Anti-tumor Necrosis Factor-α Research Articles

Treatment in Patients with Psoriatic Disease and Rheumatoid Arthritis: Seven Case Reports

The incidence of psoriasis, an intractable long-lasting inflammatory skin disease, is increasing and has many complications and comorbidities. Approximately 14% of patients have psoriatic arthritis (PsA). Rheumatoid arthritis (RA) is not a rare disease worldwide, and some patients may have both PsA and RA. In the present study, we encountered seven patients with concurrent diagnoses of RA and psoriatic disease and reported the details of clinical data, treatment efficacy, and X-ray findings. The diagnosis may require not only classification criteria but also a comprehensive judgment in collaboration with rheumatology over time. In addition to methotrexate as an anchor drug, anti-tumor necrosis factor-α agents are the first choice of biological agents for treatment, and interleukin (IL)-17 inhibitors may be effective, as IL-17 is also involved in the pathogenesis of RA. When treating patients with both PsA and RA, it may be essential to consider the treatment strategy, depending on which disease is more active.

Effects of visceral adipose tissue on anti-tumour necrosis factor-α in Crohn's disease.

It remains unclear whether visceral adipose tissue (VAT) can predict the response of patients with Crohn's disease (CD) to anti-tumour necrosis factor-α (anti-TNF-α) therapy. This study aimed to investigate whether VAT predicts the efficacy of infliximab (IFX) for different sites of CD and its relationship with serum TNF-α levels and IFX serum trough concentration. This is a multicentre retrospective study. Patients with CD treated with IFX from January 2014 to January 2021 were included. The perimeter of the visceral adipose area was obtained by a Computed Tomography (CT) scan. Participants were classified according to the lesion site (L1, L2, and L3) and visceral fat area. The participants were divided into colon-uninvolved non-visceral obesity (L1-VATL), colon-uninvolved visceral obesity (L1-VATH), colon-involved non-visceral obesity (L2 + L3-VATL), and colon involved visceral obesity (L2 + L3-VATH) groups. The end points of this study were set as disease remission status at 6 and 12 months. The final cohort included 140 patients. Regarding efficacy at 6 and 12 months, there was a significant difference between L1-VATL (73.8% versus 36.8%, p = 0.006) and L1-VATH (81.0% versus 47.4%, p = 0.008) groups. In the analysis of serum TNF-α levels and IFX serum trough concentrations, there was a significant difference between L1-VATL and L1-VATH (59.5 pg/mL versus 236.0 pg/mL, pTNF-α = 0.006), (10.0 μg/mL versus 0.4 μg/mL, pIFX = 0.000), and L1-VATH and L2 + L3-VATH (78.7 pg/mL versus 118.6 pg/mL, pTNF-α = 0.031), (0.4 μg/mL versus 6.40 μg/mL, pIFX = 0.017). In L1 patients, the VAT level predicted the efficacy of IFX, with high VAT values indicating poor efficacy. The VAT level may be a useful radiological marker to predict the efficacy of IFX in patients with various types of CD.

Systematic Review and Meta-Analysis: Association between Preoperative Ustekinumab and Surgical Complications in Crohn’s Disease Patients

Introduction: The impact of ustekinumab (UST) therapy on surgical complications in patients with Crohn’s disease (CD) remains controversial. The aim of this meta-analysis is to explore the link between these two. Methods: Databases (PubMed, Web of Science, Cochrane, and Springer Link) were searched until April 2022. Studies of CD patients who received UST and no UST prior to surgery (including no biological therapy, anti-tumor necrosis factor-α [anti-TNF-α] agent, and vedolizumab [VDZ]) were included. Primary outcomes included overall complications, infectious complications, and noninfectious complications. Results: Nine studies totaling 3,225 CD patients were enrolled; 332 patients received UST treatment. There was no evidence of difference in the overall complications (odds ratio [OR] = 0.84, p = 0.37, 95% confidence interval [CI] = [0.57–1.23], I² = 40%) between CD patients who had UST treatment preoperatively and those who had no UST treatment. There was no evidence of a difference in infectious complications (OR = 1.15, p = 0.35, 95% CI = [0.86–1.53], I² = 2%). Additionally, there was no significant evidence of difference between these groups in terms of noninfectious complications and death. Specifically, there was no evidence of difference in overall complications, infection complications (including wound complications, sepsis, abscess, and anastomotic leakage), and noninfection complications (ileus, readmission, and return to operation), compared with no biological therapy and anti-TNF-α agents. At the same time, no significant evidence of difference was discovered in the comparison of preoperative UST and VDZ therapy in terms of overall complications, infectious complications (sepsis and abscess), and noninfectious complications (intestinal obstruction, readmission, and recovery surgery). Conclusion: In general, compared with other biological agents, preoperative use of UST in the treatment of CD patients is usually safe and does not increase surgical complications.

