Modern Rheumatology
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Interstitial cystitis associated with primary Sjögren's syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review Yo Ueda, Hikaru Tomoe, Hiroyuki Takahashi, Yuko Takahashi, Hiroyuki Yamashita, Hiroshi Kaneko, Toshikazu Kano & Akio Mimori To cite this article: Yo Ueda, Hikaru Tomoe, Hiroyuki Takahashi, Yuko Takahashi, Hiroyuki Yamashita, Hiroshi Kaneko, Toshikazu Kano & Akio Mimori (2014): Interstitial cystitis associated with primary Sjögren's syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review, Modern Rheumatology To link to this article: http://dx.doi.org/10.3109/14397595.2014.895283
Published online: 11 Apr 2014.
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http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–5 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.895283
CASE REPORT
Interstitial cystitis associated with primary Sjögren’s syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review Yo Ueda1, Hikaru Tomoe2, Hiroyuki Takahashi1, Yuko Takahashi1, Hiroyuki Yamashita1, Hiroshi Kaneko1, Toshikazu Kano1, and Akio Mimori1 1Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo, Japan, and 2Department of Urology, Tokyo Women’s Medical
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University Medical Center East, Tokyo, Japan Abstract
Keywords
We report a case of interstitial cystitis (IC) associated with primary Sjögren’s syndrome (SS) successfully controlled with combination therapy of tacrolimus and a corticosteroid. In 2011, a 69-year-old female, who had been diagnosed with primary SS 23 years ago, developed IC and was successfully treated with tacrolimus and prednisolone combination therapy. The mechanism of IC, including the involved autoimmunity, has not been elucidated. Clinical observation studies suggest a potential association between SS and IC. However, IC is currently thought to be underdiagnosed in patients with SS as well as in the general population. Based on our case and others reported previously, IC associated with SS responds well to immunosuppressive therapy. In particular, a combination of a calcineurin inhibitor (tacrolimus or cyclosporine) with a corticosteroid seems to be highly effective. The possibility of IC in patients with SS complaining of lower urinary tract symptoms without features of infection or other identifiable causes should be given attention.
Calcineurin inhibiter, Interstitial cystitis, Sjögren’s syndrome, Tacrolimus History Received 21 January 2014 Accepted 14 February 2014 Published online 9 April 2014
Introduction
Case
Interstitial cystitis (IC) is a chronic inflammatory urologic condition characterized by an unpleasant sensation (pain, pressure, or discomfort) perceived to be related to the urinary bladder. IC is associated with lower urinary tract symptoms of more than 6 weeks’ duration in the absence of infection or other identifiable causes [1]. The prevalence of IC varies because of the several definitions and methods used to estimate it. Recent studies report a prevalence of 52–197/100,000 women when the diagnosis is made by a physician. IC is more common in women, with a female/male ratio that ranges from 5:1 to 10:1 [2]. Although the etiology and pathogenesis of IC remain unclear, autoimmune mechanisms are believed to be at work. Among several collagen tissue diseases, systemic lupus erythematosus (SLE) is most known to be a related condition [3]. Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands. Nearly 40% of patients with SS also develop extraglandular manifestations during progression of SS, including pulmonary, hepatic, and renal involvement. IC accompanying SS was first reported by Van De Merwe et al. in 1993 [4]. However, few cases have been reported to date.
In July 2011, a 69-year-old woman diagnosed with IC was referred to our department by the urology department of a university hospital for the purpose of immunosuppressive therapy. She had been diagnosed with primary SS at another university hospital in 1988 based on dry eye, dry mouth, positive anti-Ro (SS-A) antibody, and a positive lip biopsy result. In 1991, she developed numbness in both lower legs and paresthesia on the soles. She was observed with symptomatic treatment, but her symptoms remained unchanged. She developed urinary frequency in 2008 and bladder pain, nocturia, and decreased urinary volume in 2009. She went to the urology department of a university hospital in March 2011. A cystoscopic examination revealed ulcers with patchy hemorrhage (Hunner’s lesions) (Figure 1a). A biopsy specimen revealed subepithelial edema with infiltration by lymphocytes, mast cells, and eosinophils (Figure 2a, b). The diagnosis of IC was made. Although she was initially treated with hydrodistension and transurethral coagulation (Figure 1b), her symptoms did not improve. Because she was considered to have IC associated with primary SS, she was introduced to us. A physical examination on admission revealed dryness of the oral mucosa and tongue and Raynaud’s phenomenon with cold stimulation. No other abnormalities were seen. Laboratory data at admission were as follows. Complete blood count: white blood cell count, 3970/μl; Hb, 12.5 g/dl; and platelet count, 206,000/μl. Serum biochemistry: total protein, 7.6 g/dl; albumin, 4.2 g/dl; blood urea nitrogen, 17.1 mg/dl; creatinine, 0.65 mg/dl; sodium 139 mEq/l, potassium 4.0 mEq/l; and chloride,
Correspondence to: Yo Ueda, Division of Rheumatic Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan. Tel: ⫹ 81-3-3202-7181. Fax: ⫹ 81-3-3207-1038. E-mail: [email protected]
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Figure 2. Histopathologic features of the bladder wall biopsies. (a) Urothelial separation, edematous lamina propria, and infiltration of inflammatory cells were seen on the hematoxylin and eosin stain. (b) Mast cells were seen on the toluidine blue stain.
