Letters to the Editor

for acne. It is possible that she was previously sensitized to prednisolone by the ointment. We should be careful in using corticosteroids, because even prednisolone can cause drug eruption.



Satoko ISHII,1 Toshio HASEGAWA,1 Yusuke HIRASAWA,1 Yuichiro TSUNEMI,2 Makoto KAWASHIMA,2 Shigaku IKEDA1 1

Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, and 2Department of Dermatology, Tokyo Women’s Medical University, Tokyo, Japan

doi: 10.1111/1346-8138.12658

REFERENCES 1 Roujeau JC, Bioulac-Sage P, Bourseau C et al. Acute generalized exanthematic pustulosis: analysis of 63 cases. Arch Dermatol 1991; 127: 1333–1338. 2 Bircher AJ, Levy F, Langauer S, Lepoittevin JP. Contact allergy to topical corticosteroids and systemic contact dermatitis from prednisolone with tolerance of triamcinolone. Acta Derm Venereol 1995; 75: 490–493. 3 Demitsu T, Kosuge A, Yamada T. Acute generalized exanthematous pustulosis induced by dexamethasone injection. Dermatology 1996; 193: 56–58. 4 Mussot-Chia C, Flechet ML, Napolitano M et al. Methylprednisoloneinduced acute generalized exanthematous pustulosis. Ann Dermatol Venereol 2001; 128: 241–243.

Elevation of serum KL-6 levels during treatment with tumor necrosis factor-a inhibitor in patients with psoriasis Dear Editor, KL-6 is a serum biomarker for detection of various interstitial lung diseases.1 Herein, we investigated the correlation between biologic treatment and elevation of serum KL-6 levels in Japanese psoriatic patients. A total of 19 psoriatic patients whose serum KL-6 levels were measured before initiation of biologic therapy and followed up for at least 6 months were analyzed (Table 1). Serum KL-6 levels were measured using LUMIPULSEâ KL-6 Eisai or NANOPIAâ KL-6 Eisai (Eisia, Tokyo,

Japan) by in-house laboratory. Of these 19 patients, none showed an increase within the first year. In the patients who were followed up for more than a year, serum KL-6 levels exceeded the upper normal limit of 500 U/mL in three of seven patients treated with adalimumab. Mean serum KL-6 level at maximum during adalimumab therapy (376.9  268.6 U/mL) showed significant increase (P = 0.03, paired Student’s t-test). None had clinical symptoms or computed tomography scan findings of pneumonia. In contrast, elevation of serum KL-6

Table 1. Characteristics of the enrolled psoriatic patients Adalimumab‡ No. Sex Male (%) Female (%) Age at baseline† (years) Type of psoriasis Psoriasis vulgaris Psoriatic arthritis Generalized pustular psoriasis Follow-up period† (months) Serum KL-6 level at baseline† (U/mL) Serum KL-6 level at maximum† (U/mL) No. of patients whose serum KL-6 levels exceeded 500 U/mL Treatment history of methotrexate Past history of interstitial lung diseases


Infliximab 4

Ustekinumab§ 8

5 (71%) 2 (29%) 49.7  12.6

2 (50%) 2 (50%) 58.3  14.5

7 (88%) 1 (12%) 48.5  16.7

4 2 1 22.0  10.2 196.0  70.2 376.9  268.6 3

0 3 1 16.0  9.6 186.0  87.5 223.8  59.6 0

7 1 0 15.8  7.5 213.7  82.9 191.0  53.0 0

0 0

2¶ 0

0 0

† Mean  standard deviation. ‡One case is a switcher from infliximab. §Two cases had history of previous infliximab treatment. ¶One case is treated with combination therapy. One case had history of previous treatment.

Correspondence: Tomotaka Mabuchi, M.D., Ph.D., Department of Dermatology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Email: [email protected]


© 2014 Japanese Dermatological Association

Letters to the Editor

levels was not found in any of the patients treated with infliximab (n = 4) and ustekinumab (n = 8). Mean serum KL-6 levels at maximum during infliximab and ustekinumab therapies were 223.8  59.6 and 191.0  53.0 U/mL, respectively. There were no statistical significances between before and during treatments. A retrospective study of rheumatoid arthritis patients reported increases in serum KL-6 levels in nine (27.3%) of 33 patients treated with adalimumab, eight (18.0%) of 44 patients treated with infliximab and eight (16.0%) of 50 patients treated with etanercept at least once during the following year.2 At least 22 of these 25 patients had no apparent interstitial lung diseases.2 A clinical trial of infliximab in Japanese rheumatoid arthritis patients revealed that 48 (14.7%) of 327 patients had increased serum KL-6 levels without significant clinical events by week 54.3 KL-6 is a high-molecular-weight glycoprotein classified as a polymorphic epithelial mucin, and is highly expressed on the surface of type 2 pneumocytes.1 Circulating KL-6 in serum is thought to be derived from this expression.1 KL-6 is a submolecule of MUC1, thus KL-6/MUC1 is commonly used to denote the KL-6 molecule.1 The MUC1 extracellular domain can be shed into the pulmonary epithelial lining fluid (ELF) through the action of tumor necrosis factor (TNF)-a-converting enzyme (TACE), also known as a disintegrin and metalloproteinase 17 (ADAM17).1 The soluble form of TNF-a (sTNF-a), which is cleaved from transmembrane TNF-a (tmTNF-a) by TACE, mediates its biological activities through binding to type 1 and 2 TNF receptors (TNF-R1 and TNF-R2) of remote tissues.4 Although tmTNF-a also binds to TNF-R1 and TNF-R2, its biological activities function through mainly binding with TNF-R2.4 Upon binding to TNF receptors, both tmTNF-a and sTNF-a mediate pleiotropic effects, including cell proliferation and cytokine production.4 Infliximab binds to both tmTNF-a and

© 2014 Japanese Dermatological Association

sTNF-a, whereas adalimumab binds to tmTNF-a.4 In the presence of TNF-a inhibitors, overexpressed TACE may enhance the MUC1 extracellular domain shedding into ELF, therefore, serum KL-6 level could be increased. In conclusion, TNF-a inhibitors may increase serum KL-6 levels without the occurrence of interstitial lung diseases. In such a case, treatment with TNF-a inhibitors can be continued with careful observation.



Tomotaka MABUCHI, Hanako YAMAOKA, Mayu KAWAI, Tami OTA, Akira OZAWA Department of Dermatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan doi: 10.1111/1346-8138.12681

REFERENCES 1 Ishikawa N, Hattori N, Yokoyama A et al. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig 2012; 50: 3–13. 2 Takamura A, Hirata S, Nagasawa H et al. A retrospective study of serum KL-6 levels during treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: a report from the Ad Hoc Committee for Safety of Biological DMARDs of the Japan College of Rheumatology. Mod Rheumatol 2013; 23: 297–303. 3 Harigai M, Takamura A, Atsumi T et al. Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs. Mod Rheumatol 2013; 23: 284–296. 4 Horiuchi T, Mitoma H, Harashima S et al. Transmembrane TNF-a: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford) 2010; 49: 1215–1228.


Elevation of serum KL-6 levels during treatment with tumor necrosis factor-α inhibitor in patients with psoriasis.

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