Ludovica Franceschin ¹, Alessia Guidotti ¹, Roberto Mazzetto ¹, Jacopo Tartaglia ¹, Christian Ciolfi ¹, Mauro Alaibac ¹, Alvise Sernicola ¹

Biomolecules. 2024 Nov 27;14(12):1515. doi: 10.3390/biom14121515.

Neutrophil-mediated inflammation is a key feature of immune-mediated chronic skin disorders, but the mechanistic understanding of neutrophil involvement in these conditions remains incomplete. Dapsone, colchicine, and tetracyclines are established drugs within the dermatologist’s therapeutic armamentarium that are credited with potent anti-neutrophilic effects. Anti-neutrophilic drugs have established themselves as versatile agents in the treatment of a wide range of dermatological conditions. Some of these agents are approved for the management of specific dermatologic conditions, but most of their current uses are off-label and only supported by isolated reports or case series. Their anti-inflammatory and immunomodulatory properties make them particularly valuable in managing auto-immune bullous diseases, neutrophilic dermatoses, eosinophilic dermatoses, interface dermatitis, and granulomatous diseases that are the focus of this review. By inhibiting inflammatory pathways, reducing cytokine production, and modulating immune responses, they contribute significantly to the treatment and management of these complex skin conditions. Their use continues to evolve as our understanding of these diseases deepens, and they remain a cornerstone of dermatological therapy.

GMA is a promising alternative in patients who have failed conventional therapies for generalized pustular psoriasis, pyoderma gangrenosum, Behçet’s disease, and hidradenitis suppurativa. The strengths of GMA lie in its favorable tolerability and peculiar mode of action that is able to deplete inflammation without causing immunodeficiency.

Yujin Nishioka ¹, Goh Murayama ¹, Makio Kusaoi ¹, Daichi Takemasa ², Kenta Kaneda ², Taiga Kuga ¹, Yukitomo Hagiwara ¹, Takumi Saito ¹, Yu Yamaji ¹, Yoshifumi Suzuki ³, Tetsutaro Nagaoka ³, Ken Yamaji ¹, Naoto Tamura ¹

Ther Apher Dial. 2024 Nov 20. doi: 10.1111/1744-9987.14234. Online ahead of print.

Introduction: Granulocyte/monocyte adsorption therapy can manage mild-to-moderate inflammatory bowel disease by removing activated granulocytes and monocytes. We evaluated granulocyte/monocyte adsorption using new columns with reduced bead size and theoretically enhanced adsorption.

Methods: We assessed granulocyte/monocyte adsorption in rats with colitis by analyzing cell changes and cytokine production.

Results: Granulocyte/monocyte adsorption with the new columns improved histology in rats with colitis. Contrary to expectations, the adsorption rate of granulocytes/monocytes into the blood did not show a significant improvement. However, flow cytometry showed increased B cells in peripheral blood mononuclear cells and newly formed B cells in the bone marrow, which produced more interleukin-10 than peripheral blood B cells. Newly formed B cells adoptively transferred into colitis rats accumulated at the inflammation site and tended to inhibit intestinal shortening.

Conclusions: Newly formed B cells with strong interleukin-10 production may alleviate inflammation. The new columns suggest potential for controlling colitis.

Francisco José Fernández-Pérez ¹, Nuria Fernández-Moreno ², Estela Soria-López ², Francisco Javier Rodriguez-González ², Francisco José Fernández-Galeote ³, Ana Lifante-Oliva ⁴, Concepción Ruíz-Hernández ⁴, Elisabeth Escalante-Quijaite ⁴, Francisco Rivas-Ruiz ⁵

Gastroenterol Hepatol. 2024 Nov;47(9):502196. doi: 10.1016/j.gastrohep.2024.502196. Epub 2024 May 6. (Article in Spanish)

Introduction: Granulocyte and monocyte adsorptive apheresis (GMA) removes neutrophils and monocytes from peripheral blood, preventing their incorporation into the inflamed tissue also influencing cytokine balance. Published therapeutic efficacy in ulcerative colitis (UC) is more consistent than in Crohn’s disease (CD). We assessed clinical efficacy of GMA in UC and CD 4 weeks after last induction session, at 3 and 12 months, sustained remission and corticosteroid-free remission.

