- Email: [email protected]
The role of antinuclear autoantibodies in patients with psoriasis treated with anti–tumor necrosis factor-alpha agents: A retrospective long-term study
J AM ACAD DERMATOL
e180 Letters
MAY 2012
Funding sources: This work was supported in part by National Institutes of Health (NIH) K07 CA111653 and The ASCO Cancer Foundation (Career Development Award). Conflicts of interest: None declared. Correspondence to: Christopher D. Lao, MD, MPH, Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0848 E-mail: [email protected]
Fig 2. Histologic features of same clinically atypical nevus (hematoxylin and eosin stain) from Fig 1 at baseline (A) and at subsequent excision 4 weeks later (B). Diffuse lentiginous epidermal changes with melanocytes exhibiting variable, random cytologic atypia (arrows), and small, poorly formed nests (arrowheads) without increased atypia are noted both before and after biopsy without significant change aside from presence of scar (asterisk). (A and B, Hematoxylin-eosin stain.)
and grading scales, by definition, do not account for history. In our study, dermatoscopy alone, without history, could not independently determine whether scar-like changes evident macroscopically or on dermatoscopy were due to biopsy and scar formation or were an evolving atypical melanocytic lesion. While its use has limitations, dermatoscopy continues to be an evolving field that holds promise as an important data point for diagnosing, monitoring, and managing concerning melanocytic lesions. Hyuk C. Cha, MD, PhD,a Mandy Harting, MD,a Kelly B. Cha, MD, PhD,a Mathew W. Ludgate, MBChB, FRACP,a Stephen H. Olsen, MD,a,b Lili Zhao, PhD,d and Christopher D. Lao, MD, MPHc Departments of Dermatology,a Pathology,b and Internal Medicine,c and Biostatistics Unit,d Comprehensive Cancer Center; University of Michigan Medical Center, Ann Arbor, Michigan
REFERENCES 1. Terushkin V, Oliveria SA, Marghoob AA, Halpern AC. Use of and beliefs about total body photography and dermatoscopy among US dermatology training programs: an update. J Am Acad Dermatol 2010;62:794-803. 2. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Sammarco E, Delfino M. Epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. Comparison of the ABCD rule of dermatoscopy and a new 7-point checklist based on pattern analysis. Arch Dermatol 1998;134:1563-70. 3. Puig S, Argenziano G, Zalaudek I, Ferrara G, Palou J, Massi D, et al. Melanomas that failed dermoscopic detection: a combined clinicodermoscopic approach for not missing melanoma. Dermatol Surg 2007;33:1262-73. 4. Seidenari S, Longo C, Giusti F, Pellacani G. Clinical selection of melanocytic lesions for dermoscopy decreases the identification of suspicious lesions in comparison with dermoscopy without clinical preselection. Br J Dermatol 2006;154:873-9. 5. Bories N, Dalle S, Debarbieux S, Balme B, Ronger-Savle S, Thomas L. Dermoscopy of fully regressive cutaneous melanoma. Br J Dermatol 2008;158:1224-9. doi:10.1016/j.jaad.2011.05.028
The role of antinuclear autoantibodies in patients with psoriasis treated with antietumor necrosis factor-alpha agents: A retrospective long-term study To the Editor: Treatment with infliximab has been associated with the induction of antinuclear antibodies (ANAs).1-3 The aims of this retrospective study were (1) to evaluate the prevalence of ANA development in patients with psoriasis under longterm treatment with infliximab and (2) to assess whether the ANA profile might correlate with infusion reactions and clinical response. We reviewed charts of all psoriatic patients treated with infliximab at the Dermatology Department of the University of Rome Tor Vergata from 2002 to 2009. Our standard protocol for infliximab treatment includes testing ANAs and anti-dsDNA antibodies at baseline and at 6-month intervals until the end of treatment. Patients were excluded from the analysis if (1) treatment with infliximab was less than 12
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VOLUME 66, NUMBER 5
Table I. Demographics and clinical response of 83 patients with psoriasis receiving long-term treatment with infliximab who were ANA negative at baseline
Male/female (No.) Mean age ( y) 6 SD Mean age at disease onset ( y) 6 SD Autoimmune comorbidities (No.) PSO/PSA (No.) No. of responders ($PASI 75) Infusion reaction (No.) Mean time to development of ANA (mo) ANA [ 1:1280 (%) Anti-dsDNA (%) Mean duration of treatments (mo) 6 SD
ANA-positive at end of treatment (n = 30)
ANA-negative at end of treatment (n = 33)
P value
20/10 49.6 ( 6 13.0) 29.3 ( 6 17.3) 2* 11/19 25/30 6 26.7 40% 16% 26.7 ( 6 11.7)
24/9 52.1 ( 6 15.2) 26.2 ( 6 13.3) 6y 17/16 28/33 6 — — — 24.3 ( 6 12.2)
.40 .52 .79 .24 .25 .55 .43 — — — .82
ANA, Antinuclear antibodies; PSA, psoriatic arthritis associated with plaque-type psoriasis; PSO, plaque-type psoriasis; SD, standard deviation. *Vitiligo (n ¼ 1) and thyroiditis (n ¼ 1). y Vitiligo (n ¼ 1), thyroiditis (n ¼ 3), vasculitis (n ¼ 1), and retinitis pigmentosa (n ¼ 1).