10 years of biologic use patterns in patients with inflammatory bowel disease: treatment persistence, switching and dose intensification - a nationwide population-based study.

Treatments for inflammatory bowel diseases (IBD) have evolved in the era of biologics. However, the real-world data on their usage patterns and sequencing are still limited. We aimed to investigate treatment persistence and dose intensification of first- and second-line biologics in patients with IBD. In this retrospective, cohort study using nationwide claims data, 13,087 patients with IBD initiating biologic therapy between 2010 and 2020 were identified. Treatment persistence and dose intensification during the first 2 years and switching patterns of biologics were analysed while identifying predictors of non-persistence. As a first-line treatment of Crohn's disease (CD), ustekinumab had a lower risk for non-persistence compared to infliximab [adjusted hazard ratio (aHR), 0.69, p = 0.048]. Second-line ustekinumab and vedolizumab showed the highest and lowest persistence (79.2% and 54.9%), respectively. As a first-line treatment of ulcerative colitis (UC), golimumab had a higher risk for non-persistence compared to infliximab (aHR, 1.68, p < 0.001). Second-line golimumab also showed a significantly lower persistence rate than adalimumab and vedolizumab. The risk of non-persistence was higher in UC than in CD (first line: aHR, 1.97; second line: aHR, 1.39; p < 0.001), and in the second-line treatment than in the first-line treatment for CD (aHR, 1.55; p < 0.001). The cumulative rate of dose intensification was highest with ustekinumab for CD (first line, 43.3%, second line, 69.1%) and adalimumab for second-line UC (40.7%). It was significantly increased in second-line therapy in CD, but not in UC. Among switchers of first-line anti-tumour necrosis factor-α inhibitor therapy, after all biologics were approved, 69% of CD patients and 78.4% of UC patients switched to other classes of second-line treatment. Ustekinumab had higher persistence in the first-line treatment of CD, while golimumab had lower persistence for first- and second-line treatments of UC. Dose intensification rates varied, with the highest cumulative rates observed for ustekinumab in CD and adalimumab in second-line UC.

Vedolizumab more likely to be discontinued than ustekinumab in anti-TNF-experienced patients with fistulizing Crohn's disease.

Data on the performance of newer biologics in patients with fistulizing Crohn's disease (CD) are limited. Our study's objective was to evaluate the response to ustekinumab (UST) and vedolizumab (VDZ) in patients with fistulizing CD. Retrospective cohort. We used natural language processing of electronic medical record data to identify a retrospective cohort of individuals with fistulizing CD at a single academic tertiary-care referral center and then performed a chart review. Individuals were eligible for inclusion if a fistula was present at the time of UST or VDZ initiation. Outcomes included medication discontinuation, surgical intervention, development of a new fistula, and fistula closure. Groups were compared with unadjusted analyses and competing risk analyses using multi-state survival models. In all, 68 patients were included (48 UST and 20 VDZ). Most patients had one fistula (79%) and had prior anti-tumor necrosis factor-α treatment (98% in UST group, 80% in VDZ group, p = 0.01). VDZ was significantly more likely to be discontinued than UST (p < 0.0001), most frequently due to inadequate clinical response. Those on UST had a longer median time to surgery for CD than those on VDZ (p = 0.008). In those without surgical fistula repair, 79% on UST and 100% on VDZ still had an active fistula at 1 year (p = 0.30). In individuals with fistulizing CD, our data suggest that UST has better clinical utility than VDZ based on lower rates of discontinuation, though the sample size is small. These findings highlight the importance of further research on the treatment of perianal fistulizing Crohn's disease.

English version of Japanese guidance for use of biologics for psoriasis (the 2022 version).

This is the English version of Japanese guidance for use of biologics for psoriasis (the 2022 version). As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Moreover, after 2015, three IL-17 inhibitors, the IL-17A antibody preparations secukinumab and ixekizumab, and an anti-IL-17 receptor antibody preparation brodalumab were marketed. Furthermore, after 2018, the anti-IL23p19 antibody preparations guselkumab and risankizumab, the TNF inhibitor certolizumab pegol, the IL-23 inhibitor tildrakizumab, and the anti-IL-17A/F antibody bimekizumab were marketed. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors, and patient background factors, sharing such information with patients. The followings can be listed as points to be considered for the selection of biologics: drug effects (e.g., strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g., infections, administration-related reactions, and relationships with other comorbidities), convenience for patients (e.g., hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration), and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.

