Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study.

BACKGROUND: We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of response. METHODS: Personalised Anti-TNF therapy in Crohn's disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn's disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete. FINDINGS: Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years [IQR 22·1-46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7-43·7), 34·4% (29·9-39·0), and 34·7% (29·8-39·5), and for adalimumab 35·9% (95% CI 31·2-40·5), 32·9% (26·8-39·2), and 28·9% (21·9-36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1-10·0 mg/L for infliximab and 10·1-12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4-38·2), 54·5% (49·4-59·0), and 60·0% (54·1-65·2), and for adalimumab 32·1% (26·7-37·1), 47·2% (40·2-53·4), and 68·4% (50·9-79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45 [95% CI 0·30-0·67], adalimumab: 0·39 [0·22-0·70]). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11-1·95]), obesity (vs not obese 1·62 [1·08-2·42]), baseline white cell count (1·06 [1·02-1·11) per 1 × 109 increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 [95% CI 1·17-3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1-49·4) among patients treated with infliximab and 20·3% (13·8-26·2) among those treated with adalimumab. The development of anti-drug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 [95% CI 0·31-0·52], adalimumab 0·42 [95% CI 0·24-0·75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13-1·88]) but not for adalimumab (HR 1·60 [0·92-2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20-3·74]) or introduction of an immunomodulator after anti-TNF initiation (1·70 [1·11-2·59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3. INTERPRETATION: Only around a third of patients with active luminal Crohn's disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs. FUNDING: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion Healthcare.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Inflammatory synovial biomarkers and state of the tibiofemoral joint in the post-surgical settings: a narrative review.

Background and Objective: Knee surgery attempts to restore the native biomechanics of the knee, improve stability, and decrease the progression of osteoarthritis (OA). However, despite improvements in surgical techniques, tissue degradation and OA are common after knee surgery, occurring in higher rates in surgical knees compared to non-surgical knees. The aim of this study is to analyze previous literature to determine which synovial fluid biomarkers contribute to knee tissue degradation and decrease patient outcomes in the post-surgical setting of the knee. Methods: A narrative review of relevant literature was performed in July 2023. Studies reporting on synovial biomarkers associated with the post-surgical knee were included. Key Content and Findings: The literature reported that proinflammatory synovial biomarkers cause cartilage degradation and turnover which eventually leads to OA. The associated biomarkers are typically present prior to physical symptoms so understanding which one's correlate to OA is important for potential therapeutic treatments in the future. Studying the preoperative, early postoperative, and late postoperative synovial biomarkers will allow physicians to develop an improved understanding of how these biomarkers progress and correlate to knee tissue degradation and OA. This understanding could lead to further developments into potential treatment options. Research into inhibiting or reversing these inflammatory biomarkers to slow the progression of knee tissue degradation has already begun and has reported some promising results but is currently limited in scope. Conclusions: Synovial fluid biomarkers in the post-surgical knee setting may contribute to decreased patient outcomes and the progression of knee tissue degradation. There is no current consensus on which of these biomarkers are the most detrimental or associated with decreased patient outcomes. With an improved understanding of the individual biomarkers, potential personalized therapeutic treatment could be used by physicians in the future to improve patient outcomes after surgery.

