Humoral, hormonal and genetic determinants of cholinergic dysfunction in Sjögren's syndrome

Functional anti-muscarinic receptor autoantibodies have been demonstrated in Sjögren's syndrome (SS) in a mouse bladder contraction assay. Most patients with these antibodies complained of severe lower urinary tract disturbances, not usually recognised as a feature of SS. In a cross-sectional study, we evaluated urological, sleep and fatigue symptoms in female SS patients (n = 76) compared with osteoarthritis (OA) controls (n = 43), utilising the American Urological Symptom Index (AUA-7), the Epworth Sleepiness Scale (ESS) and the Facit-F fatigue instruments. Patients were comparable with respect to hormone-replacement therapy use, bladder operations, urinary tract infections, parity and diuretic therapy; OA patients were slightly older. Sixty-one percent of SS patients reported severe urological symptoms compared with 40% of OA patients (P = 0.04). This difference was attributable to urge incontinence and not nocturia. Daytime somnolence was more severe in SS (P = 0.02), independent of nocturia. A trend towards increased fatigue was observed in SS that did not reach statistical significance (P = 0.15). These results suggest that urological symptoms may be an under-recognised feature of SS, and that fatigue in SS may in some cases be secondary to an underlying sleep disorder such as obstructive sleep apnea due to dry airways, or circadian rhythm disorder. These symptoms are consistent with functional disturbances of muscarinic receptors, possibly mediated by muscarinic receptor autoantibodies.

Many features of SS overlap with menopausal symptoms. The T allele of the IVS1-0401 (T/C) polymorphism in the estrogen receptor alpha gene (ER-α) is thought to be associated with decreased responsiveness to estrogen. IVS1-0401 (T/C) genotyping was performed by PCR-restriction fragment length polymorphism using the restriction enzyme PvuII. No difference was seen in genotype frequencies between SS patients (n = 154) and controls (n = 163, P = 0.26). Within female SS patients who completed the AUA-7 and ESS (n = 73), the ER-α IVS1-0401 T allele was associated, in a dose-dependent manner, with increasing daytime somnolence (P = 0.003) and urological (P = 0.08) symptom severity. This polymorphism appears to influence the severity of commonly reported symptoms in SS that are also linked with estrogen deficiency. We predict that it will be a risk factor for severity of menopausal symptoms and sleep disturbances in non-SS patients.