ANAIS BRASILEIROS DE DERMATOLOGIA SEPTEMBER/OCTOBER 2022 V. 97 N. 5| 551–696 EXTENSIVE MICROPUSTULAR TINEA CAPITIS IN AN ADULT CAUSED BY TRICHOPHYTON VERRUCOSUM WITH EVOLUTION TO KERION CELSI Larangeira de Almeida Jr. H. et al Official publication of the Brazilian Society of Dermatology Dermatologia Anais Brasileiros de Volume 99 Number 2 2024 www.anaisdedermatologia.org.br Infections in the era of immunobiologicals Clinical profile of vitiligo patients and relationship with immuno-inflammatory markers Unmet needs in the management of psoriasis in Latin America: a systematic review Side effects of chronic systemic glucocorticoid therapy: what dermatologists should know Amelanotic malignant melanoma in a child Neurogenic rosacea successfully treated with neuromodulators and intense pulsed light Erythrodermic psoriasis treatment with guselkumab: report of two cases and literature review Topical aluminum chloride as a treatment option for Hailey-Hailey disease: a remarkable therapeutic outcome case report MARCH/APRIL 2024 V. 99 N. 2| 165–326
Volume 99. Number 2. March/April 2024 CONTENTS Editorial Anais Brasileiros de Dermatologia: adjustments to publication standards for authors. Expansion of Editorial Boards. Considerations about bibliometric analyses ........................................................................................... 165 Silvio Alencar Marques, Ana Maria Roselino, Hiram Larangeira de Almeida Jr and Luciana P. Fernandes Abbade Continuing Medical Education Infections in the era of immunobiologicals ............................................................................................ 167 Ricardo Romiti, André Luís da Silva Hirayama, Adriana Maria Porro, Heitor de Sá Gonçalves, Luciane Donida Bartoli Miot, Sandra Maria Barbosa Durães and Silvio Alencar Marques Original Article Adiponectin serum levels and ADIPOQ (rs2241766) polymorphism in alopecia areata Egyptian patients .................... 181 Azza Gaber Antar Farag, Eman Abd-Elfatah Badr, Banan Mohamed Gamal Abd-Elaty, Nada Farag Elnaidany and Mai Medhat Mohamed Ghanem Associations of serum gamma-linolenic acid levels with erythema severity and anxiety/depression status in patients with rosacea ................................................................................................................................ 189 Jin-Yi Tang, Mei-Ling Chen, Mei Wan, Jin-Yu Wei, Tian Qian, Yu-Kun Fan, Zhi Yang, Jian Fu and Jian Li Clinical profi le of vitiligo patients and relationship with immuno-infl ammatory markers ...................................... 196 Marta Regina Machado Mascarenhas, Mariana de Castro Oliveira, Luise Fonseca de Oliveira, Andréa Santos Magalhães and Paulo Roberto Lima Machado Management of periocular keratinocyte carcinomas with Mohs micrographic surgery and predictors of complex reconstruction: a retrospective study .................................................................................................. 202 Dominga Peirano, Sebastián Vargas, Leonel Hidalgo, Francisca Donoso, Eugenia Abusleme, Felipe Sanhueza, Consuelo Cárdenas, Katherine Droppelmann, Juan Camilo Castro, Pablo Uribe, Pablo Zoroquiain and Cristian Navarrete-Dechent METTL3-mediated HPV vaccine enhances the effect of anti PD-1 immunotherapy to alleviate the development of cutaneous squamous cell carcinoma .................................................................................................... 210 Yingjie Zhang, Yiru Wang, Shuping Guo and Hongzhou Cui Quality of systematic reviews on the treatment of vesiculobullous skin diseases. A meta-epidemiological study ......... 223 Kamilla Mayr Martins Sá, Juliana Cavaleiro Rodrigues, Lígia Borges da Silva, Giovanna Marcılio Santos, Mileny Esbravatti Stephano Colovati and Ana Luiza Cabrera Martimbianco Talaromyces marneffei infection with IFNGR1 gene mutation in a patient with negative Anti-Interferon-γ autoantibodies .............................................................................................................................. 233 Shiyang Li, Xianwei Cao, Zhuxiu Guo, Jian Wang, Jianbo Tong and Zhibin Zhang The clinicopathologic and immunohistochemical features of 60 cutaneous glomus tumor: a retrospective case series study ......................................................................................................................................... 238 Yuehua Sun, Ruiqun Qi, Ze Wu, Xiaodong Zhang and Jun Niu
Unmet needs in the management of psoriasis in Latin America: a systematic review .......................................... 244 Bruna Ossanai Schoenardie, Rodrigo Oliveira Almeida, Thaísa Hanemann, Arthur Ossanai Schoenardie, André Lucas Ribeiro and Juliana Catucci Boza Review Side effects of chronic systemic glucocorticoid therapy: what dermatologists should know .................................. 259 Lucas Campos Prudente Tavares, Lívia de Vasconcelos Nasser Caetano and Mayra Ianhez Special Article Cumulative life course impairment in patients with dermatological diseases, with a focus on psoriasis .................... 269 Ricardo Romiti, Renata Ferreira Magalhães and Gleison Vieira Duarte Letter – Research ChatGPT: performance of artifi cial intelligence in the dermatology specialty certifi cate examination ..................... 277 Thaís Barros Felippe Jabour, José Paulo Ribeiro, Alexandre Chaves Fernandes, Cecília Mirelle Almeida Honorato and Maria do Carmo Araújo Palmeira Queiroz Tinea capitis: observations and clinical approach in a pediatric population of 99 cases ....................................... 279 Carolina Gonçalves Contin, Gustavo de Sá Menezes Carvalho, Guilherme Camargo Julio Valinoto, Silvia Assumpção Soutto Mayor and John Verrinder Veasey Letter – Clinical A case of atrophic dermatofi broma: a possible role of matrix metalloproteinase-2 ............................................ 284 Misaki Kusano and Toshiyuki Yamamoto Amelanotic malignant melanoma in a child ........................................................................................... 286 Anwei Chen and Faliang Ren An unusual case of extragenital primary syphilis ..................................................................................... 289 Miguel Santos-Coelho, Joana Alves Barbosa, Margarida Moura Valejo Coelho and Alexandre João Hypertrophic scar mimicking peristomal pyoderma gangrenosum ................................................................. 