Case Report Received: December 17, 2012 Accepted after revision: April 26, 2013 Published online: October 31, 2013
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
Anti-TNF Therapy in the Treatment of Psoriasis in a Patient with Acute-on-Chronic Pancreatitis Helena Clayton a Lukas Flatz a Sonia Vollenweider-Roten c Alain Schoepfer b Michel Gilliet a Curdin Conrad a Departments of a Dermatology and b Gastroenterology and Hepatology, University Hospital CHUV, Lausanne, and c Private Practice, Vevey, Switzerland
the way for further questioning on the role of TNF in the pathogenesis of chronic and acute pancreatitis and the use of anti-TNF therapy in its treatment. © 2013 S. Karger AG, Basel
Abstract Background: Psoriasis is accepted as a multisystemic disease with several important systemic manifestations. Thus, underlying comorbidities have to be taken into account in the choice of treatment. Objective: To explore the role of anti-TNF therapy in the treatment of psoriasis in a patient with acuteon-chronic pancreatitis. Methods: Here, we present the case of a 75-year-old patient with severe psoriasis also suffering from chronic alcohol-induced pancreatitis with recurrent acute flares. A recent life-threatening episode of acute pancreatitis and ischemic liver precluded the reintroduction of methotrexate. Cyclosporine was also excluded as it has been reported to induce acute pancreatitis. Thus, an anti-TNF treatment was initiated in close collaboration with a gastroenterologist. Results: A year after starting anti-TNF therapy the patient continues to show complete clinical remission of his psoriasis. No side effects, particularly no bacterial infections, were reported. No relapses of the patient’s underlying chronic pancreatitis were observed throughout the entire treatment with regular clinical and laboratory monitoring, suggesting that chronic pancreatitis is not per se a contraindication for anti-TNF therapy. Conclusion: This case study opens
Introduction
Although psoriasis mainly affects the skin and joints, it has become increasingly important in all medical fields, beyond dermatology and rheumatology. Nowadays, psoriasis is accepted as a multisystemic disease with several important systemic manifestations and underlying comorbidities. Thus, these risks and underlying comorbidities have to be taken into account in the choice of therapy and psoriatic patients should be followed in close interdisciplinary collaboration. Over the past several years, the increasing knowledge of psoriasis pathogenesis has fundamentally changed its treatment and led to the development of biologics that target specific components of the immune system. TNF inhibitors have been available for more than 10 years and over 2 million patients have been treated, predominantly for rheumatoid arthritis as well as inflammatory bowel disease and subsequently for psoriasis [1]. Besides playing an essential role in these chronic immune-mediated diseases, TNF also plays a role in acute inflammation. TNF serum levels are elevated during
© 2013 S. Karger AG, Basel 1018–8665/13/2273–0193$38.00/0 E-Mail [email protected] www.karger.com/drm
acute pancreatitis [2, 3] and TNF has been demonstrated to play a pivotal functional role in the pathogenesis of acute pancreatitis in animal models [4, 5]. Thus, experimental data suggest a possible role for TNF inhibitors in the treatment of acute pancreatitis. Here we report the case of a 75-year-old man with severe psoriasis also suffering from recurrent episodes of acute-onchronic pancreatitis who underwent successful anti-TNF therapy. A year after starting treatment, the patient continues to show complete clinical remission of his psoriasis. In addition, the patient’s pancreatitis remained calm throughout the entire treatment, with regular clinical and laboratory monitoring. Case Report
A 75-year-old male patient presented to our specialised psoriasis clinic in March 2011 after being referred by his dermatologist. He had been suffering from extensive plaque psoriasis without joint involvement since 2007. There was no prior family history of psoriasis. He had received a variety of treatments for his psoriasis since its diagnosis in 2007, including narrow-band UVB phototherapy, PUVA phototherapy, acitretin and methotrexate. In 2008, narrow-band UVB therapy was initiated but had little impact on his condition. He then
Curdin Conrad Department of Dermatology University Hospital CHUV CH–1011 Lausanne (Switzerland) E-Mail curdin.conrad @ chuv.ch
Downloaded by: University of Florida, Gainesville and Jacksonville 128.227.24.141 - 12/1/2017 12:08:47 PM
Key Words Psoriasis · Pancreatitis · Anti-TNF therapy · Biologicals
a
194
b
Fig. 1. a Persistence of erythematous well-demarcated plaques 3 months after treatment
with etanercept in conjunction with potent topical steroids and before the introduction of adalimumab (PASI 8.9). b Complete clinical remission following 1 year of treatment with adalimumab (PASI 0).
