Cristina Suárez Ferrer 1, Eduardo Martin-Arranz 2, María Dolores Martín-Arranz, Gastroenterol Hepatol 2024 Jan 12:S0210-5705(24)00018-9. doi: 10.1016/j.gastrohep.2024.01.002. Online ahead of print.
Aim: Granulocyte and monocyte apheresis (GMA) is a potential therapeutic option when combined with various drugs for treatment of ulcerative colitis (UC). In this study, we analyze the efficacy and safety of GMA combined with vedolizumab (VDZ) during induction in patients with moderate-severe UC and incomplete response to steroids.

Patients and methods: Single-center retrospective review of patients receiving GMA+VDZ. Data on the disease and previous treatments were collected. Clinical response was classified as no response, response without remission, and remission. Available data on biochemical and endoscopic response were included. Adverse events (AEs) were recorded.

Results: The study population comprised 6 patients with UC who had received GMA+VDZ during induction after failure of an anti-TNF agent. The median number of GMA sessions was 5 (IQR 4-5; 3-10). All the patients received VDZ 300mg iv at 0, 2, and 6 weeks, and 5 (83%) received an additional dose at week 10. During maintenance, all the patients continued VDZ iv every 8 weeks. The median follow-up was 57.6 months (IQR: 39-74). Four of the 6 patients achieved clinical remission after GMA+VDZ and continued in deep remission until the end of follow-up. A median, non-significant decrease of 1378μg/g (IQR: 924-5778μg/g) was observed for calprotectin and 42.2mg/l (IQR: 15.3-113.5) for CRP vs. baseline. No patient underwent colectomy. No treatment-related AEs were observed.

Conclusions: GMA+VDZ during induction can be effective and safe in selected patients with moderate-severe UC and partial response to steroids.

Hikaru Ishihara ¹, Tatsuyuki Watanabe ², Shinsuke Kumei ², Keiichiro Kume ², Ichiro Yoshikawa ², Masaru Harada ² Clin J Gastroenterol. 2023 Dec 2. doi: 10.1007/s12328-023-01887-7.

A 68-year-old man developed immune-related adverse event (irAE) colitis after the initiation of nivolumab and ipilimumab combination therapy for malignant melanoma. We diagnosed the patient with grade 3 irAE colitis and started prednisolone (1 mg/kg/day). Although the symptom improved once, it worsened along with the tapering of prednisolone. Therefore, we started infliximab (IFX). However, symptoms did not improve after two doses of IFX. We discontinued IFX and initiated vedolizumab (VED). Because VED alone did not improve the symptom, we started granulocyte-monocyte apheresis (GMA). Twelve weeks after the onset, the colitis was in remission. Therefore, in addition to vedolizumab, GMA may be considered in cases refractory to treatment.

A case of refractory immune checkpoint inhibitor-induced colitis improved by the treatment with vedolizumab and granulocyte-monocyte apheresis combination therapy – PubMed (nih.gov)

A case of refractory immune checkpoint inhibitor-induced colitis improved by the treatment with vedolizumab and granulocyte–monocyte apheresis combination therapy | Clinical Journal of Gastroenterology (springer.com)

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.

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.

Pyoderma gangrenosum in ulcerative colitis patient treated with vedolizumab: adsorptive granulocyte/monocyte apheresis as a new therapeutic option refractory cases – a case report and literature review – PubMed (nih.gov)

Pyoderma gangrenosum in ulcerative colitis patient treated with vedolizumab: adsorptive granulocyte/monocyte apheresis as a new therapeutic option refractory cases – a case report and literature review – PMC (nih.gov)

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.

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

Francesca Ferretti ¹, Rosanna Cannatelli ¹, Maria Camilla Monico ¹, Giovanni Maconi ¹, Sandro Ardizzone 

J Clin Med  2022 Apr 20;11(9):2302. doi: 10.3390/jcm11092302.

