Clinical Case Summary

Background: Nocardiosis is an opportunistic bacterial infection usually occurring in immunocompromised patients. Patients with Ulcerative Colitis (UC) receiving immunosuppressants drugs can be predisposed to uncommon opportunistic infections.
Results: A 72-year old man with UC history since 1990, after a severe clinical and endoscopic exacerbation (pancolitis MAYO 3), was treated in another clinic for three months with Infliximab 5 mg/kg, Prednisone 25 mg, Budesonide 9 mg/day and Azathioprine 100 mg/day. In November 2020 he was admitted to our ward for diarrhea, low grade fever (37.5°C), severe asthenia and hyperglycaemia. During hospitalization we diagnosed with adrenocortical insufficiency, treated with fludrocortisone. Furthermore, microbiological blood tests were performed and a cytomegalovirus (CMV) systemic infection (treated with Gancyclovir) and blood cultures were positive for Nocardia farcinica. Subsequently, computed tomography (CT) abdominal imaging revealed splenic, hepatic and pulmonary lesions, suggestive of systemic involvement of the nocardiosis. Sudden seizures onset led to performing head CT, showing encephalic lesions by Nocardia. Therefore immunosuppressant therapy was stopped (except for Methylprednisolone 10 mg/day) and to start antibiotic therapy with Imipenem, Amikacin and Trimethoprim/sulphamethoxazole (TMP/SMX) and anticonvulsant treatment with Levetiracetam. As a result, the patient achieved clinical remission and progressive improvement of radiological findings within six months from discharge.
Conclusions: Unappropriated simultaneous administration of immunosuppressant drugs can increase the risk of opportunistic infections that may lead to life threatening systemic conditions, requiring complex therapies. Moreover, the onset of infections, contraindicates the administration of many medications used in UC, hindering the possibility to appropriately treat the patient.

Introduction

Patients with ulcerative colitis (UC) and concurrent cytomegalovirus (CMV) colitis are at higher risk of poorer outcomes, including developing steroid refractoriness or toxic megacolon. Given its relevance, the European Crohn's and Colitis Organization recommends, in case of flare-ups, to search for CMV by endoscopic biopsy, preferably with tissue polymerase chain reaction (PCR) or alternatively with immunohistochemistry (IHC).

Aims & Methods

The aims of our study were to compare the diagnostic yield of tissue and plasma CMVDNA PCR to IHC and to explore the different level of tissue viral load in both steroid-refractory and steroid-sensitive UC patients. This prospective study included consecutive patients undergoing colonoscopy or proctosigmoidoscopy for UC, independent of disease activity, in a single tertiary center betwen July 2024 and January 2025. Patients underwent the same day endoscopy with multiple biopsies (3 from sigmoid colon and 4 from rectum) and plasma sampling for CMVDNA analysis using real-time quantitative PCR assay; histological presence of CMV was evaluated using IHC and hematoxylin-eosin staining. Concordance among CMV detection techniques was calculated using K cohen concordance index. Continuous variables were compared using Mann-Whithney test. ROC analysis allowed to identify an ideal cut-off of viral load value of CMV infection.

Results

Twenty-one consecutive patients were enrolled. Twelve (57,1%) patients were male and 9 (42,9%) female, (range 19-79 years). Nine (42,8%) patients had a diagnosis of pancolitis, three (14,3%) of left-sided UC, seven (33,4%) of procto-sigmoiditis and two (9,5%) of proctitis. Six (28,6%) patients were subclassified as steroid-refractory, the remaining fifteen (71,4%) as steroid-responsive.
IHC positivity was observed in tissue samples from 3 (14,3%) patients, while CMVDNA was detected in tissue samples from 5 (23,8%) patients and in 3 (14,3%) plasma samples. Comparing IHC to plasma CMVDNA, the k index was only fair consistent (0.277 CI -0.327 to 0.758), while IHC versus tissue DNA showed a higher consistency, with a k index of 0.500 (CI 0.048 to 0.952).
Interestingly, the mean value of tissue CMVDNA in the steroid-refractory group was higher, although not significant, than the steroid-responsive group (respectively 140.00 copies/mg ±260.00 vs 98.00 copies/mg ±360.00, p value= 0.14). In order to identify a possible tissue CMVDNA level able to distinguish between the two groups, a receiver operating characteristic (ROC) curve analysis was performed: a cut-off value of 102.56 was associated with a sensitivity of 92.86% and a specificity of 33.3%, resulting in a likelihood ratio of 1.39. The area under the ROC curve (AUC) was 0.6667 ± 0.1415, indicating a modest discriminative ability.

Conclusion

This study showed a good concordance between immunohistochemistry and tissue PCR for the detection of CMV in UC patients. Steroid-refractory UC patients showed a higher tissue viral load compared to steroid-responsive patients.

Disclosure

No conflict of interest to declare

Introduction

Ulcerative colitis (UC) is often complicated by Cytomegalovirus (CMV) colitis. The importance of CMV infection for the outcome of UC is still ill-defined. Common practice consists of obtaining colonic biopsies to search for CMV in patients with UC flares and treat infections with ganciclovir.