tients with acute-on-chronic pancreatitis. There is, however, evidence from animal models suggesting that anti-TNF treatment might improve acute pancreatitis, although no clinical trials have yet been performed [4]. After a multidisciplinary discussion of the case with the patient’s consultant gastroenterologist, we decided to start etanercept (Enbrel) at a dosage of 50 mg s.c. per week. Etanercept was initially chosen due to its shortest half-life (4 days) of all available TNF blockers. Stopping alcoholic consumption was an absolute prerequisite to starting treatment. Pneumococcal vaccination had already been performed following his splenectomy. Blood levels of pancreatic enzymes (lipase and amylase) and liver function tests as well as C-reactive protein were monitored monthly. Unfortunately, only a slight improvement in the PASI score from 12.9 to 8.9 was observed after 3 months of treatment, despite frequent concomitant use of topical class IV steroids. His pruritus also remained significant. Liver function tests and blood levels of pancreatic enzymes were stable throughout treatment and no side effects were observed. Furthermore, the patient showed no sign of bacterial infections.
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
As no side effects had been observed under anti-TNF therapy, it was decided to switch anti-TNF inhibitor from the receptor fusion protein, etanercept, to the monoclonal antibody, adalimumab (Humira). After just 6 weeks of treatment, a decrease in PASI to 2.8 was observed with almost complete disappearance of his pruritus; 1 year after starting anti-TNF therapy, the patient continues to show complete clinical remission of his psoriasis (fig. 2). No episodic flares of the patient’s chronic pancreatitis were observed and blood amylase levels were stable throughout therapy (fig. 2). No side effects, in particular no bacterial infections, were reported. Discussion
We report the successful use of an anti-TNF agent, adalimumab, in the treatment of severe psoriasis in a patient with life-threatening alcohol-induced acute-onchronic pancreatitis. To our knowledge, this is the first case study to be reported in the literature. The importance of the role of TNF in psoriasis pathogenesis has been clearly established in the last 15 years with the rise of biological therapies in its treat-
Clayton /Flatz /Vollenweider-Roten / Schoepfer /Gilliet /Conrad
Downloaded by: University of Florida, Gainesville and Jacksonville 128.227.24.141 - 12/1/2017 12:08:47 PM
underwent PUVA phototherapy with some improvement of his skin condition but with an immediate relapse after stopping treatment. In 2009, acitretin was introduced but was stopped after only a few weeks due to unbearable mucosa dryness. At the end of 2009, methotrexate was successfully introduced showing a good clinical response but had to be stopped due to abnormal liver function tests on his admission to hospital. The patient also suffered from acute-on-chronic alcohol-induced pancreatitis for the previous 20 years with an average of 4 recurrent acute flares per year. He consumed on average of 1 litre of red wine a day (70 units weekly). At the end of 2010, 4 months before he presented to our clinic, he was admitted to hospital with an acute flare of his chronic pancreatitis and became critically ill. He subsequently underwent a proximal pancreatectomy by Whipple’s procedure. The diagnosis of chronic pancreatitis was based on the histology of the resected pancreatic head, a pathologically reduced faecal elastase and steatorrhea. He suffered further post-surgical complications, which included bilateral pulmonary emboli, splenic infarction (resulting in a splenectomy) and an ischaemic liver, and was admitted to intensive care. His medication on discharge included pancreatic enzymes (CREON), acenocoumarol (Sintrom) and vitamin D. In March 2011, he presented to our clinic with extensive well-defined erythemato-squamous plaques on his trunk, arms, intergluteal cleft and legs with a PASI (psoriasis area and severity