Figure 1. Pictures of the cystoscopic examination before and after therapy. (a) Ulcers with patchy hemorrhages (so-called Hunner’s lesions) were evident at the initial examination before the operation. (b) Hydrodistension and transurethral coagulation were performed.
103 mEq/l; erythrocyte sedimentation rate at 1 h, 22 mm; and serum C-reactive protein (CRP), 0.0 mg/dl; serum IgG, 1739 mg/dl; IgA, 432 mg/dl; IgM, 60 mg/dl; C3, 73 mg/dl; and C4, 16.3 mg/dl. Immunological tests: anti-nuclear-antibody, 40 ⫻ (speckled pattern); and SS-A antibody (enzyme-linked immunosorbent assay) was positive at 123.1 IU/ml. Rheumatoid factor, anti-La (SS-B) antibody, anti-double-stranded-DNA antibody, anti-U1-RNP antibody, anticentromere antibody, and anti-Scl-70 antibody were all negative. The urine sediment contained 1–5 erythrocytes, and 10–19 leukocytes per high power field. Urinary cultures yielded no growth. The Schirmer’s test was 8 mm on the right and 9 mm on the left in 5 min. Keratoconjuctivitis by both fluorescein and Rose Bengal stain was revealed. Salivary secretion was remarkably decreased to 2 ml in 10 minutes on the Gum test. Salivary gland scintigraphy
utilizing 99mTcO4 indicated decreased saliva secretion. A biopsy of the labial salivary gland was not performed at this time. No other features associated with SLE, rheumatoid arthritis, or other collagen tissue diseases were seen. She was confirmed to have primary SS from these results and the positive anti-Ro antibody according to the European Sjogren’s syndrome diagnostic criteria [5]. She had complained of numbness in both lower legs and paresthesia on her soles without obvious exacerbation for several years. On neurological examination, the Romberg test was positive, and the deep tendon reflexes in her legs were attenuated. A nerve conduction study revealed sensory neuropathy. She was considered as secondary IC associated with primary SS and started immunosuppressive therapy with a combination of 30 mg per day of prednisolone (PSL) and 3 mg per day tacrolimus (Tac). The main targeted organ for immunosuppressive therapy was cystitis, but the sensory neuropathy was not targeted for treatment with corticosteroid and Tac. After 2 weeks, we increased the PSL to 40 mg per day and added 25 mg per day hydroxyzine because of no symptomatic improvement. At the same time, intravenous Ig (400 mg/kg/day for 5 days) for the sensory neuropathy was administered, but no improvement in neurological symptoms was seen. Her urinary symptoms improved gradually. During 2 months of therapy, her average voided volume increased from 85 to 263 ml, her maximum voided volume increased from 120 to 400 ml, and her urinary frequency decreased from 17.5 to 9.5 times per day. The pretherapeutic O’Leary-Sant Interstitial Cystitis Symptoms
DOI 10.3109/14397595.2014.895283
Treatment of interstitial cystitis associated with Sjögren’s syndrome
Index (ICSI) and Interstitial Cystitis Problematic Index (ICPI) were calculated as 14 and 11 points, respectively, but decreased to 4 and 2 points, respectively, 2 months after immunosuppressive therapy [6]. The visual analog pain score improved from 7 to 3. Pretherapeutic uroflowmetry showed a maximum and average urinary flow of 11 and 3 ml/s, respectively, which increased to 31 and 11 ml/s, respectively, 2 months after immunosuppressive therapy. Figure 3 shows the uroflowmetric findings before and after immunosuppressive therapy. The cystoscopic Hunner’s lesions disappeared 2 months after immunosuppressive therapy. To date, she has been well sustained for more than 2 years without a flare-up of features associated with IC. Tac is stably continuing with 3 mg per day and PSL is tapering gradually after the initial therapy of 40 mg per day for 3 weeks; 10 mg per day after 5 months, 5 mg per day after 17 months.
