Scientific corner

MicroRNA and granulocyte-monocyte adsorption apheresis combotherapy after inadequate response to anti-TNF agents in ulcerative colitis

Esteban Sáez-González MDInés Moret-Tatay PhDGuillermo Bastida MD, PhDMariam Aguas MD, PhDMarisa Iborra MD, PhDPilar Nos MD, PhDBelén Beltrán MD, PhD  J Clin Apher. 2023 38(6); 1-10. doi:10.1002/jca.22101

Background

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract, affecting millions of individuals throughout the world, and producing an impaired health-related quality of life. Granulocyte and monocyte apheresis (GMA) is a therapeutic option for UC management to induce remission by selective removal of activated leukocytes from bloodstream. Despite the knowledge of the important role of epigenetics in UC pathogenesis, and in the response to different treatments, nothing is known about the role of microRNAs in GMA therapy in UC patients.

Methods

7 consecutively UC patients who started GMA in combo therapy with infliximab were recruited. Peripheral blood samples were taken before the apheresis session, at the start of the induction (S0) and at the end (S10). They were follow-up during the induction phase (10 sessions: 2 sessions for a week during 3 wk and 1 session for a week during 4 wk) of the treatment at a tertiary hospital (Hospital la Fe) and 6 mo after finishing the GMA induction therapy. MiRNA was extracted and analyzed by RT-PCR. R software and GraphPad were used.

Results

Clinical disease activity significantly decreased after induction therapy with GMA (median partial Mayo score 2 (IQR, 1-6) (P < .05). Fecal calprotectin value and CRP value significantly decreased after induction therapy. Five microRNAs modified their expression during GMA (unsupervised analysis): miR-342-3p, miR-215-5p, miR-376c-3p, miR-139-5p, and miR-150-5p. When a sub-analysis was performed in those patients who showed good response to apheresis treatment (n = 5), two microRNAs showed to be implicated: miR-215-5p and miR-365a-3p. These are preliminary but promising and novel results, as it is the first time, to our knowledge that microRNA profiles have been studied in the context of GMA treatment for IBD.

MicroRNA and granulocyte-monocyte adsorption apheresis combotherapy after inadequate response to anti-TNF agents in ulcerative colitis – PubMed (nih.gov)

MicroRNA and granulocyte‐monocyte adsorption apheresis combotherapy after inadequate response to anti‐TNF agents in ulcerative colitis – Sáez‐González – Journal of Clinical Apheresis – Wiley Online Library

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A case of refractory immune checkpoint inhibitor-induced colitis improved by the treatment with vedolizumab and granulocyte-monocyte apheresis combination therapy

Hikaru Ishihara 1Tatsuyuki Watanabe 2Shinsuke Kumei 2Keiichiro Kume 2Ichiro Yoshikawa 2Masaru 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)

Scientific corner

A retrospective study to investigate the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis with ulcerative colitis

Ayumi Ito 1Shun Murasugi 1Maria Yonezawa 1Teppei Omori 1Shinichi Nakamura 1Katsutoshi Tokushige 1

J Clin Apher. 2023 Nov 21. doi: 10.1002/jca.22099.

Background and aims: Primary sclerosing cholangitis has a poor prognosis and can be accompanied by ulcerative colitis. Infection control is essential, so immunosuppressive drugs should ideally be preferably. Granulocyte and monocyte adsorptive apheresis does not suppress the immune system and is used to treat ulcerative colitis. Therefore, this study investigated the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis and ulcerative colitis.

Methods: We retrospectively evaluated data from patients with primary sclerosing cholangitis with ulcerative colitis who visited our hospital from April 2000 to December 2022 and underwent granulocyte and monocyte adsorptive apheresis (n = 10, number of treatment cycles = 15). Study endpoints were remission induction rate and safety, assessed as changes in liver functions and adverse events.

Results: Seven of the 10 patients were male. The median (min-max) age was 23 (18-77) years. The most common disease type was right-dominant pancolitis. Remission occurred after 86.6% of cycles (13/15). Serum alkaline phosphatase and Aspartate transaminase were significantly lower after treatment (P = .0124, P = .002), and no negative effects on liver function were seen. The only adverse events were headache (n = 1) and decreased blood pressure (n = 1).