The effect of nonsteroidal anti-inflammatory drug use on soft tissue and bone healing in the knee: a systematic review.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to mitigate pain and inflammation associated with musculoskeletal conditions; however, there is conflicting data on the adverse effects of these drugs on tissue and bone healing. The objective of this study was to investigate the effect of NSAIDs on the healing of knee, soft tissue, and bone. Methods: A systematic literature search was conducted across PubMed/MEDLINE, Excerpta Medical Database (Embase)/Ovid, and the Cochrane Central Register of Controlled Trials databases. Clinical, animal, and in vitro studies on the effect of NSAIDs on knee healing were included. Risk of bias assessment was performed using the Cochrane bias assessment tool and Methodological Index for Non-Randomized Studies scoring system for included clinical studies, and the Systematic Review Center for Laboratory Animal Experimentation assessment tool for all included animal studies. General study population characteristics, interventions used, NSAIDs utilized, outcome measures, and study results were analyzed using descriptive statistics. Results: Fifteen articles met the inclusion criteria. Of the 15 studies, there were three clinical, ten animal, and two in vitro studies. In clinical studies, nonselective cyclooxygenase (COX) inhibitors and selective COX-2 inhibitors did not cause a significant increase in failure of anterior cruciate ligament (ACL) reconstructions or meniscal repairs with NSAID administration pre-, peri-, or post-operatively in comparison to placebo or no NSAID administration. Among animal studies assessing COX-2 inhibitor effects on soft tissue, healing was impaired (2/4), delayed but unaffected (1/4), or unaffected (1/4). In animal studies assessing COX-1 inhibitors, ligament healing was either increased (1/4), unaffected (2/4), or impaired (1/4). Meanwhile, administration of non-selective COX inhibitors in animals did not affect soft tissue (3/3) and cartilage (1/1) healing. Two in vitro studies identified a negative outcome on patellar tendon and ACL cell proliferation or viability after non-selective COX inhibition and variable results after selective COX-2 inhibition. Conclusions: Animal studies on postoperative NSAID use after knee surgery suggest that administration of selective and nonselective COX-2 inhibitors may impair healing of soft tissue, bone and tendon-to-bone; however, further clinical studies are needed to better characterize dose and duration dependent risks of NSAIDs.

Effect of anti-inflammatory treatments on patient outcomes and concentrations of inflammatory modulators in the post-surgical and post-traumatic tibiofemoral joint setting: a narrative review.

Background and Objective: There are several anti-inflammatory therapeutic options that can be used in the context of post-surgical and post-traumatic knee settings. Each of these options carries with it certain benefits, as well as potential issues depending on the duration and administration of each therapy. An understanding of how these anti-inflammatory drugs modulate various biomarkers of inflammation is also necessary in understanding how they can affect patient and objective outcomes following acute knee injury or surgery. This review covers the many traditional therapeutic options that have been used in treating knee injuries, as well as some natural therapeutics that have shown anti-inflammatory properties. Methods: A current review of the literature was conducted and synthesized into this narrative review. Key Content and Findings: Many traditional anti-inflammatory therapeutics have been shown to be beneficial in both post-traumatic and post-surgical tibiofemoral joint settings at reducing inflammation and improving patient outcomes. However, many of these treatments have risks associated with them, which becomes problematic with prolonged, repeated administration. Natural anti-inflammatory compounds may also have some benefit as adjunctive treatment options in these settings. Conclusions: There are multiple different therapeutic options that can be used in acute knee settings, but the specific mechanism of injury or surgical context should be weighed when determining the best clinical approach.

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

Cost-utility analysis of ferric derisomaltose versus ferric carboxymaltose in patients with inflammatory bowel disease and iron deficiency anemia in England.

AIMS: Anemia is the most common extraintestinal complication of inflammatory bowel disease (IBD), with approximately half of cases caused by iron deficiency (ID). Intravenous iron is the preferred ID anemia (IDA) treatment where oral iron is contraindicated, ineffective or not tolerated, or where ID correction is urgent. The objective was to evaluate the cost-utility of ferric derisomaltose (FDI) versus ferric carboxymaltose (FCM) in patients with IBD and IDA in England, in whom IV iron treatment is preferred. MATERIALS AND METHODS: A patient-level simulation model was developed, capturing quality of life (QoL) differences based on SF-36v2 data from the PHOSPHARE-IBD randomized controlled trial, monitoring and incidence of post-infusion hypophosphatemia, and number of iron infusions required. Analyses were conducted over a five-year time horizon from the Department of Health and Social Care (DHSC) perspective, with healthcare provider and societal perspectives adopted in separate analyses. Future costs and effects were discounted at 3.5% per annum and one-way and probabilistic sensitivity analyses were performed. RESULTS: FDI increased quality-adjusted life expectancy by 0.075 QALYs versus FCM from 2.57 QALYs to 2.65 QALYs per patient. Patients receiving FDI required 1.63 fewer iron infusions over the five-year time horizon, driving infusion-related cost savings of GBP 496 per patient (GBP 2,188 versus GBP 1,692) from the DHSC perspective. Costs of monitoring and treating hypophosphatemia after FCM were GBP 226, yielding total savings of GBP 722 per patient (GBP 2,414 versus GBP 1,692) over the five-year time horizon. FDI also led to reduced costs versus FCM in the societal and provider analyses and was therefore the dominant intervention across all three perspectives. LIMITATIONS: The analysis did not capture patient adherence, hypophosphatemic osteomalacia, or fractures. CONCLUSIONS: Results showed that FDI improved patient QoL and reduced direct healthcare expenditure versus FCM in patients with IBD and IDA in England.