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Discussion IC was first reported in 1915, when Hunner described it as “a rare type of bladder ulcer in women” [7]. Fister first reported a case of IC in a patient with SLE in 1938 [8]. The term, “lupus cystitis” was first used by Orth who reported six cases of IC associated with SLE in 1983 [9]. In contrast, IC accompanied by SS was first reported by Van De Merwe et al. in 1993 [4]. Although lupus cystitis is famous, there have been few case reports about IC associated with SS.
3
IC is a chronic inflammatory bladder disease of unknown etiology occurring mainly in middle aged women. The clinical diagnosis is supported by cystoscopic findings of focal glomerulations or ulcers (Hunner lesion) in the bladder wall. A histological study of the bladder wall shows mucosal edema and mononuclear cell infiltration of the interstitium. Although a strong female predominance evokes a causal role of autoimmunity in idiopathic IC, no data directly support it. However, clinical associations between IC and autoimmune diseases have been verified. Most notably, there is a strong association between IC and SS [3]. Leppilahti et al. questioned members of the Finnish SS patient association whose diagnosis had been confirmed by a physician on the prevalence of urinary symptoms and compared them with a control population. The criteria for probable IC were fulfilled by 5% of the SS cases and 0.3% of the controls by means of ICSI and ICPI [10]. In contrast, van de Merwe investigated a total of 110 patients with IC between 1992 and 2003 for accompanying clinical features of SS according to the revised European criteria for SS [3]. The prevalence of each of the investigated criteria in the IC patients was: ocular symptoms in 67.3%, oral symptoms or parotis enlargement in 60.9%, abnormal ocular test in 16.4%, abnormal salivary histology in 14.5%, and antibodies to Ro or La in 12.7%. Nevertheless, the involvement of salivary glands as demonstrated by radiology or salivary flow was not tested because of lack of reproducibility and sensitivity. A diagnosis of SS according to the European criteria was made in 7.2% of 110 patients and the other 19% met three of the criteria for SS.
Figure 3. Uroflowmetric findings before (a) and after (b) immunosuppressive therapy. The urinary flow rate and voided volume were improved.
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Table 1. Reported cases of interstitial cystitis with Sjogren’s syndrome treated with immunosuppressive therapy.
Case 1
Reference 20
Age (years)/sex 53/F
2
21
77/F
3
18
53/F
4
22
51/F
5
23
42/F
6
Our case
69/F
Disease duration of SS 14 years after the onset of dryness 10 years after the onset of dryness and the diagnosis of SS 12 months after the onset of dryness 5 months after the onset of dryness 6 years after the onset of dryness and the diagnosis of SS 23 years after the diagnosis of pSS
Other extraglandular conditions or other connective tissue diseases (duration) None Interstitial pneumonia (coincident with IC) None Rheumatoid arthritis (for 5 years) None Sensory neuropathy (for 20 years)
Therapy (efficacy of each therapy) HD (effective only temporarily), PSL 30 mg PSL 20 mg, suplatast tosilate Pulsed mPSL 500 mg, PSL 40 mg, CyA 100 mg (effective) PSL 30 mg, HD (effective) mPSL 24 mg, AZP 2 mg/kg (ineffective), CyA 100 mg (effective) HD and TC (ineffective), PSL (30 mg→40 mg), Tac 3 mg (effective), hydralazine 25 mg, IVIg (ineffective for neuropathy)
Outcome Improved Improved Improved Improved Improved Improved
AZP, azathioprine; CyA, cyclosporine; HD, hydrodistension; IC, interstitial cystitis; IVIg, intravenous immunoglobulin; mPSL, methylprednisolone; PSL, prednisolone; SS, Sjögren’s syndrome; Tac, tacrolimus; TC, transurethral coagulation.