290 Takashi Ito and Toshiyuki Yamamoto Is Merkel cell carcinoma associated with high and chronic arsenic dose exposure? ............................................. 292 Irving Llibran Reyna-Rodríguez, Valeria F. Garza-Davila, Jorge Ocampo-Candiani and Sonia Chavez-Alvarez Multiple nodules covering the forearm: a case of fi sh-sting granuloma ........................................................... 294 Teng Chao Wei, Xian Mei Lu, Fang Fang Bao and Hong Liu Neurogenic rosacea successfully treated with neuromodulators and intense pulsed light ..................................... 296 Diana Isabel Conde Hurtado, Andrea Paola Céspedes Pérez and Ricardo Flaminio Rojas López Pediatric case of trichilemmal cyst arising on the face .............................................................................. 297 Mai Endo and Toshiyuki Yamamoto Rapidly involuting congenital haemangioma (RICH) associated with transient thrombocytopenia and coagulopathy ..... 299 Ana María Palma, Tamara Gracia-Cazaña, Carmen Ruiz de la Cuesta-Martín and Yolanda Gilaberte Solitary palmar adult xanthogranuloma ................................................................................................ 302 Laura Serra-García, Cristina Carrera, Priscila Giavedoni and Constanza Riquelme-Mc Loughlin Letter - Dermatopathology Bullous dermatomyositis with anti-NPX2 antibodies, associated with breast cancer ........................................... 305 Francisca Reculé, Juana Benedetto, Catalina Silva-Hirschberg, Raúl Cabrera and Alex Castro Eruptive disseminated spitz nevus: a case report and review of the genetic aspect of the disease .......................... 307 Emre Zekey and Sehe Darakcı
Letter - Tropical/Infectious and Parasitic Dermatology Erythema nodosum triggered by kerion celsi in pediatrics: literature review and case report ................................ 312 Astrid Herzum, Ehab Garibeh, Lodovica Gariazzo, Corrado Occella and Gianmaria Viglizzo Extensive micropustular Tinea capitis in an adult caused by Trichophyton verrucosum with evolution Kerion Celsi ...... 315 Hiram Larangeira de Almeida Jr., Luiz Roberto Kramer Costa and Augusto Scott da Rocha Letter – Therapy Erythrodermic psoriasis treatment with Guselkumab: report of two cases and literature review ............................ 319 Esperanza Welsh, Jesus Alberto Cardenas-de la Garza, José Alberto García-Lozano and Diana Paola Flores-Gutierrez Topical aluminum chloride as a treatment option for Hailey-Hailey disease: a remarkable therapeutic outcome case report ........................................................................................................................................ 321 Maraya de Jesus Semblano Bittencourt, Pedro Carneiro Marinho, Thereza Christina Frade, Gabriela Athayde Amin, Lorena Silva de Carvalho and Lívia Eloi Castro Santos Correspondence Oncological aspects related to non-surgical treatment of basal cell carcinoma. Comments on: chemotherapeutical treatment of basal cell carcinoma with bleomycin via microinfusion of the drug into the skin (MMP®) ..................... 324 Ivanka Miranda de Castro Martins, Ana Cláudia Cavalcante Espósito and Hélio Amante Miot Oncological aspects related to the non-surgical treatment of basal cell carcinoma – Response .............................. 325 Paulo Rodrigo Pacola
Anais Brasileiros de Dermatologia 2024;99(2):165- 166 Anais Brasileiros de Dermatologia www.anaisdedermatologia.org.br EDITORIAL Anais Brasileiros de Dermatologia: adjustments to publication standards for authors. Expansion of Editorial Boards. Considerations about bibliometric analyses Dear Associates, The Anais Brasileiros de Dermatologia (ABD) continues to update its standards for authors and promote changes in our continuing search for greater quality and visibility, both national and international, of the scientific articles we publish. Below are listed changes/additions to the standards for publication in the ABD. Authorship: we eliminated the limitation to the number of authors in Research Letters, always trusting the academic rigor practiced by the authors. References: DOI information is now mandatory for each reference when submitting an article, with no changes in the current reference system used and available on the journal websites. Editorial Boards: in recognition of the academic contributions and to ABD in particular, provided by associates Mirian Nacagami Sotto, Cacilda da Silva Souza, Adriana Maria Porro, Neusa Yuriko Sakai Valente, we have invited them to be part of the National Editorial Board. Similarly, for the International Editorial Board, we have invited Jeffrey B Travers (USA), Raul Cabrera (Chile) and Jorge OcampoCandiani (Mexico). We also highlight observations about the bibliometric analyses related to ABD. Recently published and available on the website, there are two educational and interesting articles regarding the main metrics used in the evaluation of scientific journals. These articles show data that sup- Study conducted at the Department of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Universidade Estadual Paulista, Botucatu, SP, Brazil. port an extremely important discussion of the future of ABD and Latin American scientific production.1,2 It is never too much to recall that we are the only journal in Dermatology in Latin America indexed in PubMed/Medline and we try to accomplish this responsibility by publishing good articles with special emphasis on articles focused on tropical endemic and neglected diseases.3- 5 To successfully fulfill this mission we need the support of the Brazilian Society of Dermatology and, moreover, the support and academic recognition of several Dermatology societies from the countries that constitute the Latin America. Thus, we call on associates and the scientific community in general to submit their articles to our journal, access our websites, publicize and support, whenever relevant, the Anais Brasileiros de Dermatologia. https://www.anaisdedermatologia.org.br/ https://www.sciencedirect.com/journal/anaisbrasileiros-de-dermatologia Financial support None declared. Authors’ contributions Silvio Alencar Marques: Approval of the final version of the manuscript; drafting and editing of the manuscript. Ana Maria Roselino: Approval of the final version of the manuscript; drafting and editing of the manuscript. Hiram Larangeira de Almeida Junior: Approval of the final version of the manuscript; drafting and editing of the manuscript. https://doi.org/10.1016/j.abd.2023.11.001 0365-0596/© 2023 Sociedade Brasileira de Dermatologia. Published by Elsevier Espan˜a, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