Ferric derisomaltose (FDI) is an intravenous iron approved for the treatment of clinically diagnosed iron deficiency in the United Kingdom (UK), and can be an important therapeutic option for patients with inflammatory bowel disease (IBD), who require regular and rapid iron replenishment. Ferric carboxymaltose (FCM) is the sole alternative intravenous iron formulation available in the UK, but is associated with reduced blood phosphate levels, potentially causing fatigue and weakening of the bones. We conducted an economic analysis to weigh the costs and clinical outcomes associated with FDI and FCM in the UK, for patients with IBD and iron deficiency anemia (IDA). The main clinical difference we investigated was reduced blood phosphate levels, which occurred more often after FCM than FDI. We also incorporated recent quality of life data from a clinical study, and calculated the number of infusions (and associated costs) of each iron formulation, that patients would require over five years. Clinical data were obtained from published medical literature, while cost data came from UK sources including the 2022/2023 National Tariff Payment System and the British National Formulary. Our model showed that FDI was associated with quality of life improvements, fewer overall infusions per treatment course, and reduced costs compared to FCM, from the English Department of Health and Social Care perspective, the societal perspective, and the perspective of individual healthcare providers (namely NHS Trusts) within NHS England. FDI is therefore likely to represent the best value intravenous iron for the treatment of IDA with IBD in the UK.

Validation of the IBD-Control Questionnaire across different sociodemographic and clinical subgroups: secondary analysis of a nationwide electronic survey.

BACKGROUND: The IBD-Control Questionnaire is a simple, generic measure of patient-perceived disease control used increasingly in clinical practice and research. We aimed to address knowledge gaps in its psychometric performance, to ensure that it can be used with confidence in a variety of contexts. METHODS: We analysed 7341 responses to the IBD Registry COVID-19 survey, sent to 40 911 patients who completed an online self-assessment tool during the pandemic. Questions covered demographics, comorbidities, inflammatory bowel disease [IBD] sub-type, and IBD-Control Questionnaire and symptom scores [CD-PRO2 or UC-PRO2]. Psychometric properties of IBD-Control-8 were tested overall and within subgroups (Crohn's disease [CD], ulcerative colitis [UC] and IBD unclassified; male and female; ≤65 and >65 years; number of co-morbidities; deprivation status). RESULTS: Internal consistency was very strong overall [α: 0.84, ω: 0.89] and for each subgroup [α range: 0.81-0.85; ω: 0.86-0.90]. Construct validity was demonstrated by moderate correlation of each item with global rating [VAS] [rs range: 0.47-0.65], strong correlation between IBD-Control-8 score and VAS [rs = 0.74], moderate-to-strong with PRO2 scores [CD: rs = -0.718; UC: rs = -0.602] and significantly higher IBD-Control-8 scores for PRO2-remission vs PRO2-active, consistent across subgroups. Exploratory and confirmatory factor analyses demonstrated a two-factor model (items loading onto 'Health-related Quality of Life' [HRQoL] or 'Treatment' domains). Extensive tests for factorial invariance confirmed consistency. CONCLUSIONS: IBD-Control-8 is a psychometrically robust scale which can be used across a range of populations. It offers a quick, reliable, and valid method of assessing patient-perceived control. The construct of 'control' includes traditional HRQoL and a novel domain relating to treatment perception.

