Introduction

Ustekinumab has been recently approved for the treatment of moderately to severe ulcerative colitis (UC). Data from the UNIFI clinical trial are encouraging; nevertheless, real-world assessment is needed.

Aims & Methods

We assess the effectiveness, safety and pharmacokinetics of ustekinumab in a cohort of refractory UC patients.
Multicentre and observational study of UC patients who received ustekinumab for active disease. Values for Partial Mayo Score (PMS), endoscopic activity, C reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8, 24 and 52 weeks and at 18 and 24 months when was possible. Demographic and clinical data, previous treatments, adverse events (AEs), surgeries and hospitalizations were documented. Possible predictors of response were examined.

Results

Two patients only received the first IV dose. During follow-up, 58 patients (54%) required interval reduction (every 4 weeks (76%) and every 6 weeks (24%)) after a median of 22.3 weeks [11.6, 41.2]. Intravenous reinduction doses were administered to 20 (18.5%) after 27.7 weeks [6.64, 56.3]. Three patients required a maintenance therapy with IV administration. The clinical remission (PMS≤ 2) rates were 39.6%, 41%, 51% at 8, 24 and 52 weeks, respectively, and 61%, and 57.7% at 18 and 24 months, respectively. FC levels returned to normal (<250 μg/g) in the 39.6%, 41%, 51%, 61%, 58% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively. CRP returned to normal (<3 mg/L) in the 79%, 75%, 76.5%, 71% and 70% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively.
Fewer previous anti‐TNF agents and the loss of response to anti-TNF were associated with clinical response and with normalization of FC respectively. No variables at baseline (body mass index, serum albumin, and lymphocytes count) were associated with ustekinumab through levels. Of the 17 patients with endoscopy before and after treatment, 6 were in remission and 3 with mild activity. The AEs were recorded in 5 (4.6%) patients, 12 (11%) were hospitalized and 9 (8.3%) had surgery. A total of 23 patients (21%) discontinued ustekinumab over time, the persistence rates were 98%, 91%, 83% and 81% at 8, 24, 48 and 96 weeks respectively.

Conclusion

This is the first study to show the real‐world long-term effectiveness, persistence, endoscopic improvement and safety of ustekinumab in a cohort of highly refractory UC patients. The clinical remission preceded the FC normalization. Ustekinumab through levels and their pharmacokinetic require further investigations.

Clinical Case Summary

Introduction: Henoch Schoenlein Purpura (HSP) is an IgA immune mediated vasculitis. It is usually preceded by upper respiratory tract infection. It is more common in males. It is more predominant in paediatric population. However, its incidence in adults is extremely rare with 3.4-14.3 cases / million. Only 10-20% of patients present with gastrointestinal symptoms.
Case presentation: A 39-year-old male presented with rash, abdominal pain, vomiting and watery diarrhoea. His rash was non-itchy non-painful purpuric petechial which covered both upper and lower limbs consistent with HSP. He had diffuse angiokeratoma type lesions on the dorsum of his feet, hands, lateral side of thighs and buttocks. He upper respiratory tract infection for 1 week. Vitals signs were unremarkable. Bloods showed high CRP, ESR, IgA and WBCs. Procalcitonin was negative. ASO showed high titers. The rest of his bloodwork was negative including autoimmune screen and ANCA. Urine analysis showed persistent haematuria with negative urine culture.
CT abdomen showed jejunal wall thickening and oedema with fat stranding and mesenteric nodes. MRI small bowel found abnormal oedematous loops of small bowel proximally within the left flank. keeping with acute small bowel inflammation. However, distribution was not classical for inflammatory bowel disease. Rheumatology team started him on steroids for suspected Henoch-Schoenlein Purpura. He improved subsequently.
Discussion: This patient presented with HSP related enteritis after he had a recent upper respiratory tract infection and HSP characteristic rash. He was treated successfully with steroids.
Conclusion: Clinicians should be aware that Henoch Schoenlein Purpura could be present in adults despite being more prevalent in children. Clinicians should suspect HSP in adults when a patient presents with classic rash, abdominal symptoms and raised inflammatory makers after a recent upper respiratory infection.

