Mauro Mastronardi, Elisabetta Cavalcanti, Nunzia Labarile, Raffaele Armentano, Francesco Gabriele, Margherita Curlo, Therapeutic Advances in Chronic Disease. 2023;14. doi:10.1177/20406223231194190

Extraintestinal manifestations occur rather frequently in ulcerative colitis (UC) and Crohn’s disease patients and are usually related to an exacerbation of the underlying intestinal bowel disease but sometimes may run a course independent of the inflammatory bowel diseases (IBD). About one-third of patients with IBD develop extraintestinal manifestations, such as pyoderma gangrenosum (PG). PG is an uncommon inflammatory skin disorder of unknown pathogenesis. There are no specific serological or histological markers, and diagnosis is predominantly clinical. Topical and systemic therapies are both vital aspects of treatment and immune modulators have been used with increasing success in recent years, although immunosuppressive drugs raise some concerns due to an increased risk of serious and opportunistic infections and cancer, particularly in elderly and comorbid patients, underlining the unmet need for safer alternative therapies. Thus, in this case report, we highlighted an adsorptive granulocyte/monocyte apheresis (GMA) as a new therapeutic possibility in IBD patients with extraintestinal manifestations. We report a case of a 60-year woman with a history of UC with a Mayo grade 3 score which was associated with a PG. Given that the patients maintained clinical remission with vedolizumab, we preferred not to perform a combined treatment with other antitumor necrosis factor-alpha or ciclosporin, thus avoiding an increased risk of serious infections in the patient. Therefore, we performed the extracorporeal leukocyte apheresis. The patient progressed favorably, with progressive improvement of skin and bowel disease. Therefore, adsorptive GMA has a very favorable safety profile and has been confirmed in numerous studies. In this study, we underlined that an intensive regimen of GMA paves the way to an ideal option for patients with severe and refractory PG complicated with UC.

Mauro Mastronardi 1, Elisabetta Cavalcanti 2, Nunzia Labarile 1, Raffaele Armentano 3, Francesco Gabriele 4, Margherita Curlo 1 Ther Adv Chronic Dis. 2023 Nov 3:14:20406223231194190. doi: 10.1177/20406223231194190.

Extraintestinal manifestations occur rather frequently in ulcerative colitis (UC) and Crohn’s disease patients and are usually related to an exacerbation of the underlying intestinal bowel disease but sometimes may run a course independent of the inflammatory bowel diseases (IBD). About one-third of patients with IBD develop extraintestinal manifestations, such as pyoderma gangrenosum (PG). PG is an uncommon inflammatory skin disorder of unknown pathogenesis. There are no specific serological or histological markers, and diagnosis is predominantly clinical. Topical and systemic therapies are both vital aspects of treatment and immune modulators have been used with increasing success in recent years, although immunosuppressive drugs raise some concerns due to an increased risk of serious and opportunistic infections and cancer, particularly in elderly and comorbid patients, underlining the unmet need for safer alternative therapies. Thus, in this case report, we highlighted an adsorptive granulocyte/monocyte apheresis (GMA) as a new therapeutic possibility in IBD patients with extraintestinal manifestations. We report a case of a 60-year woman with a history of UC with a Mayo grade 3 score which was associated with a PG. Given that the patients maintained clinical remission with vedolizumab, we preferred not to perform a combined treatment with other antitumor necrosis factor-alpha or ciclosporin, thus avoiding an increased risk of serious infections in the patient. Therefore, we performed the extracorporeal leukocyte apheresis. The patient progressed favorably, with progressive improvement of skin and bowel disease. Therefore, adsorptive GMA has a very favorable safety profile and has been confirmed in numerous studies. In this study, we underlined that an intensive regimen of GMA paves the way to an ideal option for patients with severe and refractory PG complicated with UC.

