Cutaneous sarcoidosis in a patient with ulcerative colitis on infliximab

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1 Journal of Crohn's and Colitis (2012) 6, Available online at SHORT REPORT Cutaneous sarcoidosis in a patient with ulcerative colitis on infliximab Kum C. Fok a,, Watson W.S. Ng b, Christopher J.A. Henderson c, Susan J. Connor b a Department of Gastroenterology, Campbelltown Hospital, NSW, Australia University of Western Sydney, NSW, Australia b Department of Gastroenterology, Liverpool Hospital, NSW, Australia c Department of Anatomical Pathology, Sydney South West Pathology, Liverpool Hospital, NSW, Australia Received 23 July 2011; received in revised form 6 January 2012; accepted 6 January 2012 KEYWORDS Infliximab; Sarcoidosis; Side-effects; Ulcerative colitis 1. Introduction Abstract The advance of anti-tumour necrosis factor (TNF) therapy had dramatically changed the treatment algorithm of inflammatory bowel disease (IBD). This had significantly improved the quality of life for patients with Crohn's disease (CD) and ulcerative colitis (UC). 1 However, side-effects of anti-tnf treatment were unavoidable with paradoxical inflammation (for example leucocytoclastic vasculitis and psoriasis) being well-known phenomena of anti-tnf therapy. 2 Corresponding author at: Department of Gastroenterology, Royal North Shore Hospital, Sydney, Australia. Tel./fax: address: drianfok@gmail.com (K.C. Fok). The advance of anti-tumour necrosis factor (TNF) therapy had dramatically changed the treatment algorithm of inflammatory bowel disease (IBD). This had significantly improved the quality of life for patients with Crohn's disease (CD) and ulcerative colitis (UC). 1 However, side-effects of anti-tnf treatment were unavoidable with paradoxical inflammation (for example leucocytoclastic vasculitis and psoriasis) being well-known phenomena of anti-tnf therapy. 2 We report a case of infliximab induced cutaneous sarcoidosis in a patient with ulcerative colitis and review the literature. Crown Copyright 2012 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. All rights reserved. We report a case of infliximab induced cutaneous sarcoidosis in a patient with ulcerative colitis and review the literature. 2. Case report A 66-year-old Caucasian female was diagnosed with ulcerative pancolitis in She had a medical history of atrial fibrillation (on digoxin), hypertension (on verapamil), peptic ulcer disease (on pantoprazole) and depression (on dothepin and diazepam). After 2 years of therapy on mesalazine and azathioprine, her liver function tests became deranged (AST 80 U/L ALT 67 U/L GGT 333 U/L and ALP 156U/L) with portal hypertension (splenomegaly and gastro-oesophageal varices) evident on computer tomography (CT). Wedge /$ - see front matter. Crown Copyright 2012 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. All rights reserved. doi: /j.crohns

2 Cutaneous sarcoidosis in a patient with ulcerative colitis on infliximab 709 liver biopsy confirmed nodular regenerative hyperplasia most likely related to Azathioprine. Cessation of Azathioprine normalised liver function tests and Infliximab was commenced in February Twenty three months after, the patient noted increased prominence of previous scars and several painful dermal nodules over the extensor surfaces of her upper and lower limbs (Fig. 1). Biopsy of these lesions showed a non-necrotising granulomatous inflammatory infiltrate consistent with a diagnosis of sarcoidosis (Figs. 2 and 3). The granulomas were present both in scarred and non-scarred skin and distributed in both the dermis and subcutaneous tissue. Mycobacterium tuberculosis infection was excluded by a negative Quantiferon gold as well as negative Ziehl Neelson and auramine rhodamine stains on cutaneous biopsies. Fungal stains were also negative. Colonoscopy with colonic biopsies showed mucosal healing. Serum angiotensin converting enzyme (ACE) level was normal (81 U/L, reference range U/L). A normal chest x-ray with the absence of ocular, cardiac and neurological symptoms excluded systemic sarcoidosis. Colonoscopy with colonic biopsies was normal with mucosal healing. Further discussions with the patient delineated her strong feelings against surgical management, past failed immunosuppressive therapy and known efficacy to infliximab; an informed decision was hence made to continue Infliximab therapy. Infliximab doses thereafter were given pre-dosed with diphenhydramine 25 mg orally and hydrocortisone 200 mg intravenously. There was subsequent spontaneous regression of her original cutaneous lesions to normal. Further small subcutaneous nodules did recur for one to two weeks; these had subsequent with no worsening over time. Scar sarcoidosis had since not recurred over 19 dosed periods each 8 weeks apart. 3. Discussion The development of cutaneous sarcoidosis in this patient was a probable paradoxical inflammatory phenomenon of anti-tnf treatment with other granulomatous diseases excluded including tuberculosis, mycobacterium infection, Blau's syndrome or Crohn's disease. There exists no Figure 2 Histology of skin biopsy showing numerous granulomas within the upper dermis. 100 magnification. literature evidence of other possible drug-induced sarcoidosis secondary to her other regular medications of digoxin, dothepin, diazepam, pantoprazole and verapamil. Sarcoidosis is a chronic, idiopathic granulomatous disease. Subcutaneous nodular sarcoidosis (Sns) or Darier-Roussy sarcoidosis can occur without systemic disease features. These lesions are clinically firm, non tender and cm in Figure 1 Rash on extensor surface of leg. Figure 3 Higher power of skin histology showing the classical compact non-necrotizing epithelioid morphology of the granulomas. 200 magnification.