Some studies suggest that autoantibody to muscarinic-3 receptor (M3R) may cause several conditions associated with SS [11–13]. The M3R is also the receptor on detrusor cells that mediates cholinergic contraction of the normal urinary bladder and other smooth muscle tissues [14,15]. In a mouse model, blocking IgG autoantibodies to M3Rs compensatorily upregulates the number of M3Rs in detrusor muscle and causes contractions leading to urinary symptoms [16]. In addition, the binding of high-affinity autoantibodies to M3Rs on detrusor cells could cause local accumulation of mast cells by release and production of cytokines and chemokines such as tumor necrosis factor, interleukin(IL)-1β, IL-8, IL-6, and RANTES. Mast cells that are prominently present around the detrusor muscle in many patients with IC are considered to be a hallmark of the disease and to have a pathogenic role [17]. A difference may exist between lupus cystitis and IC associated with SS. In lupus cystitis, immune deposits of immunoglobin (Ig)G, IgA, IgM, or complement C1q are found frequently in the mucosa and perivascular regions of urinary bladder specimens. Shibata et al. reported in their case report of IC associated with SS that no immune deposits were observed in the urinary bladder and they suggested that the histological findings might help to differentiate IC associated with SLE or SS [18]. Additionally, lupus cystitis is accompanied by gastrointestinal symptoms [19]. However, no reports have reported cystitis accompanied with gastrointestinal symptoms in cases of SS. These results suggest that IC accompanying SLE and SS has a different pathogenesis. The treatment experience is extremely limited about the association between IC and SS. We conducted a literature review to identify published cases of IC associated with SS. We searched the Medline database using the terms “interstitial cystitis” or “cystitis”, combined with “Sjögren’s syndrome”. The search was limited to adult cases with SS with a well described clinical course including treatment regime and outcomes in the English or Japanese literature. Our Medline search identified only five patients with IC associated with SS from 1998 to date [18,20–23]. Table 1 shows the characteristics of the six cases, including our case. All reported cases were female and improved with immunosuppressive therapy. In a case review of lupus cystitis, 28 out of 40 patients improved with corticosteroid, combined with other immunosuppressive drugs in a few cases [19]. Therefore, IC associated with SLE or SS seems to respond well with immunosuppressive therapy. Although the comparison with lupus cystitis is difficult, it is interesting that cyclosporine A (CyA) in combination with corticosteroid has been effective in two cases
of IC associated with SS [18,23]. CyA has also been used to treat patients with idiopathic IC who were unresponsive to other treatments, including hydrodistension and fulguration. However, the use of CyA as well as corticosteroid is limited for adverse events in cases of idiopathic IC [24,25]. Although the mechanism of action to IC is unclear, CyA inhibits T cell activation by blocking transcription of cytokine genes and stabilizing mast cells. Tac is another newer calcineurin inhibiter similarly inhibiting T cells, and its efficacy for collagen tissue diseases such as SLE and rheumatoid arthritis was established. Although there is only one case report of IC successfully treated with a combination of Tac and corticosteroid [26], this is the first report about IC associated with SS successfully treated with a combination of Tac and corticosteroid. In our case, although intravenous Ig (IVIg) was added for treatment of sensory neuropathy, no other case report administered IVIg for IC and its efficacy for IC was unclear.
Conclusion IC associated with SS is a possibly underdiagnosed condition. It responds well to immunosuppressive therapy, such as a combination of a calcineurin inhibiter (tacrolimus or cyclosporine) with corticosteroid.
Acknowledgments This study was supported by Grants-in-Aid for Research on Intractable Diseases from the Ministry of Health, Labor, and Welfare of Japan.
Conflict of interest None.
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produces the pathophysiology of overactive bladder. Arthritis Rheum. 2004;50(11):3637–45. Sant GR, Kempuraj D, Marchand JE, Theoharides TC. The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology. 2007;69(4 Suppl):34–40. Shibata S, Ubara Y, Sawa N, Tagami T, Hosino J, Yokota M, et al. Severe interstitial cystitis associated with Sjogren’s syndrome. Intern Med. 2004;43(3):248–52. Shimizu A, Tamura A, Tago O, Abe M, Nagai Y, Ishikawa O. Lupus cystitis: a case report and review of the literature. Lupus. 2009;18(7):655–8. Higuchi M, Migita T, Yoshizawa S, Horiuchi T, Nakashima H, Niho Y. Interstitial cystitis in case of primary Sjogren’s syndrome. Ryumachi. 1998;38(1):34–8. Nagaoka M, Tamaoki J, Gotoh S, Nakazawa H, Nagai A. A case of Sjogren syndrome accompanied by interstitial cystitis and interstitial pneumonia improved by suplatast tosilate and prednisolone. Arerugi. 2003;52(4):450–3. Fukaya E, Watanabe H, Kobayashi H, Yokota T, Yamaguchi O, Kasukawa R, Sato Y. A case of interstitial cystitis accompanying Sjogren’s syndrome. Mod Rheumatol. 2005;15(1):73–6. Emmungil H, Kalfa M, Zihni FY, Karabulut G, Keser G, Sen S, Aksu K. Interstitial cystitis: a rare manifestation of primary Sjogren’s syndrome, successfully treated with low dose cyclosporine. Rheumatol Int. 2012;32(5):1215–8. Sairanen J, Forsell T, Ruutu M. Long-term outcome of patients with interstitial cystitis treated with low dose cyclosporine A. J Urol. 2004;171(6 Pt 1):2138–41. Forrest JB, Payne CK, Erickson DR. Cyclosporine A for refractory interstitial cystitis/bladder pain syndrome: experience of 3 tertiary centers. J Urol. 2012;188(4):1186–91. Kaneko G, Nishimoto K, Ito Y, Uchida A. The combination therapy of prednisolone and tacrolimus for severe painful bladder syndrome/ interstitial cystitis. Can Urol Assoc J. 2012;6(2):E46–9.
ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20
Interstitial cystitis associated with primary Sjögren's syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review Yo Ueda, Hikaru Tomoe, Hiroyuki Takahashi, Yuko Takahashi, Hiroyuki Yamashita, Hiroshi Kaneko, Toshikazu Kano & Akio Mimori To cite this article: Yo Ueda, Hikaru Tomoe, Hiroyuki Takahashi, Yuko Takahashi, Hiroyuki Yamashita, Hiroshi Kaneko, Toshikazu Kano & Akio Mimori (2014): Interstitial cystitis associated with primary Sjögren's syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review, Modern Rheumatology To link to this article: http://dx.doi.org/10.3109/14397595.2014.895283
Published online: 11 Apr 2014.
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Article views: 49
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=imor20 Download by: [University of Otago]
Date: 23 September 2015, At: 06:25
http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–5 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.895283
CASE REPORT
Interstitial cystitis associated with primary Sjögren’s syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review Yo Ueda1, Hikaru Tomoe2, Hiroyuki Takahashi1, Yuko Takahashi1, Hiroyuki Yamashita1, Hiroshi Kaneko1, Toshikazu Kano1, and Akio Mimori1 1Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo, Japan, and 2Department of Urology, Tokyo Women’s Medical
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University Medical Center East, Tokyo, Japan Abstract
Keywords
We report a case of interstitial cystitis (IC) associated with primary Sjögren’s syndrome (SS) successfully controlled with combination therapy of tacrolimus and a corticosteroid. In 2011, a 69-year-old female, who had been diagnosed with primary SS 23 years ago, developed IC and was successfully treated with tacrolimus and prednisolone combination therapy. The mechanism of IC, including the involved autoimmunity, has not been elucidated. Clinical observation studies suggest a potential association between SS and IC. However, IC is currently thought to be underdiagnosed in patients with SS as well as in the general population. Based on our case and others reported previously, IC associated with SS responds well to immunosuppressive therapy. In particular, a combination of a calcineurin inhibitor (tacrolimus or cyclosporine) with a corticosteroid seems to be highly effective. The possibility of IC in patients with SS complaining of lower urinary tract symptoms without features of infection or other identifiable causes should be given attention.
Calcineurin inhibiter, Interstitial cystitis, Sjögren’s syndrome, Tacrolimus History Received 21 January 2014 Accepted 14 February 2014 Published online 9 April 2014
Introduction
Case
Interstitial cystitis (IC) is a chronic inflammatory urologic condition characterized by an unpleasant sensation (pain, pressure, or discomfort) perceived to be related to the urinary bladder. IC is associated with lower urinary tract symptoms of more than 6 weeks’ duration in the absence of infection or other identifiable causes [1]. The prevalence of IC varies because of the several definitions and methods used to estimate it. Recent studies report a prevalence of 52–197/100,000 women when the diagnosis is made by a physician. IC is more common in women, with a female/male ratio that ranges from 5:1 to 10:1 [2]. Although the etiology and pathogenesis of IC remain unclear, autoimmune mechanisms are believed to be at work. Among several collagen tissue diseases, systemic lupus erythematosus (SLE) is most known to be a related condition [3]. Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands. Nearly 40% of patients with SS also develop extraglandular manifestations during progression of SS, including pulmonary, hepatic, and renal involvement. IC accompanying SS was first reported by Van De Merwe et al. in 1993 [4]. However, few cases have been reported to date.
