First published: 31 October 2023journal articl

Akiyama, Masashi

Hayai, Shunsaku

Muro, Yoshinao

Noguchi, Haruka

Takeichi, Takuya

Yoshikawa, Masato

The Journal of Dermatology

English

Nagoya Repository

1 Noguchi et al.   The Journal of Dermatology Manuscript ID: JDE-2023-0956 Revised Version  Letter to the Editor Pneumocystis pneumonia in a patient with severe generalized pustular psoriasis treated with biologics  Haruka Noguchi, M.D.,1 Takuya Takeichi, M.D., Ph.D.,1* Shunsaku Hayai, M.D., Ph.D.,2 Masato Yoshikawa, M.D.,3 Yoshinao Muro, M.D., Ph.D.,1 and Masashi Akiyama, M.D., Ph.D.,1*  Departments of 1Dermatology and 2Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; 3Division of Dermatology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan  *Corresponding author Takuya Takeichi, M.D., Ph.D. Tel: 81-52-744-2314, Fax: 81-52-744-2318 E-mail: takeichi@med.nagoya-u.ac.jp Masashi Akiyama, M.D., Ph.D. makiyama@med.nagoya-u.ac.jp  Short title: GPP complicated with pneumocystis pneumonia  2 Noguchi et al.   Abbreviations: GPP, generalized pustular psoriasis; PCP, pneumocystis pneumonia; TMP-SMX, trimethoprim-sulfamethoxazole  KEY WORDS: autoinflammation, complication, immunosuppression, ixekizumab, spesolimab  Word count: 500/500 words in the main text, 5/5 references, 1 figure  The authors have no conflicts of interest to declare. Prof. Masashi Akiyama is an Editorial Board member of Journal of Dermatology and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication.    3 Noguchi et al.   A 23-year-old woman presented with erythema and pustules on the trunk and the extremities (Figure 1a-c). A skin biopsy revealed Kogoj’s spongiform pustules in the epidermis (Figure 1d). The total severity score of GPP was 11, which is classified as “severe” under the Japanese guidelines for GPP. She had neither preceding plaque psoriasis, nor triggering factors. She was treated with adalimumab, but she showed high fever and knee arthralgia during this treatment (Figure 1g). Then, a combination of ixekizumab and granulocyte and monocyte absorption apheresis, and oral prednisolone in succession was tried. However, her skin condition exacerbated. The treatment was switched to anti-interleukin-36 receptor antibody, spesolimab. At one week of spesolimab administration (Figure 1h), she presented dyspnea and a high fever (>38℃). Her chest X-ray and computed tomography showed bilateral ground-glass opacities (Figure 1e,f). The laboratory tests results were white blood cell count 7,400/mm3 (normal range: 3,800–8,500/mm3), CRP 18.01 mg/dl (<0.14 mg/dl), β-D glucan 158.4 pg/ml (<11 pg/ml). We were unable to perform bronchoalveolar lavage because her general condition was too bad. She was clinically diagnosed with pneumocystis pneumonia (PCP) and treated with trimethoprim-sulfamethoxazole (TMP-SMX) in combination (4000 mg/day and 800 mg/day, respectively), prednisolone (60 mg/day), and piperacillin/tazobactam (PIPC/TAZ). There were no other apparent fungal infections. Her respiratory condition and chest radiography findings improved. The oral prednisolone was tapered, and the combination TMP-SMX was reduced to a prophylactic dose (400 mg/day and 80 mg/day). After informed consent was obtained, genomic DNA from the patient was subjected to whole-exome sequencing, which showed no pathogenic variants in known 4 Noguchi et al.   genes associated with GPP, including IL36RN, CARD14, AP1S3, MPO, and SERPINA3. Several reports have addressed PCP as an adverse event in psoriatic arthritis and rheumatoid arthritis patients treated with TNF inhibitors, especially with infliximab.1 According to post-marketing surveillance on the safety of infliximab in Japanese patients with rheumatoid arthritis, the incidence rate of PCP is 0.4%.2 It is well known that IL-17 is a key cytokine for protection against Candida albicans.3 As for the pneumocystis, serum IL-17A levels in mice infected with pneumocystis are increased, and STAT3, which is an important transcription factor for Th17 pathway, is upregulated.4 Furthermore, deficiency in IL-17 can lead to the delayed clearance of pneumocystis in the lung.4 These results may support the hypothesis that the IL-17 