Aims & Methods

The aim of the present study is to describe the characteristics and management of patients with UC and concomitant CMV infection. For this purpose, we conducted a retrospective data collection from 2 Greek hospitals for the years 2017-2023. The primary endpoint was defined as the need for colectomy in the first year after CMV infection diagnosis. The statistical program SPSS-23 was used for the analysis.

Results

In total, 47 cases of CMV infection in 37 patients with UC were reported as 7 patients experienced CMV recurrence. Most cases were observed in men (68%) with mean age of 47.5 years (SD 18.2), median UC duration 3 years (IQR 1-8) and Montreal classification E2 in 31.9% and E3 68.1% occasions. The diagnosis was established by PCR in colonic biopsies in 46.8% cases, by immunohistochemistry in another 46.8% and solely by detection of inclusion bodies in 6.4%. At the time of diagnosis of CMV infection 7 (14.9%) cases were receiving combination therapy with a biologic agent and an immunomodulator, 20 (42.6%) monotherapy with a biologic agent, and 1 (2.1%) monotherapy with an immunomodulator. Nine-teen patients (40.4%) were not on immunomodulatory therapy. Most patients (22, 46.8%) received ganciclovir and concomitant corticosteroids, while 4 (8.5%) received infliximab, corticosteroids and ganciclovir and 2 (4.3%) ustekinumab, corticosteroids and ganciclovir. One case required treatment with Foscarnet due to CMV resistance to ganciclovir, and 18 received monotherapy with ganciclovir. Regarding maintenance treatment in patients who did not require immediate colectomy, 18 (38.3%) received anti-TNF, 6 (12.7%) ustekinumab, 4 (8.5%) vedolizumab, 3 (6.4%) tofacitinib and 1 (2.1%) risankizumab. Colectomy rate in the first year after CMV infection was 21.3% with 4 patients undergoing surgery during initial hospitalization. In univariate logistic regression age >54 years (P=0.025), disease duration >6.5 years (P=0.035), serum albumin <3.8 mg/dl (P=0.026), UC PRO bowel movement >2 (P=0.016) and vedolizumab (P=0.035) as treatment at diagnosis were associated with a higher probability of colectomy in the first year. Accordingly, in multivariate logistic regression UC PRO bowel movement >2 (P=0.041) remained a statistically significant factor for colectomy while a tendency remained for albumin <3.8mg/dl (P=0.082).

Conclusion

CMV infection is more common in patients with ulcerative pancolitis under immunomodulatory treatment and should be diagnosed via a combination of immunohistochemistry and PCR in biopsies. Patients with prominent diarrhea [UC PRO bowel movement >2] may be particularly prone to colectomy.

Disclosure

GB: Advisor/lecturer for Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper; Funding (Grants/Honoraria): Pfizer, Takeda, Abbvie, Aenorasis; Research/Clinical Trials: Abbvie, Takeda
EZ: Advisor/lecturer for Pfizer, Takeda, Abbvie, Amgen, Genesis Pharma, Aenorasis, Janssen
SM: Advisory/Lecturer for Pfizer, Takeda, Abbvie, Ferring, MSD, Janssen

Introduction

Clostridioides difficile infection (CDI) represents the leading cause of nosocomial diarrhea in the Western world. Patients with ulcerative colitis (UC) have a higher risk of developing this infection, which has been associated with an increased risk of flare-ups, need for surgery, and mortality. The aim of the present study was to evaluate the impact of this infection in patients hospitalized for a UC flare-up.

Aims & Methods

Retrospective case-control study including all patients hospitalized for a UC flare-up at Reina Sofía Hospital in Córdoba between January 2000 and January 2023. To avoid potential selection biases, Propensity Matching Score (PMS) adjusted for age, gender, duration, and extent of the disease, with a 1:2 ratio was used. Primary objective was to assess the need for treatment intensification (initiation or dose escalation of biologics/small molecules or immunosuppressant). Secondary endpoints included readmission rate, colectomy, mortality, and CDI risk factors identification.

Results

During the study period, 419 patients were hospitalized for a UC flare-up, of whom 251 (59.9%) were men, with a median age of 41 (IQR 28-55) years and disease duration of 0.89 (0-5.8) years. Of all admissions, 46 (11%) had CDI. After PMS, CDI was associated with increased therapeutic intensification between 3-12 months after discharge (27.5% vs. 11.7%, p = 0.004) and a higher risk of readmission at 12 months (37.5% vs. 13.7%, p = 0.009) but not to risk of colectomy or mortality (Table 1). Infection recurrence was detected in 8 (16.7%) patients.
Classical risk factors for CDI were not found to increase the risk of CDI among UC patients, however antiTNF therapy was associated to CDI in both models: full cohort (OR 3.52, 95%CI 1.46-8.49) and PMS (OR 4.63, 95%CI 1.32-16.31).