EDITORIAL Luciana P. Fernandes Abbade: Approval of the final version of the manuscript; preparation and writing of the manuscript. Conflicts of interest None declared. References 1. Marques SA, Roselino AMF, Almeida Jr HL, Abbade LPF. Anais Brasileiros de Dermatologia: metrics related to 2022 and position in the ranking of Dermatology journals. An Bras Dermatol. 2024;99:1- 2. 2. Miot HA, Criado PR, Castro CCS, Ianhez M, Talhari C, Müller-Ramos P. Bibliometric evaluation of Anais Brasileiros de Dermatologia (2013- 2022). An Bras Dermatol. 2024;99:90- 9. 3. Barbosa BEC, Lacerda PN, Campos LM, Marques MEA, Marques SA, Abbade LPF. Nontuberculous mycobacteriosis (Mycobacterium chelonae): fatal outcome in a patient with severe systemic lupus erythematosus. An Bras Dermatol. 2023;98: 875- 81. 4. Moraes PC, Eidt LM, Koehler A, Ransan LG, Scrofeneker ML. Epidemiological characteristics of leprosy from 2000 to 2019 in a state with low endemicity in southern Brazil. An Bras Dermatol. 2023;98:602- 10. 5. Matsumoto CT, Enokihara MMSS, Ogawa MM, Yarak S. Fourth case of tegumentary leishmaniasis in Brazil by Leishmania major - is it possible for new species to be introduced in Brazil through immigration? An Bras Dermatol. 2023;98:564- 70. Silvio Alencar Marques a,∗, Ana Maria Roselino b, Hiram Larangeira de Almeida Jr c,d, Luciana P. Fernandes Abbade a a Department of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Universidade Estadual Paulista, Botucatu, SP, Brazil b Division of Dermatolody, Department of Medical Clinics, Universidade de São Paulo, Ribeirão Preto, SP, Brazil c Department of Dermatology, Universidade Federal de Pelotas, Pelotas, RS, Brazil d Department of Dermatology, Universidade Católica de Pelotas, Pelotas, RS, Brazil ∗Corresponding author. E-mail address: silvio.marques@unesp.br (S.A. Marques). 8 November 2023 Available online 18 December 2023 166
Anais Brasileiros de Dermatologia 2024;99(2):167- 180 Anais Brasileiros de Dermatologia www.anaisdedermatologia.org.br CONTINUING MEDICAL EDUCATION Infections in the era of immunobiologicals Ricardo Romiti a, André Luís da Silva Hirayama a,∗, Adriana Maria Porro b, Heitor de Sá Gon¸calves c, Luciane Donida Bartoli Miot d, Sandra Maria Barbosa Durães e, Silvio Alencar Marques d a Department of Dermatology, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brazil b Department of Dermatology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil c State Health Secretariat of Ceará, Centro de Dermatologia Dona Libânia, Fortaleza, CE, Brazil d Department of Infectology, Dermatology, Imaging Diagnosis and Radiotherapy, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil e Department of Internal Medicine, Dermatology Unit, Faculty of Medicine, Universidade Federal Fluminense, Niterói, RJ, Brazil Received 5 April 2023; accepted 27 August 2023 Available online 17 January 2024 KEYWORDS Biological products; Hepatitis, viral, human; Leprosy; Mycosis fungoides; Tuberculosis; Vaccination; Psoriasis Abstract Immunobiologicals represent an innovative therapeutic option in dermatology. They are indicated in severe and refractory cases of different diseases when there is contraindication, intolerance, or failure of conventional systemic therapy and in cases with significant impairment of patient quality of life. The main immunobiologicals used in dermatology basically include inhibitors of tumor necrosis factor-alpha (anti-TNF), inhibitors of interleukin-12 and -23 (anti-IL12/23), inhibitors of interleukin-17 and its receptor (anti-IL17), inhibitors of interleukin-23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. Their immunomodulatory action may be associated with an increase in the risk of infections in the short and long term, and each case must be assessed individually, according to the risk inherent to the drug, the patient general condition, and the need for precautions. This article will discuss the main risks of infection associated with the use of immunobiologicals, addressing the risk in immunocompetent and immunosuppressed patients, vaccination, fungal infections, tuberculosis, leprosy, and viral hepatitis, and how to manage the patient in the most diverse scenarios. © 2023 Published by Elsevier Espan˜a, S.L.U. on behalf of Sociedade Brasileira de Dermatologia. This is an open access article under the CC BY license (http://creativecommons.org/licenses/ by/4.0/). Study conducted at the Department of Dermatology, Hospital das Clínicas da Universidade de São Paulo, São Paulo, SP, Brazil. ∗ Corresponding author. E-mail: xkrandre1979@yahoo.com.br (A.L. Hirayama). https://doi.org/10.1016/j.abd.2023.08.004 0365-0596/© 2023 Published by Elsevier Espan˜a, S.L.U. on behalf of Sociedade Brasileira de Dermatologia. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
R. Romiti, A.L. Hirayama, A.M. Porro et al. Introduction Immunobiologicals (IBs) represent an innovative and effective therapeutic option in medicine and, particularly, in dermatology. They characterize a group of drugs produced by living biological systems through modern biotechnology techniques. They are classified into three main groups: monoclonal antibodies, fusion proteins, and cytokines. They interact with specific human proteins involved in the inflammatory cascade of different immune-mediated diseases, such as psoriasis, atopic dermatitis (AD), hidradenitis suppurativa, urticaria, autoimmune bullous dermatoses and connective tissue diseases.1- 3 With high complexity and structural variability, IBs have a heterogeneous active component that is difficult to characterize and replicate. Due to their complex molecular structure and the large number of steps involved in their development, they characterize high-cost medications with restricted access.4 Indicated in severe and refractory cases of different diseases; when there is contraindication, intolerance, or failure of classical systemic therapy; in cases of patients with severe deterioration in the quality of life and/or physical or psychosocial