inhibitor might potentially contribute to the development of PCP. In host defense against pneumocystis, there are complex interactions between CD4+ T cells, alveolar macrophages, neutrophils, and the soluble mediators that facilitate the clearance of the infection. IL-36 cytokines are expressed in airway epithelial cells and lung-resident macrophages. The activated IL-36 signaling stimulates the production of pro-inflammatory cytokines and chemokines, which recruit neutrophils and monocytes into the lungs.5 Thus, IL-36 inhibitors may attenuate the innate immune response in the lungs and might contribute to the development of PCP, although the role of the IL-36 pathway against pneumocystis infection is not fully understood. Our findings suggest that the prophylactic combination of oral TMP-SMX should be considered biologics are used for patients with severe GPP.  Acknowledgment statement 5 Noguchi et al.   The patient in this manuscript gave her written informed consent to the publication of her case details. We thank Ms. Haruka Ozeki and Ms. Yuka Terashita for their valuable assistance. This study was supported in part by JSPS KAKENHI Grants Number 21H02941 to M.A. and Number 20K08648 to T.T., and AMED under Grant Number JP20ek0109488 to T.T. and M.A. This research was supported by a Health and Labor Sciences Research Grant for Research on Intractable Diseases (23FC1039) from the Ministry of Health, Labor and Welfare of Japan to M.A.    6 Noguchi et al.   Figure legends  Figure 1. Clinicopathological features of the present patient with GPP. (a, b) Erythema with small pustules on the lower back (a) and the left palm and fingers (b). (c) Scaly erythema is seen on the flexor side of the legs. (d) Histopathology from a pustule on the abdomen shows spongiform pustules of Kogoj. Scale bar: 200 μm. (e, f) Computed tomography of her chest shows bilateral ground-glass opacities. An infiltrative shadow is also seen on the dorsal side from the upper to lower lobe. (g, h) Treatment and clinical course of the patient. (g) At the outpatient clinic before admission, adalimumab was administered at a dose of 80 mg every two weeks for eight weeks (only the second dose was 40 mg). Then, ixekizumab was administered at a dose of 80 mg every two weeks for six weeks. During the ixekizumab treatment, granulocyte and monocyte adsorption apheresis was administered once a week four times for three weeks, and oral prednisolone was administered at a dose of 25 mg/day for one week and 12.5 mg/day for one week. We did not introduce trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for PCP because the oral prednisolone was administered for only a 7 Noguchi et al.   short time and we were unable to definitively exclude the possibility of pregnancy. (h) The patient was clinically diagnosed with pneumocystis pneumonia on Day 8 of hospitalization. The antibiotics were changed from PIPC/TAZ to cefazolin according to a positive blood culture finding of methicillin-susceptible Staphylococcus aureus. Abbreviations: PSL, prednisolone; TMP-SMX, trimethoprim-sulfamethoxazole; PIPC/TAZ, piperacillin/tazobactam; CEZ, cefazolin; GMA, granulocyte and monocyte absorption apheresis. 8 Noguchi et al.   References 1. Saeki H, Mabuchi T, Asahina A et al. English version of Japanese guidance for use of biologics for psoriasis (the 2022 version). J Dermatol 2023; 50: e41-e68. 2. Takeuchi T, Tatsuki Y, Nogami Y, et al. Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008; 67: 189-194. 3. Sparber F, LeibundGut-Landmann S. Interleukin-17 in Antifungal Immunity. Pathogens 2019; 8: 54. 4. Rong HM, Qian XJ, Zhang C, Li T, Tong ZH. IL-17 Inversely Correlated with IL-10 via the STAT3 Gene in Pneumocystis-Infected Mice. Mediators Inflamm 2019; 2019: 6750861. 5. Zhou L, Todorovic V. Interleukin-36: Structure, Signaling and Function. Adv Exp Med Biol 2021; 21: 191-210.  

Pneumocystis pneumonia in a patient with severe generalized pustular psoriasis treated with biologics

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Pneumocystis pneumonia in a patient with severe generalized pustular psoriasis treated with biologics

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