Baseline Expression of Immune Gene Modules in Blood is Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease Patients.

BACKGROUND AND AIMS: Anti-tumour necrosis factor [anti-TNF] therapy is widely used for the treatment of inflammatory bowel disease, yet many patients are primary non-responders, failing to respond to induction therapy. We aimed to identify blood gene expression differences between primary responders and primary non-responders to anti-TNF monoclonal antibodies [infliximab and adalimumab], and to predict response status from blood gene expression and clinical data. METHODS: The Personalised Anti-TNF Therapy in Crohn's Disease [PANTS] study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF-naive Crohn's disease patients [ClinicalTrials.gov identifier: NCT03088449]. Blood gene expression in 324 unique patients was measured by RNA-sequencing at baseline [week 0], and at weeks 14, 30, and 54 after treatment initiation [total sample size = 814]. RESULTS: After adjusting for clinical covariates and estimated blood cell composition, baseline expression of major histocompatibility complex, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders vs non-responders. Expression changes from baseline to week 14 were generally of consistent direction but greater magnitude [i.e. amplified] in responders, but interferon-related genes were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at weeks 30 and 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor. CONCLUSIONS: Baseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these baseline expression differences did not predict response with sufficient sensitivity for clinical use.

The effects of extinction and an explicitly unpaired treatment on the reinforcing properties of a Pavlovian conditioned stimulus.

This series of experiments examined the effects of extinction and an explicitly unpaired treatment on the ability of a conditioned stimulus (CS) to function as a reinforcer. Rats were trained to lever press for food, exposed to pairings of a noise CS and food, and, finally, tested for their willingness to lever press for the CS in the absence of the food. Experiment 1 provided a demonstration of conditioned reinforcement (using controls that were only exposed to unpaired presentations of the CS and food) and showed that it was equivalent after one or four sessions of CS-food pairings. Experiments 2 and 3 showed that, after one session of CS-food pairings, repeated presentations of the CS alone reduced its reinforcing properties; but after four sessions of CS-food pairings, repeated presentations of the CS alone had no effect on these properties. Experiment 4 showed that, after four sessions of CS-food pairings, explicitly unpaired presentations of the CS and food completely undermined conditioned reinforcement. Finally, Experiment 5 provided within-experiment evidence that, after four sessions of CS-food pairings, the reinforcing properties of the CS were disrupted by explicitly unpaired presentations of the CS and food but spared by repeated presentations of the CS alone. Together, these findings indicate that the effectiveness of extinction in undermining the reinforcing properties of a CS depends on its level of conditioning; and that, where extinction fails to disrupt these properties, they are successfully undermined by an explicitly unpaired treatment. They are discussed with respect to findings in the literature on Pavlovian-to-instrumental transfer; and the Rescorla-Wagner model, which anticipates that an explicitly unpaired treatment will be more effective than extinction in reversing the effects of conditioning.

Complete Arthroscopic Posterior Knee Capsulotomy in Patients With Knee Extension Deficit: Preliminary Results of a Clinical Trial.