disability, IBs basically include tumor necrosis factor-alpha inhibitors (anti-TNF), interleukin-12 and -23 inhibitors (anti-IL12/23), inhibitors of interleukin17 and its receptor (anti-IL17), inhibitors of interleukin 23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. For the treatment of psoriasis, which represents the dermatological disease with the highest number of IB approvals, the following can be highlighted, among the drugs with anti-TNF action: infliximab (chimeric monoclonal antibody), etanercept (fusion protein), adalimumab (humanized monoclonal antibody) and certolizumab pegol (pegylated anti-TNF); those with anti-IL12/23 action (ustekinumab), anti-IL23 action (guselkumab, risankizumab), anti-IL17 (secukinumab, ixekizumab, bimekizumab) and anti-IL17 receptor action (brodalumab). Spesolimab (antiIL36 receptor) was approved in 2023 for the treatment of exacerbations of generalized pustular psoriasis in adults.5- 8 IBs do not have specific toxicity for any organ or system; however, their immunomodulatory effect may be associated with the occurrence of short- and long-term adverse effects, such as severe opportunistic infections. Therefore, before introducing specific IB therapy, the therapeutic decision must be shared with the patient and a series of actions and precautions are essential. During treatment, caution must be constant, both on the part of the prescribing physician and the patient. Different specific situations, such as vaccination, surgery and pregnancy, may occur, and it is up to the specialist to discuss the most appropriate course of action with the patient, aiming to reduce the risk of undesirable complications.9 Next, the real risk of infections associated with IBs is discussed, both in immunocompetent and immunocompromised patients, the risk of fungal infections and leprosy when taking immunobiological therapy, the appropriate management of cases of co-infection with hepatitis B and C and the importance of adequate vaccination schemes. Risk of infection with different immunobiologicals used in dermatology In patients with immune-mediated diseases treated with IBs, the occurrence of infections may be due to the risk inherent to the underlying disease itself, the immunomodulatory effect of the recommended treatment, the association with immunosuppressive therapies and the presence of different comorbidities, such as obesity and diabetes mellitus. The high prevalence of skin infections in patients with AD has been well established. Changes in the skin barrier associated with a wide range of immunological changes increase susceptibility to different infections, especially caused by viruses such as herpes simplex, molluscum contagiosum and verruca vulgaris, and by S. aureus.10 In patients with psoriasis, there are high rates of hospital admission due to infections when compared to the general population, mainly related to the severity of psoriasis and not to the systemic treatments used.11 In the case of hidradenitis suppurativa, high rates of cutaneous and extracutaneous infections are observed, possibly resulting from the breakdown of the skin barrier and immune system dysregulation.12 The real risk of infection associated with the use of IBs has been evaluated in controlled and randomized studies, in population registries and in systematic reviews of the literature. The indication for psoriasis shows the greatest variety of therapeutic options and a long follow-up period, and the current consensus is that such IBs pose no risk or only minimal risk of infection when compared to classic systemic treatments.13 Pharmacovigilance registries developed long term evaluation, such as the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) in the United Kingdom, PsoBest in Germany and BIOBADADERM in Spain, have not, to date, shown any warning sign for risk of infections, especially when pretreatment screening and annual follow-up are carried out appropriately.1 On the other hand, Dobry et al., evaluating infection rates in 5,889 patients in the USA, identified an increased risk of severe infections in psoriasis cases using IBs when compared to patients treated with non-IBs (adjusted hazzard ratio [aHR]: 1.31; 95% confidence interval [CI]: 1.02- 1.68), specifically for skin and soft tissue infections (aHR = 1.75; 95%CI 1.19- 2.56).14 However, comments subsequent to this publication emphasized the low infection rates in both groups of reported patients (with and without immunobiological treatment) and the relevance of the risk of serious infections inherent to the severity of psoriasis itself, considering that patients with severe disease are more likely to receive treatment with immunobiological drugs.15 Real-life data evaluating the risk of severe infections in 11,560 new IB treatments in patients with psoriasis and psoriatic arthritis identified a reduced risk of serious infections in patients treated with anti-IL17 and anti-IL12/23, when 168
Anais Brasileiros de Dermatologia 2024;99(2):167- 180 compared to the use of anti-TNF in patients without previous exposure to IBs. In bio-experienced patients, there was no difference in the occurrence of serious infections between these three classes.16 In general, skin and respiratory infections are the most prevalent when using IBs. On the other hand, one must highlight that the occurrence of granulomatous infections, such as tuberculosis, and fungal infections, mainly by Candida, characterizes a special situation associated with the inherent mechanism of the anti-TNF and anti-IL17 classes, respectively.6 Regarding dupilumab, a human monoclonal antibody targeting the subunit of the IL4 and IL13 receptor and approved for the treatment of moderate to severe AD, the most commonly reported adverse effect is conjunctivitis. Systematic literature reviews and clinical practice metaanalyses show conjunctivitis rates of 26.1% in a total of 908 AD patients. Herpes simplex virus infections were identified in 5.8% of 546 AD cases.17 Rituximab features a chimeric anti-CD20 monoclonal antibody that depletes B lymphocytes that have the CD20 surface antigen. It is indicated for a wide variety of diseases, including neoplasms, rheumatological diseases and primary immunodeficiencies, and in some countries (including the United States and Europe), also for pemphigus vulgaris. Off-label indications in