index) score of 12.9 (fig. 1). He also presented with disabling generalised pruritus, which prevented him from sleeping and for which treatment with a range of anti-histamines and topical anti-pruritic lotions had failed to alleviate. Although no joint involvement was observed, systemic treatment was clearly warranted given the severity of disease and previous failure of various therapies. However, his recent life-threatening episode of acute-on-chronic pancreatitis and postoperative complications including an ischemic liver precluded the re-introduction of methotrexate. Acitretin was also not an option, as he had not tolerated its side effects. Cyclosporine was also not considered a viable alternative as it has been reported to induce and exacerbate acute pancreatitis [6]. A biological therapy, such as a TNFinhibitor, was therefore considered. There are, however, no cases in the literature on the effect of anti-TNF treatments in pa-
Etanercept
Etanercept Adalimumab
15
U/l
PASI 5
a
AST
150
10
0
Adalimumab
200
ALT Alk. phosphatase
100
Amylase Lipase
50
0
3
6 9 Time (months)
12
15
0
b
0
3
6 9 Time (months)
12
15
Fig. 2. a PASI progression under anti-TNF treatment with etanercept and adalimumab. b Liver enzymes, lipase, and amylase serum levels remained stable during treatment with etanercept and adalimumab. AST = Aspartate transaminase; ALT = alanine aminotransferase; Alk. phosphatase = alkaline phosphatase.
Anti-TNF Psoriasis Therapy in a Patient with Acute-on-Chronic Pancreatitis
it was again verified that he had received the pneumococcal vaccine after his splenectomy. As this was the first case in which a TNF blocker was used in a patient with acuteon-chronic pancreatitis and due to the increased risk of bacterial infections, etanercept was initially chosen for its shortest halflife so that treatment could be stopped rapidly. As no side effects were observed in our patient after 3 months of treatment with etanercept, and once it became obvious that the therapeutic response was insufficient, adalimumab was substituted for etanercept, leading to complete clinical remission of his psoriasis. During 1 year of therapy with adalimumab, our patient has not presented with any flares of his chronic pancreatitis. Indeed his amylase levels have remained normal throughout treatment. Quiescence of his pancreatitis was probably due to alcohol abstinence and the proximal pancreatectomy, aimed at relieving obstruction to pancreatic secretion. To what extent antiTNF therapy has been an additional factor remains unclear, but this case does provide evidence that anti-TNF therapy is not per se contraindicated in patients with acute-onchronic pancreatitis. Conclusion
We report, for the first time, the successful use of an anti-TNF agent in a patient with severe psoriasis also suffering from acute-on-chronic life-threatening pancreatitis. Our patient did not
present any acute exacerbations of his underlying pancreatitis under anti-TNF treatment. Furthermore, his psoriasis was successfully treated with a reduction in PASI score from 12.9 to 0 after 1 year of treatment. This case study opens the way forward to the treatment of future patients with chronic inflammatory diseases also suffering from chronic pancreatitis and raises questions as to the role of TNF in the pathogenesis of chronic and acute pancreatitis and the use of anti-TNF therapy in its treatment. Disclosure Statement
No funding was obtained for this study. The authors report no conflicts of interest. References 1 Sfikakis PP: The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr Dir Autoimmun 2010; 11: 180– 210. 2 Kaufmann P, Tilz GP, Lueger A, Demel U: Elevated plasma levels of soluble tumor necrosis factor receptor (sTNFRp60) reflect severity of acute pancreatitis. Intensive Care Med 1997; 23:841–848. 3 Brivet FG, Emilie D, Galanaud P: Pro- and anti-inflammatory cytokines during acute severe pancreatitis: an early and sustained response, although unpredictable of death. Parisian Study Group on Acute Pancreatitis. Crit Care Med 1999;27:749–755.
