To report the ocular complications of primary Sjögren syndrome (SS) in men.
Retrospective cohort study.
setting : Tertiary-care SS center. patient population : Total of 163 consecutive primary Sjögren syndrome patients evaluated between January 2007 and March 2013. main outcome measure : Frequency of extraglandular ocular and systemic manifestations and serologic results in men compared to women.
Fourteen of the 163 primary SS patients (9%) were men. On initial presentation, men were a decade older (61 vs 50 years, P < .01) and less likely than women to have a prior diagnosis of SS (43% vs 65%, P = .09). A majority of men reported dry eye on presentation (92%), albeit less chronic compared to women (5.9 vs 10.8 years, P = .07). Men were more likely to present with serious ocular complications than women (43% vs 11%, P = .001). Extraglandular systemic complications of SS (ie, vasculitis, interstitial nephritis) were also more common in men (64% vs 40%, P = .07). Further, men were more likely to be negative for anti-SSA/Ro, anti-SSB/La, and antinuclear antibodies than women (36% men vs 11% women, P = .01).
Men with primary SS have a higher frequency of serious ocular and systemic manifestations. Although primary Sjögren syndrome is typically considered a disease of middle-aged women, it may be underdiagnosed and consequentially more severe in men. Physicians should have a lower threshold to test for SS in men with dry eye.
Sjogren syndrome (SS) is a chronic autoimmune disorder characterized by xerostomia and xerophthalmia. However, other organ involvement may also occur, including glomerulonephritis, lymphoproliferative disorders, thyroiditis, and peripheral neuropathy. Recent research suggests that patients with extraglandular manifestations of SS may have a significantly higher mortality risk compared to those with only sicca findings.
Similar to other autoimmune diseases, the vast majority of patients with SS are women. Retrospective studies have estimated female-to-male ratios ranging from 9:1 to as high as 20:1. There is relatively little known about the clinical presentation and disease course in men with SS owing to this strong predominance of women. Several studies have reported men to have a lower prevalence of positive serologic tests (such as anti-SSA and anti-SSB); however, there is no clear consensus regarding the frequency of extraglandular manifestations by sex. Despite the higher incidence rate of SS in women, the mortality rate has been noted to be almost 3 times higher in men compared to women. This disparity in the severity of clinical manifestations may be attributable to sex differences in the pathophysiology of the disease. Interestingly, other autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis have also been reported to be more severe in men.
SS is well known to be underrecognized, but likely this is worse in men owing to a lower degree of suspicion. The role of ophthalmologists in recognizing the various extraglandular ocular manifestations of SS has been previously highlighted. However, there have been no studies reporting the frequency or severity of extraglandular ocular findings in men with primary SS. In this retrospective study, we aimed to compare the ocular and systemic manifestations of men vs women with primary SS and evaluated the usefulness of serologic test results.
Patients and Methods
The Johns Hopkins University Institutional Review Board approved this retrospective cohort study and informed consent form prior to patient enrollment. The study protocol adhered to the Health Insurance Portability and Accountability Act and was conducted in accordance with the Declaration of Helsinki.
Patients and Evaluations
All new and return patients evaluated at the Johns Hopkins Medical Institutions in Baltimore, Maryland between January 3, 2007 and May 29, 2011 with a primary diagnosis of SS were considered for this retrospective study. The patients were evaluated for various symptoms and clinical findings for either diagnosis or management of their presenting condition or a complication, in a multidisciplinary fashion. A detailed description of the ocular and systemic examinations can be found elsewhere.
Diagnosis of Sjögren Syndrome
Diagnosis of SS was based on the American-European Consensus Group (AECG) 2002 revised criteria and required at least 4 of the 6 criteria (or 3 out of 4 objective criteria), which included subjective and objective ocular dryness, subjective and objective evidence of salivary gland involvement, presence of Sjögren-specific antibody A (SSA)/Ro and/or Sjögren-specific antibody B (SSB)/La, and positive minor salivary gland biopsy. All patients were required to have either positive SSA/SSB serology or presence of positive minor salivary gland biopsy for the diagnosis of primary SS. This set of criteria was applied to new patients as well as return patients presenting with a prior diagnosis of SS. All other patients, including those with secondary SS, SS suspects, or patients with incomplete evaluation, were excluded from this study.