Brazilian dermatology clinical practice include pemphigus, systemic lupus erythematosus and angioedema.18,19 Among the adverse effects, rituximab is associated with the risk of hypogammaglobulinemia and infections. Although initial studies did not show a significant increase in the risk of infections, reports have shown rates of severe infections of up to 5.2 per 100 patientyears, compared to 3.7 per 100 patient-years in the placebo group, in addition to cases of prolonged and symptomatic hypogammaglobulinemia.20,21 Tuberculosis The probability of latent tuberculosis reactivation is greater in patients using anti-TNF. Since the introduction of latent tuberculosis investigation, tuberculosis reactivation rates have decreased dramatically. Therefore, a thorough history regarding current or past contact with tuberculosis is essential. Screening aimed at diagnosing individuals infected with M. tuberculosis should include tuberculin skin testing, which uses the standard purified protein derivative (PPD) preparation, and chest radiography (Fig. 1).22 Tests carried out in vitro for the detection of latent tuberculosis, based on the quantification of IFN- production, help with diagnosis, but still have a high cost.23 The first versions of these tests (Quantiferon-TB®, Cellestis Limited, Carnegie, Australia), approved by the Food and Drug Administration (FDA) in 2001, used PPD as a stimulating antigen, leading to the same specificity problems observed in skin tests.24 Quantiferon-TB-Gold® is an assay using ESAT-6 and CFP-10 as stimulatory antigens. This last assay uses whole blood and quantifies the presence of IFN- using the ELISA (enzymelinked immunosorbent assay) method. The T-SPOT TB® test (Oxford® Immunotec, Marlborough, USA) uses an ELISPOT (enzyme-linked-immunospot) assay using IFN-y-producing peripheral mononuclear cells in response to stimuli such as ESAT-6 and CFP-10.25,26 Use of immunobiologicals in immunocompromised patients The most important immunocompromised patient populations, in numbers, are patients with HIV (human immunodeficiency virus) and patients undergoing solid organ transplantation. Although both groups are immunocompromised, they have different types of immunosuppression. HIV infection leads to a progressive impairment of cell immunity, and patients who use ART (antiretroviral therapy) experience restoration of this immunity, with an increase in the serum count of CD4 + T lymphocytes and a decrease in the viral load, which may remain undetectable. When that occurs, patients tend to have longer survival rates and, as a result, can develop autoimmune diseases, inflammatory bowel disease (IBD), and even neoplasms, sometimes generating IB indications.27 Solid organ transplantation recipients, in turn, experience more important, complex, and irreversible immunosuppression, as long as the use of immunosuppressive medications persists, which prevents the risk of rejection of the transplanted organ.28 It is important to highlight that these two populations are usually excluded from IB clinical studies. Therefore, what is known in this regard is extracted from case reports and series, and few review studies. HIV infection and immunobiologicals HIV infection can trigger and worsen psoriasis, and this probability increases in patients with greater immunosuppression, who have a low count of CD4 + T lymphocytes. Patients with CD4 counts <200 cells/mm3 are at increased risk for severe psoriasis.29 In a systematic review published in 2019, the authors reviewed cases of psoriasis in special populations, who received treatment with IB between 1989 and 2018. A decrease in CD4 was not observed in patients with HIV infection who received anti-TNF IBs (etanercept, infliximab or adalimumab), nor an increase in the number of opportunistic infections (OIs). The only anti-IL included in this review was ustekinumab (anti-IL12/23), which shows good efficacy and safety profile in this group, including improvement in CD4 count and viral load in some patients.30 A multicenter retrospective study assessed 23 patients with HIV infection (five with AIDS) who had moderate to severe psoriasis and used IBs (etanercept, infliximab or ustekinumab) between 2008 and 2016. The mean follow-up was three years: 76% achieved PASI 75, and CD4 was stable or even increased in some patients. One patient who received infliximab developed miliary tuberculosis. The authors concluded that these IBs were effective and had an acceptable safety profile in this population.31 In an Italian series of ten patients with HIV infection and psoriasis, published in 2017, six received anti-TNF (four etanercept and two adalimumab), and four received ustekinumab. All achieved PASI 75 within three months. The mean 169
R. Romiti, A.L. Hirayama, A.M. Porro et al. Figure 1 Flowchart of the investigation of latent tuberculosis (TB) in patients candidates for the use of immunobiologicals. follow-up was 35 months, and none of the patients experienced OIs during this period.32 A report of two patients with HIV and erythrodermic psoriasis who received anti-IL17 (one secukinumab and the other ixekizumab) showed they had rapid control of the erythroderma, without infectious complications.33 There are also reports of the use of anti-IL23 to treat psoriasis in patients with HIV infection, demonstrating its efficacy and safety.34 A recently published systematic review on the use of dupilumab in patients with HIV infection assessed 27 cases (23 published and four from the authors personal experience). Of these, 96% showed improvement in asthma or AD, without changes in the viral load in 100% of them and no changes in CD4 in 80%. The authors concluded this medication is safe if used in patients with stable CD4 counts and a low viral load.35 Solid organ transplantation and immunobiologicals A systematic review published in 2021 evaluated the safety of using IBs in solid organ transplantation recipients. A total of 111 articles were reviewed, 57 of which were case series, with a total of 187 patients. Of these, 141 had received liver transplants, 42 kidney transplants, three heart transplants, and one kidney-liver transplant. Regarding the immunosuppressive medications used by these patients, the most frequently used were calcineurin inhibitors, followed by corticosteroids, sodium mycophenolate and, finally, mTOR inhibitors. Regarding