Grisell Starita-Fajardo 1, David Lucena-López 1, María Asunción Ballester-Martínez 2, Montserrat Fernández-Guarino 2, Andrés González-García Int J Mol Sci. 2023 Oct 26;24(21):15622. doi: 10.3390/ijms242115622

Neutrophilic dermatoses (NDs) are a group of noninfectious disorders characterized by the presence of a sterile neutrophilic infiltrate without vasculitis histopathology. Their physiopathology is not fully understood. The association between neutrophilic dermatoses and autoinflammatory diseases has led some authors to propose that both are part of the same spectrum of diseases. The classification of NDs depends on clinical and histopathological features. This review focuses on the recent developments of treatments in these pathologies.

Masi L, Ciuffini C, Petito V, Pisani LF, Lopetuso LR, Graziani C, Pugliese D, Laterza L, Puca P, Di Vincenzo F, Pizzoferrato M, Napolitano D, Turchini L, Amatucci V, Schiavoni E, Privitera G, Minordi LM, Mentella MC, Papa A, Armuzzi A, Gasbarrini A and Scaldaferri F Front. Gastroenterol. 1:1022530. doi: 10.3389/fgstr.2022.1022530

Inflammatory bowel diseases (IBD) are chronic disabling conditions with a complex and multifactorial etiology, which is still not completely understood. In the last 20 years, anti-TNF-α antagonists have revolutionized the treatment of IBD, but many patients still do not respond or experience adverse events. Therefore, new biological therapies and small molecules, targeting several different pathways of gut inflammation, have been developed of which some have already been introduced in clinical practice while many others are currently investigated. Moreover, therapeutic procedures such as leukocytapheresis, fecal microbiota transplant and stem cell transplantation are currently being investigated for treating IBD. Lastly, complementary and alternative medicine has become a field of interest for gastroenterologist to reduce symptom burden in IBD patients. In this comprehensive and updated review, a novel classification of current and developing drugs is provided.

Frontiers | Innovative, complementary and alternative therapy in inflammatory bowel diseases: A broad 2020s update (frontiersin.org)

I. Rodríguez-Lago1, F. Cañete2, E. Guerra3, C. Herrera de Guise4, E. Iglesias-Flores5, E. Leo-Carnerero6, Y. Zabana7, M. Barreiro de Acosta8, D. Ginard Vicens9, J.L. Cabriada Nuño1

UEG journal 2023 SUPPLEMENT ABSTRACT UEG Week 2023 Poster Presentations 15 October 2023 page 1067

Introduction: Granulocyte–monocyte apheresis (GMA) selectively removes activated leukocytes and immune mediators, and it has shown to be safe and effective in treating ulcerative colitis (UC). Previous reports
have also described its combination with biologics.
Aims & Methods: The aim of our study was to evaluate the efficacy and safety of combining GMA after primary non-response (PNR) or loss of response (LOR) to tofacitinib (TOFA) in patients with UC. A retrospective, multicentre study was performed in 7 IBD Units, including all patients with refractory UC who received combined plus GMA and TOFA. The number of GMA sessions, its frequency, filtered blood volume and length of each
session were compiled, along with the clinical data. Efficacy was assessed 1 and 6 months after finishing GMA by partial Mayo score, CRP and faecal calprotectin. Data regarding TOFA intensification, need for new immunomodulators/biologics and colectomy were also compiled. Descriptive statistics and non-parametric tests were used in the statistical analysis.

Results: Twelve patients with UC were included (median 46 years [IQR, 37-58]; 67% female; 67% E3; 75% non-smokers). Patients were receiving TOFA10 mg bid (75%), 5 mg bid (16%), or 15 mg bid (8%), with 33% receiving
steroids at baseline. All patients had prior exposure to anti-TNF agents, 42% to vedolizumab and 8% ustekinumab. Median baseline Mayo score was 7 (IQR, 5-7), median CRP of 11 mg/L (IQR, 5-32) and faecal calprotectin 800 mg/kg (IQ, 715-2,094). GMA was started mostly after PNR (73%), and the median number of GMA sessions was 11 (IQR, 3-20) and 50% received maintenance GMA. Partial Mayo score significantly decreased 1 month after the last GMA session (p=0.027). Four patients (36%) were switched to a new therapy and no patient required colectomy during follow-up. All patients under steroids at baseline were able to stop them. No patient reported adverse events related to the combination therapy.