Anti-tumor necrosis factor-α is potentially better than tumor necrosis factor-α as the biomarker for sarcopenia: Results from the I-Lan longitudinal aging study

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine involved in the pathogenesis of sarcopenia, but its short half-life and inconsistent reproducibility limit the potential of TNF-α to be an ideal sarcopenia biomarker. Anti-TNF-α, a natural consequent autoantibody to TNF-α, is an indicator of relatively prolonged TNF-α exposure, has more stable concentrations than TNF-α and should be a better alternative as a biomarker of sarcopenia. Data from 484 participants from the I-Lan Longitudinal Aging Study were used for this study, and sarcopenia was defined by the Asian Working Group for Sarcopenia 2019 consensus. Plasma levels of anti-TNF-α were determined by a sandwich ELISA approach, and levels of TNF-α were determined by an immunoassay. Compared to nonsarcopenic participants, 43 sarcopenic participants had higher levels of anti-TNF-α (0.73 ± 0.19 vs. 0.79 ± 0.25 OD, p = 0.045). Plasma levels of anti-TNF-α were positively correlated with TNF-α (r = 0.24, p < 0.001), and plasma levels of anti-TNF-α were positively correlated with adiposity (r = 0.16, p < 0.001) and negatively correlated with lean body mass (r = −0.14, p = 0.003). Individuals with increasing levels of anti-TNF-α had higher odds of being sarcopenic (OR 5.4, 95 % CI: 1.1–25.8, p = 0.035), and these associations were stronger among women and younger adults. An association between TNF-α and sarcopenia was noted only in middle-aged adults (OR 6.2, 95 % CI: 1.8–21.7, p = 0.004). Plasma anti-TNF-α levels were positively correlated with TNF-α and were significantly associated with sarcopenia. Anti-TNF-α may be a more appropriate biomarker than TNF-α for sarcopenia, but further investigations are needed to confirm its roles in sarcopenia diagnosis and treatment response evaluation.

S8 How Can We Predict the Development of Antibodies to Infliximab in Crohn’s Disease?

Background: Anti-tumour necrosis factor-α (anti-TNF-α) therapy is an effective treatment for the management of Crohn’s disease (CD). However, treatment failure is common. The aim of this study was to identify predictors of anti-TNF-α therapy failure. Methods: Retrospective single-center study including anti-TNF-α naïve patients with CD, who started on intravenous infliximab, between January 2019 and December 2021. Biochemical parameters included erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), faecal calprotectin, infliximab serum concentrations and the presence of antibodies to infliximab (ATI). Anti-TNF-α therapy failure was defined as the development of ATI at 6 and 12 months, absence of clinical response at 6 months, absence of clinical remission or absence of objective response at 12 months. Clinical response was defined as a reduction in Harvey-Bradshaw index (HBI) of ≥3 points comparing with initial value or HBI <5 points if initial HBI ≥7 points and clinical remission as HBI ≤4 points. Objective response was assessed by endoscopic studies, defined by improvement of mucosal inflammation and absence of deep ulcerations, or imaging, defined as improvement in bowel wall thickness, inflammatory fat, mural blood flow and hyper-enhancement. Results: A total of 53 CD patients were included, 30 were female (56.6%), with a mean age at the beginning of treatment of 39 ± 2 years. Considering the Montreal classification, 31 patients had ileal disease (58.5%), 7 colonic (13.2%) and 15 ileocolonic disease (28.3%); 22 patients had nonstricturing, nonpenetrating disease (41.5%), 22 stricturing (41.5%) and 9 penetrating disease (17.0%). Eleven patients had perianal disease (20.8%). A total of 26 patients (49.1%) were treated with combination of anti-TNF-α and immunomodulatory therapy (thiopurine or methotrexate). Anti-TNF-α therapy failure occurred in 21 patients (39.6%). At 6 months, the development of ATI occurred in 6 patients (11.3%) and absence of clinical response in 9 patients (17.0%). At 12 months, absence of clinical remission was seen in 13.6% of patients and absence of objective response in 27.0% of patients. At 6 months, the development of ATI was significantly higher in patients with lower infliximab serum concentrations at week 14 (with antibodies 5.9 ± 3.2 µg/mL vs without 14.3 ± 7.7 µg/mL, P < 0.001). Additionally, the development of ATI was significantly higher in patients with a higher initial value of ESR (with antibodies median 35 vs without median 13, P = 0.045). The infliximab serum concentrations at week 14 (AUC 0.828; P = 0.009; with sensitivity 0.833 and specificity 0.404 for values ≤11.6) and the initial value of ESR (AUC 0.754; P = 0.045; with sensitivity 0.833 and specificity 0.468 for values ≥15) had very good and good discriminative capacity, respectively, in predicting the development of ATI. No statistically significant differences were found in initial values of CRP and faecal calprotectin, between both groups. Moreover, the other definers of anti-TNF-α therapy failure were not associated with the combination with immunomodulatory therapy, infliximab serum concentrations at week 14 or initial values of ESR, CRP and faecal calprotectin. Conclusion(s): Infliximab serum concentration after induction therapy is the most important factor in the development of ATI, influencing treatment response, regardless of the combination of anti-TNF-α therapy with immunomodulatory therapy. A higher initial value of ESR can also predict the development of ATI.

