Tofacitinib Efficacy/Safety in Patients with Ankylosing Spondylitis by Baseline Body Mass Index: A Post Hoc Analysis of Phase 2/3 Trials.

We assessed tofacitinib efficacy and safety in ankylosing spondylitis (AS) by body mass index (BMI) category. Data were pooled from phase 2/3 trials; analyses included patients with active AS randomized (1:1) to tofacitinib 5 mg twice daily or placebo, who were stratified by baseline BMI into < 25, ≥ 25 to < 30, and ≥ 30 kg/m2 categories. Efficacy was assessed at week 12 and safety to week 16. Of 370 patients, 153, 131, and 86 had a baseline BMI  of < 25, ≥ 25 to < 30, and ≥ 30 kg/m2, respectively. At baseline, patients with BMI < 25 kg/m2 were younger and more likely to be current smokers/Asian, and patients with BMI ≥ 30 kg/m2 had higher mean waist circumference/swollen joint count (SJC) and were more likely to have enthesitis, high-sensitivity C-reactive protein (hsCRP) > 5 mg/L, an inadequate response to tumor necrosis factor inhibitors (TNFi), and prior biologic disease-modifying anti-rheumatic drug (bDMARD) use versus other categories. Across categories, tofacitinib responses/improvements were greater than with placebo, except for ≥ 40% Assessment of SpondyloArthritis international Society improvement (ASAS40), ASAS partial remission, 50% improvement from baseline in the Bath Ankylosing Spondylitis Disease Activity Index score (BASDAI50), and Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) inactive disease rates, which were similar for tofacitinib and placebo in the BMI ≥ 30 kg/m2 category. Treatment effects were similar across categories, except for BASDAI50, which was smaller in the BMI ≥ 30 category versus  the < 25 kg/m2 category. More adverse events (AEs) and serious adverse events (SAEs) with tofacitinib were reported in the BMI < 25 kg/m2 category, which had a higher proportion of current smokers versus other categories. Regardless of baseline BMI category, efficacy was greater with tofacitinib versus placebo in patients with AS, and no treatment effect differences between categories were observed, with exceptions for BMI ≥ 30 kg/m2 (more active/treatment-refractory disease and a smaller sample size). Overall, tofacitinib safety was generally comparable across categories; however, AE/SAE rates with tofacitinib were higher in the BMI < 25 kg/m2 category (which had more current smokers). This post hoc analysis demonstrates that tofacitinib can be considered as a treatment option for AS, regardless of baseline BMI category; however, interpretation was limited by small sample sizes and differences in sample sizes and baseline characteristics across categories. ClinicalTrials.gov identifiers, NCT01786668 and NCT03502616.

Norton H ，Sliwinska-Stanczyk P ，Hala T ，El-Zorkany B ，Stockert L ，Mundayat R ，Wang L ，Ritchlin CT ... -  《-》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Oral budesonide for induction of remission in ulcerative colitis.

Sherlock ME ，MacDonald JK ，Griffiths AM ，Steinhart AH ，Seow CH ... -  《Cochrane Database of Systematic Reviews》

Infliximab for medical induction of remission in Crohn's disease.

Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α), which is present in high levels in the blood serum, mucosa and stool of people with Crohn's disease. To evaluate the benefits and harms of infliximab alone or in combination with another agent for induction of remission in Crohn's disease compared to placebo or active medical therapies. On 31 August 2021 and 4 March 2023, we searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and World Health Organization ICTRP. Randomised control trials (RCTs) comparing infliximab alone or in combination with another agent to placebo or another active comparator in adults with active Crohn's disease. Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were clinical remission, clinical response and withdrawals due to adverse events. Our secondary outcomes were endoscopic remission, histological remission, endoscopic response, and serious and total adverse events. The search identified 10 RCTs with 1101 participants. They were conducted between 1999 and 2019, and 7/10 RCTs included biologically naive participants. All but one RCT, which did not provide information, were multicentre and funded by pharmaceutical companies, and their authors declared conflicts. The age of the participants ranged from 26 to 65 years. Results were based on one study unless otherwise stated. Infliximab 5 mg/kg to 10 mg/kg may be more effective than placebo at week four for clinical remission (30/55 versus 3/25; RR 4.55, 95% CI 1.53 to 13.50; number needed to treat for an additional beneficial outcome (NNTB) 3) and response (36/55 versus 4/25; RR 4.09, 95% CI 1.63 to 10.25, NNTB 3). The evidence was low certainty. The study did not report withdrawals due to adverse events. We could not draw conclusions on the effects of infliximab 5 mg/kg to 10 mg/kg compared to placebo for fistulating participants for clinical remission (29/63 versus 4/31; RR 3.57, 95% CI 1.38 to 9.25; NNTB 4), response (48/106 versus 15/75; RR 1.94, 95% CI 1.10 to 3.41; NNTB 6; 2 studies) or withdrawals due to adverse events (2/63 versus 0/31; RR 2.50, 95% CI 0.12 to 50.54). The evidence was very low certainty. Infliximab used in combination with purine analogues is probably more effective than purine analogues alone for clinical remission at weeks 24 to 26 (182/301 versus 95/302; RR 1.92, 95% CI 1.59 to 2.32, NNTB 4; 4 studies; moderate-certainty evidence) and clinical response at week 26 (107/177 versus 66/178; RR 1.64, 95% CI 1.31 to 2.05; NNTB 5; 2 studies; moderate-certainty evidence). There may be little or no difference in withdrawals due to adverse events at week 26 (62/302 versus 53/301; RR 0.87, 95% CI 0.63 to 1.21; 4 studies; low-certainty evidence). Infliximab alone may be more effective than purine analogues alone at week 26 for clinical remission (85/177 versus 57/178; RR 1.50, 95% CI 1.15 to 1.95; NNTB 7; 2 studies) and response (94/177 versus 66/178; RR 1.44, 95% CI 1.13 to 1.82; NNTB 7; 2 studies). There may be little or no difference in withdrawals due to adverse events (30/177 versus 43/178; RR 0.70, 95% CI 0.46 to 1.06; 4 studies). The evidence was low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) and response (22/27 versus 24/28; RR 1.63, 95% CI 1.08 to 2.46). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg in an exclusively fistulating population for clinical remission (17/31 versus 12/32; RR 1.46, 95% CI 0.84 to 2.53), response (21/31 versus 18/32; RR 1.20, 95% CI 0.82 to 1.78), or withdrawals due to adverse events (1/31 versus 1/32; RR 1.03, 95% CI 0.07 to 15.79). The evidence was very low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 20 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) or response (22/27 versus 18/28; RR 1.27, 95% CI 0.91 to 1.76). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 10 mg/kg compared to 20 mg/kg for clinical remission (11/28 versus 11/28; RR 1.00, 95% CI 0.52 to 1.92) or response (14/28 versus 18/28; RR 0.78, 95% CI 0.49 to 1.23). The evidence was very low certainty. Withdrawals due to adverse events were not reported. There may be little or no difference between infliximab and a CT-P13 biosimilar at week six for clinical remission (47/109 versus 49/111; RR 0.98, 95% CI 0.72 to 1.32), response (67/109 versus 70/111; RR 0.97, 95% CI 0.79 to 1.20) and withdrawals due to adverse events (21/109 versus 17/111; RR 1.26, 95% CI 0.70 to 2.25). The evidence was low certainty. Infliximab in combination with purine analogues is probably more effective than purine analogues alone in inducing clinical remission and clinical response. Infliximab alone may be more effective in inducing clinical remission and response than purine analogues alone or placebo. Infliximab may be similar in efficacy to a CT-P13 biosimilar and there may be little or no difference in withdrawals due to adverse events. We were unable to draw meaningful conclusions as to whether infliximab alone is effective when used for exclusively fistulating populations. There was evidence that there may be little or no difference in withdrawal due to adverse events between infliximab plus purines compared with purines alone, as well as infliximab alone compared with purines alone. Meaningful conclusions cannot be drawn on all other outcomes related to adverse events due to very low certainty evidence.

Gordon M ，Sinopoulou V ，Akobeng AK ，Radford SJ ，Eldragini MEAA ，Darie AM ，Moran GW ... -  《Cochrane Database of Systematic Reviews》

Does the Presence of Missing Data Affect the Performance of the SORG Machine-learning Algorithm for Patients With Spinal Metastasis? Development of an Internet Application Algorithm.

