Introduction

Tumor necrosis factor inhibitors (anti-TNF) are associated with several adverse effects, including paradoxical reactions like psoriasiform lesions and less common drug-induced sarcoidosis-like reactions. They present significant diagnostic and therapeutic challenges, as they require careful differential diagnosis and often necessitate the discontinuation of treatment. Initially described in patients with inflammatory rheumatic diseases, sarcoidosis-like lesions induced by anti-TNF therapy have been sparsely documented only through case reports in the context of Inflammatory Bowel Diseases (IBD).

Aims & Methods

This study aimed to comprehensively describe epidemiological, diagnostic and therapeutic features of sarcoidosis-like lesions in IBD patients treated anti-TNF therapy, along with patient outcomes.
We conducted a nationwide observational case series across 59 institutions affiliated with the Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID). The diagnosis of anti-TNF-induced sarcoidosis was based on typical clinical and radiological signs, histological evidence of non-necrotizing granuloma, exclusion of differential diagnoses, and a timeline consistent with drug exposure. Each case was reviewed by a pharmacovigilance expert to confirm drug causality.

Results

We identified 12 cases of sarcoidosis-like lesions during anti-TNF therapy, with an equal distribution of male and female and a median age of 39 years (range 25-55). Underlying conditions were Crohn’s Disease (58.3%), Ulcerative Colitis (33.3%) and Inflammatory Bowel Disease Unclassified (8.3%). The median duration of IBD prior to diagnosis was 14 years (range 5-29).
The anti-TNF medications involved were infliximab (58.3%), adalimumab (33.3%) and golimumab (8.3%), with the majority of patients (75%) being first-time users of biotherapy.
6 patients had optimized treatment. The median time from anti-TNF initiation to diagnosis was 22.7 months (range 3-91).
The most commonly observed clinical manifestations were dyspnea (75%) and fever (58.3%). Affected organs included the lungs (100%), liver (16.7%), extrathoracic adenopathy (16.7%), spleen (16.7%), parotid gland (8.3%), and kidneys (8.3%). There was a case of Löfgren syndrome and one of meningitis. Eight patients discontinued anti-TNF therapy and started oral steroids, resulting in complete resolution of symptoms in five cases and improvement in two. One patient with multivisceral sarcoidosis required azathioprine addition due to renal insufficiency. Anti-TNF discontinuation was the only intervention in 2 cases, giving clinical remission in both. In 2 other cases, resolution of symptoms was observed with addition of steroids without anti-TNF discontinuation. Median time from steroid initiation (daily dose of 30 or 60 mg) to clinical remission was 91 days (range 11-305).
After a median follow-up of 48 months (range 18-175), one case showed persistent sarcoidosis activity, while no relapses were noted in the others. Anti-TNF therapy was resumed in only one patient, without recurrence of granulomatous lesions. Of the 10 patients who discontinued anti-TNF, all needed a new line of treatment, which was mostly vedolizumab. At last follow-up, IBD activity was noted in 4 patients.

Conclusion

Sarcoidosis-like lesions represent a rare but significant adverse reaction to anti-TNF therapy in IBD patients. This diagnosis should be considered when patients present with persistent respiratory or systemic symptoms after ruling out mycobacterial infection. Management involves discontinuation of anti-TNF and introduction of steroids.

Introduction

In the recent years, the therapeutic options for inflammatory bowel disease (IBD) have expanded. Multiple Janus kinase (JAK) inhibitors have been licensed: First Tofacitinib (TOFA) for Ulcerative Colitis (UC), followed, most recently, by Filgotinib (FIL) in UC and Upadacitinib (UPA) in UC and Crohn’s Disease (CD).

Aims & Methods

The aim of the study was to explore the real-world effectiveness and safety of UPA in a multicenter Belgium refractory cohort of patients with moderate-to-severe CD.
This is an observational, national, retrospective multicenter study including all patients with active CD initiating UPA between September 2022 and January 2024 from 16 Belgian centers. Clinical remission and response were defined using the two-component patient reported outcome. Endoscopic response was defined as a decrease in baseline Simple Endoscopic Score (SES-CD) with ≥ 50%. Endoscopic remission was defined as SES-CD ≤ 4 or disappearance of baseline ulcers. Effectiveness endpoints were evaluated at week 12, 24 and 52, while CD-related hospitalization, surgery and safety were assessed throughout follow-up.