Table 1. Hospitalisation characteristics, evolution and complications

Conclusion

CDI in UC was associated with a greater need for therapeutic intensification and a higher readmission rate at one year. There was no evidence of an increased risk of colectomy or mortality in these patients. Classical risk factors for CDI were not identified but patients on antiTNF were at higher risk of CDI.

Disclosure

Beatriz Gros has served as a consultant for Galapagos and Abbvie and as a Speaker for Abbvie, Janssen, Takeda, Pfizer and Galapagos.

Clinical Case Summary

A 59-year-old male with ulcerative colitis presented with steroid-dependent disease with adverse reactions to sulfasalazine and azathioprine. Vedolizumab was started in 2018 but switched to Adalimumab from October 2020 for symptomatic flare with active endoscopic inflammation. In June 2022, despite supratherapeutic Adalimumab levels without anti-drug antibodies, elevated biomarkers with persistent endoscopic activity prompted restarting Vedolizumab alongside Adalimumab. Financial constraints and ischemic heart disease precluded the use of Ustekinumab and Tofacitinib respectively.
In January 2023, his previously normal platelet count dropped to 56x10⁹/L. Despite stopping Adalimumab, this fell further to a nadir of 16x10⁹/L over one month. Other cell lines were unaffected. He remained in clinical remission and had no bleeding manifestations.
Anti-nuclear antibodies and anti-double-stranded DNA antibodies returned positive. Complement levels, C-reactive protein, urine studies and renal function, however, remained normal. Rheumatology deemed drug-induced lupus unlikely, given the absence of clinical features and noting the not uncommon development of autoantibodies with anti-tumour necrosis factor (TNF) use. Bone marrow examination, arranged after Haematology consult, showed normocellular marrow without evidence of lymphoproliferative or myeloproliferative disorders. Our patient was eventually diagnosed with immune thrombocytopenia and started on Prednisolone at a dose of 1mg/kg/day. He responded well to steroids with normalisation of his platelet count within one week and remains well on follow up with tapering steroids and Vedolizumab.
Immune thrombocytopenia is a rare but significant complication of anti-TNF use. Posited mechanisms include anti-TNF interaction with platelet membrane glycoprotein receptors with antibody formation and excess Th2 lymphocyte antibody production. Anti-TNF cessation and systemic corticosteroids are the cornerstones of treatment.

References

Table 1. Platelet count trend in relation to Adalimumab cessation and corticosteroid initiation.

Introduction

Ulcerative colitis (UC) is an idiopathic chronic inflammatory bowel disease. The current goal of UC treatment is to modify the natural history of the disease and prevent long-term bowel damage and subsequent disability by using appropriate therapy and monitoring at appropriate intervals.
In 2015, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) committee proposed a treat-to-target (T2T) approach and recommended that the therapeutic target in UC should be both clinical and patient-reported outcomes (PRO) remission as well as endoscopic remission with Mayo endoscopic subscore (MES) 0 and 1. However, in STRIDE II, only MES 0 of endoscopic remission is the treatment target and histologic remission is also considered to be a treatment target. Previous studies have demonstrated that patients who achieve an MES of 0 are more likely to have a longer duration of clinical remission than patients without endoscopic remission. Additionally, several studies have shown that histologic remission is a distinct treatment target from endoscopic remission in UC and better predicts clinical remission.
The current treatment target of UC is endoscopic remission with MES 0 as well as clinical remission, but distinguishing between MES 0 and MES 1 is difficult. In our previous study, we demonstrated that histologic activity predicts clinical relapse in UC patients with MES 0 or 1. However, there is no study on whether histologic remission can predict another target, such as endoscopic remission. The aim of this study was to evaluate whether histologic activity can predict the maintenance of endoscopic remission in UC patients with MES 0 or 1.

Aims & Methods

The aim of this study was to evaluate whether histologic activity can predict the maintenance of endoscopic remission in UC patients with Mayo endoscopic subscore (MES) 0 or 1. Four hundred ninety-two UC patients who underwent histologic evaluation at Samsung Medical Center from January 2018 to December 2020 were included in this study. Patients were divided into two groups based on their histologic activity: histologic remission and active. Endoscopic activity was assessed during follow-up, and the primary outcome was endoscopic remission according to histologic activity. Endoscopic remission was defined as an MES of 0, while histologic remission was defined as a Geboes score of < 3.1.

Results

Among the 492 patients, 435 were evaluated for endoscopic activity during the first colonoscopic follow-up, and 146 patients were evaluated during the second follow-up. The median time for the first follow-up colonoscopy was 27.3 months. The histologic active group at index colonoscopy was more likely to experience endoscopic relapse than the histologic remission group (hazard ratio (HR)= 1.63, P < 0.001). In subgroup analysis in patients without clinical relapse, the histologic active group was still more likely to experience endoscopic relapse than the histologic remission group (HR = 1.53, P = 0.030).

Conclusion

The patients who achieve histologic remission are more likely to maintain endoscopic remission compared to those with histologic activity.

References

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