In July 2011, a 69-year-old woman diagnosed with IC was referred to our department by the urology department of a university hospital for the purpose of immunosuppressive therapy. She had been diagnosed with primary SS at another university hospital in 1988 based on dry eye, dry mouth, positive anti-Ro (SS-A) antibody, and a positive lip biopsy result. In 1991, she developed numbness in both lower legs and paresthesia on the soles. She was observed with symptomatic treatment, but her symptoms remained unchanged. She developed urinary frequency in 2008 and bladder pain, nocturia, and decreased urinary volume in 2009. She went to the urology department of a university hospital in March 2011. A cystoscopic examination revealed ulcers with patchy hemorrhage (Hunner’s lesions) (Figure 1a). A biopsy specimen revealed subepithelial edema with infiltration by lymphocytes, mast cells, and eosinophils (Figure 2a, b). The diagnosis of IC was made. Although she was initially treated with hydrodistension and transurethral coagulation (Figure 1b), her symptoms did not improve. Because she was considered to have IC associated with primary SS, she was introduced to us. A physical examination on admission revealed dryness of the oral mucosa and tongue and Raynaud’s phenomenon with cold stimulation. No other abnormalities were seen. Laboratory data at admission were as follows. Complete blood count: white blood cell count, 3970/μl; Hb, 12.5 g/dl; and platelet count, 206,000/μl. Serum biochemistry: total protein, 7.6 g/dl; albumin, 4.2 g/dl; blood urea nitrogen, 17.1 mg/dl; creatinine, 0.65 mg/dl; sodium 139 mEq/l, potassium 4.0 mEq/l; and chloride,
Correspondence to: Yo Ueda, Division of Rheumatic Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan. Tel: ⫹ 81-3-3202-7181. Fax: ⫹ 81-3-3207-1038. E-mail: [email protected]
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Figure 2. Histopathologic features of the bladder wall biopsies. (a) Urothelial separation, edematous lamina propria, and infiltration of inflammatory cells were seen on the hematoxylin and eosin stain. (b) Mast cells were seen on the toluidine blue stain.
Figure 1. Pictures of the cystoscopic examination before and after therapy. (a) Ulcers with patchy hemorrhages (so-called Hunner’s lesions) were evident at the initial examination before the operation. (b) Hydrodistension and transurethral coagulation were performed.
103 mEq/l; erythrocyte sedimentation rate at 1 h, 22 mm; and serum C-reactive protein (CRP), 0.0 mg/dl; serum IgG, 1739 mg/dl; IgA, 432 mg/dl; IgM, 60 mg/dl; C3, 73 mg/dl; and C4, 16.3 mg/dl. Immunological tests: anti-nuclear-antibody, 40 ⫻ (speckled pattern); and SS-A antibody (enzyme-linked immunosorbent assay) was positive at 123.1 IU/ml. Rheumatoid factor, anti-La (SS-B) antibody, anti-double-stranded-DNA antibody, anti-U1-RNP antibody, anticentromere antibody, and anti-Scl-70 antibody were all negative. The urine sediment contained 1–5 erythrocytes, and 10–19 leukocytes per high power field. Urinary cultures yielded no growth. The Schirmer’s test was 8 mm on the right and 9 mm on the left in 5 min. Keratoconjuctivitis by both fluorescein and Rose Bengal stain was revealed. Salivary secretion was remarkably decreased to 2 ml in 10 minutes on the Gum test. Salivary gland scintigraphy
utilizing 99mTcO4 indicated decreased saliva secretion. A biopsy of the labial salivary gland was not performed at this time. No other features associated with SLE, rheumatoid arthritis, or other collagen tissue diseases were seen. She was confirmed to have primary SS from these results and the positive anti-Ro antibody according to the European Sjogren’s syndrome diagnostic criteria [5]. She had complained of numbness in both lower legs and paresthesia on her soles without obvious exacerbation for several years. On neurological examination, the Romberg test was positive, and the deep tendon reflexes in her legs were attenuated. A nerve conduction study revealed sensory neuropathy. She was considered as secondary IC associated with primary SS and started immunosuppressive therapy with a combination of 30 mg per day of prednisolone (PSL) and 3 mg per day tacrolimus (Tac). The main targeted organ for immunosuppressive therapy was cystitis, but the sensory