I Rodríguez-Lago, D Ginard, R J Díaz Molina, M Vicuña, E Domenech, M Abanades, O Moralejo Lozano, G Bastida, A D Sánchez Capilla, E Iglesias, F Rancel-Medina, M D M Blasco, M Bosca-Watts, M Calvo Iñiguez, C Herrera deGuisé, E Leo, A Viejo Almanzor, V Hernández Ramirez, C Suárez Ferrer, L Quilez Pérez, M Muñoz, F Fernández Pérez, J M Huguet, P Fradejas, C López Ramos, A M Fuentes Coronel, C Reygosa Castro, N Rull Murillo, P Zapico, J L Cabriada
Journal of Crohn’s and Colitis, Volume 18, Issue Supplement_1, January 2024, Page i1011, doi.org=10.1093/ecco-jcc/jjad212.0641

Background
The clinical efficacy of granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn in patients (pts) with inflammatory bowel disease (IBD) has been reported in several clinical trials (CT), with significant clinical remission rates. However, evidence on real-world effectiveness of GMA with Adacolumn in ulcerative colitis (UC) or Crohn’s disease (CD) patients who were underrepresented in CT is still limited.

Methods
GRACE is a multicentric, prospective observational study conducted at 31 centres in Spain. The study included adults (≥18 years) diagnosed with UC or CD who had been scheduled to receive GMA with Adacolumn in clinical practice. The study consisted of a baseline (GMA initiation) and 3 follow-up visits at 4, 24, and 48 weeks after the last GMA session. The primary endpoint is the steroid-free remission rate at 24 weeks. This interim analysis is focused on clinical characterization of patients and their management and outcome 4 weeks after GMA treatment.

Results
A total of 95 evaluable patients were included at data cut-off date (25 Sept 2023) (median age: 54 years; 50% men: 81% outpatients). Overall, 89.4% (n=84) of patients had UC, being moderate-to-severe in 85.5%; 57,8% had pancolitis, and the median Mayo score was 5 (interquartile range [IQR], 3-6). Out of the 10 patients (10.6%) with CD, all had B1, and 3 patients had L1, 4 L2 and 3 L3. Overall, 17% had extraintestinal manifestations. Regarding IBD-related therapy, 52.6% of patients had previously received anti-TNF agents, 37.9% thiopurines, and 17.8% JAK inhibitors. Overall, 85.3% of patients received concomitant treatment with GMA, most commonly 5-ASA (60%), corticosteroids (51,6%), ustekinumab (20%), vedolizumab (17.9%), and anti-TNF therapy (11.6%). A total of 71 patients reached the 4-week visit after receiving a median of 10 (IQR, 8-10) GMA sessions (weekly: 26.3%, biweekly: 36.8%, and weekly/biweekly: 31.6%). At week 4, clinical remission was achieved by 50.7% of patients (UC: 49.2%; CD: 66.7%), being 50% and 53.3% in patients concomitantly treated with ustekinumab and vedolizumab. Steroid-free remission rate was 26.1% (UC: 22.2%; CD: 66.7%) at week 4. Overall, 11,2% of patients experienced AEs related to GMA, most of them being mild (73%) or moderate (22.4%). Most common AEs were headache and asthenia. No SAEs were observed.

Conclusion
Preliminary data at 4 weeks show that Adacolumn is a safe and effective treatment in a cohort of IBD refractory patients with previous failure to multiple therapies including thiopurines, biologics and JAK inhibitors. Half of patients were concomitantly treated with biologics, and their clinical remission rate was similar to the overall population. Long-term results of this study (48 weeks) are required to confirm these findings.

Satoshi Tanida 1 2, Ryoji Kubo 3, Shoichiro Yoshii 3, Takuya Takahama 2, Shun Sasoh 2, Yoshimasa Kubota 2, Tesshin Ban 2, Tomoaki Ando 2, Makoto Nakamura 2, Takashi Joh 2 Case Reports J Clin Med Res . 2023 Dec;15(10-11):446-455. doi: 10.14740/jocmr5005. Epub 2023 Nov 3.

A 44-year-old woman who had been diagnosed with ulcerative colitis (UC) at 22 years old was diagnosed with severe flare-up of UC based on endoscopic findings associated with new-onset active pyoderma gangrenosum (PG) on both lower legs after she decided to discontinue UC treatment. Systemic treatment with intravenous prednisolone at 30 mg/day had achieved insufficient response to UC and PG, resulting in a diagnosis of corticosteroid-refractory UC and PG. Combination therapy with upadacitinib at 45 mg/day plus intensive granulocyte and monocyte adsorptive apheresis (GMA) was started to achieve clinical remission of UC. Ten weeks after starting this combination therapy, clinical improvement of UC was achieved with PG ulcer healing on both lower legs. A combination of upadacitinib plus intensive GMA may offer an effective therapeutic option for patients with active PG in addition to UC but has yet to be approved for induction or maintenance treatment of PG worldwide. PG is a dermatological involvement in UC patients that requires attention.

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.

Tomoyoshi Shibuya,Osamu Nomura,Kei Nomura,Mayuko Haraikawa,Keiichi Haga,Dai Ishikawa,Taro Osada,Ken Yamaji,Shigaku Ikeda,Akihito Nagahara

Ther Apher Dial 2022 Mar 5. doi: 10.1111/1744-9987.13823. Online ahead of print.

