PostScript
LETTERS
Anti-TNF-α-induced psoriasiform lesions in IBD: an abnormal immune activation or a ‘patchy cutaneous’ immune suppression? We read with interest the original article by Tillack et al who reported the characteristics of psoriasiform skin lesions induced by antitumour necrosis factor (anti-TNF)-α in patients with IBD.1 The authors show by immunohistochemical analysis that cutaneous lesions are characterised by interferon (IFN)α expression, infiltrates of interleukin (IL)-17A/IL-22-secreting T helper (Th)17 cells and IFNγ-secreting Th1 cells. They also demonstrate that therapy with ustekinumab, an anti-IL-12/IL-23 antibody, is highly effective in treating anti-TNF-α antibody-induced psoriasis and psoriasiform lesions. Our group is interested in the pathogenesis of psoriasiform lesions induced by anti-TNF-α antibodies in IBD patients. We
found an interesting case of an 18-year-old man diagnosed with ileo-colonic Crohn’s disease in 2003. In June 2009, the patient presented with back pain and impaired spinal mobility and was diagnosed with ankylosing spondylitis by lumbar MRI. Since symptoms did not improve with steroids and physiotherapy, he switched to adalimumab (40 mg every other week following 160/80 mg induction regimen). He observed a rapid and dramatic improvement, which lasted for 1 year. At the beginning of 2012, he developed itchy (pruriginous), erythematous and scaly plaques on his elbows, knees and pubis, suggestive for psoriasiform lesions at histology, despite the presence of few plasma cells (figure 1A and B). Following our evaluation, adalimumab was stopped and lesions resolved completely in 1 month. His back and intestinal symptoms arose again a couple of months later when he started methotrexate following a short course of steroids. The patient is now in remission with no evidence of cutaneous lesions. Following informed consent, cutaneous (from healthy and diseased skin) biopsies were collected 15 days after the last ADA administration at about 2 months from the beginning of symptoms. One biopsy was used for RNA extraction. The other one
was maintained in Dulbecco’s Modified Eagle Medium supplemented with10% fetal bovine serum for 48 h when supernatants were collected. A multiplex approach (BIO-PLEX Pro Assays, BIO-RADBio-Plex Pro Human Cytokine 17-plex Assay) was used to measure cytokines levels in supernatants. Real time quantitative PCR was used to measure FOXP3, ROR-γ and IL-17 mRNA levels. Cutaneous lesions displayed increased levels of FOXP3 and decreased levels of ROR-γ and IL-17 (figure 1C). Furthermore, decreased levels of detectable chemokines (IL-8, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β) as well as of TNF-α, IΛ–12 and IL-6 were detected in diseased compared with healthy skin while levels of IL-17, IL-10 and IFN-γ were similar (figure 2A and B). Our case suggests that some forms of psoriasiform or psoriasis-like lesions could be associated with a decrease in chemokines and inflammatory cytokines compared with healthy skin, with regulatory prevailing on pro-inflammatory (ie, IL-17 pathway) mechanisms. This observation opens interesting speculations on the possibility that anti-TNF-α could induce a ‘patchy cutaneous’ immune suppression leading to psoriasiform or psoriasis-like lesions.
Figure 1 Characterisation of anti-TNF-α antibody-induced psoriasiform skin lesions. (A) Pictures of representative cutaneous lesions, of the leg (left) and of the arm (right), together with histological evaluation (H&E). Histology of cutaneous lesions shows regular epidermal hyperplasia with parakeratosis and perivascular lymphocytic infiltrate in the superficial dermis with exocytosis and few numbers of plasma cells. (B) Relative amounts of the indicated mRNA in diseased compared with healthy skin. Results are expressed as a ratio between the values obtained for the corresponding biopsies and are representative of three independent evaluations. Gut April 2014 Vol 63 No 4
699
PostScript
Figure 2 Chemokine and cytokine expression on healthy and diseased skin. (A) Chemokines: interleukin (IL)-8; monocyte chemoattractant protein-1 (MCP-1); macrophage inflammatory protein 1β (MIP-1β). (B) Cytokines: tumour necrosis factor α (TNF-α); IL-12; IL-6; IL-17; IL-10; interferon-γ (INF-γ ). (Results are representative of three independent evaluations.) Conversely, it cannot be excluded that this condition is just an initial sign of resolution of skin lesions, being the expression of an immune system attempt to counterbalance the inflammatory infiltrate. Moreover, we suggest that the assessment of inflammatory and regulatory balance in both healthy and diseased skin could probably help in 700
selecting people undergoing spontaneous resolution just by stopping anti-TNF-α, without further modifying IL-17 axis with different therapeutic approaches. Franco Scaldaferri,1 Valentina Petito,1 Alfredo Papa,1 Monica Cesarini,2 Vincenzo Arena,3 Loris Riccardo Lopetuso,1 Maddalena Corbi,4 Francesca Perino,5
Giacomo Caldarola,5 Angelo Carbone,5 Enrico Corazziari,2 Alessandro Sgambato,4 Antonio Gasbarrini,1 Clara De Simone5 Gastroenterology Division, ‘Policlinico A. Gemelli’ Hospital, Catholic University of the Sacred Hearth, Rome, Italy Gastroenterology Division, ‘Policlinico Umberto I’ Hospital, University ‘La Sapienza’, Rome, Italy 3 Institute of Pathology, Catholic University of the Sacred Hearth, Rome, Italy 1