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
195
Downloaded by: University of Florida, Gainesville and Jacksonville 128.227.24.141 - 12/1/2017 12:08:47 PM
ment. Nowadays, TNF inhibitors are considered ‘gold standard therapy’ in psoriasis and are used as a bench mark in clinical and preclinical studies [7, 8]. TNF has also been demonstrated as one of the key mediators in acute pancreatitis. Elevated levels of TNF are observed in the serum of animals with experimental acute pancreatitis [9] as well as in patients with acute pancreatitis [10–12]. Evidence, both in vitro and in animal models, suggests that TNF contributes to the progression of the systemic inflammatory response as well as to the end-organ dysfunction observed in severe pancreatitis [9]. Inhibition of TNF in rat models of acute pancreatitis results in an improvement in disease severity and increased survival [4]. Therefore, TNF has been evaluated as a potential pharmacological target for the treatment of acute pancreatitis. Although promising results have been observed in animal models, the high risk of bacterial infection during acute pancreatitis remains a matter of concern and no clinical trials have been designed so far. Intriguingly, treatment with infliximab and systemic steroids showed increased mortality as a result of infections in patients with alcoholic hepatitis – another condition associated with a high prevalence of severe infections [13]. Since pneumococcal vaccination is recommended – and standard – for all postsplenectomy patients [14] and suggested for patients starting anti-TNF treatment [15], it was an absolute prerequisite in our patient. Thus, prior to initiating anti-TNF therapy,
196
8 Tonel G, Conrad C, Lagger U, Di Meglio P, Grys K, McClanahan TK, Blumenschein WM, Qin JZ, Xin H, Oldham E, Kastelein R, Nickoloff BJ, Nestle FO: Cutting edge: a critical functional role for IL-23 in psoriasis. J Immunol 2010;185:5688–5691. 9 Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S: Role of tumor necrosis factor-α in acute pancreatitis: from biological basis to clinical evidence. Shock 2007;28:130–140. 10 Granger J, Remick D: Acute pancreatitis: models, markers, and mediators. Shock 2005; 24(suppl 1):45–51. 11 Kilciler G, Musabak U, Bagci S, Yesilova Z, Tuzun A, Uygun A, Gulsen M, Oren S, Oktenli C, Karaeren N: Do the changes in the serum levels of IL-2, IL-4, TNFα, and IL-6 reflect the inflammatory activity in the patients with post-ERCP pancreatitis? Clin Dev Immunol 2008;2008:481560.
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
12 Malmstrom ML, Hansen MB, Andersen AM, Ersboll AK, Nielsen OH, Jorgensen LN, Novovic S: Cytokines and organ failure in acute pancreatitis: inflammatory response in acute pancreatitis. Pancreas 2012;41:271–277. 13 Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broet P, Emilie D: A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004;39:1390–1397. 14 Davies JM, Barnes R, Milligan D: Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med 2002;2:440–443. 15 Nordgaard-Lassen I, Dahlerup JF, Belard E, Gerstoft J, Kjeldsen J, Kragballe K, Ravn P, Sorensen IJ, Theede K, Tjellesen L: Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNFα treatment. Dan Med J 2012;59:C4480.
Clayton /Flatz /Vollenweider-Roten / Schoepfer /Gilliet /Conrad
Downloaded by: University of Florida, Gainesville and Jacksonville 128.227.24.141 - 12/1/2017 12:08:47 PM
4 Hughes CB, Gaber LW, Mohey el-Din AB, Grewal HP, Kotb M, Mann L, Gaber AO: Inhibition of TNFα improves survival in an experimental model of acute pancreatitis. Am Surg 1996;62:8–13. 5 Ramudo L, Manso MA, Sevillano S, de Dios I: Kinetic study of TNFα production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile-pancreatic duct obstruction. J Pathol 2005;206:9–16. 6 Hackert T, Pfeil D, Hartwig W, Fritz S, Gebhard MM, Klar E, Werner J: Ciclosporin aggravates tissue damage in ischemia reperfusion-induced acute pancreatitis. Pancreas 2006;32:145–151. 7 Conrad C, Boyman O, Tonel G, Tun-Kyi A, Laggner U, de Fougerolles A, Kotelianski V, Gardner H, Nestle FO: α1β1 integrin is crucial for accumulation of epidermal t cells and the development of psoriasis. Nat Med 2007; 13: 836–842.