neuropathy was not targeted for treatment with corticosteroid and Tac. After 2 weeks, we increased the PSL to 40 mg per day and added 25 mg per day hydroxyzine because of no symptomatic improvement. At the same time, intravenous Ig (400 mg/kg/day for 5 days) for the sensory neuropathy was administered, but no improvement in neurological symptoms was seen. Her urinary symptoms improved gradually. During 2 months of therapy, her average voided volume increased from 85 to 263 ml, her maximum voided volume increased from 120 to 400 ml, and her urinary frequency decreased from 17.5 to 9.5 times per day. The pretherapeutic O’Leary-Sant Interstitial Cystitis Symptoms
DOI 10.3109/14397595.2014.895283
Treatment of interstitial cystitis associated with Sjögren’s syndrome
Index (ICSI) and Interstitial Cystitis Problematic Index (ICPI) were calculated as 14 and 11 points, respectively, but decreased to 4 and 2 points, respectively, 2 months after immunosuppressive therapy [6]. The visual analog pain score improved from 7 to 3. Pretherapeutic uroflowmetry showed a maximum and average urinary flow of 11 and 3 ml/s, respectively, which increased to 31 and 11 ml/s, respectively, 2 months after immunosuppressive therapy. Figure 3 shows the uroflowmetric findings before and after immunosuppressive therapy. The cystoscopic Hunner’s lesions disappeared 2 months after immunosuppressive therapy. To date, she has been well sustained for more than 2 years without a flare-up of features associated with IC. Tac is stably continuing with 3 mg per day and PSL is tapering gradually after the initial therapy of 40 mg per day for 3 weeks; 10 mg per day after 5 months, 5 mg per day after 17 months.
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Discussion IC was first reported in 1915, when Hunner described it as “a rare type of bladder ulcer in women” [7]. Fister first reported a case of IC in a patient with SLE in 1938 [8]. The term, “lupus cystitis” was first used by Orth who reported six cases of IC associated with SLE in 1983 [9]. In contrast, IC accompanied by SS was first reported by Van De Merwe et al. in 1993 [4]. Although lupus cystitis is famous, there have been few case reports about IC associated with SS.
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IC is a chronic inflammatory bladder disease of unknown etiology occurring mainly in middle aged women. The clinical diagnosis is supported by cystoscopic findings of focal glomerulations or ulcers (Hunner lesion) in the bladder wall. A histological study of the bladder wall shows mucosal edema and mononuclear cell infiltration of the interstitium. Although a strong female predominance evokes a causal role of autoimmunity in idiopathic IC, no data directly support it. However, clinical associations between IC and autoimmune diseases have been verified. Most notably, there is a strong association between IC and SS [3]. Leppilahti et al. questioned members of the Finnish SS patient association whose diagnosis had been confirmed by a physician on the prevalence of urinary symptoms and compared them with a control population. The criteria for probable IC were fulfilled by 5% of the SS cases and 0.3% of the controls by means of ICSI and ICPI [10]. In contrast, van de Merwe investigated a total of 110 patients with IC between 1992 and 2003 for accompanying clinical features of SS according to the revised European criteria for SS [3]. The prevalence of each of the investigated criteria in the IC patients was: ocular symptoms in 67.3%, oral symptoms or parotis enlargement in 60.9%, abnormal ocular test in 16.4%, abnormal salivary histology in 14.5%, and antibodies to Ro or La in 12.7%. Nevertheless, the involvement of salivary glands as demonstrated by radiology or salivary flow was not tested because of lack of reproducibility and sensitivity. A diagnosis of SS according to the European criteria was made in 7.2% of 110 patients and the other 19% met three of the criteria for SS.
Figure 3. Uroflowmetric findings before (a) and after (b) immunosuppressive therapy. The urinary flow rate and voided volume were improved.
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Table 1. Reported cases of interstitial cystitis with Sjogren’s syndrome treated with immunosuppressive therapy.