S7 Crohn’s Disease: What to Do After Antitumour Necrosis Factor-α Therapy Fails?

Background: Ustekinumab and vedolizumab are commonly used for the treatment of Crohn’s disease (CD) after antitumour necrosis factor-α (anti-TNF-α) therapy fails. The optimal choice is still debated. However, some evidence suggests the superiority of Ustekinumab. The aim of this study was to compare the effectiveness of ustekinumab and vedolizumab as second line therapy in CD patients. Methods: Retrospective single-center study including patients with CD who started on ustekinumab or vedolizumab, after failure of or intolerance to anti-TNF-α therapy, between January 2017 and December 2021. Clinical response was defined as a reduction in Harvey-Bradshaw index (HBI) of ≥3 points comparing with initial value or HBI<5 points if initial HBI≥7 points and clinical remission as HBI≤4 points. Biochemical outcomes were erythrocyte sedimentation rate (ESR), c-reactive protein (CRP) and faecal calprotectin, 6 and 12 months after initiating treatment. Objective response at 12 months was assessed by endoscopic studies, defined by improvement of mucosal inflammation and absence of deep ulcerations, or through imaging, defined as improvement in bowel wall thickness, inflammatory fat, mural blood flow and hyper-enhancement. Results: Totally, 52 CD patients were included, 37 patients were treated with ustekinumab (71.2%) and 15 with vedolizumab (28.8%). Among patients with ustekinumab, 26 were female, with a mean age at beginning of treatment of 41.05 ± 15.04 years. Considering the Montreal classification, 14 ustekinumab patients had ileal disease, 2 had colonic and 21 ileocolonic disease; 10 patients had nonstricturing, nonpenetrating disease, 15 had stricturing and 12 penetrating disease. Among patients with vedolizumab, 10 were female, with a mean age at beginning of treatment of 36.47 ± 12.87 years. According to Montreal classification, 3 vedolizumab patients had ileal disease and 12 had ileocolonic disease; 3 patients had nonstricturing, nonpenetrating disease, 8 had stricturing and 4 penetrating disease. No statistically significant differences were found between both groups regarding sex (P = 0.216), age (P = 0.305), disease behavior (P = 0.787) or location (ileal or ileocolonic) (P = 0.171). At 6 months, clinical response was observed in 15 ustekinumab patients (40.5%) and 9 vedolizumab patients (60.0%), without statistically significant differences (P = 0.202). Clinical remission occurred in 14 ustekinumab patients (37.8%) and 6 vedolizumab patients (40.0%), without statistically significant differences (P = 0.885). Furthermore, no statistically significant differences were found in biochemical parameters at 6 months, between the 2 groups. At 12 months, clinical response and remission was similar between both groups. Moreover, all biochemical parameters evaluated decreased in both groups, although without statistically significant differences, ESR (ustekinumab median -4.5 vs vedolizumab median -2.0, P = 0.393), CRP (ustekinumab median -2.35 vs vedolizumab median -2.10, P = 0.878), and faecal calprotectin (ustekinumab mean -329.5 vs vedolizumab mean -52.4, P = 0.077). An objective response at 12 months was observed in 58.8% ustekinumab patients and 50.0% vedolizumab patients, with no statistically significant differences (P = 0.149). Conclusion(s): In CD patients after anti-TNF-α therapy failure, both ustekinumab and vedolizumab showed clinical and biochemical improvements. After 1 year of treatment, about half of patients from both groups had positive objective response, assessed by endoscopic or imaging studies.