The patient list was electronically generated using a diagnosis of “sicca syndrome” (International Classification of Diseases [ICD-9] code 710.2) among patients who were evaluated at the Johns Hopkins Medical Institutions during 2007–2011. A detailed description of the data collection and variables extracted from the chart review can be found elsewhere. Demographic information, history of dry eye, serologic results, review of systems, and ocular and systemic findings present at initial visit were recorded. All subsequent visit records were reviewed to determine the development of autoimmune extraglandular ocular or systemic findings within the follow-up period. If the patient was seen for a return visit during the specified time period, all prior records were reviewed to assess clinical findings at initial presentation (oldest record dating to October 1999). The data collection was complete with data from all visits up to March 2013.
The autoimmune extraglandular ocular and systemic findings noted at initial visit and developed during follow-up were recorded for all patients. Of the various ocular findings, sterile corneal ulcer/infiltration, corneal melt/perforation, cicatrizing conjunctivitis, uveitis, episcleritis/scleritis, optic neuropathy, and retinal vasculitis were considered to be “vision-threatening.” Specific attention was paid to the extraglandular systemic manifestations of primary SS, including peripheral and central neuropathy, interstitial nephritis, autoimmune lung disease, vasculitis, primary biliary cirrhosis, autoimmune hepatitis, lymphoma, and autoimmune thyroid disease. Student t test was used to compare all continuous variables (for example, age at diagnosis, duration of dry eye symptoms) by sex. The χ 2 test was used to compare differences in proportion by sex for all binary outcomes: (1) specific extraglandular ocular findings present at initial visit and during follow-up; (2) extraglandular systemic findings present at initial visit and during follow-up; (3) seropositivity for several diagnostic tests (anti-SSA, anti-SSB, antinuclear antibodies [ANA], rheumatoid factor [RF], anti–cyclic citrullinated peptide [CCP] antibodies). Fisher exact test was substituted for manifestations with an inadequate sample size (n < 5). All odds ratios (OR) were calculated using binary logistic regression models. Data analysis was performed with STATA version 12 (STATA Corp, College Station, Texas, USA).
Two hundred forty-six consecutive patients with an ICD-9 diagnostic code of 710.2 were evaluated between 2009 and 2013. The final statistical analysis included 163 patients with primary SS, after exclusion of patients who did not meet the AECG classification criteria.
Of the 163 patients (which included 132 new patients and 31 follow-up patients), 14 were men (9%) and 149 were women (91%), a female-to-male ratio of 10:1. Men were a decade older than women at the time of diagnosis (50 vs 61 years, P = .008). Further, men were less likely to have a known diagnosis of SS on presentation, although this did not reach statistical significance (43% vs 65%, P = .09). Men also tended to report a shorter duration of dry eye symptoms at presentation than women (5.9 vs 10.8 years, P = .06). Ethnic distribution, primary symptoms at presentation (ocular vs other), proportion having follow-up, and duration of follow-up did not differ by sex ( Table 1 ).
|All Patients (n = 163)||Women||Men||P Value a|
|Women, n (%)||163 (100%)||149 (91%)||14 (9%)||–|
|Ethnicity, n (%)||–|
|White||136 (83%)||125 (84%)||11 (79%)|
|African American||14 (9%)||11 (7%)||3 (21%)|
|Hispanic||2 (1%)||2 (1%)||0 (0%)|
|Asian||9 (6%)||9 (6%)||0 (0%)|
|Other||2 (1%)||2 (1%)||0 (0%)|
|Sjögren diagnosis known at presentation, n (%)||103 (63%)||97 (65%)||6 (43%)||.09|
|Age at diagnosis of Sjogren syndrome, years (mean ± SD)||51 ± 14||50 ± 14||61 ± 16||.008|
|Primary symptoms at presentation, n (%)||–|
|Ocular||39 (24%)||36 (24%)||3 (21%)|
|Other||124 (76%)||113 (76%)||11 (79%)|
|Symptoms of dry eye b , n (%)||158 (98%)||146 (99%)||12 (92%)||–|
|Duration (years) of dry eye symptoms at presentation, median/mean||7.9/10.4||8.1/10.8||4.0/5.9||.06|
|Patients with follow-up, n (%)||146 (90%)||132 (89%)||13 (93%)||–|
|Duration (years) of follow-up, median (range)||3.0 (0–13.0)||2.9 (0–13.0)||3.0 (0–13.0)||–|
Table 2 compares the frequency of various autoimmune extraglandular ocular findings in men vs women. Extraglandular ocular findings at initial presentation or during the follow-up period were present in 8 of 14 men (57%) and 49 of 149 women (33%) ( P = .12). Two patients, both men, had more than 1 extraglandular finding. One or more vision-threatening ocular finding occurred in 6 of the 14 men vs 16 of the 149 women (43% vs 11%, P = .001). Particularly, corneal melt or perforation was significantly more frequent in men (4 of 14, 28.6%) vs women (3 of 149, 2%) ( P = .001). Other individual extraglandular ocular findings could not be compared because of insufficient sample size. Overall, men had 6.25 greater odds than women to have a vision-threatening ocular finding either during initial presentation or during follow-up (95% confidence interval [CI] = 1.9–20.2, P = .002).