Conclusions: Granulocyte and monocyte adsorptive apheresis has high efficacy for intestinal lesions and improves alkaline phosphatase and aspartate transaminase levels (high levels are a poor prognosis factor). It appears to be a treatment option in patients with primary sclerosing cholangitis associated with ulcerative colitis.

A retrospective study to investigate the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis with ulcerative colitis – PubMed (nih.gov)

A retrospective study to investigate the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis with ulcerative colitis – Ito – Journal of Clinical Apheresis – Wiley Online Library

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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

Mauro Mastronardi 1Elisabetta Cavalcanti 2Nunzia Labarile 1Raffaele Armentano 3Francesco Gabriele 4Margherita 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)

Scientific corner

Real-world effectiveness and safety of advanced therapies for the treatment of moderate-to-severe ulcerative colitis (UC): evidence from a systematic literature review (SLR)

Makoto Naganuma 1Taku Kobayashi 2Reiko Kunisaki 3Katsuyoshi Matsuoka 4Shojiro Yamamoto 5Ami Kawamoto 6Daisuke Saito 7Kosaku Nanki 8Kazuyuki Narimatsu 9Hisashi Shiga 10Motohiro Esaki 11Shinichiro Yoshioka 12Shingo Kato 13Masayuki Saruta 14Shinji Tanaka 15Eriko Yasutomi 16Kaoru Yokoyama 17Kei Moriya 18Yoshikazu Tsuzuki 19Makoto Ooi 20Mikihiro Fujiya 21Atsushi Nakazawa 22Takayuki Abe 23Tadakazu Hisamatsu 6Japanese 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)

Scientific corner

Severe and refractory gastrointestinal toxicity due to immune checkpoint inhibitors: clinical experience in a tertiary referral hospital

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

Scientific corner

Adsorptive cytapheresis in ulcerative colitis: A non-pharmacological therapeutic approach revisited

Filippo Vernia 1Angelo Viscido 1Giovanni 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

Scientific corner

Intensive Frequent Granulocyte Adsorptive Apheresis Therapy for Acute Fulminant Ulcerative Colitis: Two Consecutive Case Reports

Yoshitaka Furuto 1Rikimaru Sawada 2Akio Namikawa 1Nobuyuki Matsuhashi 2Yuko Shibuya 1 Cureus. 2023 Aug 16;15(8):e43599. doi: 10.7759/cureus.43599.

Granulocyte/monocyte adsorptive apheresis (GMA) therapy is a treatment method for ulcerative colitis (UC). Twice-weekly GMA regimens are usually administered to treat severe UC. Although GMA efficacy is considered frequency-dependent, there is no uniformly accepted optimal GMA regimen, and there is insufficient evidence regarding optimal GMA therapy frequency for acute fulminant UC. Case 1 was of a 33-year-old man, and case 2 was of a 20-year-old woman. They were diagnosed with acute fulminant UC and treated with steroid therapy, but exhibited exacerbated UC, and their conditions worsened. We, therefore, initiated intensive frequent GMA therapy (conducted 10-11 times during a 13-day period). In both cases, remission was achieved within two weeks of therapy induction. Herein, we describe two consecutive cases in which rapid remission of acute fulminant UC was achieved without adverse events using intensive frequent GMA therapy. These cases suggest that intensive frequent GMA therapy might induce rapid remission in acute fulminant UC cases and may be more effective than twice-weekly GMA regimens.

Intensive Frequent Granulocyte Adsorptive Apheresis Therapy for Acute Fulminant Ulcerative Colitis: Two Consecutive Case Reports – PubMed (nih.gov)

Intensive Frequent Granulocyte Adsorptive Apheresis Therapy for Acute Fulminant Ulcerative Colitis: Two Consecutive Case Reports – PMC (nih.gov)

Scientific corner

An in vitro analysis of the interaction between infliximab and granulocyte-monocyte apheresis

Iago Rodríguez-Lago 1Leticia Abecia 2Iratxe Seoane 2Juan Anguita 3José Luis Cabriada 4Gastroenterol Hepatol. 2023 Jul 6:S0210-5705(23)00370-9. doi: 10.1016/j.gastrohep.2023.07.001.[Article in English, Spanish]

Objective: Primary non-response and secondary loss of response to anti-TNF agents are common in inflammatory bowel disease. Increasing drug concentrations are correlated to better clinical response and remission rates. Combination of granulocyte-monocyte apheresis (GMA) with anti-tumor necrosis factor (TNF) agents could be an option in these patients. The objective of our study was to perform an in vitro assay to determine if the GMA device can lead to infliximab (IFX) adsorption.