S41 Unusual Case of Tongue Deviation

Case: Background: Anti-tumor necrosis factor-α (TNFα) therapy is the mainstay of treatment for inflammatory bowel disease such as Crohn’s Disease (CD) and ulcerative colitis (UC). Despite its widespread use, anti-TNFα leads to significantly altered inflammatory response and increased risk of severe skin and soft tissue infections. Here, we highlight an uncommon presentation of severe soft tissue infection in a patient with ileal CD maintained on anti-TNFα therapy. Case Presentation: A 50-year-old female with a 25-year history of Crohn's ileitis maintained on certolizumab for 3 years presented to the emergency department (ED) with an expanding left, lateral neck mass resulting in decreased cervical range of motion. This was accompanied by a left-sided tongue deviation. She first presented to our ED 8 weeks earlier with severe throbbing headaches without focal neurologic symptoms. A head MRI only showed non-specific T2/FLAIR hyperintensities. Her vital signs and labs were normal, and these headaches were presumed to be complex migraines. Three weeks after her first presentation, she came back to the ED with worsening headaches, neck pain and a new left-sided tongue deviation. Again, her vital signs and laboratory evaluation were normal apart from an ESR of 68 mm/hr (nl: 0-30 mm/hr) and CRP of 10.34 mg/dL (nl<0.5 mg/dL). Her repeat imaging studies did not show any evidence of stroke; however, opacification of the paranasal sinuses and left mastoid air cells were observed. Nonetheless, given her lack of systemic inflammatory symptoms, she was discharged home with close outpatient otolaryngology (ENT) referral. As an outpatient, she was diagnosed with bacterial sinusitis which was treated with a 15-day course of cefdinir and dexamethasone. Her symptoms initially improved; however, she eventually experienced dysphagia with pus drainage from her sinuses. Another antibiotic and steroid course was prescribed. Despite this, approximately 8 weeks after her initial presentation, she developed a rapidly expanding neck mass which prompted her return to the ED. Physical examination revealed a tender neck mass limiting her cervical range of motion and a more pronounced tongue deviation. She was afebrile, non-tachycardiac, and normotensive. Laboratory testing again revealed elevated inflammatory markers (ESR 83 mm/hr, CRP 8.59 mg/dL) but otherwise her WBC was normal (8310 cells/ µL, nl: 10400 cells/µL) with no evidence of sepsis-related end-organ dysfunction (Cr 0.89 mg/dL, AST 20, ALT 55 mg/dL, T-bili 0.3 mg/dL, platelets 348000 platelets/µL). Neck imaging showed multifocal ring-enhancing collections within the left paravertebral soft tissue with left hypoglossal nerve involvement. Intravenous vancomycin, cefepime, and metronidazole were started. Surgical debridement of the left posterior paraspinal abscess was performed. Intraoperative cultures were positive for Streptococcus anginosus. She completed a 6-week course of ceftriaxone but follow up imaging 2 weeks later showed recurrence of her neck abscesses. This again required surgical debridement. Her infections finally cleared with 24 weeks of piperacillin/tazobactam. Her certolizumab remains permanently discontinued. Conclusions: Hallmark symptoms of severe infection may not be present in patients on anti-TNF therapy. A high index of suspicion for an underlying infectious etiology must be maintained when treating this population.

Risk of Reactivation of Latent Tuberculosis in Psoriasis Patients on Biologic Therapies: A Retrospective Cohort from a Tertiary Care Centre in Northern Italy.

Psoriatic patients with latent tuberculosis infection and properly treated active tuberculosis need careful management when prescribing modern biological drugs. Although data and guidelines regarding tumour necrosis factor-α inhibitors advise caution and initiation of prophylactic therapy in patients with latent tuberculosis infection, the same indications do not seem to find equal force for interleukin (IL)-23 and IL-17 inhibitors. In order to evaluate the risk of reactivation in patients with latent tuberculosis infection or properly treated active tuberculosis, an observational retrospective study was conducted on the population referred to our centre at Dermatologic Clinic of University of Turin, Italy. In the last 10 years at the clinic 19 psoriatic patients were found to be at risk of tuberculosis reactivation: 10 patients were QuantiFERON- TB-positive at baseline, 2 became positive during treatment, 6 reported prior tuberculous infection, and 1 was QuantiFERON-TB-negative at baseline and developed disseminated tuberculosis during treatment with anti-tumour necrosis factor-α. Overall, 10.5% of this group of patients developed active tuberculosis; however, stratifying by biologic therapy, zero cases were observed among patients treated with anti-IL-17, -23, or -12/23 over a relatively long follow-up (48.1 months) A review of the available literature following our experience confirms the increased risk of tuberculosis reactivation with tumour necrosis factor-α inhibitors. Concerning anti-IL-23 and IL-17 drugs, available data showed high safety in patients at risk of tuberculosis reactivation. Screening of patients who should be taking IL-17 and IL-23 inhibitors is recommended for public health purposes. In case of a positive result with these therapies, consulting with an infectious diseases specialist is suggested in order to weigh up the risks and benefits of prophylactic treatment.