Conclusion: Combination of GMA with TOFA can be an effective and safe therapy in selected cases of UC after PNR or LOR to this drug.

N.D. Salazar Parada1, M. Algara San Nicolas1,A. Suárez-Saro Fernández1, A. Masedo1, C. Yela San Bernardino1,C. Begoña1, P. Martínez Montiel1, I. Fernández Vázquez1

UEG journal 2023 SUPPLEMENT ABSTRACT UEG Week 2023 Poster Presentations 15 October 2023 page 1047

Introduction: Despite the importance of granulocytoapheresis (GCA) in the treatment of inflammatory bowel disease (IBD), its effectiveness in steroid-dependent and steroid-refractory IBD has not been widely evaluated, the approaches are heterogeneous and data on efficacy and safety remain limited in our population.
Aims & Methods: This study aims to assess the effectiveness of GCA for induction of remission and maintenance in patients with steroid-dependent and steroid-refractory IBD in the real-world practice.
Retrospective cohort of patients with steroid-dependent and steroid-refractory colonic IBD, in which GCA was used as induction of remission and maintenance treatment between January-2015 to January-2023. We
analyze demographics, disease characteristics, prior exposure including biologic agents. The success of GCA was defined on a decrease of at least 3 points in the True-love score for Ulcerative Colitis (UC) and a decrease of
at least 100 points in the CDAI for Crohn Disease (CD). To analyze predictive factors of treatment success we performed a univariate and multivariable analysis.
Results: 49 patients were included. 5 cycles of apheresis were performed in the first 3 weeks as induction and at least 10 cycles of apheresis as maintenance in the next 6 months.

75 % (37 / 49) had UC, 86.4 % (32 / 37) were steroid-refractory while 13.6 % (5 / 37) steroid-dependent, 54 % (20 / 37) male; median age 60 ± 10.5 years with a mean of 10.5 years from diagnosis. 67.7 % (25 / 37) had received at least 1 biological treatment in the past, 43.5 % (17 / 39) ≥ 2 biological. After induction, 75 % (28 / 37) responded to treatment, 62 % (23 / 37) continued with maintenance therapy of which 67 % (15 / 23) responding. Mean PCR and calprotectin were 3,16 mg / dl and 2038 mg / dl before treatment, 1.45mg / dl and 1025 mg / dl after induction, 1.15 mg / dl and 900 mg / dl after maintenance, respectively.

25 % (12 / 49) had CD, 50 % (6/12) male; median age 62 ± 9.8 years, 75% (9 / 12) steroid-refractory and 25 % (3 / 12) steroid-dependent, with a mean of 9 years from diagnosis, 67.7 % had received at least one biological
treatment in the past. After induction, 58 % (7 / 12) responded, 80 % (10 /12) continued with maintenance with 50 % (5 / 10) responding. Mean CRP and calprotectin were 3.16 mg / dl and 3645 mg / dl before treatment, 1.7
mg / dl and 2473 mg / dl after induction, 1.14 mg / dl and 623 mg / dl after maintenance.
Factors such as smoking, extent of disease, longer disease course and lack of response to previous treatments, were not significantly related to response in either induction or maintenance.
No patient had major adverse events recorded.
Conclusion: GCA appears to be safe and effective for inducing and maintaining clinical remission in patients with IBD, especially in patients with UC. No significant differences were found in disease extension, duration or
lack of response to previous treatments.