Patients and method: Retrospective observational study of UC and CD patients treated with GMA. Partial Disease Activity Index-DAIp in UC and Harvey-Bradshaw Index-HBI in CD assessed efficacy of Adacolumn® with induction and optional maintenance sessions.

Results: We treated 87 patients (CD-25, UC-62), 87.3% corticosteroid-dependent (CSD), 42.5% refractory/intolerant to immunomodulators. In UC, remission and response were 32.2% and 19.3% after induction, 35.5% and 6.5% at 12 weeks and 29% and 6.5% at 52 weeks. In CD, remission rates were 60%, 52% and 40% respectively. In corticosteroid-dependent and refractory or intolerant to INM patients (UC-41, CD-14), 68.3% of UC achieved remission or response after induction, 51.2% at 12 weeks and 46.3% at 52 weeks, and 62.3%, 64.3% and 42.9% in CD. Maintained remission was achieved by 66.6% in CD and 53.1% in UC. Up to 74.5% of patients required corticosteroids at some timepoint. Corticosteroid-free response/remission was 17.7% in UC and 24% in CD.

Conclusions: GMA is a good therapeutic tool for both in UC and CD patients. In corticosteroid-dependent and refractory or intolerant to INM patients it avoids biological therapy or surgery in up to 40% of them in one year.

Maki Setake ¹, Ryosaku Tomiyama ¹, Tomoya Kuda ², Kanetaka Maeshiro ³, Akira Hokama ⁴

Rev Esp Enferm Dig. 2024 Oct 4. doi: 10.17235/reed.2024.10795/2024. 

A 17-year-old man with ulcerative colitis (UC) presented to our hospital with neck pain and fever after vomiting. On examination, a snowflake sensation was noted in the neck. A chest radiograph showed extensive subcutaneous emphysema in the chest. CT scans showed extensive subcutaneous emphysema in the neck, shoulders and axilla, as well as pneumomediastinum and pneumothorax. A diagnosis of pneumomediastinum with exacerbation of UC was made, and he was fasted and treated with antibiotics. Intensive granulocyte and monocyte adsorption apheresis (GMA) was started for exacerbation of UC. His symptoms and the radiological findings of pneumomediastinum improved. He remained in remission on azathioprine. UC is a chronic inflammatory bowel disease (IBD) associated with extraintestinal manifestations (EIM). Very few cases have been complicated by pneumomediastinum. The increase in alveolar pressure due to vomiting and systemic inflammation-related pleural or esophageal damage may cause pneumomediastinum in this case. Prevention of progression to mediastinitis and treatment of exacerbated UC are contradictory. GMA was successful because it was not an immunosuppressive therapy. Our case highlights that rare EIM may complicate exacerbation of UC.

Maria-Bernadette Madel ¹, Lidia Ibáñez ¹, Thomas Ciucci ², Julia Halper ¹, Antoine Boutin ¹, Ghada Beldi ¹, Alice C Lavanant ³, Henri-Jean Garchon ⁴, Matthieu Rouleau ¹, Christopher G Mueller ³, Laurent Peyrin-Biroulet ⁵, David Moulin ⁶, Claudine Blin-Wakkach ⁷, Abdelilah Wakkach ⁸

Mucosal Immunol.. 2025 Feb;18(1):90-104. doi: 10.1016/j.mucimm.2024.09.005. Epub 2024 Sep 26.

Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn’s disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.