The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA) was developed to predict the survival of patients with spinal metastasis. The algorithm was successfully tested in five international institutions using 1101 patients from different continents. The incorporation of 18 prognostic factors strengthens its predictive ability but limits its clinical utility because some prognostic factors might not be clinically available when a clinician wishes to make a prediction. We performed this study to (1) evaluate the SORG-MLA's performance with data and (2) develop an internet-based application to impute the missing data. A total of 2768 patients were included in this study. The data of 617 patients who were treated surgically were intentionally erased, and the data of the other 2151 patients who were treated with radiotherapy and medical treatment were used to impute the artificially missing data. Compared with those who were treated nonsurgically, patients undergoing surgery were younger (median 59 years [IQR 51 to 67 years] versus median 62 years [IQR 53 to 71 years]) and had a higher proportion of patients with at least three spinal metastatic levels (77% [474 of 617] versus 72% [1547 of 2151]), more neurologic deficit (normal American Spinal Injury Association [E] 68% [301 of 443] versus 79% [1227 of 1561]), higher BMI (23 kg/m 2 [IQR 20 to 25 kg/m 2 ] versus 22 kg/m 2 [IQR 20 to 25 kg/m 2 ]), higher platelet count (240 × 10 3 /µL [IQR 173 to 327 × 10 3 /µL] versus 227 × 10 3 /µL [IQR 165 to 302 × 10 3 /µL], higher lymphocyte count (15 × 10 3 /µL [IQR 9 to 21× 10 3 /µL] versus 14 × 10 3 /µL [IQR 8 to 21 × 10 3 /µL]), lower serum creatinine level (0.7 mg/dL [IQR 0.6 to 0.9 mg/dL] versus 0.8 mg/dL [IQR 0.6 to 1.0 mg/dL]), less previous systemic therapy (19% [115 of 617] versus 24% [526 of 2151]), fewer Charlson comorbidities other than cancer (28% [170 of 617] versus 36% [770 of 2151]), and longer median survival. The two patient groups did not differ in other regards. These findings aligned with our institutional philosophy of selecting patients for surgical intervention based on their level of favorable prognostic factors such as BMI or lymphocyte counts and lower levels of unfavorable prognostic factors such as white blood cell counts or serum creatinine level, as well as the degree of spinal instability and severity of neurologic deficits. This approach aims to identify patients with better survival outcomes and prioritize their surgical intervention accordingly. Seven factors (serum albumin and alkaline phosphatase levels, international normalized ratio, lymphocyte and neutrophil counts, and the presence of visceral or brain metastases) were considered possible missing items based on five previous validation studies and clinical experience. Artificially missing data were imputed using the missForest imputation technique, which was previously applied and successfully tested to fit the SORG-MLA in validation studies. Discrimination, calibration, overall performance, and decision curve analysis were applied to evaluate the SORG-MLA's performance. The discrimination ability was measured with an area under the receiver operating characteristic curve. It ranges from 0.5 to 1.0, with 0.5 indicating the worst discrimination and 1.0 indicating perfect discrimination. An area under the curve of 0.7 is considered clinically acceptable discrimination. Calibration refers to the agreement between the predicted outcomes and actual outcomes. An ideal calibration model will yield predicted survival rates that are congruent with the observed survival rates. The Brier score measures the squared difference between the actual outcome and predicted probability, which captures calibration and discrimination ability simultaneously. A Brier score of 0 indicates perfect prediction, whereas a Brier score of 1 indicates the poorest prediction. A decision curve analysis was performed for the 6-week, 90-day, and 1-year prediction models to evaluate their net benefit across different threshold probabilities. Using the results from our analysis, we developed an internet-based application that facilitates real-time data imputation for clinical decision-making at the point of care. This tool allows healthcare professionals to efficiently and effectively address missing data, ensuring that patient care remains optimal at all times. Generally, the SORG-MLA demonstrated good discriminatory ability, with areas under the curve greater than 0.7 in most cases, and good overall performance, with up to 25% improvement in Brier scores in the presence of one to three missing items. The only exceptions were albumin level and lymphocyte count, because the SORG-MLA's performance was reduced when these two items were missing, indicating that the SORG-MLA might be unreliable without these values. The model tended to underestimate the patient survival rate. As the number of missing items increased, the model's discriminatory ability was progressively impaired, and a marked underestimation of patient survival rates was observed. Specifically, when three items were missing, the number of actual survivors was up to 1.3 times greater than the number of expected survivors, while only 10% discrepancy was observed when only one item was missing. When either two or three items were omitted, the decision curves exhibited substantial overlap, indicating a lack of consistent disparities in performance. This finding suggests that the SORG-MLA consistently generates accurate predictions, regardless of the two or three items that are omitted. We developed an internet application ( https://sorg-spine-mets-missing-data-imputation.azurewebsites.net/ ) that allows the use of SORG-MLA with up to three missing items. The SORG-MLA generally performed well in the presence of one to three missing items, except for serum albumin level and lymphocyte count (which are essential for adequate predictions, even using our modified version of the SORG-MLA). We recommend that future studies should develop prediction models that allow for their use when there are missing data, or provide a means to impute those missing data, because some data are not available at the time a clinical decision must be made. The results suggested the algorithm could be helpful when a radiologic evaluation owing to a lengthy waiting period cannot be performed in time, especially in situations when an early operation could be beneficial. It could help orthopaedic surgeons to decide whether to intervene palliatively or extensively, even when the surgical indication is clear.

Huang CC ，Peng KP ，Hsieh HC ，Groot OQ ，Yen HK ，Tsai CC ，Karhade AV ，Lin YP ，Kao YT ，Yang JJ ，Dai SH ，Huang CC ，Chen CW ，Yen MH ，Xiao FR ，Lin WH ，Verlaan JJ ，Schwab JH ，Hsu FM ，Wong T ，Yang RS ，Yang SH ，Hu MH ... -  《-》