months, (2) baseline ANA data were unavailable, (3) concurrent immunosuppressive drug was taken; or (4) patient transferred to another medical center. Of 151 patients who received infliximab during that time period, we excluded 82 patients for the following reasons: baseline ANA values unavailable (n ¼ 11), concomitant treatment with methotrexate (n ¼ 13), patient transfer to another medical center after the induction period (n ¼ 33), and infliximab treatment for less than 12 months (n ¼ 25). In the latter group 18 patients discontinued the therapy because of lack of efficacy and 7 discontinued because of adverse events. Reasons for discontinuation included TBC reactivation (n ¼ 2), allergic reaction (n ¼ 3), pregnancy (n ¼ 1), and infusion reaction with hypertension and shaking (n ¼ 1). The remaining 69 patients were included in the study. The mean period of treatment was 26 months. At baseline 63 patients were ANA negative and 6 patients were ANA positive. Thirty patients who were ANA negative at baseline (48%) became ANA positive during treatment (Table I). None of the patients developed a lupus-like syndrome. Clinical response was defined as a greater than 75% reduction in the Psoriasis Area and Severity Index (PASI 75). In the ANA-negative group, patients were classified as responders (n ¼ 53) or nonresponders (n ¼ 10). To identify factors associated with clinical response, we performed a logistic regression analysis, using independent variables of age, sex, duration of psoriasis, autoimmune comorbidities, ANA status, and clinical type of psoriasis (Table II). We did not identify any variable associated with a positive response to infliximab. Moreover, the presence of ANA, even at high levels ([1:2560) and, together with antidsDNA, did not interfere with the efficacy of the
Table II. Logistic regression analysis with PASI 75 as dependent variable Variables
Sex Age ANA ( positive/negative) ANA titer [ 1:1280 PSO duration PSO/PSA
OR
CI for 95% of OR
P value
0.87 1.01 1.58 0.58 0.96 0.30
0.18-4.10 0.96-1.07 0.35-7.20 0.08-4.30 0.90-1.02 0.07-1.22
.86 .59 .55 .60 .22 .09
ANA, Antinuclear antibodies; CI, confidence interval; OR, odds ratio; PSA, psoriatic arthritis associated with plaque-type psoriasis; PSO, plaque-type psoriasis.