the IB indication, 81% of patients had IBD, 7.5% had rheumatological indications, 6% had hereditary periodic fever and psoriasis was present in 5%. The most frequently used IB class was anti-TNF (78% of patients). It was found that 29% of the patients had infections, most frequently bacterial and viral infections by cytomegalovirus and herpes simplex. Neoplasms occurred in 9% of the patients, mainly colorectal tumors and non-melanoma skin cancer. There were nine deaths among the 187 patients, but the authors conclude that it is difficult to establish a direct relationship between the use of IBs and death, due to the large number of variables involved.28 Regarding anti-TNF, several articles mention an increased risk of non-melanoma skin cancer and severe infections, also as a cause of death, in solid organ recipients.36,37 As for anti-IL, the number of publications is small, especially because they are IBs with more recent use. There are published reports on the use of anti-IL12/23 (ustekinumab) for psoriasis and IBD with good response to treatment and no complications.38,39 Regarding anti-IL17, there are two reports of patients with psoriasis who received ixekizumab, with good psoriasis control and without complications.40 The psoriasis treatment guideline of the American Academy of Dermatology mentions that IBs (anti-TNF, antiIL12/23, anti-IL17 and anti-IL23) can be used in patients with HIV infection, provided they are receiving ART, have normal CD4, undetectable viral load and do not have recent OIs. There is no mention of the use of IBs in solid organ transplantation recipients.41 The Brazilian Consensus on Psoriasis 2020 also suggests that IBs can be used in patients with HIV infection, assessed on a case-by-case basis, and that they would possibly be safer for these patients than immunosuppressants such as methotrexate and cyclosporine. There is no mention of their use in transplanted patients in this Consensus, either.6 In conclusion, regarding the use of IBs in immunocompromised patients, studies suggest that, in patients with HIV infection, among the IBs, anti-IL can be preferably used only in those receiving regular ART therapy, with undetectable viral load, normal CD4 count, and no recent infections. IB use 170
Anais Brasileiros de Dermatologia 2024;99(2):167- 180 should be avoided in solid organ transplant recipients, but when absolutely necessary, anti-ILs seem to be safer than anti-TNFs. Fungal infections and immunobiological therapy The real risk of fungal infections secondary to IB use is difficult to determine due to the inherent predisposition to fungal infections in patients with autoimmune diseases, the concomitant use of immunosuppressants and the geographic endemicity of some mycoses.42 Anti-TNF As early as in the first decade of their use, some reviews drew attention to the association of fungal infections with anti-TNF drugs,43,44, and in 2008 the FDA warned about the increased risk of invasive fungal infections after 240 cases of histoplasmosis.45 Two decades later, there is some evidence of OIs occurring with the use of these drugs.42,43 Anti-TNF drugs have been associated with a small but significant increase in the risk of severe infections. Adalimumab and infliximab are associated with a higher risk of OIs, including fungal infections such as histoplasmosis, coccidioidomycosis, candidiasis, and aspergillosis, than etanercept.46 However, after a larger number of patients have been treated over time, it can be considered that fungal infections are infrequent. In a study of more than 30,000 patients treated with anti-TNF during 2007- 2009, 158 patients (0.51%) developed mycoses or mycobacterioses; about half of these infections were fungal, including histoplasmosis, pneumocystosis, cryptococcosis, coccidioidomycosis, and blastomycosis.47 Regarding the new anti-TNFs, a recent study found that the risk of severe infection with certolizumab was not significantly higher than with other anti-TNFs.48 The safety of golimumab was verified in a recent large series in which infections were the most common adverse effect; however, no fungal infections were observed.49 Anti-IL Psoriatic patients using ustekinumab had a lower frequency of severe infections than those observed during treatment with infliximab and other IBs. A long-term safety assessment included 1,482 patients with at least four years of exposure to ustekinumab and no fungal infections were reported.50 Primary immunodeficiencies that result from mutations in the genes encoding IL17 increase susceptibility to Candida infections. As expected, in patients who received anti-IL17 (brodalumab, secukinumab and ixekizumab) there was an increased incidence of candidiasis. However, most of the time the therapeutic response was good, without the need to withdraw the anti-IL17 treatment.51 Fig. 2 depicts a case of oral candidiasis while using anti-IL17. The risk of systemic fungal infections with anti-IL23 treatment in patients with psoriasis was investigated in 16 randomized controlled trials. No cases of severe funFigure 2 Oral candidiasis with the use of anti-IL17. gal infections were observed in patients treated with risankizumab, guselkumab, and tildrakizumab.52 A meta-analysis including eight controlled trials showed that patients treated with dupilumab had a lower risk of skin infection and a non-significant increase in herpes infections. The normalization of the skin barrier, microbiome, and treatment of the aberrant immune response in AD are possible explanations.53 Rituximab The risk of invasive fungal infections following treatment with anti-CD20 monoclonal antibodies seems to be low and pneumocystosis could be an exception, as some studies have suggested a possible increased risk.54 However, current evidence supports that anti-pneumocystis prophylaxis should be considered only in those also receiving other concomitant immunosuppressive drugs.55 Autoimmune diseases already carry an inherent risk of infections and therefore it is important to assess the specific risk of infection from immunosuppressive medications in each disease. Despite some variability, in systemic immunemediated diseases, there is a greater probability of using multiple immunosuppressants and in higher doses, differently from what occurs in dermatological patients. The concomitant use of other immunosuppressants is a wellestablished factor in increasing the risk of fungal infections in patients taking anti-TNF drugs.56 A review of 19 studies to evaluate the incidence of fungal infections in patients taking IBs for psoriasis included 4,547 patients taking etanercept, infliximab, adalimumab, or ustekinumab. There was one case of coccidioidomycosis in a patient using adalimumab, and no severe fungal infections were reported.57 A recent retrospective study verified the benefit of prophylaxis with co-trimoxazole for the risk of Pneumocystis 171