|Extraglandular Ocular Finding||Finding Present at Initial Visit or During Follow-up a N (%)|
|All Patients (N = 163)||Women (N = 149)||Men (N = 14)||P Value|
|Corneal haze/scarring||9 (5.5%)||8 (5.4%)||1 (7.1%)||–|
|Sterile corneal ulcer/infiltration b||2 (1.2%)||1 (0.8%)||1 (7.1%)||–|
|Corneal melt/perforation b||7 (4.3%)||3 (2.0%)||4 (28.6%)||.001|
|Papillary conjunctivitis||14 (8.6%)||13 (8.7%)||1 (7.1%)||–|
|Follicular conjunctivitis||6 (3.7%)||6 (4.0%)||0 (0.0%)||–|
|Cicatrizing conjunctivitis b||3 (1.8%)||3 (2.0%)||0 (0.0%)||–|
|Bulbar conjunctiva (n = 5)|
|Conjunctival chemosis||3 (1.8%)||3 (2.0%)||0 (0.0%)||–|
|Uveitis b||5 (3.0%)||4 (2.7%)||1 (7.1%)||–|
|Episcleritis/scleritis b||3 (1.8%)||2 (1.3%)||1 (7.1%)||–|
|Optic neuropathy/neuritis b||3 (1.8%)||3 (2.0%)||0 (0.0%)||–|
|Orbital inflammation||3 (1.8%)||3 (2.0%)||0 (0.0%)||–|
|Retinal vasculitis b||1 (0.6%)||0 (0%)||1 (7.1%)||–|
|Significant ocular findings c||22 (14%)||16 (11%)||6 (43%)||.001|
Table 3 compares concomitant systemic autoimmune disorders in men and women. Overall, men were more likely than women to have an extraglandular systemic autoimmune disorder (64.3% vs 39.6%, P = .07), although this difference was not statistically different. A greater proportion of men had vasculitis compared to women (21.4% vs 4.7%, P = .04). There was no significant difference in the proportion of patients with neurological findings, interstitial nephritis, and autoimmune lung disease ( P > .05). Comparisons could not be made in the remaining systemic diseases because of the inadequate sample size in men.
|Concomitant Systemic Autoimmune Findings||Finding Present at Initial Visit or During Follow-up, a N (%)|
|All Patients (N = 163)||Women (N = 149)||Men (N = 14)||P Value|
|Neurological findings b||46 (28%)||42 (28%)||6 (43%)||–|
|Interstitial nephritis b||8 (4.9%)||6 (4.0%)||2 (14.3%)||–|
|Autoimmune lung disease b||4 (2.5%)||3 (2.0%)||1 (7.1%)||–|
|Pericarditis||1 (0.6%)||1 (0.7%)||0 (0%)||–|
|Vasculitis b||10 (6.1%)||7 (4.7%)||3 (21.4%)||.04|
|Hematologic abnormalities||3 (1.8%)||3 (2.1%)||0 (0%)||–|
|Immune thrombocytopenic purpura||2 (1.2%)||2 (1.4%)||0 (0%)||–|
|Thrombotic thrombocytopenic purpura||1 (0.6%)||1 (0.7%)||0 (0%)||–|
|Inflammatory bowel disease||6 (3.7%)||6 (4.0%)||0 (0%)||–|
|Primary biliary cirrhosis b||1 (0.6%)||1 (0.7%)||0 (0%)||–|
|Autoimmune hepatitis b||1 (0.6%)||1 (0.7%)||0 (0%)||–|
|MALT lymphoma b||5 (3.1%)||5 (3.4%)||0 (0%)||–|
|Hashimoto/Graves disease b||9 (5.5%)||8 (5.4%)||1 (7.1%)||–|
|Thyroid disease (unspecified etiology)||24 (14.7%)||23 (15.4%)||1 (7.1%)||–|
|Psoriasis||2 (1.2%)||2 (1.4%)||0 (0%)||–|
|Granuloma annulare||2 (1.2%)||2 (1.4%)||0 (0%)||–|
|Interstitial cystitis||1 (0.6%)||1 (0.7%)||0 (0%)||–|
|Presence of any extraglandular systemic manifestation||68 (41.7%)||59 (39.6%)||9 (64.3%)||.07|