therapy. Notably, the 5 anti-dsDNAepositive patients were all responders receiving long-term treatment. The rate of clinical response was similar in patients in whom ANAs developed and in those who remained ANA negative. This finding is in contrast to the results of Pink et al4 who reported that development of ANA and anti-dsDNA antibodies on anti-TNF-alpha treatment could act as a marker of forthcoming treatment failure. In conclusion, we observed development of ANAs in 48% of patients receiving long-term infliximab treatment, but found no association with loss of efficacy, increased infusion reactions, or development of lupus-like syndrome. These findings suggest that formation of ANAs should not lead to treatment suspension because of concerns about loss of efficacy, adverse events, or development of autoimmune diseases. Rosita Saraceno, MD,a Francesca Specchio, MD,a Tiago Torres, MD,c Steven Paul Nistico, MD,a Stefano Rizza, MD,b and Sergio Chimenti, MDa
J AM ACAD DERMATOL
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MAY 2012
Departments of Dermatologya and Internal Medicine,b University of Rome Tor Vergata, Italy, and the Department of Dermatology, Hospital Santo Ant onio, Porto, Portugalc Funding sources: None. Conflicts of interest: Dr Chimenti has received speaker fees, consultancy fees and research grants from Schering-Plough/Merck, the manufacturers of infliximab. Dr Saraceno has received a speaker fee from ScheringPlough/Merck. Correspondence to: Rosita Saraceno, MD, Department of Dermatology, Policlinico tor Vergata, Viale Oxford 81 00133, Rome REFERENCES 1. Eriksson C, Engstrand S, Sundqvist KG, Rantap€a€a-Dahlqvist S. Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF-alpha. Ann Rheum Dis 2005;64:403-7. 2. Fusconi M, Vannini A, Dall’Aglio AC, Pappas G, Bianchi FB, Zauli D. Etanercept and infliximab induce the same serological autoimmune modifications in patients with rheumatoid arthritis. Rheumatol Int 2007;28:47-9. 3. Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P. Autoimmunity and anti-TNF-alpha agents. Ann N Y Acad Sci 2005;1051:559-69. 4. Pink AE, Fonia A, Allen MH, Smith CH, Barker JN. Antinuclear antibodies associated with loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study. Br J Dermatol 2010;162:780-5. doi:10.1016/j.jaad.2011.06.008
A high serum concentration of chemerin in pustular dermatitis paradoxically induced by etanercept To the Editor: Etanercept is an antietumor necrosis factor-a (TNF-a) antagonist with a TNF-a receptor and IgG Fc chimeric structure, which is used for alleviating excessive inflammation in rheumatoid arthritis,1 psoriasis, and psoriatic arthritis.2 However, etanercept occasionally may show paradoxical cutaneous side effects, including psoriasis and pustular dermatitis.1 Chemerin is a recently identified chemokine, which stimulates chemotaxis of plasmacytoid dendritic cells ( pDCs) and neutrophils,3 and is expressed specifically at the early stage of psoriatic lesions. Herein, we report a case of pustular dermatitis caused by etanercept with a high serum chemerin concentration. A 71-year-old woman was referred to our department for evaluation of a pustular eruption. She had suffered from rheumatoid arthritis for 2 years. There was no personal or familial history of
psoriasis. After an intravenous administration of etanercept for the second time, she developed erythematous lesions on her bilateral legs and abdomen. Physical examination revealed scaly erythematous macules with pustules on her bilateral lower legs and abdomen (Fig 1, A). A skin biopsy specimen taken from her left thigh showed acanthotic epidermis with exocytosis of neutrophils and dermal infiltration of neutrophils and lymphocytes (Fig 1, B). We diagnosed the skin eruption as pustular dermatitis caused by etanercept. Injections of etanercept were discontinued, and the skin lesions were remarkably improved by an application of a topical corticosteroid. To investigate the pathomechanism of pustular dermatitis caused by TNF-a inhibitor, we examined the percentages of circulating pDCs by flow cytometry with anti-CD123 antibody (BD Biosciences, Franklin Lakes, NJ) and anti-lineage markers cocktail antibodies (Lin1; BD Biosciences). We also measured the serum levels of interferon alfa (IFNa), interleukin 17 (IL-17), and chemerin by using enzyme-linked immunosorbent assay kits for human IFN-a (Bender Med Systems, Vienna, Austria), human IL-17 (R & D Systems, Minneapolis, MN), and human chemerin (Millipore Corporation, Billerica, MA). The frequency of circulating pDCs in the peripheral blood was elevated at 6.83% (normal value, 2.38 6 0.29%, n ¼ 5) in the patient, which was decreased to 3.47% on 28 days after withdrawal of etanercept (Fig 1, C ). The serum concentrations of IFN-a (Fig 1, D) and chemerin (Fig 1, E ) were increased at 317.2 pg/mL and 61.0 ng/ml, respectively, compared with 5 healthy individuals; these serum levels of the patient’s IFN-a and chemerin declined along with improvement. The serum concentration of IL-17 at the first visit was within a normal range (4.0 pg/mL; normal, 0.04-18.4 pg/mL, n ¼ 5). TNF-a has been suggested to negatively regulate IFN-a production and to inhibit the maturation of pDCs from hematopoietic progenitors. Therefore the inhibition of TNF-a possibly induces IFN-a production by pDCs, which lead to a psoriasiform eruption and pustular dermatisis.4,5 In our study, the serum concentration of chemerin was elevated, whereas serum IL-17 level was within a normal range. This result suggests that chemerin plays an important role in the formation of pustular dermatitis caused by the TNF-a inhibitor, although we currently cannot propose the exact mechanism underlying the chemerin elevation by etanercept. It has been reported that chemerin directly activates neurtophils.3 Considering that IFN-a is unable to directly attract neutrophils, the cooperation
e180 Letters
MAY 2012
Funding sources: This work was supported in part by National Institutes of Health (NIH) K07 CA111653 and The ASCO Cancer Foundation (Career Development Award). Conflicts of interest: None declared. Correspondence to: Christopher D. Lao, MD, MPH, Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0848 E-mail: [email protected]
Fig 2. Histologic features of same clinically atypical nevus (hematoxylin and eosin stain) from Fig 1 at baseline (A) and at subsequent excision 4 weeks later (B). Diffuse lentiginous epidermal changes with melanocytes exhibiting variable, random cytologic atypia (arrows), and small, poorly formed nests (arrowheads) without increased atypia are noted both before and after biopsy without significant change aside from presence of scar (asterisk). (A and B, Hematoxylin-eosin stain.)