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
Anti-TNF Therapy in the Treatment of Psoriasis in a Patient with Acute-on-Chronic Pancreatitis Helena Clayton a Lukas Flatz a Sonia Vollenweider-Roten c Alain Schoepfer b Michel Gilliet a Curdin Conrad a Departments of a Dermatology and b Gastroenterology and Hepatology, University Hospital CHUV, Lausanne, and c Private Practice, Vevey, Switzerland
the way for further questioning on the role of TNF in the pathogenesis of chronic and acute pancreatitis and the use of anti-TNF therapy in its treatment. © 2013 S. Karger AG, Basel
Abstract Background: Psoriasis is accepted as a multisystemic disease with several important systemic manifestations. Thus, underlying comorbidities have to be taken into account in the choice of treatment. Objective: To explore the role of anti-TNF therapy in the treatment of psoriasis in a patient with acuteon-chronic pancreatitis. Methods: Here, we present the case of a 75-year-old patient with severe psoriasis also suffering from chronic alcohol-induced pancreatitis with recurrent acute flares. A recent life-threatening episode of acute pancreatitis and ischemic liver precluded the reintroduction of methotrexate. Cyclosporine was also excluded as it has been reported to induce acute pancreatitis. Thus, an anti-TNF treatment was initiated in close collaboration with a gastroenterologist. Results: A year after starting anti-TNF therapy the patient continues to show complete clinical remission of his psoriasis. No side effects, particularly no bacterial infections, were reported. No relapses of the patient’s underlying chronic pancreatitis were observed throughout the entire treatment with regular clinical and laboratory monitoring, suggesting that chronic pancreatitis is not per se a contraindication for anti-TNF therapy. Conclusion: This case study opens
Introduction
Although psoriasis mainly affects the skin and joints, it has become increasingly important in all medical fields, beyond dermatology and rheumatology. Nowadays, psoriasis is accepted as a multisystemic disease with several important systemic manifestations and underlying comorbidities. Thus, these risks and underlying comorbidities have to be taken into account in the choice of therapy and psoriatic patients should be followed in close interdisciplinary collaboration. Over the past several years, the increasing knowledge of psoriasis pathogenesis has fundamentally changed its treatment and led to the development of biologics that target specific components of the immune system. TNF inhibitors have been available for more than 10 years and over 2 million patients have been treated, predominantly for rheumatoid arthritis as well as inflammatory bowel disease and subsequently for psoriasis [1]. Besides playing an essential role in these chronic immune-mediated diseases, TNF also plays a role in acute inflammation. TNF serum levels are elevated during
© 2013 S. Karger AG, Basel 1018–8665/13/2273–0193$38.00/0 E-Mail [email protected] www.karger.com/drm
acute pancreatitis [2, 3] and TNF has been demonstrated to play a pivotal functional role in the pathogenesis of acute pancreatitis in animal models [4, 5]. Thus, experimental data suggest a possible role for TNF inhibitors in the treatment of acute pancreatitis. Here we report the case of a 75-year-old man with severe psoriasis also suffering from recurrent episodes of acute-onchronic pancreatitis who underwent successful anti-TNF therapy. A year after starting treatment, the patient continues to show complete clinical remission of his psoriasis. In addition, the patient’s pancreatitis remained calm throughout the entire treatment, with regular clinical and laboratory monitoring. Case Report
A 75-year-old male patient presented to our specialised psoriasis clinic in March 2011 after being referred by his dermatologist. He had been suffering from extensive plaque psoriasis without joint involvement since 2007. There was no prior family history of psoriasis. He had received a variety of treatments for his psoriasis since its diagnosis in 2007, including narrow-band UVB phototherapy, PUVA phototherapy, acitretin and methotrexate. In 2008, narrow-band UVB therapy was initiated but had little impact on his condition. He then
Curdin Conrad Department of Dermatology University Hospital CHUV CH–1011 Lausanne (Switzerland) E-Mail curdin.conrad @ chuv.ch
Downloaded by: University of Florida, Gainesville and Jacksonville 128.227.24.141 - 12/1/2017 12:08:47 PM
Key Words Psoriasis · Pancreatitis · Anti-TNF therapy · Biologicals
a
194
b
Fig. 1. a Persistence of erythematous well-demarcated plaques 3 months after treatment
with etanercept in conjunction with potent topical steroids and before the introduction of adalimumab (PASI 8.9). b Complete clinical remission following 1 year of treatment with adalimumab (PASI 0).