D. Kioroglu1 , J.L. Cabriada2, U. M. Marigorta1,3, I. Rodríguez-Lago Ueg journal

Volume11, Issue S8 Supplement: 31st United European Gastroenterology Week 2023 October 2023 Pages 799

Introduction: Granulocyte–monocyte apheresis (GMA) is a non-pharmacological therapy approved for the treatment of ulcerative colitis (UC), mainly in steroid-dependent cases. Its mechanism of action is based onthe removal of activated leukocytes, but its exact immunological changes have not been fully described yet. Aims & Methods: Our aim was to characterize the response in the transcriptome at the single-cell resolution level and cell population effects of GMA device. We analysed scRNASeq data from peripheral blood mono-nuclear cells (PBMC) of two UC patients undergoing their first GMA session. Their gene expression profile was compared before (PRE) and one month after (POST) the GMA treatment, from the inflow and outflow lines, respectively. The analytical pipeline included quality control and filtering, cell-type annotation, differential gene expression and pathway enrichment analysis. Results: Two patients with UC (mean age 59 years; both E2) were included.Overall, the cell populations that appear to have been affected by the GMA treatment were natural killer cells and monocytes with both populations being reduced after the treatment. The distribution of the annotated cell-types was 2,369 B cells (PRE:50%, POST:49%), 11,462 CD4+ (PRE:49%,POST:50%) and 8,845 CD8+ T-cells (PRE:51%, POST:48%), 47 dendritic cells (PRE:40%, POST:59%), 3,773 natural killer cells (PRE:54%, POST:45%) and 2,352 monocytes (PRE:59%, POST:40%). Annotation at higher resolution identified 27 cell-types with monocytes being subannotated as 1,972 CD14 (PRE:62%, POST:37%) and 380 CD16 (PRE:48%, POST:51%) monocytes. Differential gene expression analysis identified in total 86 significant genes across six cell-types (CD4+ naive and central memory T-cells, natural killer cells, B intermediate cells, double-negative T-cells and CD14monocytes) with 63% of these genes being downregulated after the GMA treatment. Pathway enrichment analysis identified higher contribution of the double-negative T-cells to the enriching genes. More specifically, after the treatment the double-negative T-cells exhibited upregulation of the NEFL that is associated with the MAPK cascade and downregulation of genes related to immune response and signalling pathways. Regarding the CD14 monocytes, after the GMA treatment we observed significant downregulation of the genes LINC02315, IGHEP1 and IGHE, with the latter being linked to innate immune response pathways. Conclusion: GMA induces a range of modifications in the gene expression profile across different cell types that change the immunological environment of UC patients.

Makoto Naganuma ¹, Taku Kobayashi ², Reiko Kunisaki ³, Katsuyoshi Matsuoka ⁴, Shojiro Yamamoto ⁵, Ami Kawamoto ⁶, Daisuke Saito ⁷, Kosaku Nanki ⁸, Kazuyuki Narimatsu ⁹, Hisashi Shiga ¹⁰, Motohiro Esaki ¹¹, Shinichiro Yoshioka ¹², Shingo Kato ¹³, Masayuki Saruta ¹⁴, Shinji Tanaka ¹⁵, Eriko Yasutomi ¹⁶, Kaoru Yokoyama ¹⁷, Kei Moriya ¹⁸, Yoshikazu Tsuzuki ¹⁹, Makoto Ooi ²⁰, Mikihiro Fujiya ²¹, Atsushi Nakazawa ²², Takayuki Abe ²³, Tadakazu Hisamatsu ⁶; Japanese UC Study Group J Gastroenterol. 2023 Dec;58(12):1198-1210. doi: 10.1007/s00535-023-02048-w. 

Background: This multicenter observational cohort study aimed to evaluate the utilization and short-term efficacy of advanced therapy (AT) in hospitalized patients with acute severe ulcerative colitis (ASUC).

Methods: In total, 221 patients with ASUC were enrolled between August 2020 and July 2021. The primary endpoint was clinical remission (CR, defined as a patient-reported outcome score < 2 with no blood in the stool) rate on Day 7 and 14 in hospitalized patients who received corticosteroids (CS) and AT.

Results: Among patients with ASUC, 120 and 101 patients received CS or any AT as first-line treatment, respectively. The CR rates on Day 7 and 14 were 22.5% and 35.0%, respectively, in hospitalized patients who received CS as first-line treatment. Most patients who used ATs had CS-dependent or frequent recurrences. Eight different ATs (apheresis, tacrolimus, infliximab, golimumab, tofacitinib, vedolizumab, ustekinumab, and cyclosporine) were used as first-line treatment in patients with ASUC, and the CR rates on Day 7 and 14 were 16.8% and 29.7%, respectively. Twenty-five patients received the second ATs after hospitalizations, and the CR rates on Day 7 and 14 were 0% and 12%, respectively. The CR rates on Day 14 were significantly higher in patients who changed to AT than in those whose dose of CS increased (34.0% vs 10.7%, p = 0.020) among patients who had already used CS before hospitalization.

