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Interstitial Cystitis and Sjögren's Syndrome

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Interstitial Cystitis and Sjögren's Syndrome □ EDITORIAL □ Interstitial Cystitis and Sjögren’s Syndrome Key words: interstitial cystitis, Sjögren’s syndrome, organ- disease possesses many of the clinical and pathological fea- specific disease, progression, immunosuppres- tures of autoimmune diseases, suggesting that interstitial cys- sive therapy titis may be a chronic condition of the bladder involving an autoimmune response. In this regard, immunization of mice with a syngeneic bladder homogenate was shown to induce an experimental autoimmune cystitis in mice very similar to An interesting and rare case of interstitial cystitis associ- the human disease, and adoptive transfer of splenic cells was ated with Sjögren’s syndrome (SS) is presented in this issue found to induce the disease in non-immunized, sygeneic (1). mice (17). Interstitial cystitis is associated with several known See also p 248. autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and Hashimoto’s thyroiditis (15, Interstitial cystitis is a chronic inflammatory disease of the 18, 19). Bladder involvement in SLE has been described in bladder of unknown etiology occurring mainly in women several patients (20, 21), as well as cystitis, in which the uri- (90%), primarily during middle age (2). It is characterized nary bladder wall contained deposits of IgG, IgM, IgA and symptomatically by suprapubic, pelvic, urethral, vaginal, complement (22). This condition, called lupus cystitis, sug- and/or perineal pain on bladder filling, urgency, and frequent gested that bladder involvement may be a primary manifesta- urination due to small capacity bladder. This pain is relieved tion of SLE (23). The occurrence, severity and nature of by emptying of the bladder. The clinical diagnosis is sup- lower urinary tract symptoms, especially irritable bladder ported by cystoscopic findings of focal glomerulations or ul- symptoms, was shown to be greater among patients suffering cers (Hunner’s ulcer) in the bladder wall (3, 4, Table 1). from SS or SLE than among age- and sex-matched controls SS is a chronic organ-specific autoimmune disease char- (8). In an examination of 10 interstitial cystitis patients for acterized by lymphocytic infiltration of the salivary and the presence of systemic autoimmune diseases, it was found lacrimal glands, resulting in keratoconjunctivitis sicca and that two of these patients fulfilled the classification criteria xerostomia. However, half of the SS patients develop sys- for SS, while 3 other patients showed positive results on lip temic disorders associated with various autoantibodies, espe- biopsy, indicating an association between interstitial cystitis cially anti-Ro/SS-A and anti-La/SS-B antibodies (5). During and SS (6). the progression of SS, lymphocytes infiltrate many organs. Although the etiology of SS and its mechanism of pro- Systemic disorders associated with SS include those of the gression are not known, two factors may be important for un- pulmonary, hepatic, renal, hematologic, and dermatologic, derstanding this complex disorder. The first is the and various other systems. Interestingly, the organ involved microenvironment of the organ, which facilitates the migra- is different in each individual, suggesting that organ selectiv- tion of specific lymphocytes from the blood stream. The sec- ity is one of the outstanding characteristics of SS. Interstitial ond is the continuity of lymphocyte aggression, which is cystitis was recently observed in several patients with SS (1, probably mediated by antigen stimulation and dysregulation 6–8), indicating that bladder involvement may also be asso- of apoptosis. The organ specificity observed in SS may be ciated with SS. caused by homing of lymphocytes to specific organs that ex- Interstitial cystitis demonstrates some of the characteris- press adhesion molecules such as MadCAM-1 or E-selectin tics of an autoimmune disease, including the presence of on their vessel walls or epithelial cells (24). The latter may autoantibodies, chronic inflammation, episodic waxing and be due to activation of the cells by viral infection (25) or an- waning of the disease, and, in some cases, its resolution by other, as yet unknown, mechanism of activation. The homing steroid therapy (1, 7). Histologically, lymphocytic infiltration of lymphocytes expressing 47orE7 may be facilitated of the bladder of patients with interstitial cystitis has been by the expression of MadCAM-1 or E-selectin on the vessel observed (9). These infiltrates consist of B cell nodules, in- wall. In SS, the aberrant expression of class II molecules, in cluding germinal centers, plasma cells and dense sheets of T conjunction with autoantigens such as Ro/SS-A (26) or - cells (9). Increased numbers of mast cells and deposits of fodrin (27) and costimulating molecules such as B7.1 and immunoglobulin and complement have been reported in B7.2 (28), on the surface of stimulated ductal cells may be these patients (10–13), and autoantibodies have been de- the important step in the initiation and self-perpetuation of tected in patients with interstitial cystitis (14–16). This the local autoimmune reaction in various organs. 