Marion Thomas ¹, Olivier Fogel ¹, Omar Al Tabaa ¹, Alice Combier ¹, Sandrine Ninino ², Patricia Detre ², Yannick Allanore ¹, Jérôme Avouac ³

Joint Bone Spine. 2024 Dec;91(6):105781. doi: 10.1016/j.jbspin.2024.105781. Epub 2024 Sep 24.

Sneha Annie Sebastian ¹, Oroshay Kaiwan ², Edzel L Co ³, Meghana Mehendale ⁴, Babu P Mohan

Spartan Med Res J. 2024 Sep 9;9(3):123397. doi: 10.51894/001c.123397. eCollection 2024.

Introduction: Ulcerative colitis (UC) is a chronic inflammatory bowel disorder (IBD) with periods of relapse and remission. Current advancements in clinical research have led to the development of more refined and effective medical therapy for UC.

Summary of the evidence: Traditional therapeutic agents such as 5-aminosalicylates (5-ASAs), sulfasalazine (SASP), corticosteroids, and immunomodulatory drugs have remained the gold standard for decades. However, their novel formulations and dosage regimens have changed their sequences in the medical management of UC. Several other novel drugs are in the final phases of clinical development or have recently received regulatory approval designed to target specific mechanisms involved in the inflammatory cascade for UC.

GMA has shown its efficacy in mild to moderate UC and refractory UC (steroid-dependent UC or biologic/immunologic resistant UC or lost their response to biologics) for remission induction.

Conclusions: This narrative review sought to provide a comprehensive knowledge of the potential benefits of standard and emerging therapies, including novel formulations, new chemical entities, and novel therapeutic approaches in managing UC. Keywords: Ulcerative colitis, 5- Aminosalicylic acid, sulfasalazine, corticosteroids, biologics, immunomodulators, novel formulations.

Ryo Hisamune ¹, Kazuma Yamakawa ¹, Katsuhide Kayano ¹, Noritaka Ushio ¹, Takeshi Wada ², Kohei Taniguchi ³, Akira Takasu ¹ Acute Med Surg. . 2024 Aug 29;11(1):e70003. doi: 10.1002/ams2.70003. eCollection 2024 Jan-Dec.

Aims: SARS-CoV-2 causes systemic immune dysfunction, leading to severe respiratory dysfunction and multiorgan dysfunction. Granulocyte and monocyte adsorptive apheresis (GMA) therapy is designed to regulate an excessive inflammatory response and has been proposed as a potential therapeutic strategy for coronavirus disease 2019 (COVID-19). We aimed to investigate a targeted subset of granulocytes and monocytes to be removed after GMA therapy in patients with severe COVID-19 infection.

Methods: We established an ex vivo experimental system to study the effects of GMA. Blood samples were collected into EDTA-treated tubes and a mixture of blood samples and cellulose acetate beads was used in GMA. After GMA, blood samples were removed, and the granulocyte and monocyte subtypes before and after GMA were determined by CyTOF mass cytometry. To analyze mass cytometry data with a self-organizing map, hierarchical clustering was used to determine the appropriate number of metaclusters from t-distributed stochastic neighbor embedding.

Results: We included seven patients with severe COVID-19 and four age- and sex-matched volunteers. Granulocyte subsets removed by GMA strongly expressed CD11b, CD16, and CD66b, and weakly expressed CD11c, consistent with mature and activated neutrophils. Monocyte subsets strongly expressed CD14, weakly expressed CD33 and CD45RO, and did not express CD16. These subsets were indicated to promote the release of inflammatory cytokines and activate T cells.

Conclusions: The identification of the granulocyte and monocyte subsets removed after GMA in patients with severe COVID-19 may help explain the potential mechanism underlying the effectiveness of GMA in COVID-19 and other inflammatory diseases.