and grading scales, by definition, do not account for history. In our study, dermatoscopy alone, without history, could not independently determine whether scar-like changes evident macroscopically or on dermatoscopy were due to biopsy and scar formation or were an evolving atypical melanocytic lesion. While its use has limitations, dermatoscopy continues to be an evolving field that holds promise as an important data point for diagnosing, monitoring, and managing concerning melanocytic lesions. Hyuk C. Cha, MD, PhD,a Mandy Harting, MD,a Kelly B. Cha, MD, PhD,a Mathew W. Ludgate, MBChB, FRACP,a Stephen H. Olsen, MD,a,b Lili Zhao, PhD,d and Christopher D. Lao, MD, MPHc Departments of Dermatology,a Pathology,b and Internal Medicine,c and Biostatistics Unit,d Comprehensive Cancer Center; University of Michigan Medical Center, Ann Arbor, Michigan
REFERENCES 1. Terushkin V, Oliveria SA, Marghoob AA, Halpern AC. Use of and beliefs about total body photography and dermatoscopy among US dermatology training programs: an update. J Am Acad Dermatol 2010;62:794-803. 2. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Sammarco E, Delfino M. Epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. Comparison of the ABCD rule of dermatoscopy and a new 7-point checklist based on pattern analysis. Arch Dermatol 1998;134:1563-70. 3. Puig S, Argenziano G, Zalaudek I, Ferrara G, Palou J, Massi D, et al. Melanomas that failed dermoscopic detection: a combined clinicodermoscopic approach for not missing melanoma. Dermatol Surg 2007;33:1262-73. 4. Seidenari S, Longo C, Giusti F, Pellacani G. Clinical selection of melanocytic lesions for dermoscopy decreases the identification of suspicious lesions in comparison with dermoscopy without clinical preselection. Br J Dermatol 2006;154:873-9. 5. Bories N, Dalle S, Debarbieux S, Balme B, Ronger-Savle S, Thomas L. Dermoscopy of fully regressive cutaneous melanoma. Br J Dermatol 2008;158:1224-9. doi:10.1016/j.jaad.2011.05.028
The role of antinuclear autoantibodies in patients with psoriasis treated with antietumor necrosis factor-alpha agents: A retrospective long-term study To the Editor: Treatment with infliximab has been associated with the induction of antinuclear antibodies (ANAs).1-3 The aims of this retrospective study were (1) to evaluate the prevalence of ANA development in patients with psoriasis under longterm treatment with infliximab and (2) to assess whether the ANA profile might correlate with infusion reactions and clinical response. We reviewed charts of all psoriatic patients treated with infliximab at the Dermatology Department of the University of Rome Tor Vergata from 2002 to 2009. Our standard protocol for infliximab treatment includes testing ANAs and anti-dsDNA antibodies at baseline and at 6-month intervals until the end of treatment. Patients were excluded from the analysis if (1) treatment with infliximab was less than 12
J AM ACAD DERMATOL
Letters e181
VOLUME 66, NUMBER 5
Table I. Demographics and clinical response of 83 patients with psoriasis receiving long-term treatment with infliximab who were ANA negative at baseline
Male/female (No.) Mean age ( y) 6 SD Mean age at disease onset ( y) 6 SD Autoimmune comorbidities (No.) PSO/PSA (No.) No. of responders ($PASI 75) Infusion reaction (No.) Mean time to development of ANA (mo) ANA [ 1:1280 (%) Anti-dsDNA (%) Mean duration of treatments (mo) 6 SD
ANA-positive at end of treatment (n = 30)
ANA-negative at end of treatment (n = 33)
P value
20/10 49.6 ( 6 13.0) 29.3 ( 6 17.3) 2* 11/19 25/30 6 26.7 40% 16% 26.7 ( 6 11.7)
24/9 52.1 ( 6 15.2) 26.2 ( 6 13.3) 6y 17/16 28/33 6 — — — 24.3 ( 6 12.2)
.40 .52 .79 .24 .25 .55 .43 — — — .82
ANA, Antinuclear antibodies; PSA, psoriatic arthritis associated with plaque-type psoriasis; PSO, plaque-type psoriasis; SD, standard deviation. *Vitiligo (n ¼ 1) and thyroiditis (n ¼ 1). y Vitiligo (n ¼ 1), thyroiditis (n ¼ 3), vasculitis (n ¼ 1), and retinitis pigmentosa (n ¼ 1).