tients with acute-on-chronic pancreatitis. There is, however, evidence from animal models suggesting that anti-TNF treatment might improve acute pancreatitis, although no clinical trials have yet been performed [4]. After a multidisciplinary discussion of the case with the patient’s consultant gastroenterologist, we decided to start etanercept (Enbrel) at a dosage of 50 mg s.c. per week. Etanercept was initially chosen due to its shortest half-life (4 days) of all available TNF blockers. Stopping alcoholic consumption was an absolute prerequisite to starting treatment. Pneumococcal vaccination had already been performed following his splenectomy. Blood levels of pancreatic enzymes (lipase and amylase) and liver function tests as well as C-reactive protein were monitored monthly. Unfortunately, only a slight improvement in the PASI score from 12.9 to 8.9 was observed after 3 months of treatment, despite frequent concomitant use of topical class IV steroids. His pruritus also remained significant. Liver function tests and blood levels of pancreatic enzymes were stable throughout treatment and no side effects were observed. Furthermore, the patient showed no sign of bacterial infections.
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
As no side effects had been observed under anti-TNF therapy, it was decided to switch anti-TNF inhibitor from the receptor fusion protein, etanercept, to the monoclonal antibody, adalimumab (Humira). After just 6 weeks of treatment, a decrease in PASI to 2.8 was observed with almost complete disappearance of his pruritus; 1 year after starting anti-TNF therapy, the patient continues to show complete clinical remission of his psoriasis (fig. 2). No episodic flares of the patient’s chronic pancreatitis were observed and blood amylase levels were stable throughout therapy (fig. 2). No side effects, in particular no bacterial infections, were reported. Discussion
We report the successful use of an anti-TNF agent, adalimumab, in the treatment of severe psoriasis in a patient with life-threatening alcohol-induced acute-onchronic pancreatitis. To our knowledge, this is the first case study to be reported in the literature. The importance of the role of TNF in psoriasis pathogenesis has been clearly established in the last 15 years with the rise of biological therapies in its treat-
Clayton /Flatz /Vollenweider-Roten / Schoepfer /Gilliet /Conrad
Downloaded by: University of Florida, Gainesville and Jacksonville 128.227.24.141 - 12/1/2017 12:08:47 PM
underwent PUVA phototherapy with some improvement of his skin condition but with an immediate relapse after stopping treatment. In 2009, acitretin was introduced but was stopped after only a few weeks due to unbearable mucosa dryness. At the end of 2009, methotrexate was successfully introduced showing a good clinical response but had to be stopped due to abnormal liver function tests on his admission to hospital. The patient also suffered from acute-on-chronic alcohol-induced pancreatitis for the previous 20 years with an average of 4 recurrent acute flares per year. He consumed on average of 1 litre of red wine a day (70 units weekly). At the end of 2010, 4 months before he presented to our clinic, he was admitted to hospital with an acute flare of his chronic pancreatitis and became critically ill. He subsequently underwent a proximal pancreatectomy by Whipple’s procedure. The diagnosis of chronic pancreatitis was based on the histology of the resected pancreatic head, a pathologically reduced faecal elastase and steatorrhea. He suffered further post-surgical complications, which included bilateral pulmonary emboli, splenic infarction (resulting in a splenectomy) and an ischaemic liver, and was admitted to intensive care. His medication on discharge included pancreatic enzymes (CREON), acenocoumarol (Sintrom) and vitamin D. In March 2011, he presented to our clinic with extensive well-defined erythemato-squamous plaques on his trunk, arms, intergluteal cleft and legs with a PASI (psoriasis area and severity