References

Nevrekar RP, Bhandare P, Khandeparkar A. Clinical Spectrum of Henoch Schonlein Purpura in Adults: A Hospital Based Study. J Assoc Physicians India. 2022;70(2):11-12.

Introduction

Hypermobile Ehlers-Danlos syndrome (hEDS) is a hereditary non-inflammatory disorder of connective tissue laxity characterized by joint hyperextensibility in association with musculoskeletal symptoms. The prevalence of gastrointestinal (GI) symptoms, such as abdominal pain, nausea, and constipation is high in hEDS. Research on the relationship between EDS and GI symptoms has mostly been restricted to disorders of the gut-brain axis, whereas the relationship between hEDS and GI dysmotility remains to be clarified.

Aims & Methods

This study aimed to explore antro-duodenal manometry (ADM) patterns in patients with hEDS presenting with GI symptoms.

In a prospective open-label study, patients with hEDS and GI symptoms presumed to be the results of GI dysmotility underwent a 6-hour high resolution ADM. The manometry tracings were analyzed by two investigators (KS and JC) independently. Antral contraction frequency (contractions per minute) < 1.0 was considered as antral hypomotility. Pylorospasm was defined as isolated pyloric pressure waves within 60 minutes postprandial. The following neuropathic enteric patterns were scored: presence of retrograde peristalsis, bursts, clustered contractions, and absence of phase III contractions. Abnormal ADM was defined as having antral hypomotility and/ or pylorospasm and/ or neuropathic enteric patterns.

Results

Fifty patients (48 women, mean age 30.4 ± 11.1 yrs.) were included. At baseline, 74% of patients were dependent on enteral feeding and the mean BMI was 20.4 ± 4.4 kg/m².
Overall, ADM tracings with one or more abnormal patterns were identified in 53% of patients. Antral hypomotility and pylorospasm were detected in 29% and 15% of patients, respectively. Neuropathic enteric patterns were only seen in 17% of patients. In all cases, no more than one neuropathic pattern was identified. Among the observed neuropathic enteric patterns, 15% of patients showed retrograde peristalsis, 13% absence of phase III contractions, and 2% bursts. Clustered contractions were not identified in this cohort.

Conclusion

Hypermobile Ehlers-Danlos patients presenting with gastrointestinal symptoms showed low numbers of abnormal ADM patterns. In particular, enteric dysmotility was observed in only a small minority of cases. Antroduodenal dysmotility therefore does not appear to be a principle pathomechanism in the majority of hEDS cases studied. Further research is needed to understand the mechanisms that underlie GI symptom generation in this population.

Introduction

Celiac disease, a chronic autoimmune enteropathy caused by exposure to gluten in genetically predisposed individuals, is characterized by a broad clinical spectrum often with multisystem involvement. Symptoms related to the reproductive system include delayed menarche, early menopause, fertility disorders, miscarriages, and prematurity.

Aims & Methods

To study the impact of celiac disease on fertility in a female Greek population. A retrospective review of all patient records from the celiac disease outpatient clinic at our hospital.

Results

Medical histories of 231 female patients were reviewed (69% of the total patient population) with a mean age of 44.3 years and a mean age at diagnosis of 35.3 years. The mean age of menarche was 12.7 years. Menstrual irregularities were reported in 27% (20% instability, 7% dysmenorrhea). A total of 28% (65/231) were in menopause, with an average age of menopause onset at 50.7 years. A history of miscarriages was recorded in 15% of all women (35/231), but in 29% of women in menopause (19/65). 82% (53/65) of women in menopause had children, with 98% (52/53) having been pregnant before the diagnosis of the disease. Among all women who gave birth, only 12/113 (11%) had been diagnosed before pregnancy. 56% (63/113) and 44% (50/113) had a vaginal delivery and cesarean section, respectively. Pregnancy complications were recorded in 24 women (18 preterm births, 15 low birth weight infants, 1 intrauterine death).