3 710 K.C. Fok et al. Table 1 Author (reference) Gonzalez- Lopez A collection of 21 cases of anti-tnf therapy induced sarcoidosis. Age/ sex Underlying rheumatologic disease Anti-TNF drug and dose 70/M AS Phillips 37/M PsA twice Almodovar 34/M AS Infliximab Verschueren 53/F RA Verschuen 46/F RA O'Shea 34/M PsA Infliximab Vavricka 73/M RA Adalimumab 40 mg Peno-Green 50/F RA Bachmeyer 39/M AS Toussirot et al. Toussirot et al. Duration of anti- TNF treatment Clinical manifestations of sarcoid 21 months Skin. Intrathoracic LNs Investigations Skin biopsy. Scintigraphy 18 months Lung Transbronchial biopsy 28 months Lung Pulmonary biopsies Treatment plan for sarcoid Nil specific tx Nil else Infliximab No tx 6 months Lung Mediastinoscopy withdrawn/ corticosteroids for lung disease 12 months Skin (erythema nodosum) Lung Mediastinoscopy withdrawn, no specific tx 58 months Lung Mediastinoscopy Infliximab. Corticosteroids (40 mg/day) 12 months Lung Lung biopsy Adalimumab showing withdrawn necrotizing anti-tb tx for granulomas 6months suggestive of TB but culture neg for myco 2 months Skin and lung Transbronchial biopsies withdrawn, corticosteroid tx 1 month Skin Skin biopsy maintained. Skin lesion tx with top steroids 22months Lung Transbronchial Infliximab biopsy 27/M AS Infliximab 49/F RA 26 months Lung Transbronchial. aanti TB tx for 6months 46/M PsA 2 months Skin Mantoux ACE XrayCTchest 72/F RA + 18 months Skin ACE X-ray CT methotrexate Chest 69/F RA + prednisolone 27 months Skin and uveitis ACE CT chest Outcome Radiological remission within 12 months of effusion but persistance of hilar adenopathies No regression of pulm lesions s +3 months of anti-tb tx continued No improvement. Unable to wean steroids off