The main goals of Ulcerative Colitis (UC) treatment are to both induce and maintain the clinical and endoscopic remission of disease, reduce the incidence of complications such as dysplasia and colorectal carcinoma and improve quality of life. Although a curative medical treatment for UC has not yet been found, new therapeutic strategies addressing specific pathogenetic mechanisms of disease are emerging. Notwithstanding these novel therapies, non-biological conventional drugs remain a mainstay of treatment. The aim of this review is to summarize current therapeutic strategies used as treatment for ulcerative colitis and to briefly focus on emerging therapeutic strategies, including novel biologic therapies and small molecules. To date, multiple therapeutic approaches can be adopted in UC and the range of available compounds is constantly increasing. In this era, the realization of well-designed comparative clinical trials, as well as the definition of specific therapeutic models, would be strongly suggested in order to achieve personalized management for UC patients. They also presented other non-Pharmacological Therapies for UC including probiotics, cytapheresis and fecal transplantation.

https://pubmed.ncbi.nlm.nih.gov/35566428/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104748/

Masanao Nakamura ¹, Takeshi Yamamura ¹, Keiko Maeda ², Tsunaki Sawada ², Yasuyuki Mizutani ¹, Eri Ishikawa ¹, Ayako Ohashi ¹, Go Kajikawa ¹, Kazuhiro Furukawa ¹, Eizaburo Ohno ¹, Takashi Honda ¹, Hiroki Kawashima ¹, Masatoshi Ishigami ¹, Mitsuhiro Fujishiro ¹

Intern Med. 2020 Dec 1;59(23):3009-3014. doi: 10.2169/internalmedicine.5302-20. Epub 2020 Jul 28.

Granulocyte and monocyte adsorptive apheresis (GMA) is occasionally introduced as an alternative combination therapy after loss of response to biologics in ulcerative colitis (UC) patients. However, there have been no reports of the concomitant use of vedolizumab (VDZ) and GMA for the initial induction of UC. A 20-year-old man with refractory UC was admitted for recrudescence. VDZ monotherapy had previously been introduced but was ineffective. Therefore, he received scheduled combination of VDZ and GMA and achieved clinical remission. The combination of two different approaches to inhibit the migration of leukocytes into the inflamed tissue led to satisfactory clinical outcomes.

https://pubmed.ncbi.nlm.nih.gov/32727993/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759717/

Tomoyoshi Shibuya,Keiichi Haga,Michio Saeki,Mayuko Haraikawa,Hitoshi Tsuchihashi,Koki Okahara,Osamu Nomura,Hirofumi Fukushima,Takashi Murakami Dai Ishikawa,Shigaku Ikeda,Akihito Nagahara

J Clin Apher.  2020 Sep;35(5):488-492. doi: 10.1002/jca.21821. Epub 2020 Aug 7.

Pyoderma gangrenosum (PG) is an extra-intestinal skin lesion in inflammatory bowel disease (IBD) as is erythema nodosum. Vedolizumab (VED) is a monoclonal antibody that targets α4β7 integrin and has an intestinal selective mechanism. Despite good therapeutic effects on colitis, the effect on extra-intestinal manifestations (EIMs) remains unclear. Here we report a case of ulcerative colitis complicated by PG during treatment with VED, which was successfully treated with prednisolone in combination with adsorptive granulocyte and monocyte apheresis (GMA). The patient was a 50-year-old woman with a past medical history of extensive ulcerative colitis managed by golimumab (GLM). She developed flare symptoms due to loss of response to GLM, and treatment was switched to VED. Her gastrointestinal symptoms were improved with VED treatment with less frequent bowel movements. However, infiltrative erythema with pain appeared on the right lower leg and right knee, and expanded and gradually ulcerated. Her skin lesions were treated with corticosteroid, but showed poor improvement. Therefore, granulocyte and monocyte apheresis (GMA) treatment was administered in combination with prednisolone. After 3 months, the ulcer gradually improved, and at the time of this writing, the eruptions were nearly replaced by epithelial tissue. This case study showed that patients with UC and EIMS may respond well to combination therapy of VED and GMA. GMA has a very favorable safety profile. On the other hand, the causal connection between VED and PG is still unclear. We believe that a combination therapy involving VED and GMA in IBD patients with EIMs warrants consideration.

https://pubmed.ncbi.nlm.nih.gov/32767842/