R. Romiti, A.L. Hirayama, A.M. Porro et al. pneumonia (PCP) in patients with pemphigus using rituximab. The medical records of 494 patients were reviewed, of which 235 received co-trimoxazole, whereas 259 did not. The incidence of PCP was low, with no significant difference between the groups (p = 0.84). The authors concluded that there is no consensus on the need for prophylaxis due to the low incidence of PCP complications in these patients, and it is not mandatory to treat all pemphigus patients with rituximab.58 Endemic fungal infections in Brazil Paracoccidioidomycosis (PCM) is a systemic mycosis caused by Paracoccidioides brasiliensis and Paracoccidioides lutzii, endemic and limited to Latin America, from Mexico to Argentina. Although uncommon, PCM has been reported in patients with immunosuppression, with the majority of these cases occurring in patients with HIV. Only three cases of IB-related PCM have been reported.59- 61 In these patients, the infection appeared more than a year after the introduction of the medication. In recent decades, sporotrichosis has emerged as an endemic mycosis associated with feline transmission in southern and southeastern Brazil. As with PCM, disseminated sporotrichosis has been described in patients with AIDS, and there are few reports of the disease in patients with other immunosuppressive conditions and few with biological therapy.62 As the use of IBs is increasing, these cases, although rare, demonstrate the importance of including PCM and sporotrichosis in the OI list in patients from endemic areas on long-term immunotherapy.63 Leprosy and immunobiologicals In 2004, data from the FDA Adverse Event Reporting System (FAERS) were analyzed to verify the incidence of granulomatous infections during anti-TNF use. Up to that date, 346,000 patients had been treated with infliximab and etanercept, and 639 infectious adverse events had occurred. In the infliximab group, there was only one case of leprosy, but no additional information was provided about the patient.43 A Brazilian multicenter study assessed data from 1,037 patients (750 treated with IBs and 287 controls). Infections occurred in 23% of patients using IBs, most of them in the upper airways, three cases of tuberculosis and only one case of tuberculoid leprosy.64 In 2020, a systematic review analyzed the incidence of leprosy in patients using anti-TNF. In the end, ten patients developed leprosy in Brazil (n = 6), the United States (n = 2), Greece (n = 1) and Spain (n = 1). Leprosy is endemic in Brazil and India and the latter reports the highest number of leprosy cases globally, with 114,451 cases in 2019; thus, the authors state that patients from India should be on this list. They considered that financial difficulties and lack of availability could reduce the use of IB products in endemic countries and explain the absence of leprosy cases in India.65 A recent cohort study evaluated the risk of leprosy in patients using IBs and conventional immunosuppressants for dermatological and rheumatological diseases. A total of 405 patients were included (268 immunosuppressed) from 2014 to 2019. Ten cases of leprosy were diagnosed (nine in immunosuppressed patients). Corticosteroid use has been associated with an increased risk of leprosy, and anti-TNF use has been associated with a lower risk of leprosy when compared to corticosteroids.66 Treatment of leprosy reactions with immunobiologicals Leprosy reactions are acute immunoinflammatory events that occur in some patients in response to Mycobacterium leprae antigens. They are often accompanied by neuritis and increase the chance of disability. The small number of published cases, nine in total, indicates that anti-TNF drugs may be useful in treating individuals with chronic refractory reactions or those unable to tolerate standard therapies due to adverse effects. Since even chronic reactional states tend to progress with decreasing severity and frequency over time, randomized clinical trials are needed to establish the role of anti-TNF drugs in the treatment of severe reactions.65,67 Hepatites and immunobiologicals The exact risk of hepatitis B and C reactivation in patients undergoing biological therapy is not defined due to the fact that these patients cannot participate in pivotal studies of the medications, due to exclusion criteria. It is estimated that hepatitis B may affect more than 370 million people worldwide. The prevalence of hepatitis B in psoriasis in the United States is 0.5% and of hepatitis C is 1.3%, and there is no prevalence data available in Brazil to date in this population.6,68,69 In patients with pemphigus, studies estimate that the prevalence of hepatitis B is 0.6%- 1.2%.70,71 All patients must undergo serology tests for hepatitis B and hepatitis C before starting immunobiological therapy. Hepatitis B It is recommended that before starting immunobiological therapy, all patients undergo serology for hepatitis B, including Anti-HBc (antibody against the core of the hepatitis B virus), AgHBs (surface antigen of the hepatitis B virus) and Anti-HBs (antibody against the surface antigen of the hepatitis B virus). Table 1 shows possible serological profiles and their interpretations.69- 71 All susceptible patients should be vaccinated against hepatitis B, whenever possible, before starting immunobiological treatment. All patients with a history of hepatitis B must have their viral DNA measured before starting IB treatment; therefore, AgHbs-positive patients must have their viral DNA tested. The test should also be considered in the case of negative AgHBs with positive anti-HBc, in an attempt to detect occult hepatitis B.6,72- 75 The risk of hepatitis B reactivation seems to be higher in patients with chronic hepatitis B infection and lower in patients with previous infection or occult hepatitis.6,72,73 172