Conclusion: Most first-use ATs were effective for patients with ASUC, while second-use ATs might have had limited benefits in inducing CR. These findings may contribute to considerations for the management of hospitalized patients.

Real-world efficacy and safety of advanced therapies in hospitalized patients with ulcerative colitis – PubMed (nih.gov)

Real-world efficacy and safety of advanced therapies in hospitalized patients with ulcerative colitis | Journal of Gastroenterology (springer.com)

Elena Céspedes Martínez, Virginia Robles Alonso, Claudia Herrera-De Guise, Luis Mayorga, Francesc Casellas, María Roca-Herrera, Natalia Borruel, Rev Esp Enferm Dig 2023;115(10):567-573

Introduction: immune checkpoint inhibitors (ICI) are increasingly used to treat several types of cancer. These drugs lead to a wide range of toxicities. Immune-related gastrointestinal adverse events are common and potentially severe. In this manuscript, we recount the real clinical experience in a tertiary center. Methods: a retrospective and observational study was conducted in adult patients under ICI treatment. Included patients had been referred to the Gastrointestinal Service of Hospital Universitario Vall d’Hebron for evaluation of severe toxicities, from January 2017 to January 2020, for whom the clinical, epidemiological and evolutive data were collected. Results: a total of 18 patients were included. Fifty-five percent received anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (anti PD-L1), 11 % received anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and 33 % received both treatments. The toxicities were manifested as enterocolitis, microscopic colitis and gastritis. Upper gastrointestinal endoscopy was performed in seven patients; all were proved to have histological changes on duodenum biopsies. Treatment was stopped in all patients and steroids were initiated. Sixty-six per cent achieved clinical remission with steroids. Five patients received anti-TNF treatment (infliximab). Only one of the five had responded. Two anti-TNF refractory patients received ustekinumab, with an appropriate clinical response. One patient received apheresis granulocyte as concomitant treatment. A patient with a steroid-dependent course started vedolizumab. Three patients had other immune-related adverse events. Conclusion: gastrointestinal immune-related adverse events are acquiring a higher profile in daily practice and gastroenterologists play an even greater role in the management of these patients.

Severe and refractory gastrointestinal toxicity due to immune checkpoint inhibitors: clinical experience in a tertiary referral hospital – PubMed (nih.gov)

REED – Revista Española de Enfermedades Digestivas

Filippo Vernia ¹, Angelo Viscido ¹, Giovanni Latella ¹J Clin Apher. 2023 Dec;38(6):746-754

Adsorptive cytapheresis proves effective in a proportion of patients affected by ulcerative colitis. Relatively high cost and the need for apheresis facilities, prevented the widespread use of this therapeutic approach. More so following the introduction of anti-TNFα biosimilars which proved both effective and inexpensive. Anti-TNFα agents, however, are burdened by high rate of primary and secondary non-response and prompt switching to new, high-cost biologics, and small molecules. The present review analyzes advantages and disadvantages of adsorptive cytapheresis in the present clinical scenario and suggests its repositioning in the therapeutic workup of selected subgroups of ulcerative colitis patients. The extremely favorable safety profile makes adsorptive cytapheresis a viable therapeutic option in elderly and high-risk UC patients, as well as potential second-line treatment in corticosteroid-dependent patients and poor responders to first-line biologics.

Adsorptive cytapheresis in ulcerative colitis: A non-pharmacological therapeutic approach revisited – PubMed (nih.gov)

Adsorptive cytapheresis in ulcerative colitis: A non‐pharmacological therapeutic approach revisited – Vernia – 2023 – Journal of Clinical Apheresis – Wiley Online Library