Case 1
Reference 20
Age (years)/sex 53/F
2
21
77/F
3
18
53/F
4
22
51/F
5
23
42/F
6
Our case
69/F
Disease duration of SS 14 years after the onset of dryness 10 years after the onset of dryness and the diagnosis of SS 12 months after the onset of dryness 5 months after the onset of dryness 6 years after the onset of dryness and the diagnosis of SS 23 years after the diagnosis of pSS
Other extraglandular conditions or other connective tissue diseases (duration) None Interstitial pneumonia (coincident with IC) None Rheumatoid arthritis (for 5 years) None Sensory neuropathy (for 20 years)
Therapy (efficacy of each therapy) HD (effective only temporarily), PSL 30 mg PSL 20 mg, suplatast tosilate Pulsed mPSL 500 mg, PSL 40 mg, CyA 100 mg (effective) PSL 30 mg, HD (effective) mPSL 24 mg, AZP 2 mg/kg (ineffective), CyA 100 mg (effective) HD and TC (ineffective), PSL (30 mg→40 mg), Tac 3 mg (effective), hydralazine 25 mg, IVIg (ineffective for neuropathy)
Outcome Improved Improved Improved Improved Improved Improved
AZP, azathioprine; CyA, cyclosporine; HD, hydrodistension; IC, interstitial cystitis; IVIg, intravenous immunoglobulin; mPSL, methylprednisolone; PSL, prednisolone; SS, Sjögren’s syndrome; Tac, tacrolimus; TC, transurethral coagulation.
Some studies suggest that autoantibody to muscarinic-3 receptor (M3R) may cause several conditions associated with SS [11–13]. The M3R is also the receptor on detrusor cells that mediates cholinergic contraction of the normal urinary bladder and other smooth muscle tissues [14,15]. In a mouse model, blocking IgG autoantibodies to M3Rs compensatorily upregulates the number of M3Rs in detrusor muscle and causes contractions leading to urinary symptoms [16]. In addition, the binding of high-affinity autoantibodies to M3Rs on detrusor cells could cause local accumulation of mast cells by release and production of cytokines and chemokines such as tumor necrosis factor, interleukin(IL)-1β, IL-8, IL-6, and RANTES. Mast cells that are prominently present around the detrusor muscle in many patients with IC are considered to be a hallmark of the disease and to have a pathogenic role [17]. A difference may exist between lupus cystitis and IC associated with SS. In lupus cystitis, immune deposits of immunoglobin (Ig)G, IgA, IgM, or complement C1q are found frequently in the mucosa and perivascular regions of urinary bladder specimens. Shibata et al. reported in their case report of IC associated with SS that no immune deposits were observed in the urinary bladder and they suggested that the histological findings might help to differentiate IC associated with SLE or SS [18]. Additionally, lupus cystitis is accompanied by gastrointestinal symptoms [19]. However, no reports have reported cystitis accompanied with gastrointestinal symptoms in cases of SS. These results suggest that IC accompanying SLE and SS has a different pathogenesis. The treatment experience is extremely limited about the association between IC and SS. We conducted a literature review to identify published cases of IC associated with SS. We searched the Medline database using the terms “interstitial cystitis” or “cystitis”, combined with “Sjögren’s syndrome”. The search was limited to adult cases with SS with a well described clinical course including treatment regime and outcomes in the English or Japanese literature. Our Medline search identified only five patients with IC associated with SS from 1998 to date [18,20–23]. Table 1 shows the characteristics of the six cases, including our case. All reported cases were female and improved with immunosuppressive therapy. In a case review of lupus cystitis, 28 out of 40 patients improved with corticosteroid, combined with other immunosuppressive drugs in a few cases [19]. Therefore, IC associated with SLE or SS seems to respond well with immunosuppressive therapy. Although the comparison with lupus cystitis is difficult, it is interesting that cyclosporine A (CyA) in combination with corticosteroid has been effective in two cases
of IC associated with SS [18,23]. CyA has also been used to treat patients with idiopathic IC who were unresponsive to other treatments, including hydrodistension and fulguration. However, the use of CyA as well as corticosteroid is limited for adverse events in cases of idiopathic IC [24,25]. Although the mechanism of action to IC is unclear, CyA inhibits T cell activation by blocking transcription of cytokine genes and stabilizing mast cells. Tac is another newer calcineurin inhibiter similarly inhibiting T cells, and its efficacy for collagen tissue diseases such as SLE and rheumatoid arthritis was established. Although there is only one case report of IC successfully treated with a combination of Tac and corticosteroid [26], this is the first report about IC associated with SS successfully treated with a combination of Tac and corticosteroid. In our case, although intravenous Ig (IVIg) was added for treatment of sensory neuropathy, no other case report administered IVIg for IC and its efficacy for IC was unclear.
Conclusion IC associated with SS is a possibly underdiagnosed condition. It responds well to immunosuppressive therapy, such as a combination of a calcineurin inhibiter (tacrolimus or cyclosporine) with corticosteroid.
Acknowledgments This study was supported by Grants-in-Aid for Research on Intractable Diseases from the Ministry of Health, Labor, and Welfare of Japan.
Conflict of interest None.
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