João Vilaça ¹, Orhan Yilmaz ², Tiago Torres ^1 3

Pharmaceutics. . 2024 Jul 6;16(7):908. doi: 10.3390/pharmaceutics16070908.

Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients’ quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional treatments, such as retinoids, methotrexate, and even biologics, which although effective in some cases, may be associated with significant side effects, necessitating more effective and safe options. The pathophysiology of Generalized Pustular Psoriasis is complex and not fully understood, but there is some overlap with the pathogenesis of Plaque Psoriasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and imsidolimab, two recently developed therapeutic agents, target the IL-36 inflammatory pathway by binding to the IL-36 receptor (IL-36R). Both biologics have already been evaluated in phase 1 and 2 clinical trials and have shown promising results in terms of safety and efficacy. IL-36 receptor inhibitors demonstrated great efficacy and good safety profile in the management of patients with GPP, demonstrating their potential to emerge as a leading treatment option. This review aims to explore and summarize the current scientific literature on the most recently developed treatments for GPP.

Xiping Liao ^# 1 2, Ji Liu ^# 3, Xiaolong Guo ¹, Ruiping Meng ¹, Wei Zhang ¹, Jianyun Zhou ¹, Xia Xie ^1 2, Hongli Zhou ¹

J Inflamm Res. 2024 May 13:17:2897-2914. doi: 10.2147/JIR.S450801. eCollection 2024.

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic disease resulting from the interaction of various factors such as social elements, autoimmunity, genetics, and gut microbiota. Alarmingly, recent epidemiological data points to a surging incidence of IBD, underscoring an urgent imperative: to delineate the intricate mechanisms driving its onset. Such insights are paramount, not only for enhancing our comprehension of IBD pathogenesis but also for refining diagnostic and therapeutic paradigms. Monocytes, significant immune cells derived from the bone marrow, serve as precursors to macrophages (Mφs) and dendritic cells (DCs) in the inflammatory response of IBD. Within the IBD milieu, their role is twofold. On the one hand, monocytes are instrumental in precipitating the disease’s progression. On the other hand, their differentiated offsprings, namely moMφs and moDCs, are conspicuously mobilized at inflammatory foci, manifesting either pro-inflammatory or anti-inflammatory actions. The phenotypic spectrum of these effector cells, intriguingly, is modulated by variables such as host genetics and the subtleties of the prevailing inflammatory microenvironment. Notwithstanding their significance, a palpable dearth exists in the literature concerning the roles and mechanisms of monocytes in IBD pathogenesis. This review endeavors to bridge this knowledge gap. It offers an exhaustive exploration of monocytes’ origin, their developmental trajectory, and their differentiation dynamics during IBD. Furthermore, it delves into the functional ramifications of monocytes and their differentiated progenies throughout IBD’s course. Through this lens, we aspire to furnish novel perspectives into IBD’s etiology and potential therapeutic strategies.

Dimitrii Pogorelov ¹, Anne Tschesche ¹, Galina Balakirski ¹, Silke C Hofmann ¹

Cureus. 2024 May 7;16(5):e59832. doi: 10.7759/cureus.59832. eCollection 2024 May.

Generalized pustular psoriasis of pregnancy (GPPP) is a rare dermatological condition that significantly affects maternal health and pregnancy outcomes. The treatment of this disease might be very challenging, as only a limited number of effective therapeutic options are available. If the use of systemic drugs is considered, they should ideally effectively control the systemic inflammation without harming the fetus. Here, we report the successful treatment of a severe case of GPPP in a 28-year-old woman using the tumor necrosis factor-alpha inhibitor (TNFi) certolizumab pegol. Additionally, we review the existing literature on the use of this class of drugs for treating GPPP. To date, there are only 11 reported cases of this severe skin condition treated with a TNFi. We also discuss the pathogenesis of GPPP and the rationale behind using TNFi for its treatment.

Ken Okamura 1, Mariko Nikaido 1, Toru Saito 1, Yosuke Arai 1, Chiharu Yoshioka 1, Makoto Yagi 2, Hitomi Komoriya 3, Nana Takahashi 3, Yutaka Hozumi 1, Tamio Suzuki J Dermatol . 2024 Mar 20. doi: 10.1111/1346-8138.17198.

Mingdan Zhao, Fujun Huang, Lei Tang, Xun Zhou,Miao Zhang, Mengxue Liao,Lirong Liu,Mengya Huang, Front. Immunol. 2024, 15,doi.org=10.3389/fimmu.2024.1354578

Acute generalized pustular psoriasis (GPP) is a serious illness. Despite various treatment methods, there is still lack of effective treatment plans for refractory cases with multiple comorbidities. This case report presents a 67-year-old woman with acute GPP, stage 4 chronic kidney disease (CKD), type 2 diabetes, and cardiovascular disease, in whom skin symptom disappearance and kidney function improvement were observed after the use of oral tacrolimus as the sole therapy. This is the first report on the application of tacrolimus in the treatment of acute GPP, especially refractory acute GPP. The successful treatment indicates that there are shared immune pathways between acute GPP and CKD, and the pathways can be interdicted by tacrolimus. Further studies are needed to optimize the therapy to maximize efficacy and minimize toxicity.