Patients and methods: A blood sample was obtained from a healthy control. It was incubated with three concentrations of IFX (3, 6, and 9μg/ml) at room temperature for 10min. At that time, 1ml was collected to determine the IFX concentration. Then, 10ml of each drug concentration was incubated with 5ml of cellulose acetate (CA) beads from the GMA device at 200rpm for 1h at 37°C to simulate physiological human conditions. A second sample of each concentration was collected and IFX levels were determined.

Results: No statistically significant differences were observed in the IFX levels in the blood samples before and after incubation with the CA beads (p=0.41) and after repeated measurements (p=0.31). Mean change was 3.8μg/ml.

Conclusions: The in vitro combination of GMA and IFX did not change the circulating levels of IFX at the three concentrations tested, suggesting that there is no interaction between the drug and the apheresis device in vitro and that they might be safely combined with each other.

An in vitro analysis of the interaction between infliximab and granulocyte-monocyte apheresis – PubMed (nih.gov)

An in vitro analysis of the interaction between infliximab and granulocyte–monocyte apheresis – ScienceDirect

Scientific corner

Sustained effect of leukocytapheresis/ granulocytapheresis versus anti-human TNF-α monoclonal antibody on ulcerative colitis: A 2-year retrospective study

Masahiro Sakai 1Koichi Hayashi 2Tomoyuki Ito 3Haruka Otani 3Yuya Mori 3Shinsuke Ito 1Keita Endo 1Hiroto Matsuda 4Kaede Yoshino 1Koichi Kitamura 1Eiji Kubota 5Yasuaki Motomura 6Yasuhiro Suzuki 7Shigeki Fujitani 8Toshihiko Suzuki 1Medicine (Baltimore). 2023 Apr 21;102(16):e33368. doi: 10.1097/MD.0000000000033368.

Although anti-tumor necrosis factor-α monoclonal antibody biological preparations (BP) agents are widely used as an established treatment tool for refractory ulcerative colitis (UC), whether leukocytapheresis /granulocytapheresis (L/G-CAP) has similar beneficial impact on the disease activity remains undetermined. Furthermore, the costs defrayed for the treatment with these 2 modalities have not been compared. We retrospectively evaluated whether L/G-CAP offered sustained beneficial effects over 2-year period. The patients who had moderately to severely active UC (Rachmilewitz clinical activity index (CAI) ≧ 5) and were treated with a series (10 sessions) of L/G-CAP (n = 19) or BP (n = 7) as an add-on therapy to conventional medications were followed. Furthermore, the cost-effectiveness pertaining to the treatment with L/G-CAP and BP was assessed over 12 months. At baseline, L/G-CAP and BP groups manifested similar disease activity (CAI, L/G-CAP; 7.0 [6.0-10.0], BP; 10.0 [6.0-10.0], P = .207). The L/G-CAP and BP treatment suppressed the activity, with CAI 1 or less attained on day 180. When the L/G-CAP group was dichotomized into L/G-CAP-high and L/G-CAP-low group based on CAI values (≥3 or < 3) on day 365, CAI was gradually elevated in L/G-CAP-high group but remained suppressed in L/G-CAP-low group without additional apheresis for 2 years. Anemia was corrected more rapidly and hemoglobin levels were higher in BP group. The cost of the treatment with L/G-CAP over 12 months was curtailed to 76% of that with BP (1.79 [1.73-1.92] vs 2.35 [2.29-3.19] million yen, P = .028). L/G-CAP is as effective as BP in a substantial number of patients over 2 years. The cost for the treatment of UC favors L/G-CAP although the correction of anemia may prefer BP. Thus, L/G-CAP can effectively manage the disease activity with no additional implementation for 2 years although further therapeutic modalities might be required in a certain population with high CAI observed on day 365.

Sustained effect of leukocytapheresis/granulocytapheresis versus anti-human TNF-α monoclonal antibody on ulcerative colitis: A 2-year retrospective study – PubMed (nih.gov)

Sustained effect of leukocytapheresis/granulocytapheresis versus anti-human TNF-α monoclonal antibody on ulcerative colitis: A 2-year retrospective study – PMC (nih.gov)

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