Tomoyuki Nakamura, Kazuhiro Moriyama, Toshikazu Sakai, Yu Kato & Osamu Nishida 

Ren Replace Ther 10, 51 (2024). https://doi.org/10.1186/s41100-024-00565-9

Background

Sepsis 3 definitions have shifted the focus from nonspecific inflammation to sepsis as an organ dysfunction caused by a dysregulated host response to infection. Neutrophils have become therapeutic targets because of their intimate but complex involvement in sepsis. We conducted ex vivo and animal experiments to apply a granulocyte and monocyte adsorption column, which is clinically used for inflammatory bowel disease, in sepsis. In this study, the biocompatibility was evaluated in sepsis-like hypercytokinemia.

Methods

Six female outbred pigs were anesthetized. Extracorporeal direct hemoperfusion (DHP) with an Adacolumn or a sham column was initiated after lipopolysaccharide (LPS) administration. The DHP was performed for 2 h at a blood flow rate (QB) of 30 or 60 mL/min. Blood samples were collected before and during the DHP (30, 60, 90, and 120 min). The percentage change in white blood cell count, platelet count, and cytokine concentration was compared between the Adacolumn and sham columns.

Results

The percentage change in white blood cells were 96 (95–98)% and 106 (101–108)% in the Adacolumn and sham groups, respectively, at QB = 60 mL/min (p < 0.01). The percentage change in platelets were 95 (90–96)% and 97 (93–99)% in the in the Adacolumn and sham groups, respectively, at QB = 60 mL/min (not significant; n.s.). At QB = 60 mL/min, the percentage change in tumor necrosis factor-α, interleukin (IL)-6, and IL-10 were 92 (81–106)%, 95 (93–102)%, and 98 (95–100)%, respectively, for the Adacolumn and 100 (95–102)%, 98 (87–104)%, and 97 (93–99)%, respectively, for the sham column. The percentage change in white blood cell counts, platelet counts, and all cytokines at QB = 30 and 60 mL/min showed similar trends.

Conclusion

The biocompatibility of the Adacolumn was evaluated using a porcine LPS-induced inflammation model. No decrease in platelet counts or significant cytokine production was observed, suggesting that the Adacolumn could be safely used in patients with sepsis with QB = 30–60 mL/min for 2 h. However, production of mediators other than cytokines remains unknown and requires further investigation.

Lluís Puig ¹, Hideki Fujita ², Diamant Thaçi ³, Min Zheng ⁴, Ana Cristina Hernandez Daly ⁵, Craig Leonardi ⁶, Mark G Lebwohl ⁷, Jonathan Barker ⁸

Dermatol Ther (Heidelb). 2024 Sep;14(9):2331-2378. doi: 10.1007/s13555-024-01230-z. Epub 2024 Aug 1.

Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules, with or without systemic inflammation. GPP can significantly reduce patients’ quality of life (QoL). Several therapeutic approaches have been described in the literature, but there is no consensus on optimal treatment. In this review, we summarize published literature on efficacy, safety and QoL outcomes associated with current treatment of GPP with both approved and non-approved products. Embase and MEDLINE databases were searched (1980-September 2023). A search protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on the PROSPERO database (CRD42021215437). Details on publication, population, intervention, efficacy, safety and QoL were captured and checked by independent reviewers. In total, 118 publications were included, with only 19% of publications reporting on the results of clinical trials. Treatment modalities reported for GPP included non-biologic systemic therapies such as retinoids, cyclosporine and methotrexate, topical agents, biologics and small molecules, among others. Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials; based on this, spesolimab is now approved for GPP treatment in regions including the USA, Japan, China, the EU and several other countries. Some other biologics are approved exclusively in Japan and Taiwan for the treatment of GPP based on open-label studies with small patient numbers in lieu of double-blind studies. Non-standardization of clinical outcomes across studies remains a major hurdle in reaching a consensus on optimal treatment. However, recently trials have been conducted using well-defined, disease-specific endpoints to evaluate GPP-targeted treatments, which will hopefully advance patient care. In conclusion, this review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

GMA was approved for the treatment of GPP in Japan in 2012