months, (2) baseline ANA data were unavailable, (3) concurrent immunosuppressive drug was taken; or (4) patient transferred to another medical center. Of 151 patients who received infliximab during that time period, we excluded 82 patients for the following reasons: baseline ANA values unavailable (n ¼ 11), concomitant treatment with methotrexate (n ¼ 13), patient transfer to another medical center after the induction period (n ¼ 33), and infliximab treatment for less than 12 months (n ¼ 25). In the latter group 18 patients discontinued the therapy because of lack of efficacy and 7 discontinued because of adverse events. Reasons for discontinuation included TBC reactivation (n ¼ 2), allergic reaction (n ¼ 3), pregnancy (n ¼ 1), and infusion reaction with hypertension and shaking (n ¼ 1). The remaining 69 patients were included in the study. The mean period of treatment was 26 months. At baseline 63 patients were ANA negative and 6 patients were ANA positive. Thirty patients who were ANA negative at baseline (48%) became ANA positive during treatment (Table I). None of the patients developed a lupus-like syndrome. Clinical response was defined as a greater than 75% reduction in the Psoriasis Area and Severity Index (PASI 75). In the ANA-negative group, patients were classified as responders (n ¼ 53) or nonresponders (n ¼ 10). To identify factors associated with clinical response, we performed a logistic regression analysis, using independent variables of age, sex, duration of psoriasis, autoimmune comorbidities, ANA status, and clinical type of psoriasis (Table II). We did not identify any variable associated with a positive response to infliximab. Moreover, the presence of ANA, even at high levels ([1:2560) and, together with antidsDNA, did not interfere with the efficacy of the
Table II. Logistic regression analysis with PASI 75 as dependent variable Variables
Sex Age ANA ( positive/negative) ANA titer [ 1:1280 PSO duration PSO/PSA
OR
CI for 95% of OR
P value
0.87 1.01 1.58 0.58 0.96 0.30
0.18-4.10 0.96-1.07 0.35-7.20 0.08-4.30 0.90-1.02 0.07-1.22
.86 .59 .55 .60 .22 .09
ANA, Antinuclear antibodies; CI, confidence interval; OR, odds ratio; PSA, psoriatic arthritis associated with plaque-type psoriasis; PSO, plaque-type psoriasis.
therapy. Notably, the 5 anti-dsDNAepositive patients were all responders receiving long-term treatment. The rate of clinical response was similar in patients in whom ANAs developed and in those who remained ANA negative. This finding is in contrast to the results of Pink et al4 who reported that development of ANA and anti-dsDNA antibodies on anti-TNF-alpha treatment could act as a marker of forthcoming treatment failure. In conclusion, we observed development of ANAs in 48% of patients receiving long-term infliximab treatment, but found no association with loss of efficacy, increased infusion reactions, or development of lupus-like syndrome. These findings suggest that formation of ANAs should not lead to treatment suspension because of concerns about loss of efficacy, adverse events, or development of autoimmune diseases. Rosita Saraceno, MD,a Francesca Specchio, MD,a Tiago Torres, MD,c Steven Paul Nistico, MD,a Stefano Rizza, MD,b and Sergio Chimenti, MDa
J AM ACAD DERMATOL
e182 Letters
MAY 2012
Departments of Dermatologya and Internal Medicine,b University of Rome Tor Vergata, Italy, and the Department of Dermatology, Hospital Santo Ant onio, Porto, Portugalc Funding sources: None. Conflicts of interest: Dr Chimenti has received speaker fees, consultancy fees and research grants from Schering-Plough/Merck, the manufacturers of infliximab. Dr Saraceno has received a speaker fee from ScheringPlough/Merck. Correspondence to: Rosita Saraceno, MD, Department of Dermatology, Policlinico tor Vergata, Viale Oxford 81 00133, Rome REFERENCES 1. Eriksson C, Engstrand S, Sundqvist KG, Rantap€a€a-Dahlqvist S. Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF-alpha. Ann Rheum Dis 2005;64:403-7. 2. Fusconi M, Vannini A, Dall’Aglio AC, Pappas G, Bianchi FB, Zauli D. Etanercept and infliximab induce the same serological autoimmune modifications in patients with rheumatoid arthritis. Rheumatol Int 2007;28:47-9. 3. Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P. Autoimmunity and anti-TNF-alpha agents. Ann N Y Acad Sci 2005;1051:559-69. 4. Pink AE, Fonia A, Allen MH, Smith CH, Barker JN. Antinuclear antibodies associated with loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study. Br J Dermatol 2010;162:780-5. doi:10.1016/j.jaad.2011.06.008