Durable medication-free remission of sarcoidosis following discontinuation of anti-tumor necrosis factor-α therapy

BackgroundMonoclonal antibodies against tumor necrosis factor-alpha (TNF-α) have been used successfully in the treatment of sarcoidosis, but optimal duration of their use is unclear. Published studies have consistently suggested that withdrawal of therapy typically results in prompt disease relapse. The aim of this study is to identify and characterize patients with sarcoidosis in whom medication-free disease remissions were induced and sustained following treatment with and subsequent discontinuation of anti-TNF-α antibodies. MethodsA retrospective chart review was conducted to identify patients satisfying three criteria: (1) histopathological documentation of sarcoidosis; (2) disease remission induced by anti-TNF-α antibodies, since discontinued; and (3) subsequent maintained clinical, radiological, and laboratory remission for at least one year without ongoing immunomodulatory medications. ResultsEight patients whose sarcoidosis remained in medication-free remissions were identified. The duration of remissions ranged from 22 to 132 months. All patients had previously had inadequate response to corticosteroid therapy and at least one steroid-sparing agent, prompting the use of anti-TNF-α antibodies. Before anti-TNF-α therapy was discontinued, all eight patients had been able to remain off systemic corticosteroid therapy for at least a year (range 12–130 months). ConclusionsThese observations suggest that in select sarcoidosis patients, anti-TNF-α antibodies may induce prolonged medication-free remissions. The sustained capacity to remain off corticosteroids during anti-TNF-α therapy may be a favorable prognostic indicator for maintained disease remission. These findings may help to develop principles for optimal utilization of these agents and to shed light onto the potential pathogenic role of TNF-α in this disease.

Effectiveness and Safety of Ustekinumab for Moderate to Severely Active Crohn's Disease: Results from an Early Access Program in Brazil.

This prospective, observational, open-label study aimed to provide access to ustekinumab prior to market authorization and assess its safety and effectiveness in patients with Crohn's disease (CD) refractory to anti-tumor necrosis factor-α and conventional drugs in Brazil. Patients with a diagnosis of moderate-to-severe active CD for ≥3 months before screening received ustekinumab in a single intravenous induction dose (~6 mg/kg) at week 0, and a 90 mg maintenance dose, subcutaneously, every 8 or 12 weeks, from week 8 through to 80. Serious adverse events (SAE), adverse drug reactions (ADR), clinical response (per CD Activity Index and Harvey Bradshaw Index (HBI) scores), remission (per HBI scores), biomarkers (C-reactive protein (CRP) and fecal calprotectin (FC)) and endoscopic improvement rate over 80 weeks were assessed. Patients with a mean age of 39.9 years were assessed. Discontinuation rate was low (23%) and most adverse events were mild (68.7%). The SAE rate was 21% (mostly infections/infestations or gastrointestinal disorder), and ADR rate was 44%. The CD Activity Index and HBI scores decreased (by 74% and 81%, respectively) with 50% of patients showing normalized CRP and FC, and 63% achieved endoscopic improvement. Ustekinumab was fairly safe, well tolerated and effective in a Brazilian cohort of CD patients.

Acetaminophen changes the RNA m6A levels and m6A-related proteins expression in IL-1β-treated chondrocyte cells