Conclusion

Women with celiac disease tend to have relatively late menarche and an increased rate of miscarriages. However, the disease does not seem to significantly affect fertility.

References

1.Ehud Galron MD, Rayna Boyarsky MD,Ido Sold MD, Chen Ben David MD,and Eyal Gal MD,Interactions between celiac disease and pregnancy:A literature review, Isr Med Assoc J.2023 Dec;25(12):830-835
2.Giovanni Casella et. Al. Celiac disease and obstetrical-gynecological contribution, Gastroenterol Hepatol Bed Bench. 2016 Autumn; 9(4): 241–249.
3.Stephanie M. Moleski et. Al., Increased rates of pregnancy complications in women with celiac disease, Annals of Gastroenterology (2015) 28, 236-240
4.Nafeesa N. Dhalwani et Al., Women With Celiac Disease Present With Fertility ProblemsNo More Often Than Women in the General Population, Gastroenterology 2014;147:1267–1274

Clinical Case Summary

A 2-week-old full-term female infant presented to the pediatric emergency department with five days of vomiting, loss of appetite, and bloody stools. Initially fed a cow milk-based formula, she did not gain weight. On admission, she appeared lethargic, with vital signs indicating low blood pressure, elevated heart rate, increased respiratory rate, and a body temperature of 36.6°C. Cold extremities, delayed capillary refill time, and marbled skin were noted. Abdominal examination revealed distension without peritonitis or skin discoloration, and no hepatosplenomegaly was present. Laboratory tests showed metabolic acidosis with an elevated anion gap and high lactate levels. The patient vomited stomach contents and fecal material, prompting the use of a nasogastric tube, which drained extensively. An abdominal x-ray revealed diffuse pneumatosis in the intestinalis without bowel perforation. Managed in the pediatric intensive care unit with nil per os, total parenteral nutrition, and empirical parenteral antibiotics. Blood and urine cultures, as well as stool PCR testing for common viral and bacterial pathogens, were negative. The infant showed improvement after two weeks of conservative treatment, including abdominal X-rays, which revealed normal gas patterns without signs of pneumatosis intestinalis. Introduction of an amino acid-based formula was well-tolerated without recurrence of symptoms.

Pneumatosis intestinalis mainly occurs during the neonatal period and is more common among preterm neonates. The main etiology is necrotizing enterocolitis (NEC). However, it can present among term neonates, infants, children, and even adults. The differential diagnosis is wide, including cow’s milk protein allergy, infectious diseases, trauma, ischemia, child abuse, and intestinal failure.
The working diagnosis of this case was pneumatosis intestinalis secondary to milk protein allergy, which was managed successfully and conservatively without any invasive procedure.

References

1. Im J, Anjum F. Pneumatosis Intestinalis. [Updated 2023 Apr 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564381/
2. Abramov A, Luks VL, De Bie F, Hwang R, Allukian M 3rd, Nace GW Jr. Pneumatosis intestinalis in children beyond the neonatal period: is it always benign?. Pediatr Surg Int. 2022;38(3):399-407
3. Overman RE Jr, Criss CN, Gadepalli SK. Necrotizing enterocolitis in term neonates: A different disease process? J Pediatr Surg. 2019 Jun;54(6):1143-1146.
4. Narumoto S, Sakamoto S, Uchida H, et al. Necrotizing enterocolitis in the setting of milk allergy after pediatric living donor liver transplantation. Pediatr Transplant. 2018 Feb;22(1).
5. Reppucci ML, Nolan MM, Cooper E, et al. Pneumatosis Intestinalis in Children With Intestinal Failure: The Result of Intestinal Stress From Enteral Feeding?. J Pediatr Gastroenterol Nutr. 2023;76(5):560-565.

