hemodialysis after 1 year of follow-up. For mild forms of GN without active urine sediment and stable renal function, a watchful waiting policy and close monitoring is another proposal. The role of other immunosuppressive agents such as azathioprine or B cell depletion is unclear.

19.4Painful Bladder Syndrome/Interstitial Cystitis and Primary Sjögren’s Syndrome

19.4.1Historical Aspects

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic pelvic pain syndrome [51–54] that has been associated with SS. IC with the characteristic cytoscopic finding of Hunner’s ulcer was originally described by Hanash and Pool [55]. Subsequently, Messing and Samey described the more frequent nonulcerative form of IC [56]. Since then, many definitions of IC have been used but the European Society for the study of IC (ESSIC) proposed a convenient system for nomenclature and classification based upon the presence of chronic pelvic pain, which is related to the urinary bladder [54]. In 1993, Van de Merve et al. evaluated ten patients with IC and diagnosed focal lymphocytic sialadenitis and keratoconjuctivitis in almost half of them, implying an association between SS and IC [57].

19.4.2Clinical, Cytoscopic, and Histologic Features

Painful bladder syndrome/interstitial cystitis (PBS/IC) presents with chronic pelvic pain, pressure, or discomfort related to the urinary bladder [54]. Pain, a fundamental feature of the syndrome, is usually accompanied by other urinary symptoms such as frequency, urge to void, and nocturia. Some patients also experience dyspareunia [58]. There is a considerable overlap between PBS/IC and other painful conditions including irritable bowel syndrome, fibromyalgia, and various chronic pelvic pain syndromes [58, 59]. Urodynamics may reveal abnormal uroflow and lower median volumes for certain urodynamic parameters [60, 61]. Cytoscopy is usually normal but Hunner’s ulcers may be observed. Hunner’s lesion is an inflammatory and reddened area of the mucosa that becomes apparent only after hydrodistention during cytoscopy [54]. Although biopsy is not always indicated, the most common histologic features are inflammatory infiltrates, granulation tissue, detrusor mastocytosis, and intrafascicular fibrosis [54]. Although pain or equivalent pressure/discomfort related to the bladder is a prerequisite of PBS/IC the typical cytoscopic or histologic features are not always present. Thus, the term IC is reserved for such cases [54].

19.4.3Pathogenesis and Association with Sjögren’s Syndrome

The etiology of PBS/IC remains obscure, but neurogenic inflammation mediated by mast cells, epithelial permeability due to disruption of the glycosaminoglycan (GAG) layer, and autoimmunity have been proposed to play a role in the pathogenesis of the syndrome [62]. Several findings though support the autoimmunity theory. Antinuclear antibodies have been detected in 36% of patients with PBS/IC [63] and immune deposits have been found in the urinary bladder vessel wall of patients with IC [64]. In addition, HLA class I molecules seem to be overexpressed by most cells of the urinary bladder of patients with IC and along with the increased number of CD8, suggest a direct CD8 cytotoxicity [65, 66]. On the other hand, the increased number of CD4 lymphocytes and the expression of HLA-DR molecules within the bladder of patients with IC may contribute to disease pathogenesis [65, 66].

Two recent studies further support the association between SS and PBS/IC. In a study from Finland, 36 SS patients were included and the frequency of lower urinary tract problems was found significantly higher compared to normal individuals [67]. Leppilahti et al. recruited 870 SS patients from the Finnish SS organization and 1,304 normal controls and tried to estimate the prevalence of IC by using a specific questionnaire [68]. Forty-five SS patients (5%) versus four controls (0.3%) fulfilled the criteria for probable IC and the prevalence rate ratio was 15 (95% CI: 4.8–50). Although epidemiologic data clearly point out an association between SS and IC, the possible underlying pathogenetic mechanisms have not been elucidated yet. Autoantibodies against muscarinic M3 receptors have been detected in patients with SS and these antibodies have been proposed in the literature to play a role in the pathogenesis of IC by affecting the muscarinic receptors of the bladder [69]. However, this hypothesis needs further investigation to be confirmed.

19.4.4Differential Diagnosis

Differential diagnosis of PBS/IC includes all the so-called “confusable diseases” as defined by the ESSIC [54]. These entities may produce overlap symptoms with PBS/ IC and must be excluded before the diagnosis of PBS/IC is established. The most important are infections, urogenital prolapse, bladder stone, carcinoma of the urinary bladder, and overactive bladder (OAB). The majority of these conditions can be easily distinguished from PBS/IC by medical history, physical examination, and simple routine tests such as urinalysis, urine cultures, and ultrasound [54]. If there is a high suspicion for carcinoma, cytoscopy and biopsy should be performed. Overactive bladder is more common than PBS/IC and may present with urgency and frequency with or without incontinence. However, these patients are usually males and they experience urgency as a needing action rather than a strong desire to void like IC patients who urinate to alleviate pain. In difficult cases, urodynamic studies can differentiate the two conditions. Because SS affects mainly females, the confusable diseases that concern the prostate are of low clinical significance.