A high serum concentration of chemerin in pustular dermatitis paradoxically induced by etanercept To the Editor: Etanercept is an antietumor necrosis factor-a (TNF-a) antagonist with a TNF-a receptor and IgG Fc chimeric structure, which is used for alleviating excessive inflammation in rheumatoid arthritis,1 psoriasis, and psoriatic arthritis.2 However, etanercept occasionally may show paradoxical cutaneous side effects, including psoriasis and pustular dermatitis.1 Chemerin is a recently identified chemokine, which stimulates chemotaxis of plasmacytoid dendritic cells ( pDCs) and neutrophils,3 and is expressed specifically at the early stage of psoriatic lesions. Herein, we report a case of pustular dermatitis caused by etanercept with a high serum chemerin concentration. A 71-year-old woman was referred to our department for evaluation of a pustular eruption. She had suffered from rheumatoid arthritis for 2 years. There was no personal or familial history of
psoriasis. After an intravenous administration of etanercept for the second time, she developed erythematous lesions on her bilateral legs and abdomen. Physical examination revealed scaly erythematous macules with pustules on her bilateral lower legs and abdomen (Fig 1, A). A skin biopsy specimen taken from her left thigh showed acanthotic epidermis with exocytosis of neutrophils and dermal infiltration of neutrophils and lymphocytes (Fig 1, B). We diagnosed the skin eruption as pustular dermatitis caused by etanercept. Injections of etanercept were discontinued, and the skin lesions were remarkably improved by an application of a topical corticosteroid. To investigate the pathomechanism of pustular dermatitis caused by TNF-a inhibitor, we examined the percentages of circulating pDCs by flow cytometry with anti-CD123 antibody (BD Biosciences, Franklin Lakes, NJ) and anti-lineage markers cocktail antibodies (Lin1; BD Biosciences). We also measured the serum levels of interferon alfa (IFNa), interleukin 17 (IL-17), and chemerin by using enzyme-linked immunosorbent assay kits for human IFN-a (Bender Med Systems, Vienna, Austria), human IL-17 (R & D Systems, Minneapolis, MN), and human chemerin (Millipore Corporation, Billerica, MA). The frequency of circulating pDCs in the peripheral blood was elevated at 6.83% (normal value, 2.38 6 0.29%, n ¼ 5) in the patient, which was decreased to 3.47% on 28 days after withdrawal of etanercept (Fig 1, C ). The serum concentrations of IFN-a (Fig 1, D) and chemerin (Fig 1, E ) were increased at 317.2 pg/mL and 61.0 ng/ml, respectively, compared with 5 healthy individuals; these serum levels of the patient’s IFN-a and chemerin declined along with improvement. The serum concentration of IL-17 at the first visit was within a normal range (4.0 pg/mL; normal, 0.04-18.4 pg/mL, n ¼ 5). TNF-a has been suggested to negatively regulate IFN-a production and to inhibit the maturation of pDCs from hematopoietic progenitors. Therefore the inhibition of TNF-a possibly induces IFN-a production by pDCs, which lead to a psoriasiform eruption and pustular dermatisis.4,5 In our study, the serum concentration of chemerin was elevated, whereas serum IL-17 level was within a normal range. This result suggests that chemerin plays an important role in the formation of pustular dermatitis caused by the TNF-a inhibitor, although we currently cannot propose the exact mechanism underlying the chemerin elevation by etanercept. It has been reported that chemerin directly activates neurtophils.3 Considering that IFN-a is unable to directly attract neutrophils, the cooperation