Anais Brasileiros de Dermatologia 2024;99(2):167- 180 Table 1 Interpretation of hepatitis B serological profiles. Profile 1 Anti-HBs Negative Susceptible Anti-HBc Negative AgHBs Negative Profile 2 Anti-HBs Positive Previous exposure Anti-HBc Positive AgHBs Negative Profile 3 Anti-HBs Positive Immunized by the vaccine Anti-HBc Negative AgHBs Negative Profile 4 Anti-HBs Negative Acute infection Anti-HBc Positive Anti-HBc IgM Positive AgHBs Positive Profile 5 Anti-HBs Negative Chronic infection Anti-HBc Positive Anti-HBc IgM Negative AgHBs Positive Profile 6 Anti-HBs Negative 4 possible scenariosa Anti HBc Positive AgHBs Negative Adapted source: Lok ASF, Bounis PAL. 2023.75 a Possible scenarios: 1) Patient recovering from acute hepatitis B; 2) Patient may have a previous infection and the test might not be sensitive enough to detect very low levels of anti-HBs; 3) False positive for anti-HBc; 4) Possible undetectable level of HBsAg, and patient is chronically infected - possible occult hepatitis B (anti-HBs can be positive in these cases too). Use of chemoprophylaxis The use of chemoprophylaxis is recommended for patients with chronic hepatitis B and should be considered in patients with previous infections and occult hepatitis B who are undergoing immunosuppression. Some authors consider that prophylaxis should only be used in patients with cancer undergoing chemotherapy and solid organ transplant patients.76,77 It must be started before treatment and continued for six to 18 months after its end. The drugs of choice are tenofovir and entecavir.78 Fig. 3 summarizes the conduct in cases of IB use and hepatitis B. Hepatitis B and the use of IBs The use of TNF-alpha antagonists seems to be associated with higher rates of hepatitis B reactivation when compared to ustekinumab and secukinumab.72,73 There are studies, however, that place ustekinumab at a moderate risk for hepatitis B reactivation, which may be associated with IL12 blockade, which would play an important role in controlling viral replication.78,79 Some authors suggest that, in patients with psoriasis and chronic or previous hepatitis B infection, the first choice should be the use of anti-IL17, followed by anti-IL23; however, the evidence to support this recommendation is scarce and more studies are needed to support it.72 Hepatitis B and dupilumab The safety of dupilumab in patients with hepatitis B is uncertain. Pivotal dupilumab studies excluded patients with hepatitis B.80 Case reports suggest there is no increased risk of hepatitis B reactivation with the use of dupilumab.81 Despite little evidence regarding patients with chronic or previous hepatitis B infection, some authors suggest that in cases of severe AD in which the use of systemic therapy is indicated, dupilumab should be the drug of choice, before other immunosuppressants.82 Hepatitis B and rituximab Data on hepatitis B reactivation in patients with pemphigus using rituximab are scarce. Studies suggest that the risk of hepatitis B reactivation in these patients is not as high as in patients with hematological malignancies or solid organ transplant recipients using rituximab. The use of rituximab in the treatment of patients with pemphigus seems to be safer than the use of high doses of corticosteroids, causing lower rates of hepatitis B reactivation.71 In these cases, it is suggested that antiviral prophylaxis be started before the use of IBs and maintained during treatment for up to 18 months after its end, with monitoring of viral DNA and transaminases.71 Hepatitis C and the use of IBs Regarding hepatitis C and psoriasis, the use of IBs is contraindicated during acute hepatitis.69,83- 86 173
R. Romiti, A.L. Hirayama, A.M. Porro et al. Figure 3 Conduct in cases of immunobiological use and hepatitis B. Adapted source: Romiti R, et al. 2020.6 The risk of hepatitis C reactivation in patients with chronic hepatitis C and low levels of viral RNA seems to be very low.69,83- 86 IBs can be used with caution, under the supervision of a specialist. Measurements of transaminases and viral RNA must be performed quarterly. Previous studies have even demonstrated that the use of anti-TNF led to reductions in the patients viral load. Anti-IL17 drugs seem to have a favorable safety profile in this population. The safety of anti-IL23 drugs in patients with psoriasis and chronic hepatitis C remains uncertain.69,83- 86 To date, there is no clear evidence that the use of rituximab worsens the course of hepatitis C in patients with pemphigus. The risk-benefit of using the medication must be discussed with the specialist (gastroenterologist; hepatologist; infectious disease specialist) and compared to other available therapies to provide the best option for each case.87 There is scarce data in the literature on the use of dupilumab in patients with hepatitis C, and the safety profile remains uncertain. However, some authors recommend the use of dupilumab as the first-choice therapy in patients with severe AD who require the use of immunosuppressants to control the disease.82 Vaccination: how to proceed in patients undergoing immunobiological therapy The risk of infections is greater in patients with chronic immune-mediated diseases, such as psoriasis, AD and pemphigus vulgaris. Moreover, there is a higher rate of certain types of infections in patients on IB therapy, particularly respiratory infections, followed by herpes zoster.88,89 The greater occurrence of herpes zoster in the elderly and immunocompromised individuals generates significant morbidity, which can result in pain, depression, post-herpetic neuralgia, encephalitis, an ophthalmological disease with loss of vision and neurological manifestations such as Ramsay-Hunt syndrome. In immunocompromised patients, ophthalmological involvement occurs in up to 25% of patients and post-herpetic neuralgia in up to 30% of them.90 Reactivation of hepatitis B with IB treatments is low. Therefore, vaccination is one of the preventive measures with the greatest impact on reducing the occurrence of hepatitis, its complications and sequelae in any age group.6 Due to greater susceptibility to infections, it is suggested that updating the vaccination record of patients who have indications for IB therapy be implemented, aiming 174
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