Payal M Patel 1, Stephanie N Sanchez-Melendez 2 3, Vinod E Nambudiri Exp Dermatol. 2023 Aug;32(8):1227-1234. doi: 10.1111/exd.14787

Generalized pustular psoriasis (GPP) is a clinical entity distinct from psoriasis, associated with a poor clinical prognosis, often resulting in severe systemic complications and mortality. The relapsing nature of the disease with recurrent or intermittent flares imposes a significant burden on patients’ quality of life (QoL). Although inadequately studied, QoL data in GPP patients has been a recent point of investigation. We conducted a literature search on PubMed/MEDLINE using the following search terms: ‘generalized pustular psoriasis’ OR ‘pustular psoriasis’ AND ‘quality of life’. We identified 12 relevant articles that provide insight into the large impact of GPP on the QoL of patients, the burden of the disease and the treatment, and the success of new treatment options in making a clinically important difference to QoL. This review illustrates a need for routine assessment of the QoL in interventional clinical trials for GPP and during physician encounters. This information can help guide clinicians on how to tailor the treatment approach from the patient’s perspective or illustrate whether new therapies offer meaningful benefits to patient care as we enter an era of exciting new treatments for this challenging condition.

Yaroslav Ugolkov, Antonina Nikitich, Cristina Leon,Gabriel Helmlinger, Kirill Peskov, Victor Sokolov, Alina Volkova, Front. Immunol. 2024, 15:1371620.doi: 10.3389/fimmu.2024.1371620

The research & development (R&D) of novel therapeutic agents for the treatment of autoimmune diseases is challenged by highly complex pathogenesis and multiple etiologies of these conditions. The number of targeted therapies available on the market is limited, whereas the prevalence of autoimmune conditions in the global population continues to rise. Mathematical modeling of biological systems is an essential tool which may be applied in support of decision-making across R&D drug programs to improve the probability of success in the development of novel medicines. Over the past decades, multiple models of autoimmune diseases have been developed. Models differ in the spectra of quantitative data used in their development and mathematical methods, as well as in the level of “mechanistic granularity” chosen to describe the underlying biology. Yet, all models strive towards the same goal: to quantitatively describe various aspects of the immune response. The aim of this review was to conduct a systematic review and analysis of mathematical models of autoimmune diseases focused on the mechanistic description of the immune system, to consolidate existing quantitative knowledge on autoimmune processes, and to outline potential directions of interest for future model-based analyses. Following a systematic literature review, 38 models describing the onset, progression, and/or the effect of treatment in 13 systemic and organ-specific autoimmune conditions were identified, most models developed for inflammatory bowel disease, multiple sclerosis, and lupus (5 models each). ≥70% of the models were developed as nonlinear systems of ordinary differential equations, others – as partial differential equations, integro-differential equations, Boolean networks, or probabilistic models. Despite covering a relatively wide range of diseases, most models described the same components of the immune system, such as T-cell response, cytokine influence, or the involvement of macrophages in autoimmune processes. All models were thoroughly analyzed with an emphasis on assumptions, limitations, and their potential applications in the development of novel medicines.

Mariko Seishima 1, Hideki Hachiken 1, Takuma Furukawa 1, Junichiro Yamamoto, Ther Apher Dial. 2024 Mar 12. doi: 10.1111/1744-9987.14118

Introduction: Granulocyte and monocyte adsorption apheresis (GMA) is usually performed weekly for refractory skin diseases, such as generalized pustular psoriasis and psoriatic arthritis (PsA).

Methods: Four patients with PsA who were refractory to previous treatments were enrolled. They received five or ten sessions of GMA. We assessed the clinical conditions of each patient and laboratory findings before and after GMA.

Results: GMA was effective in plaque-type skin eruptions in all four patients with PsA. It was also effective in joint symptoms in three patients with PsA with mild symptoms, but was ineffective in one patient with severe joint symptoms.

Conclusion: GMA may be recommended to PsA patients with skin eruptions and mild joint symptoms.

Mariko Seishima 1, Hideki Hachiken 1, Takuma Furukawa 1, Junichiro Yamamoto 2
Ther Apher Dial. 2024 Mar 12. doi: 10.1111/1744-9987.14118. Online ahead of print.

Introduction: Granulocyte and monocyte adsorption apheresis (GMA) is usually performed weekly for refractory skin diseases, such as generalized pustular psoriasis and psoriatic arthritis (PsA).

Methods: Four patients with PsA who were refractory to previous treatments were enrolled. They received five or ten sessions of GMA. We assessed the clinical conditions of each patient and laboratory findings before and after GMA.

Results: GMA was effective in plaque-type skin eruptions in all four patients with PsA. It was also effective in joint symptoms in three patients with PsA with mild symptoms, but was ineffective in one patient with severe joint symptoms.

Conclusion: GMA may be recommended to PsA patients with skin eruptions and mild joint symptoms.

Hiromu Morikubo, Ryuta Tojima, Tsubasa Maeda, Katsuyoshi Matsuoka, Minoru Matsuura, Jun Miyoshi, Satoshi Tamura & Tadakazu Hisamatsu Sci Rep 14, 4386 (2024). doi.org=10.1038/s41598-024-55126-1

Predicting the therapeutic response to biologics before administration is a key clinical challenge in ulcerative colitis (UC). We previously reported a model for predicting the efficacy of vedolizumab (VDZ) for UC using a machine-learning approach. Ustekinumab (UST) is now available for treating UC, but no model for predicting its efficacy has been developed. When applied to patients with UC treated with UST, our VDZ prediction model showed positive predictive value (PPV) of 56.3% and negative predictive value (NPV) of 62.5%. Given this limited predictive ability, we aimed to develop a UST-specific prediction model with clinical features at baseline including background factors, clinical and endoscopic activity, and blood test results, as we did for the VDZ prediction model. The top 10 features (Alb, monocytes, height, MCV, TP, Lichtiger index, white blood cell count, MCHC, partial Mayo score, and CRP) associated with steroid-free clinical remission at 6 months after starting UST were selected using random forest. The predictive ability of a model using these predictors was evaluated by fivefold cross-validation. Validation of the prediction model with an external cohort showed PPV of 68.8% and NPV of 71.4%. Our study suggested the importance of establishing a drug-specific prediction model.