174 Internal Medicine Vol. 43, No. 3 (March 2004) Table 1. Consensus Criteria for Diagnosis of Interstitial Susumu SUGAI Cystitis (37) Hematology & Immunology, Internal Medicine, Kanazawa Medical University Automatic Exclusions and Kudou General Hospital, 920-0293 Less than 18 years old Benign or malignant bladder tumors References Radiation cystitis Bacterial cystitis 1) Shibata S, Ubara Y, Sawa N, et al. Severe interstitial cystitis associated Vaginitis with Sjögren’s syndrome. Intern Med 43: 248–252, 2004. Cyclophosphamide cystitis 2) Propert KJ, Schaeffer AJ, Brensinger CM, et al. A prospective study of Symptomatic urethral diverticulum interstitial cystitis: results of longitudinal followup of the interstitial Uterine, cervical, vaginal, or urethral cancers cystitis data base cohort. The Interstitial Cystitis Data Base Study Active herpes Group. J Urol 163: 1434–1439, 2000. Bladder or lower urethral calculi 3) Messing EM, Stamey TA. Interstitial cystitis: early diagnosis, pathol- Waking frequency less than five times in 12 h ogy, and treatment. Urology 12: 381–392, 1978. Nocturia less than twice nightly 4) Sant GR. Interstitial cystitis. Monogr Urol 12: 37, 1991. 5) Fox RI. Clinical features, pathogenesis, and treatment of Sjögren’s syn- Symptoms relieved by antibiotics, urinary antiseptics, uri- drome. Curr Opin Rheumatol 8:438–445, 1996. nary analgesics (e.g., phenazopyridine hydrochloride) 6) Van de Merwe J, Kamerling R, Arendsen E, et al. Sjögren’s syndrome Duration less than 12 months in patients with interstitial cystitis. J Rheumatol 20: 962–966, 1993. Involuntary bladder contractions (urodynamics) 7) Segawa C, Wada T, Furuichi K, et al. Steroid pulse therapy in lupus Capacity greater than 400 ml, absence of sensory urgency cystitis. Intern Med 35: 155–158, 1996. Automatic Inclusions 8) Haarala M, Alanen A, Hietarinta M, et al. Lower urinary tract symp- Hunner’s ulcer toms in patients with Sjögren’s syndrome and systemic lupus Positive Factors erythematosus. Int Urogynecol J Pelvic Floor Dysfunct 11: 84–86, Pain on bladder filling relieved by emptying 2000. Pain (suprapubic, pelvic, urethral, vaginal, or perineal) 9) Harrington DS, Fall M, Johansson SL. Interstitial cystitis: bladder mucosa lymphocyte immunophenotyping and peripheral blood flow Glomerulations after hydrodistention on cystoscopy cytometry analysis. J Urol 144: 868–871, 1990. 10) Larsen S, Thompson SA, Hald T, et al. Mast cells in interstitial cystitis. Br J Urol 54:283–286, 1982. 11) Mattila J, Linder E. Immunoglobulin deposits in bladder epithelium Endothelial overgrowth and intraepithelial lymphocytic and vessels in interstitial cystitis: possible relationship to circulating infiltration, especially with dense infiltration of lymphocytes anti-intermediate filament autoantibodies. Clin Immunol Immunopathol in the submucosal area, have been observed in the bladder of 32: 81–89, 1984. patients with autoimmune diseases (1, 9, 29, 30), suggesting 12) Aldenborg F, Fall M, Enerback L. Proliferation and transepithelial mi- that autoimmune epithelitis (31) may contribute substantially gration of mucosal mast cells in interstitial cystitis. Immunology 58: 411–416, 1986. to the pathophysiology of organ involvement in SS. During 13) Johansson SL, Fall M. Clinical features and spectrum of light micro- this process organ-specific autoantigens may be expressed by scopic changes in interstitial cystitis. J Urol 143: 1118–1124, 1990. apoptotic cells (27, 32). Continuous stimulation by auto- 14) Oravisto KJ. Interstitial cystitis as an autoimmune disease. A review. antigens can activate T cells, leading to the expression of Eur Urol 6: 10–13, 1980. CD40L on the cell surface. The binding of CD40L on T cells 15) Anderson JB, Parivar F, Lee G, et al. The enigma of interstitial cystitis－an autoimmune disease? Br J Urol 63: 58–63, 1989. to CD40 on B cells is a critical component of B cell stimula- 16) Ochs RL, Stein TW Jr, Peebles CL, et al. Autoantibodies in interstitial tion. In addition, overexpression of Bcl-2, in the absence of cystitis. J Urol 151: 587–592, 1994. chromosomal translocation, may occur during this T cell-B 17) Bullock AD, Becich MJ, Klutke CG, et al. Experimental autoimmune cell interaction, resulting in inhibition of apoptosis of B cells. cystitis: a potential murine model for ulcerative interstitial cystitis. J Increased secretion by lymphocytes of cytokines
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