BackgroundAcetaminophen is commonly recommended for the early analgesia of osteoarthritis. However, the molecular mechanism by which it acts remains unknown. The aim of this study is to investigate the effect of acetaminophen on inflammation and extracellular matrix degradation in human chondrocytes, and the possible molecular mechanisms involved in its effect.MethodsThe normal chondrocyte cell line C28/I2 was treated with interleukin-1β to mimic the inflammatory state. Acetaminophen and the methylation inhibitor (cycloleucine) were used to treat interleukin-1β-induced C28/I2 cells. The expression of RNA N6-methyladenosine -related proteins was detected by RT-qPCR and western blot. The total RNA N6-methyladenosine level was measured by dot blot analysis and enzyme linked immunosorbent assay. The levels of interleukin-6, interleukin-8 and anti-tumor necrosis factor-α were measured by enzyme linked immunosorbent assay. The extracellular matrix synthesis and degradation were examined by western blot.ResultsAfter interleukin-1β stimulated C28/I2 cells, the intracellular RNA N6-methyladenosine level increased, and the expression of regulatory proteins also changed, mainly including the increased expression of methyltransferase like 3 and the downregulated expression of AlkB family member 5. The use of cycloleucine inhibited interleukin-1β-induced inflammation and extracellular matrix degradation by inhibiting RNA N6-methyladenosine modification. In contrast, acetaminophen treatment counteracted interleukin-1β-induced changes in RNA N6-methyladenosine levels and regulatory protein expression. Furthermore, acetaminophen treatment of interleukin-1β-induced C28/I2 cells inhibited the secretion of interleukin-6, interleukin-8 and anti-tumor necrosis factor-α, down-regulated the expression of matrix metalloproteinase-13 and Collagen X, and up-regulated the expression of collagen II and aggrecan. In addition, AlkB family member 5 overexpression activated interleukin-1β-induced chondrocyte viability and suppressed inflammation and extracellular matrix degradation.ConclusionAcetaminophen affects inflammatory factors secretion and extracellular matrix synthesis of human chondrocytes by regulating RNA N6-methyladenosine level and N6-methyladenosine-related protein expression.Graphical abstractStimulation of the normal chondrocyte cell line C28/I2 with the cytokine IL-1β (10 μM) mimics the inflammatory state in vitro. Acetaminophen (Ace, 50 μg/mL) changes the m6A related proteins expression and the total RNA m6A levels in IL-1β-treated chondrocyte cells. Furthermore, regulation of RNA m6A levels (by methylation inhibitor Cyc and/or Ace) affects IL-1β-induced inflammatory cytokines secretion and extracellular matrix synthesis in C28/I2 cells.

Low Risk of Lymphoma in Pediatric Patients Treated for Inflammatory Bowel Disease.

Despite the effectiveness of immune-suppressing therapies in treating pediatric inflammatory bowel diseases (IBDs), concerns of lymphoma may limit their use. We used a large administrative claims database to evaluate the risk of lymphoma in pediatric IBD and conducted a case series analysis of medication exposure in children diagnosed with lymphoma. We analyzed administrative claims from the 2007 to 2018 IQVIA database and identified pediatric (≤18 years) patients with Crohn's disease or ulcerative colitis using International Classification of Diseases, 9th or 10th Revision codes and pharmacy claims. Lymphoma cases were identified by diagnosis codes and confirmed by independent claim-by-claim review by a pediatric oncologist and gastroenterologist. We calculated incidence rates for lymphoma among patients with and without pharmacy claims for treatment followed by treatment description among those who developed lymphoma during follow-up. A total of 10,777 pediatric patients with IBD received ≥1 IBD therapy (median age 15 years [12-17], 45% female and 61% diagnosed with Crohn's disease) during 28,292 patient-years of follow-up. Among treated patients, 5 lymphoma cases were identified (incidence rate 17.7/100,000 patient-years; 95% confidence interval 6.5-39.2). Of these, 4 were treated with a thiopurine before lymphoma diagnosis, and none received anti-tumor necrosis factor-α (anti-TNF) monotherapy. The overall lymphoma incidence was low among our cohort of treated pediatric patients with IBD. We observed no cases of lymphoma among patients prescribed anti-TNF monotherapy. These findings reinforce the relative safety of anti-TNF monotherapy for the treatment of pediatric IBD.

Biologics improve endothelial, vascular and left ventricular myocardial function in patients with psoriatic arthritis

