Clinical Case Summary

Introduction. Differential diagnosis between extra-intestinal manifestations of inflammatory bowel disease and side effects of biologics is challenge. Even in the known setting of anti-tumor necrosis factor α agents (anti TNF α), cutaneous T-cell lymphoma (CTCL) carries potential risk to be missed due to indefinite early features mimicking psoriasis or eczema.
Case presentation. Thirty-two years non-smoker female had ulcerative colitis for 13 years. In September 2015, she suffered severe relapse followed by Infliximab introduction (the first dose was administrated on 10 October in 2015). She was good responder, disease remission confirmed on histology. In September 2018, patient reports frequent dermatology visits due to itchy skin lesion on her left earlobe (erythema, erosion, crust, squams) that progressed infiltrating almost half auricle despite local application of steroids and antibiotics. Skin biopsy was performed twice, and acquired samples were examined by two pathologists. First sample is considered for psoriasis. Second sample (acquired afterward) combined with revision of the first sample imposed multiple skin CTCL differentials due to indeterminate histology and biological behavior.
Our patient had her last infliximab administration on 25 February 2019. Since infliximab dismissal, we have followed up patient for 5 years and 2 months. Complete spontaneous regression, absence of CTCL recurrence implied that CTCL was biologics side effect.
Conclusion. Despite multidisciplinary approach diagnosing among justified differentials was a challenge, as follows: extra-intestinal manifestations of ulcerative colitis (Sweet syndrome) versus dermatological side effects of infliximab (eczema, anti TNF induced psoriasis and CTCL). Furthermore, indeterminate histology followed by unpredictable evolution of CTCL created slippery diagnostic path, that could be only hacked through afterward biopsy combined with revision of initial sample.

References

Mariette X, Tubach F, Bagheri H et al. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis. 2010;69(2):400-408.
Mercer LK, Galloway JB, Lunt M et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2016
Rojas-Feria M, Eslam M, Castro- Fernandez M, et al. Cutaneous lymphoma in a patient with ulcerative colitis after immunosuppressive therapy. J Crohns Colitis 2011; 5: 608–11

Introduction

The temporal trend of mortality rates among young individuals with gastric cancer has sparked a contentious debate over the past few decades. Additionally, there remains an ambiguous distribution alteration of disease burden among different countries.

Aims & Methods

​​​​This population-based systematic analysis was conducted to investigate changes in health inequality related to mortality caused by young gastric cancer from 1990 to 2019. We performed a secondary analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 by extracting cross-sectional data on young gastric cancer (<40 years). The age-specific mortality rate was used to determine deaths attributed to young gastric cancer. A prediction of young gastric cancer mortality rate and case number up to 2030 was performed using the Norpred APC model. The slope index of inequality (SII) and the health concentration index were used to quantitatively measure absolute and relative changes in health inequalities, taking into account the socio-demographic indexes (SDI) level. The data was further analysed across different GBD regions and sexes.

Results

The global mortality rate of young gastric cancer declined from 1.61 (95% Uncertainty interval [UI]: 1.49 to 1.72) per 100,000 in 1990 to 0.94 (95% UI: 0.87 to 1.02) per 100,000 in 2019, with an annual rate of change -0.42% (95% Confidence interval (CI): -0.47 to -0.35). The projected data suggests that the number of global mortality case and rate of young gastric cancer would decrease to 24,450 and 0.761 per 100,000 by 2030. Countries belong to the lower 50% of SDI accounted for 49.9% and 52.3% of the global young gastric cancer deaths in 1990 and 2019, respectively. Although the absolute cross-national inequality (SII) of mortality rate fell from 0.133 (95%CI: -0.533 to 0.416) in 1990 to -0.239 (95%CI: -0.432 to -0.046) in 2019, the relative inequality (concentration index) for global young gastric cancer mortality increased from 1990 (−0.058, 95%CI: −0.532 to 0.416) to 2019 (−0.104, 95%CI: −0.526 to 0.317). The observed rise in absolute health inequality was evident in both sexes, but relative health inequality increased in females only. The regions of Sub-Saharan Africa (including Western and Southern), Central Asia, and Central Europe exhibited an increase in both absolute and relative health disparities in young gastric cancer mortality.

Conclusion

Although there has been a decline in the global young gastric cancer mortality rate, health inequality has increased over the past three decades, especially in females and some low SDI countries. It is imperative to prioritize efforts in addressing inequality to further reduce the global burden of young gastric cancer mortality.

Clinical Case Summary

A 29 year old women was diagnosed with Crohn’s disease with ileocolonic involvement and a penetrating behaviour (Montreal classification A2L3B3). After the pre imunosupression workup we proposed the patient to start Infliximab (IFX) with a dosage of 5 mg/kg.
During the first infusion the patient referred sudden visual impairment. There were no visible inflamation of the sclera, conjunctiva or peri orbital area. The patient reported no pain and there were no signs of ophthalmoparesis. We stopped the infusion immediately and asked for an urgent observation by Ophtalmology. Although the fundoscopic examination didn’t detect any abnormalities, there was a significant decrease in the visual acuity of the left eye.
The patient regained full visual acuity the day after the event. We decided to switch the biologic therapy to Ustekinumab. The patient was reevaluated in the outpatient clinic two weeks after discharge, she maintained full visual acuity and showed significant improvement of her symptoms.
IFX is a generally well tolerated drug, participating in the therapeutic approach of a wide variety of autoimmune conditions. Despite its favorable safety profile, IFX is associated with rare paradoxical adverse events that correspond to the development or exacerbation of an inflammatory condition during IFX therapy. Ocular adverse events represent part of this group of complications known as paradoxical adverse events. In the literature we can find reports of: uveitis, optic neuritis, endophthalmitis and orbital apex syndrome.
We report a case of a paradoxical adverse event manifested as a transitory sudden asymmetric loss of visual acuity.
From our research, this is the first report in the literature of transitory visual loss due to IFX. We intend to publish this case to further amplify the medical knowledge regarding the therapy with this drug and better inform both patients and physicians regarding the potential advserse events of IFX.