Clinical Case Summary

A 25-year-old man, a law graduate, denied significant medical history, except for an appendectomy in 2014. He was diagnosed with chronic idiopathic ulcerative colitis in 2016 and was previously treated with mesalazine 4.5g every 24 hours. A colonoscopy in 2019 showed pancolitis Mayo 3 (Montreal S2-E3). Due to the lack of response to conventional treatment, prednisone cycles were initiated, and infliximab was started at a dose of 5mg/kg since 2019 with an adequate clinical response. On 12/24/2020, calprotectin was 5149 mcg/g.
In September 2021, he presented with asthenia, adynamia, dizziness, and unquantified fever, so he went to the hospital, where systemic inflammatory response syndrome was evident (tachycardia, fever of 39°C, and leukocytosis, dyspnea). Serial blood cultures and bacilloscopies were negative, and a chest CT scan showed a solid nodule-like pulmonary lesion in the right middle lobe (image 1). In November 2021, a thoracotomy with right middle lobectomy was performed, revealing abundant purulent material and a suggestive lesion of a lung abscess; it was positive for Nocardia farcinica, and histopathological results were positive for Nocardia spp. The patient subsequently developed cerebellar syndrome, and an MRI on November 5, 2021, showed cerebellar abscesses in the left hemisphere and hydrocephalus (image 1), requiring a ventriculoperitoneal shunt placement and surgical decompression, draining abscess, and isolating Nocardia spp.
Directed antibiotic therapy (trimethoprim-sulfamethoxazole) was started and continued until December 2021 with clinical improvement. Anti-TNF was discontinued, and mesalazine, steroid, and azathioprine were continued to maintain clinical remission of the disease without neurological and respiratory sequelae.

References

1. Abreu C, Rocha-Pereira N, Sarmento A, Magro F. Nocardia infections among immunomodulated inflammatory bowel disease patients: A review. World J Gastroenterol. 2015 Jun 7;21(21):6491-8. Doi: 10.3748/wjg.v21.i21.6491. PMID: 26074688; PMCID: PMC4458760.
2. Margalit I, Goldberg E, Ben Ari Y, Ben-Zvi H, Shostak Y, Krause I, Muhsen K. Clinical correlates of nocardiosis. Sci Rep. 2020 Aug 31;10(1):14272. Doi: 10.1038/s41598-020-71214-4. PMID: 32868850; PMCID: PMC7459281.
3. Garner O, Ramirez-Berlioz A, Iardino A, Mocherla S, Bhairavarasu K. Disseminated Nocardiosis Associated with Treatment with Infliximab in a Patient with Ulcerative Colitis. Am J Case Rep. 2017 Dec 21;18:1365-1369. Doi: 10.12659/ajcr.906391. PMID: 29263313; PMCID: PMC5742452.

Disclosure

Patients with Inflammatory Bowel Disease (IBD) undergoing anti-TNFa treatment are at risk of opportunistic infections, including nocardiosis, caused by Nocardia, gram-positive bacteria that can cause local (lung, skin, and brain) or disseminated infections. In the literature, only 11 cases of nocardiosis related to anti-TNFa have been reported¹.TNFa is an important mediator of inflammation for granuloma formation, and Nocardia spp. is one of the pathogens that generate these granulomas². The diagnosis of nocardiosis should have a high clinical suspicion, especially in patients with risk factors, as it is one of the least reported opportunistic infections, in our case, with the use of anti-TNF in the context of IBD. There are no official reports on prevalence and incidence in the literature².
The most frequent sites of dissemination are the lungs and skin, leading to the central nervous system and any organ³. The diagnostic confirmation is made through pathogen isolation in a clinical sample, which was performed through histopathology of a pulmonary segment².
Treatment is based on antimicrobial therapy and restoration of complications, in our case, a segmentectomy was necessary due to pulmonary infection, and a ventriculoperitoneal shunt placement was necessary due to central nervous system involvement. TMP/SMX has been considered the first-line antimicrobial for 50 years², but targeted therapy based on isolation is recommended, with alternatives including amikacin, carbapenems, and third-generation cephalosporins². The response to TMP/SMX was appropriate in this case.