index) score of 12.9 (fig. 1). He also presented with disabling generalised pruritus, which prevented him from sleeping and for which treatment with a range of anti-histamines and topical anti-pruritic lotions had failed to alleviate. Although no joint involvement was observed, systemic treatment was clearly warranted given the severity of disease and previous failure of various therapies. However, his recent life-threatening episode of acute-on-chronic pancreatitis and postoperative complications including an ischemic liver precluded the re-introduction of methotrexate. Acitretin was also not an option, as he had not tolerated its side effects. Cyclosporine was also not considered a viable alternative as it has been reported to induce and exacerbate acute pancreatitis [6]. A biological therapy, such as a TNFinhibitor, was therefore considered. There are, however, no cases in the literature on the effect of anti-TNF treatments in pa-
Etanercept
Etanercept Adalimumab
15
U/l
PASI 5
a
AST
150
10
0
Adalimumab
200
ALT Alk. phosphatase
100
Amylase Lipase
50
0
3
6 9 Time (months)
12
15
0
b
0
3
6 9 Time (months)
12
15
Fig. 2. a PASI progression under anti-TNF treatment with etanercept and adalimumab. b Liver enzymes, lipase, and amylase serum levels remained stable during treatment with etanercept and adalimumab. AST = Aspartate transaminase; ALT = alanine aminotransferase; Alk. phosphatase = alkaline phosphatase.
Anti-TNF Psoriasis Therapy in a Patient with Acute-on-Chronic Pancreatitis
it was again verified that he had received the pneumococcal vaccine after his splenectomy. As this was the first case in which a TNF blocker was used in a patient with acuteon-chronic pancreatitis and due to the increased risk of bacterial infections, etanercept was initially chosen for its shortest halflife so that treatment could be stopped rapidly. As no side effects were observed in our patient after 3 months of treatment with etanercept, and once it became obvious that the therapeutic response was insufficient, adalimumab was substituted for etanercept, leading to complete clinical remission of his psoriasis. During 1 year of therapy with adalimumab, our patient has not presented with any flares of his chronic pancreatitis. Indeed his amylase levels have remained normal throughout treatment. Quiescence of his pancreatitis was probably due to alcohol abstinence and the proximal pancreatectomy, aimed at relieving obstruction to pancreatic secretion. To what extent antiTNF therapy has been an additional factor remains unclear, but this case does provide evidence that anti-TNF therapy is not per se contraindicated in patients with acute-onchronic pancreatitis. Conclusion
We report, for the first time, the successful use of an anti-TNF agent in a patient with severe psoriasis also suffering from acute-on-chronic life-threatening pancreatitis. Our patient did not
present any acute exacerbations of his underlying pancreatitis under anti-TNF treatment. Furthermore, his psoriasis was successfully treated with a reduction in PASI score from 12.9 to 0 after 1 year of treatment. This case study opens the way forward to the treatment of future patients with chronic inflammatory diseases also suffering from chronic pancreatitis and raises questions as to the role of TNF in the pathogenesis of chronic and acute pancreatitis and the use of anti-TNF therapy in its treatment. Disclosure Statement
No funding was obtained for this study. The authors report no conflicts of interest. References 1 Sfikakis PP: The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr Dir Autoimmun 2010; 11: 180– 210. 2 Kaufmann P, Tilz GP, Lueger A, Demel U: Elevated plasma levels of soluble tumor necrosis factor receptor (sTNFRp60) reflect severity of acute pancreatitis. Intensive Care Med 1997; 23:841–848. 3 Brivet FG, Emilie D, Galanaud P: Pro- and anti-inflammatory cytokines during acute severe pancreatitis: an early and sustained response, although unpredictable of death. Parisian Study Group on Acute Pancreatitis. Crit Care Med 1999;27:749–755.