4 Cutaneous sarcoidosis in a patient with ulcerative colitis on infliximab 711 Table 1 (continued) Author (reference) Age/ sex Underlying rheumatologic disease Anti-TNF drug and dose Duration of anti- TNF treatment diameter. Sns is often seen with non-severe systemic disease and can spontaneously resolve in a few. Scar sarcoidosis is a distinct entity diagnostically important as in some cases the only cutaneous sign of sarcoidosis. As a form of Koebner's phenomenon, it is relatively characteristic for sarcoidosis to preferentially localise to scars or sites of trauma as in this case. The histopathological appearances are typical of those of classical cases of sarcoidosis; namely the presence of compact granulomas composed of epithelioid histiocytes with occasional multinucleated giant cells, which may contain classical Schaumann bodies or asteroid bodies and an absence of necrosis. Sarcoidosis in anti-tnf therapy is a rare paradoxical inflammatory phenomenon. Anti-TNF therapy induced sarcoidosis had not been reported in patients with IBD but had been well documented in rheumatology literature. Its prevalence in the seropositive/seronegative arthropathies is estimated to be in 1/ compared with a prevalence of 6/100,000 in the general population. In 2008, Toussirot et al. published the first report of 2 cases of anti-tnf therapy induced sarcoidosis. 4 To date, there are 21 case reports in the patients with rheumatological diseases who were treated with anti-tnf agents (Table 1). This paradoxical inflammatory phenomenon occurred with infliximab, adalimumab and etanercept, but is yet to be reported with certolizumab. 3 6 Manifestations ranged from constitutional symptoms with weight loss and fever, cutaneous nodules, to more serious organ involvement (pulmonary and ophthalmic). The majority of anti-tnf therapy induced sarcoidosis regressed with treatment cessation (5 of 21; 24% did not regress), the mean time for regression being 4, 6 and 8 months for infliximab, adalimumab and etanercept respectively. Clinical manifestations of sarcoid Investigations 38/F AS 18 months Lung ACE X ray CT chest Treatment plan for sarcoid, 20 mg prednisolone 49/F RA 26 months Lung ACE CT Chest +6 months of anti-tb tx 54/F AS Infliximab 5mg/kg 50/M AS Infliximab 51 months Weight loss, asthenia 14 months Skin and lungs ACE CT Chest Infliximab ACE CT chest Infliximab 27/M AS Infliximab 17 months Asymptomatic ACE CT chest Infliximab 53/F RA Adalimumab 21 months Weight loss, asthenia, skin ACE Ct chest 51/F SAPHO Adalimumab 4 weeks Fever ACE hypercalcaemia CT chest Adalimumab Adalimumab Outcome Incomplete Incomplete It is uncertain why anti-tnfα agents cause sarcoidosis a granulomatous process dependent on Th1 and TNFα. While sarcoidosis secondary to a reactivated latent infection from anti-tnfα therapy can be an attractive answer, there exists no known infectious aetiology osis. If TNFα is quintissential in granuloma formation, one postulates that perhaps not all signalling pathways or genotypes/polymorphisms of TNFα are inhibited by the drugs. as an example incompletely inhibits the p75 signalling pathways of TNFα receptors leading to incomplete Th1 inactivation. Certain TNFα polymorphisms are also known to be associated with sarcoid disease onset, drug response and serum TNFα levels. 7 Depending on the anti-tnf agent used, most cases of anti-tnf induced sarcoidosis do improve on therapy cessation. On of sarcoidosis, a longer rechallenge interval with anti-tnf therapy was associated with a lower likelihood of recurrence on rechallenge. 5 Areviewofavailable rheumatologic literature also recommended against the continuation of anti-tnf therapy with the onset of sarcoidosis. 3 We should be mindful however that the above experience had been formulated on a small handful of case reports. Given that our patient had no disease recurrence despite ongoing infliximab therapy, it is possible that specific TNFα genotypes and/or other unknown factors might play a role in predicting the uneventful continuation of anti-tnfα therapy in a setting of paradoxical sarcoidosis. Sarcoidosis is a rare paradoxical inflammatory phenomenon that can occur in anti-tnfα therapy for inflammatory bowel disease. Once diagnosed, the decision to continue TNFα therapy will have to be dependent on other available therapies for IBD that can achieve clinical remission and

5 712 K.C. Fok et al. possibly mucosal healing; there is little clinical evidence within current literature to suggest otherwise for inflammatory bowel disease. Conflict of interest statement There are no financial conflicts of interests for all authors. References 1. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359(9317): Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr Dir Autoimmun 2010;11: Daïen CI, Monnier A, Claudepierre P, Constantin A, Eschard JP, Houvenagel E, et al. Sarcoid-like granulomatosis in patients treated with tumour necrosis factor blockers: 10 cases. Rheumatology 2009;48: Toussirot E, Pertuiset E, Kantelip B, Wendling D. Sarcoidosis occuring during anti-tnf-α treatment for inflammatory rheumatic diseases:report of two cases. Clin Exp Rheumatol 2008;26: van der Stoep D, Braunstahl GJ, van Zeben J, Wouters J. Sarcoidosis during anti-tumour necrosis factor-α therapy: no relapse after rechallenge. J Rheumatol 2009;36: Bulger K, O'Riordan M, Purdy S, O'Brien M, Lennon J. Gastrointestinal sarcoidosis resembling Crohn's disease. Am J Gastroenterol 1998;83: Sharma S, Ghosh B, Sharma SK. Association of TNF polymorphism with sarcoidosis, its prognosis and tumour necrosis factor (TNF)-α levels in Asian Indians. Clin Exp Immunol 2008;151(2):251 9.