Introduction

Chronic complications are common among patients with ulcerative colitis (UC) undergoing Ileal Pouch-Anal Anastomosis (IPAA)^1,2. To predict who may benefit most from IPAA, we focused on patients maintaining a normal pouch phenotype for over a decade, seeking which biomarkers identify this unique group.

Aims & Methods

All patients with UC after IPAA who were followed at the Rabin Medical Center comprehensive pouch clinic and consented to prospective observational follow-up were included. Patients with familial adenomatous polyposis or ileostomy were excluded.
“Ultra-normal” pouch phenotype was defined as both clinically and endoscopically normal pouch phenotype, with no episodes of acute pouchitis over 10 years post-ileostomy closure. We assessed demographic data; disease course; peri-operative factors; and inflammatory, serology, and genetic markers. We compared “ultra-normal” patients to “rapid complicators”, defined by the development of chronic pouchitis or Crohn’s-like disease of the pouch within five years post-ileostomy closure.

Results

Of over 400 patients, 174 consented to prospective follow-up; of these, 18 were excluded due to FAP and 8 due to ileostomy. Of the 148 qualifying for final analysis, 26 (17.5%) maintained an “ultra-normal” phenotype over an average of 20±7.14 years since ileostomy closure, while 32 (21%) were classified as “rapid complicators”.
The “ultra-normal” group (mean age, 55.2±13.3 years; females: 50%) had an average age at UC diagnosis of 23.7±10.0 years and age at surgery of 34.9±12.3 years. In comparison, the “rapid complicators” group had an average age at diagnosis of 22.3±15.1 years (p=0.25) and age at surgery of 31.1±16.9 years (p=0.2).
Repeated measurements during our study follow-up period found that “ultra-normal” patients maintained an average BMI of 27.2±6.2 kg/m² and hemoglobin, C-reactive protein, and fecal calprotectin levels of 14.0±1.45 g/dl, 0.63±0.56 mg/dL, and 190.8±169.0 μg/g, respectively. Their average Short Inflammatory Bowel Disease Questionnaire (SIBDQ) score was 55.6±10.2; average Pouchitis Disease Activity Index (PDAI) score was 2.7±1.7. None required post-operative steroidal, immunomodulator, or biologic treatment. Probiotics were intermittently used by 12 patients (46%).
Non-Ashkenazi Jewish origin was more common in the “ultra-normal” group (62% vs. 34%) than Ashkenazi Jewish (38% vs. 41%) and Arabs (0% vs. 22%), p=0.016. No patient in the “ultra-normal” group had NOD2 polymorphism, compared to 3 heterozygotes among “rapid complicators” (p=0.23).
Pre-operative disease extent was similar between groups (p=0.64), as was the indication for IPAA, with 77% of “ultra-normal” patients and 78% of “rapid complicators” having refractory or severe disease as the surgery indication (p>0.99). However, pre-operative biologic therapy, mostly with anti-tumor necrosis factor agents, was independently significantly more common among “rapid complicators” (75% vs. 19% in “ultra-normal”, p<0.001).

Conclusion

“Ultra-normal”, uncomplicated pouch phenotype for two decades after IPAA is sustained in a minority (~ fifth) of patients. While similar to “rapid complicators” in pre-operative disease course and indication for surgery, patients with “ultra-normal” pouch received less pre-IPAA biologic therapy. These findings may contribute to post-IPAA prognostication and, if validated, may affect pre-operative treatment decisions.

References

(1) Yanai H, Ben-Shachar S, Mlynarsky L, et al. The outcome of ulcerative colitis patients undergoing pouch surgery is determined by pre-surgical factors. Aliment Pharmacol Ther. 2017;46(5):508-515. doi:10.1111/apt.14205
(2) Kayal M, Plietz M, Rizvi A, et al. Inflammatory Pouch Conditions Are Common After Ileal Pouch Anal Anastomosis in Ulcerative Colitis Patients. Inflamm Bowel Dis. 2020;26(7):1079-1086. doi:10.1093/ibd/izz227

Disclosure

Jacob E Ollech: Has received grant support from Pfizer, consulting fees from Takeda, and
speaker fees from Abbvie, Janssen, Pfizer, Takeda, Novartis, and Bristol Myers Squibb.

Iris Dotan: consultation fee or honorarium from: Abbott, Abbvie, Athos, Arena, Altman
Research, Cambridge Healthcare, Celltrion, Celgene/BMS, Eli-Lilly, Ferring, Falk Pharma, Food
Industries Organization, Gilead, Galapagos, Iterative Scopes, Integra Holdings, Janssen,
Neopharm, Pfizer, Rafa laboratories, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda,
Wildbio. Grants: Altman Research, BMS, Pfizer