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
195
Downloaded by: University of Florida, Gainesville and Jacksonville 128.227.24.141 - 12/1/2017 12:08:47 PM
ment. Nowadays, TNF inhibitors are considered ‘gold standard therapy’ in psoriasis and are used as a bench mark in clinical and preclinical studies [7, 8]. TNF has also been demonstrated as one of the key mediators in acute pancreatitis. Elevated levels of TNF are observed in the serum of animals with experimental acute pancreatitis [9] as well as in patients with acute pancreatitis [10–12]. Evidence, both in vitro and in animal models, suggests that TNF contributes to the progression of the systemic inflammatory response as well as to the end-organ dysfunction observed in severe pancreatitis [9]. Inhibition of TNF in rat models of acute pancreatitis results in an improvement in disease severity and increased survival [4]. Therefore, TNF has been evaluated as a potential pharmacological target for the treatment of acute pancreatitis. Although promising results have been observed in animal models, the high risk of bacterial infection during acute pancreatitis remains a matter of concern and no clinical trials have been designed so far. Intriguingly, treatment with infliximab and systemic steroids showed increased mortality as a result of infections in patients with alcoholic hepatitis – another condition associated with a high prevalence of severe infections [13]. Since pneumococcal vaccination is recommended – and standard – for all postsplenectomy patients [14] and suggested for patients starting anti-TNF treatment [15], it was an absolute prerequisite in our patient. Thus, prior to initiating anti-TNF therapy,
196
8 Tonel G, Conrad C, Lagger U, Di Meglio P, Grys K, McClanahan TK, Blumenschein WM, Qin JZ, Xin H, Oldham E, Kastelein R, Nickoloff BJ, Nestle FO: Cutting edge: a critical functional role for IL-23 in psoriasis. J Immunol 2010;185:5688–5691. 9 Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S: Role of tumor necrosis factor-α in acute pancreatitis: from biological basis to clinical evidence. Shock 2007;28:130–140. 10 Granger J, Remick D: Acute pancreatitis: models, markers, and mediators. Shock 2005; 24(suppl 1):45–51. 11 Kilciler G, Musabak U, Bagci S, Yesilova Z, Tuzun A, Uygun A, Gulsen M, Oren S, Oktenli C, Karaeren N: Do the changes in the serum levels of IL-2, IL-4, TNFα, and IL-6 reflect the inflammatory activity in the patients with post-ERCP pancreatitis? Clin Dev Immunol 2008;2008:481560.
Dermatology 2013;227:193–196 DOI: 10.1159/000351714
12 Malmstrom ML, Hansen MB, Andersen AM, Ersboll AK, Nielsen OH, Jorgensen LN, Novovic S: Cytokines and organ failure in acute pancreatitis: inflammatory response in acute pancreatitis. Pancreas 2012;41:271–277. 13 Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broet P, Emilie D: A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004;39:1390–1397. 14 Davies JM, Barnes R, Milligan D: Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med 2002;2:440–443. 15 Nordgaard-Lassen I, Dahlerup JF, Belard E, Gerstoft J, Kjeldsen J, Kragballe K, Ravn P, Sorensen IJ, Theede K, Tjellesen L: Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNFα treatment. Dan Med J 2012;59:C4480.
Clayton /Flatz /Vollenweider-Roten / Schoepfer /Gilliet /Conrad
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