Abstract Background/Introduction Psoriatic arthritis is characterized by systemic inflammation leading to an increased risk of cardiovascular diseases. Purpose We aimed to investigate the effects of biologics on endothelial glycocalyx, vascular and left ventricular (LV) myocardial function in patients with psoriatic arthritis. Methods One hundred twenty patients (mean age: 51±11 years) with psoriatic arthritis were randomized to receive biologics [n=60; anti-tumor necrosis factor-α (etanercept, adalimumab, infliximab), anti-interleukin (IL)-12/23 (ustekinumab) or anti-IL-17 (secukinumab)] or nonbiologics (n=60; methotrexate or cyclosporine). At baseline and 4 months post-treatment, we measured: (1) Perfused boundary region (PBR) of the sublingual microvessels with a diameter 5–25μm using Sidestream Dark Field camera (Microscan, Glycocheck). Increased PBR indicates impaired glycocalyx integrity. (2) Pulse wave velocity (PWV - Complior; ALAM Medical), (3) Coronary flow reserve (CFR) in the distal left anterior descending coronary artery, (4) Flow-mediated dilation (FMD) of the brachial artery and (5) LV global longitudinal strain (GLS) using speckle-tracking echocardiography. Results Compared with baseline, all patients had reduced PWV (11±2.1 versus 10.3±1.5m/s, p=0.001) and increased FMD (5.45±3.2 versus 9.77±4.7, p=0.004) at 4 months. PBR remained unchanged in both study groups (p&amp;gt;0.05). Compared with nonbiologics, biologics resulted in a greater reduction of PWV (−10% versus −4%) and in a greater increase of CFR (+11% versus −1%), FMD (+102% versus +56%) and GLS (+10% versus −2%) (p&amp;gt;0.05 for all comparisons) 4 months post-treatment. In patients treated with biologics, the percent increase of GLS post-treatment was related with the percent reduction of PWV (r=−0.28, p=0.034) and with the percent increase of FMD (r=0.42, p=0.006). Conclusion In psoriasis arthritis, biologics confers a greater improvement of endothelial, vascular and LV myocardial function compared with nonbiologics after 4-month treatment. Funding Acknowledgement Type of funding sources: None.

Dietary polyphenols in the treatment of inflammatory bowel diseases

Ulcerative colitis and Crohn's disease, caused by chronic inflammation in the digestive tract, are inflammatory bowel diseases and have similar symptoms. Abnormal immune responses play a pretty important role in the pathogenesis of the disease. Proinflammatory mediators trigger inflammation, stimulate cell signaling molecules, and induce disease onset. Corticosteroids, anti-tumor necrosis factor-α antibodies, and immunosuppressants are some drugs used to treat the disease. However, these drugs have some side effects. In addition, surgical methods might be used in the treatment, but these methods may have some complications. Due to the negative impact on treatment options, alternative methods for reliable, inexpensive, and effective treatment are being sought. Secondary plant compounds with an aromatic or phenolic ring structure, so-called polyphenols or phenolic compounds, may modulate cellular signaling pathways and reduce intestinal inflammation due to their antioxidant and anti-inflammatory effects. Polyphenols may be evaluated as alternative methods for inflammatory bowel disease based on these properties. This review aims to investigate the effect of some polyphenols on inflammatory bowel disease.

Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease

Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. Among 81 patients (CD: n= 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

Effects of Dexamethasone and Pentoxifylline on Mania-like and Depression-like Behaviors in Rats.

Several studies support the notion that inflammation plays a role in the pathophysiology and treatment approaches of psychiatric illnesses, particularly mood disorders. Congruently, classic anti-inflammatory drugs were found efficacious in randomized clinical trials of patients with mood disorders. Moreover, accumulating data indicate that psychotropic drugs exhibit some anti-inflammatory effects. This study was undertaken to examine the efficacy of dexamethasone (a potent corticosteroid) and pentoxifylline (a methylxanthine drug with proven anti-tumor necrosis factor-α inhibitory activity) in behavioral models in rats, which were treated intraperitoneally with either dexamethasone or pentoxifylline for two weeks and then subjected to a battery of behavioral tests. Treatment with pentoxifylline, but not dexamethasone, was associated with antidepressant-like and anti-manic-like effects. The beneficial behavioral effects of pentoxifylline were accompanied by a prominent reduction in pro-inflammatory mediator levels in the brain. For the first time, the current work proves the efficacy of pentoxifylline against both mania-like and depressive-like behaviors. These results suggest that pentoxifylline may be a promising therapeutic intervention for patients with mood disorders. Taking into account the excellent tolerability profile of pentoxifylline in humans, it is warranted to conduct randomized clinical trials to investigate its therapeutic efficacy in patients with psychiatric disorders.

Ankylosing spondylitis: what all should anaesthesiologist know?

Ankylosing Spondylitis (AS) may present significant issues to the anaesthesiologist as potential difficult airway, respiratory and cardiovascular complications, and the concomitant medication therapy to modify symptoms and disease. Awake fibreoptic intubation (AFOI) is a safe option in anticipated difficult airway, as it permits neurological monitoring throughout the attempt at achieving definitive airway. Central neuraxial blockade and peripheral nerve blocks may have good application for these cases. This morbidity renders the patients to greater risk of neurological complications in the peri-surgical period. Neurophysiological monitoring assists the clinician in timely diagnosis and intervention during surgery for cervical spine deformity correction. Addition of anti-tumour necrosis factor-α agents to the medical management has resulted in improved outcomes, however, with concomitant increased potential for wound infections in treated patients. Understanding of potential issues can pave the way for appropriate perioperative management.