachymetry maps, 47.83% of eyes had an oval pattern, and round, decentred oval, and decentred round were observed in 41.30%, 8.70%, and 2.18% of eyes, respectively. CONCLUSION The information on regional corneal thickness, corneal elevation and axial corneal curvature obtained with the Orbscan corneal topography system from normal eyes provides a reference for comparison with diseased corneas. The Orbscan corneal topography system is a useful tool to evaluate both corneal topography and corneal thickness.

Objective: To investigate the relationship of fatigue severity to other clinical features in primary Sjögren's syndrome (SS) and to identify factors contributing to the physical and mental aspects of fatigue.Methods: We identified 94 subjects who met the American‐European Consensus Group criteria for the classification of primary SS. Fatigue was assessed with a visual analog scale, the Fatigue Severity Scale (FSS), and the Profile of Fatigue (ProF). Associations with fatigue were compared using multivariate regression.Results: Abnormal fatigue, defined as an FSS score ≥4, was present in 67% of the subjects. Pain, helplessness, and depression were the strongest predictors of fatigue according to the FSS and the somatic fatigue domain of the ProF (ProF‐S), both with and without adjustment for physiologic and serologic characteristics. Depression was associated with higher levels of fatigue; however, the majority of subjects with abnormal fatigue were not depressed. Anti‐Ro/SSA–positive subjects were no more likely to report fatigue than seronegative subjects. The regression models explained 62% of the variance in FSS and 78% of the variance in ProF‐S scores. Mental fatigue was correlated with depression and helplessness, but the model predicted only 54% of the variance in mental fatigue scores.Conclusion: Psychosocial variables are determinants of fatigue, but only partially account for it. Although fatigue is associated with depression, depression is not the primary cause of fatigue in primary SS. Investigation of the pathophysiologic correlates of physical and mental aspects of fatigue is needed to guide the development of more effective interventions.

Objective: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female‐predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls.Methods: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single‐nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction.Results: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67–86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18–123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients.Conclusion: The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female‐biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

Herpes simplex keratitis: challenges in diagnosis and clinical management Tayaba N Azher,1 Xiao-Tang Yin,1 Deena Tajfirouz,1 Andrew JW Huang,2 Patrick M Stuart1 1Department of Ophthalmology, Saint Louis University, 2Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO, USA Herpes simplex virus is responsible for numerous ocular diseases, the most common of which is herpetic stromal keratitis. This is a recurrent infection of the cornea that typically begins with a subclinical infection of the cornea that establishes a latent infection of sensory ganglia, most often the trigeminal ganglia. Recurring infections occur when the virus is reactivated from latency and travels back to the cornea, where it restimulates an inflammatory response. This inflammatory response can lead to decreased corneal sensation, scarring, and blindness. The diagnosis of these lesions as the result of a recurrent herpes simplex virus infection can at times be problematic. Currently, herpetic stromal keratitis is diagnosed by its clinical presentation on the slit-lamp examination, but the literature does not always support the accuracy of these clinical findings. Other diagnostic tests such as polymerase chain reaction assay, enzyme-linked immunosorbent assay, immunofluorescent antibody, and viral cultures have provided more definitive diagnosis, but also have some limitations. That said, accurate diagnosis is necessary for proper treatment, in order to prevent serious consequences. Current treatment reduces the severity of lesions and controls further viral spread, but does not provide a cure.