Results

Of the 66 patients who started UPA, 52 patients were analysed (6 excluded for ostomy and 8 for not having yet reached 24 weeks of follow-up) with a median follow-up of 21 weeks (IQR: 4-24). Patients were predominately female (54%), median age at baseline was 37 years old (IQR: 19-62) and median disease duration was 13 years (IQR: 0-29). 12% of the patients had ileal CD, 12% colonic CD, 76% ileocolonic CD with 17% concomitant upper gastrointestinal CD and 42% concomitant perianal disease. The majority of the patients (87%) was exposed to ≥ 3 biologics and 54% had previously undergone a CD-related surgery.
At week 24, 58% and 44% of overall eligible patients achieved steroid-free clinical response and remission, respectively. Endoscopic data were available in 17 out of the 52 patients of whom 65% and 47% reached endoscopic response and remission respectively within the first 24 weeks. Sixteen out of eighteen patients that used concomitant steroids at baseline were able to stop it by week 24.
Overall, 21 patients (40%) discontinued their treatment during follow-up with a median exposure duration of 16 weeks (IQR: 4-24): 11 due to primary non response, 3 due to secondary loss of response, 7 due to adverse event (AE). Among these 21 patients, 4 patients underwent CD-related surgery (2 intestinal resections and 2 diverting ostomies) after a median duration of 15 weeks (IQR: 11-24), while the others switched to another medical therapy. In total, 21%% (11/52) patients required hospitalization within 24 weeks.
Twenty-seven AEs were reported in 19 (37%) patients, with 7 leading to treatment discontinuation (2 allergic skin rash, 1 severe acne, 1 folliculitis, 1 lip oedema, 1 severe stomatitis and 1 loss of appetite). The most common reported AEs were herpes simplex reactivation, respiratory tract infection, cutaneous reactions and acne. No herpes zoster infection, thrombotic or cardiovascular event were reported.

Conclusion

In this real-world cohort of highly refractory CD patients, UPA effectively induced steroid-free clinical remission and endoscopic remission by week 24 and was relatively well tolerated with respect to adverse events.

Disclosure

Dr Anneline Cremer has received lecture and advisory board fees from Galapagos, Abbvie, Janssen (2009-2014); lecture fees from Celltrion (2019-2024), Pfizer (2018-2023); advisory board fees from Takeda (2018-2023).
Dr Denis Franchimont has received lecture and/or advisory board fees from Abbvie, AstraZeneca, Dr. Falk Pharma, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Amgen and research grants from Abbvie, Janssen, Takeda, Celltrion and Amgen (2019-2024).

Clinical Case Summary

Colorectal lymphomas are a rare cause of colonic neoplasia (0.2-0.6% malignant neoplasms of large bowel). Approximately 10% are primary colorectal lymphomas, while the rest correspond to colonic extension of systemic lymphoproliferative diseases.
We present the case of a 66-year-old woman with a history of rectum and pancreas adenocarcinoma (both in remission). During a follow-up CT, a thickening of the cecal pole was identified, with no adenopathy or other relevant findings (Photo1). The patient had no abdominal pain or B symptoms (night sweats, weight loss or fever).
The diagnosis was completed with a PET-CT that showed pathological uptake in the cecum (Photo2), so a colonoscopy was performed, which revealed a large polypoid lesion (30 mm) at the ileocecal level, with nodular areas with small ulcerations and no clear loss of the glandular pattern (Photo 3), from which multiple biopsies were taken.
Biopsies showed lymphoid proliferation with a ‘starry sky’ pattern, mitosis and apoptosis, and positive immunohistochemistry for CD45, CD20, CD10, BCL6, BCL2 and C-MYC, together with a high proliferation index (Ki-67 > 95%), all compatible with high-grade B-lymphoproliferative syndrome with Burkitt morphology (Photo 4).
Burkitt's lymphoma is a rare B-cell lymphoma (15% of GI lymphomas), associated with chromosomal translocation (8:14, 8:22 and 2:8) and overexpression of c-myc oncogene.
There are three clinical variants: endemic (common in Africa and associated with EBV and malaria), HIV-associated and sporadic (20%).
It is common in children and its most frequent symptoms are abdominal pain and weight loss, so diagnosis is often delayed. Although the yield of endoscopic biopsies is low (<20%), it is a key tool in its diagnosis, along with targeted biopsy of abdominal adenopathies.
Despite its aggressiveness, treatment with targeted chemotherapy achieves rates of more than 90%, and early diagnosis is essential to avoid complications and ensure adequate medical treatment.

References

- Photo 1: Thickening of the cecal pole seen in CT-Scan.
- Photo 2: Pathological uptake in the caecal area as seen on PET-CT Scan.
- Photo 3: Polypoid lesion in ileocecal area at colonoscopy
- Photo 4: Pathological anatomy of endoscopic biopsies: starry sky imaging and immunohistochemistry of Bcl-2 and C-myc

Clinical Case Summary

A 21-year-old male, smoker, presented to the Emergency Room (ER) of our hospital due to rectal bleeding, causing severe anemia (Hemoglobin (Hb) 7g/dL), and referred to Proctology consultation.
Initial assessment revealed profuse bleeding, hemorrhoidal prolapse and low output symptoms. Proctologic examination showed congestive and tender left internal hemorrhoids. Instrumental therapy was postponed due to suspected perianal abscess, later ruled out post-endoanal endoscopy and pelvic MRI. Endoscopic studies did not identify other causes for anemia.
Polidocanol foam sclerotherapy provided significant symptom relief and improved quality of life. However, after 4 months, recurrent episodes of bleeding and symptomatic anemia (Hb 5.7g/dl) occurred, requiring transfusions and iron supplementation. Hemorrhoid artery ligation with recto-anal repair (HAL-RAR) was performed. Within 15 days, he recurred 3 times to ER for rectal bleeding, and in the last he had with syncope and Hb 6.4g/dL, leading to hospitalization for hemostasis review and surgical reintervention.
During hospitalization, another episode of profuse bleeding with a minimum Hb of 4g/dL required surgical reintervention. Following multidisciplinary consultation, despite no active bleeding on CT angiography, conventional angiography with superselective embolization of right upper rectal arteries was performed, resulting in symptom and anemia resolution, allowing discharge.
At 3-month follow-up, occasional rectal bleeding was described; proctologic examination revealed mucosal prolapse with defecation straining, mildly congestive internal hemorrhoids and distal rectal scarring. Blood analysis showed no anemia (Hb 15g/dL) or iron deficiency.
This case underscores the challenge of managing refractory hemorrhoidal disease in young patients and the need of a multidisciplinary approach. Indeed, this clinical scenario was only resolved by a minimally invasive strategy, essential in complex cases.