2
Gut April 2014 Vol 63 No 4
PostScript 4 Institute of General Pathology, Catholic University of the Sacred Hearth, Rome, Italy 5 Institute of Dermatology, ‘Policlinico A. Gemelli’ Hospital, Catholic University of the Sacred Hearth, Rome, Italy
Correspondence to Professor Antonio Gasbarrini, UOC Medicina Interna e Gastroenterologia, Catholic University of the Sacred Hearth, l.go Gemelli 8, Rome 00168, Italy; [email protected] and Professor Alessandro Sgambato, Institute of General Pathology, Catholic University of the Sacred Hearth, l.go Francesco Vito 1, Rome 00168, Italy; [email protected] AS, AG, CDeS, FS, AP and VP contributed equally. Contributors FS, AP, VP, LRL, AG, EC, AS and CDeS wrote, revised the manuscript and analysed data. VP and FS performed culturing of the skin biopsies. VA analysed histopathology. MC performed RT-PCR, Bioplex and analysed these data. FP, GC, AC and CDeS performed the dermatological evaluation, gave informed consent to the patient and performed the cutaneous biopsy. MC and EC clinically managed the patient. Funding This work was supported by PRIN 2008 and Fondazione di Ricerca in Medicina. Competing interests None. Patient consent Obtained. Ethics approval Catholic University of The Sacred Hearth, Rome, Italy. Provenance and peer review Not commissioned; internally peer reviewed. To cite Scaldaferri F, Petito V, Papa A, et al. Gut 2014;63:699–701. Received 18 June 2013 Revised 6 October 2013 Accepted 9 October 2013 Published Online First 19 November 2013
▸ http://dx.doi.org/10.1136/gutjnl-2012-302853 Gut 2014;63:699–701. doi:10.1136/gutjnl-2013-305478
REFERENCE 1
Tillack C, Ehmann LM, Friedrich M, et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/ IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut 2014;63: 567–77.
Gut April 2014 Vol 63 No 4
701
LETTERS
Anti-TNF-α-induced psoriasiform lesions in IBD: an abnormal immune activation or a ‘patchy cutaneous’ immune suppression? We read with interest the original article by Tillack et al who reported the characteristics of psoriasiform skin lesions induced by antitumour necrosis factor (anti-TNF)-α in patients with IBD.1 The authors show by immunohistochemical analysis that cutaneous lesions are characterised by interferon (IFN)α expression, infiltrates of interleukin (IL)-17A/IL-22-secreting T helper (Th)17 cells and IFNγ-secreting Th1 cells. They also demonstrate that therapy with ustekinumab, an anti-IL-12/IL-23 antibody, is highly effective in treating anti-TNF-α antibody-induced psoriasis and psoriasiform lesions. Our group is interested in the pathogenesis of psoriasiform lesions induced by anti-TNF-α antibodies in IBD patients. We
found an interesting case of an 18-year-old man diagnosed with ileo-colonic Crohn’s disease in 2003. In June 2009, the patient presented with back pain and impaired spinal mobility and was diagnosed with ankylosing spondylitis by lumbar MRI. Since symptoms did not improve with steroids and physiotherapy, he switched to adalimumab (40 mg every other week following 160/80 mg induction regimen). He observed a rapid and dramatic improvement, which lasted for 1 year. At the beginning of 2012, he developed itchy (pruriginous), erythematous and scaly plaques on his elbows, knees and pubis, suggestive for psoriasiform lesions at histology, despite the presence of few plasma cells (figure 1A and B). Following our evaluation, adalimumab was stopped and lesions resolved completely in 1 month. His back and intestinal symptoms arose again a couple of months later when he started methotrexate following a short course of steroids. The patient is now in remission with no evidence of cutaneous lesions. Following informed consent, cutaneous (from healthy and diseased skin) biopsies were collected 15 days after the last ADA administration at about 2 months from the beginning of symptoms. One biopsy was used for RNA extraction. The other one
was maintained in Dulbecco’s Modified Eagle Medium supplemented with10% fetal bovine serum for 48 h when supernatants were collected. A multiplex approach (BIO-PLEX Pro Assays, BIO-RADBio-Plex Pro Human Cytokine 17-plex Assay) was used to measure cytokines levels in supernatants. Real time quantitative PCR was used to measure FOXP3, ROR-γ and IL-17 mRNA levels. Cutaneous lesions displayed increased levels of FOXP3 and decreased levels of ROR-γ and IL-17 (figure 1C). Furthermore, decreased levels of detectable chemokines (IL-8, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β) as well as of TNF-α, IΛ–12 and IL-6 were detected in diseased compared with healthy skin while levels of IL-17, IL-10 and IFN-γ were similar (figure 2A and B). Our case suggests that some forms of psoriasiform or psoriasis-like lesions could be associated with a decrease in chemokines and inflammatory cytokines compared with healthy skin, with regulatory prevailing on pro-inflammatory (ie, IL-17 pathway) mechanisms. This observation opens interesting speculations on the possibility that anti-TNF-α could induce a ‘patchy cutaneous’ immune suppression leading to psoriasiform or psoriasis-like lesions.
