Cyclosporine A in the Treatment of Interstitial Cystitis

..............................................................................................................9 INTRODUCTION .................................................................................................... 10 REVIEW OF THE LITERATURE............................................................................ 12 Painful bladder syndrome / interstitial cystitis (PBS/IC) ............................................ 12 Definition / Name of the disease............................................................................ 12 NIDDK criteria ..................................................................................................... 13 Epidemiology............................................................................................................ 14 Etiology .................................................................................................................... 15 Epithelial dysfunction............................................................................................ 15 Mast cell activation ............................................................................................... 16 Neural upregulation............................................................................................... 18 Infection................................................................................................................ 18 Autoimmunity ....................................................................................................... 19 Urinary markers ........................................................................................................ 20 Epidermal growth factor (EGF) ............................................................................. 21 Urinary EGF in PBS/IC .................................................................................... 22 Interleukin-6 (IL-6) ............................................................................................... 23 Urinary IL-6 in PBS/IC ..................................................................................... 23 Antiproliferative factor (APF) ............................................................................... 24 Diagnosing PBS/IC ................................................................................................... 25 Urinary diaries .......................................................................................................... 25 Symptom questionnaires ........................................................................................... 26 The O`Leary-Sant questionnaire (Interstitial Cystitis Symptom and Problem Indices) ........................................................................................................................... 26 Visual analogue scale (VAS) for pain.................................................................... 27 Potassium sensitivity test (PST) / KCL-test ........................................................... 27 Global response assessment (GRA) ....................................................................... 28 Quality of life of patients with PBS/IC...................................................................28 Treatment of PBS/IC .................................................................................................30 Pentosan polysulfate sodium......................................................................................31 Mechanism of action of PPS in PBS/IC .................................................................32 Pentosan polysulfate sodium (PPS) in the treatment of PBS/IC..............................32 Cyclosporine A..........................................................................................................33 Cyclosporine A in autoimmune diseases ................................................................35 Adverse effects of CyA therapy .............................................................................36 Dimethyl sulfoxide ....................................................................................................37 DMSO in the treatment of PBS/IC.........................................................................37 Bacillus Calmette-Guerin ..........................................................................................38 BCG in the treatment of PBS/IC............................................................................38 AIMS OF THE STUDY............................................................................................39 METHODS ...............................................................................................................40 PATIENTS AND METHODS (I) ..............................................................................40 PATIENTS AND METHODS (II-III)........................................................................41 Potassium sensitivity test (III)................................................................................42 PATIENTS AND METHODS (IV) ...........................................................................42 Determination of IL-6 and EGF (IV) .....................................................................43 PATIENTS AND METHODS (V) ............................................................................43 STATISTICAL METHODS (I – V) ..........................................................................44 RESULTS .................................................................................................................45 Long-term CyA therapy had an impact on voiding diaries (I).....................................45 CyA had superior efficacy in PBS/IC-related symptoms compared with PPS (II).......47 Six months’ treatment on PBS/IC with CyA may change positive PST to negative (III) .................................................................................................................................48 PBS/IC treatment with CyA but not with PPS reduces urinary EGF levels (IV) .........49 The HRQOL questionnaire was sensitive to treatment response after CyA, PPS, BCG or DMSO therapy (V) ............................................................................................... 50 DISCUSSION........................................................................................................... 54 Therapeutic effect of CyA on PBS/IC (I-II)............................................................... 54 Therapeutic effect of PPS on PBS/IC (II) .................................................................. 55 Safety of CyA and PPS (I-II)..................................................................................... 56 Necessity of conducting PST in patients with PBS/IC (III) ........................................ 57 Changes in urinary markers reflect the treatment effect of CyA on PBS/IC (IV)........ 58 The need for assessment of health-related quality of life in the follow-up of patients with PBS/IC (V) ....................................................................................................... 59 Future research in the field of PBS/IC ....................................................................... 60 SUMMARY AND CONCLUSIONS ........................................................................ 62 ACKNOWLEDGMENTS......................................................................................... 64 REFERENCES ......................................................................................................... 67 APPENDIX............................................................................................................... 83 The O`Leary-Sant symptom and problem indices ...................................................... 83 Finnish version of the O`Leary-Sant questionnaire .................................................... 84 Health-related quality of life questionnaire ................................................................ 85