References

Endoscopic image, angiographic image and short video

Introduction

Patients with primary biliary cholangitis (PBC) are at an increased risk of developing cirrhosis and eventually experiencing hepatic decompensation. While there is increasing evidence for more prevalent aetiologies of cirrhosis that a successful removal/suppression of the underlying aetiological factor can induce significant improvements in liver function and even enable hepatic recompensation, similar insights in PBC are scarce.

Aims & Methods

In this study, we aimed to explore clinical implications of hepatic recompensation according to the novel Baveno VII criteria in PBC, while considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris-II criteria as surrogate marker of a successful aetiological treatment. Specifically, we included cirrhotic PBC patients at the time of first hepatic decompensation (ascites, hepatic encephalopathy [HE], variceal bleeding) and analysed their subsequent clinical disease course. In accordance with Baveno VII criteria, we defined hepatic recompensation as (i) resolution of ascites and HE despite discontinuation of diuretics and HE treatment, (ii) absence of variceal bleeding and (iii) sustained improvements in biochemical liver function.

Results

This study enrolled 42 PBC patients with decompensated cirrhosis (age: 63.5 [IQR:51.9-69.2] years; 88.1% female) who were followed-up for a median of 41.9 (IQR:11.0-70.9) months after decompensation. The cause of index decompensation was ascites in 54.8%, variceal bleeding in 35.7% and HE in 9.5% of cases. At time of decompensation, the median MELD-Na was 14 (IQR:11-15). Overall, 33 patients were treated with UDCA for at least 1 year (median dose: 12.5 [IQR:10.7-15.0] mg/kg) and 36% of those (12/33) achieved the Paris-II response criteria.
Over the course of the study, 7 patients (16.7%) achieved recompensation. In a competing risk model, baseline parameters linked to a higher probability of recompensation included a lower MELD-Na (SHR: 0.90; 0.047), a lower Child-Pugh score (SHR: 0.59; p=0.019), lower bilirubin (SHR: 0.44; p=0.005), lower alkaline phosphatase (SHR: 0.96; p=0.001) and variceal bleeding as index decompensation (SHR: 4.37; p=0.069). Interestingly, while 5/12 (42%) UDCA responders recompensated and a response at 1 year was linked to a higher probability of recompensation (SHR: 5.08; p=0.041), 2/21 (10%) patients without UDCA response still eventually achieved recompensation.
Regarding prognostic implications, recompensation was linked to a numerically improved transplant-free survival in a time-dependent Cox regression model (HR: 0.46; p=0.335). Specifically, 3 recompensated patients survived without any further complications or the need for liver transplantation over a follow-up time of 35, 40 and 294 months after recompensation. Nevertheless, the remaining 4 recompensated patients presented with liver-related complications after developing hepatic malignancies and/or portal vein thrombosis (PVT) and two eventually died (18 and 29 months after recompensation). In contrast, of the patients who remained decompensated, 10 underwent liver transplantation (29%) and 17 died (49%).

Conclusion

Patients with decompensated cirrhosis due to PBC may achieve hepatic recompensation under UDCA therapy, particularly if the degree of liver dysfunction at index decompensation is less pronounced. Nonetheless, recompensated patients should be monitored carefully for the development of hepatic malignancy and PVT, as liver transplantation may still be required.

Disclosure

Albert Friedrich Stättermayer: Speaker and/or consultant and/or advisory board member for Boehringer Ingelheim, Gilead, and MSD. Benedikt Simbrunner: Travel support from AbbVie and Gilead. Mattias Mandorfer: Speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Gilead, and W. L. Gore & Associates; Travel support from AbbVie and Gilead. Michael Trauner: Grant support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and UltraGenyx; Honoraria for consulting from Albireo, Boehringer Ingelheim, BiomX, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, Pliant, Regulus and Shire; Speaker fees from Bristol-Myers Squibb, Falk, Gilead, Intercept and MSD; Travel support from AbbVie, Falk, Gilead and Intercept. Thomas Reiberger: Grant support from Abbvie, Boehringer-Ingelheim, Gilead, Gore, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, and Siemens; Speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; Consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; Travel support from Abbvie, Boehringer-Ingelheim, Gilead and Roche.