Figure 1 Characterisation of anti-TNF-α antibody-induced psoriasiform skin lesions. (A) Pictures of representative cutaneous lesions, of the leg (left) and of the arm (right), together with histological evaluation (H&E). Histology of cutaneous lesions shows regular epidermal hyperplasia with parakeratosis and perivascular lymphocytic infiltrate in the superficial dermis with exocytosis and few numbers of plasma cells. (B) Relative amounts of the indicated mRNA in diseased compared with healthy skin. Results are expressed as a ratio between the values obtained for the corresponding biopsies and are representative of three independent evaluations. Gut April 2014 Vol 63 No 4
699
PostScript
Figure 2 Chemokine and cytokine expression on healthy and diseased skin. (A) Chemokines: interleukin (IL)-8; monocyte chemoattractant protein-1 (MCP-1); macrophage inflammatory protein 1β (MIP-1β). (B) Cytokines: tumour necrosis factor α (TNF-α); IL-12; IL-6; IL-17; IL-10; interferon-γ (INF-γ ). (Results are representative of three independent evaluations.) Conversely, it cannot be excluded that this condition is just an initial sign of resolution of skin lesions, being the expression of an immune system attempt to counterbalance the inflammatory infiltrate. Moreover, we suggest that the assessment of inflammatory and regulatory balance in both healthy and diseased skin could probably help in 700
selecting people undergoing spontaneous resolution just by stopping anti-TNF-α, without further modifying IL-17 axis with different therapeutic approaches. Franco Scaldaferri,1 Valentina Petito,1 Alfredo Papa,1 Monica Cesarini,2 Vincenzo Arena,3 Loris Riccardo Lopetuso,1 Maddalena Corbi,4 Francesca Perino,5
Giacomo Caldarola,5 Angelo Carbone,5 Enrico Corazziari,2 Alessandro Sgambato,4 Antonio Gasbarrini,1 Clara De Simone5 Gastroenterology Division, ‘Policlinico A. Gemelli’ Hospital, Catholic University of the Sacred Hearth, Rome, Italy Gastroenterology Division, ‘Policlinico Umberto I’ Hospital, University ‘La Sapienza’, Rome, Italy 3 Institute of Pathology, Catholic University of the Sacred Hearth, Rome, Italy 1
2
Gut April 2014 Vol 63 No 4
PostScript 4 Institute of General Pathology, Catholic University of the Sacred Hearth, Rome, Italy 5 Institute of Dermatology, ‘Policlinico A. Gemelli’ Hospital, Catholic University of the Sacred Hearth, Rome, Italy
Correspondence to Professor Antonio Gasbarrini, UOC Medicina Interna e Gastroenterologia, Catholic University of the Sacred Hearth, l.go Gemelli 8, Rome 00168, Italy; [email protected] and Professor Alessandro Sgambato, Institute of General Pathology, Catholic University of the Sacred Hearth, l.go Francesco Vito 1, Rome 00168, Italy; [email protected] AS, AG, CDeS, FS, AP and VP contributed equally. Contributors FS, AP, VP, LRL, AG, EC, AS and CDeS wrote, revised the manuscript and analysed data. VP and FS performed culturing of the skin biopsies. VA analysed histopathology. MC performed RT-PCR, Bioplex and analysed these data. FP, GC, AC and CDeS performed the dermatological evaluation, gave informed consent to the patient and performed the cutaneous biopsy. MC and EC clinically managed the patient. Funding This work was supported by PRIN 2008 and Fondazione di Ricerca in Medicina. Competing interests None. Patient consent Obtained. Ethics approval Catholic University of The Sacred Hearth, Rome, Italy. Provenance and peer review Not commissioned; internally peer reviewed. To cite Scaldaferri F, Petito V, Papa A, et al. Gut 2014;63:699–701. Received 18 June 2013 Revised 6 October 2013 Accepted 9 October 2013 Published Online First 19 November 2013
▸ http://dx.doi.org/10.1136/gutjnl-2012-302853 Gut 2014;63:699–701. doi:10.1136/gutjnl-2013-305478
REFERENCE 1
Tillack C, Ehmann LM, Friedrich M, et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/ IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut 2014;63: 567–77.
Gut April 2014 Vol 63 No 4
701