Introduction: In recent years, the prevalence of inflammatory bowel diseases has been increasing in Japan due to the westernization of lifestyles. Many patients have been reported to have extra-intestinal manifestations (EIMs) at least once. Skin lesions occur with a high degree of frequency among EIMs, with erythema nodosum (EN) and pyoderma gangrenosum (PG) the main complications. Cytapheresis is again attracting attention as a treatment with few side effects. Methods: We investigated the therapeutic effect of cytapheresis on ulcerative colitis (UC) and cutaneous EIMs. Between 2008 and 2021, 240 patients with active UC had induction therapy by cytapheresis at our hospital. Results: Remission and response rates were 50.0% and 67.5%, respectively. Apheresis was performed on seven patients with PG and five patients with EN with a good response. Serious adverse events were not observed. Conclusion: This retrospective assessment of efficacy showed that EN and PG responded favorably to cytapheresis.

https://pubmed.ncbi.nlm.nih.gov/35247233/

Yuko Higashi,Atsuko Ibusuki,Naoko Baba,Miho Hatanaka,Ko-Ichi Tada,Takuro Kanekura, therapeutic apheresis and dialysis  First published: 09 August 2021

Pyoderma gangrenosum (PG), a chronic aseptic inflammatory skin disease characterized by skin ulcers with elevated and undermined borders, is resistant to conventional therapies. PG is elicited by activated neutrophils and macrophages and is often associated with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis, aortitis syndrome, and hematopoietic disorders. This single-center study assessed the efficacy and safety of selectively depleting myeloid-lineage leukocytes in patients with PG. Patients with PG, aged 20 or over, received 5 or 10 treatment sessions of granulocyte and monocyte adsorption apheresis (GMA), once or twice a week. Treatment efficacy was assessed based on the rate of skin ulcer reduction, the visual analog scale of pain, and the physician’s global assessment of the skin lesions. A complete response (CR) was obtained in eight patients, a nearly complete response (nCR) in three patients, and a partial response (PR) in two patients. In four of the other six, the disease remained stable (SD) and in two we observed disease progression (PD). No severe adverse events were recorded. Our results suggest that GMA is a useful and safe treatment modality for PG.

https://onlinelibrary.wiley.com/doi/10.1111/1744-9987.13720

Yumiko WATANABE,Hiromichi YAMADA, https://doi.org/10.1111/j.1346-8138.2008.00572.x

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1346-8138.2008.00572.x

Munenori Kawai, Chiharu Kawanami, Akihisa Fukuda & Hiroshi Seno

Clin J Gastroenterol. 2021 Oct;14(5):1561-1566. doi: 10.1007/s12328-021-01460-0. Epub 2021 Jun 8.

An 18-year-old woman was admitted to our hospital with fever, diarrhea and painful skin ulcers in both pretibial areas starting 19 days earlier. The skin lesions appeared deep necrotic ulcers with violaceous undermined borders. She had been diagnosed as ulcerative colitis and primary sclerosing cholangitis (PSC) 6 and 5 years before, respectively, and had stopped having regular check-up and refused medication for years. Her clinical history and skin lesions led us to suspect of pyoderma gangrenosum (PG). The skin biopsy showed aseptic abscess formation with neutrophils infiltration in the dermis without bacteria. Thus, she was diagnosed with PG. 1 mg/kg/day of prednisolone was administered and ten sessions of granulocyte and monocyte adsorption apheresis (GMA) were started. Magnetic resonance cholangiography showed multifocal bile duct strictures due to PSC. Total colonoscopy revealed ulcerative pancolitis with spared normal mucosa in the rectum. After the treatments, her symptoms and the skin lesion improved dramatically. She was discharged on the 45th day with 25 mg/day of prednisolone. In conclusion, this is the first reported case of PG with PSC-associated colitis that showed dramatic response to the concomitant GMA therapy with corticosteroids. Together with previous reports, concomitant GMA therapy with corticosteroids may be an effective treatment for PG.

https://pubmed.ncbi.nlm.nih.gov/34101129/

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/

Kentaro Tominaga, Kenya Kamimura, Hiroki Sato, Masayoshi Ko, Yuzo Kawata, Takeshi Mizusawa, Junji Yokoyama, and Shuji Terai, World J Clin Cases. 2020 Jun 6; 8(11): 2092–2101.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis clinically characterized by the presence of painful skin ulcerations with erythematous. As it is frequently associated with inflammatory bowel diseases, including ulcerative colitis, gastroenterologists should be familiar with the disease including therapeutic options. Pyoderma gangrenosum is one of the neutrophilic dermatoses often complicated with ulcerative colitis. The corticosteroid and other immune modulator have been used for the treatment, however, as its disease mechanism has not been clarified, there is no additional option for those who showed poor response and refractory to the conventional therapies. Therefore, we have conducted a review focusing on the cytapheresis for PG in cases of inflammatory bowel diseases. A literature search was conducted to extract studies published in the last 20 years, with information on demographics, clinical symptoms, treatment, and the clinical course from a total of 22 cases reported and our recent case. In most patients, cytapheresis was associated with improvement or resolution of PG after failure of conventional therapeutic options such as corticosteroids, antibiotics, immunosuppressive agents and immunoglobulin. Based on the recent reports, we have summarized the clinical course of 23 cases and efficacy of cytapheresis..Cytapheresis is helpful in the majority of patients with PG refractory to medical treatment associated with inflammatory bowel diseases and could be further studied in a multicenter, randomized trial.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281039/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281039/pdf/WJCC-8-2092.pdf