Background: Guided physiotherapy and surgical arthrolysis are effective in most patients with knee extension deficit. However, in refractory cases, posterior knee capsulotomy may be needed. Purpose: To assess extension restoration, pain reduction, and functional improvement after arthroscopic complete posterior knee capsulotomy in patients with extension deficit refractory to guided physiotherapy and surgical arthrolysis. Study Design: Case series; Level of evidence, 4. Methods: Included were patients with symptomatic asymmetric extension deficit >3° refractory to at least 6 months of guided physiotherapy and initial arthrolysis (15 patients with 12-month follow-up and 8 patients with 24-month follow-up). The mean duration of extension deficit was 24.6 months. An arthroscopic complete posterior knee capsulotomy was performed with transection of the posteromedial, posterolateral and central capsule, and the posterior septum. The primary outcome measure was knee extension, with hyperextension denoted as negative knee extension values. Secondary outcome measures included visual analog scale (VAS) for pain during maximum effort and exercise, International Knee Documentation Committee (IKDC) score, and Knee injury and Osteoarthritis Outcome Score (KOOS). Results: The mean patient age was 40.0 years (range, 26-70 years); 6 out of 15 patients had developed knee contracture after isolated anterior cruciate ligament reconstruction. The mean knee extension deficit decreased from 16.9° (range, 7° to 45°) preoperatively to -0.2° (range, -5° to 5°) at 12-month follow-up (P = .003) and to -0.3° (range, -5° to 5°) at 24-month follow-up (P = .035). The mean VAS pain score decreased from 3.5 (range, 1-6) preoperatively to 1.1 (range, 0-2) at 12-month follow-up (P = .004) and to 1.5 (range, 0-4) at 24-month follow-up (P = .005). The mean IKDC increased from 37.9 (range, 21-62) preoperatively to 63.9 (range, 46-87) at 12-month follow-up (P < .001) and to 60.9 (range, 39-80) at 24-month follow-up (P = .003). The mean KOOS increased from 45.0 (range, 30-62) preoperatively to 75.3 (range, 49-94) at 12-month follow-up (P < .001) and to 72.3 (range, 49-92) at 24-month follow-up (P = .003). There were no significant differences between 12- and 24-month follow-up in extension deficit or functional outcomes. One patient had a midcalf subcutaneous hematoma 5 weeks postoperatively, requiring evacuation. Conclusion: Arthroscopic complete posterior knee capsulotomy was able to restore knee extension, reduce pain, and improve function, with 12-month follow-up results sustained at 24-month follow-up. Registration: NCT05385393 (ClinicalTrials.gov identifier).

Inconsistent Return to Sport Despite Improved Outcomes After Re-revision Anterior Cruciate Ligament Reconstruction: An Updated Systematic Review.

PURPOSE: The primary objective was to systematically review the literature evaluating patient-reported outcomes and return to sport after re-revision anterior cruciate ligament reconstruction (ACLR) procedures. The secondary objectives were 2-fold: to identify the risk factors that lead to revision ACLR failure and to assess the secondary knee structure injuries after the initial revision ACLR. METHODS: A systematic review of the literature was performed using the MEDLINE/PubMed and Cochrane databases. The inclusion criteria were outcomes of re-revision ACLR, minimum of 2 years' follow-up, human studies, and English language. Basic science articles, epidemiologic studies, editorials, surgical technique articles, surveys, cadaveric studies, and animal studies were excluded. RESULTS: Fifteen studies met the inclusion criteria and were considered for review. There were 6 Level III and 9 Level IV studies that included 399 patients undergoing re-revision ACLR. The rate of concomitant meniscal lesions at the time of re-revision ranged from 35% to 90%. The prevalence of concomitant cartilaginous lesions at the time of re-revision ranged from 13.6% to 90%. Compared with preoperative scores, patient-reported outcomes overall improved after re-revision ACLR, with mean preoperative Lysholm scores ranging from 38.4 to 73.15 that improved to postoperative scores ranging from 68 to 87.8. However, return to sport at preinjury levels was inconsistent, with rates ranging from 12.5% to 80%. CONCLUSIONS: Re-revision ACLR was found to restore knee stability and improve functional outcomes. Despite this improvement, there was a low rate of return to sport at the preinjury level. Functional outcomes were also inferior when compared with primary ACLR. In addition, concomitant knee pathologies were found to rise in prevalence compared with revision and primary ACLR cases. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies.

Antibody responses to Influenza vaccination are diminished in patients with inflammatory bowel disease on infliximab or tofacitinib.

BACKGROUND AND AIMS: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with IBD. METHODS: We conducted a prospective study including 213 IBD patients and 53 healthy controls; 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination and interval between vaccination and sampling. RESULTS: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (Geometric Mean Ratio 0.35 [95% CI 0.20-0.60], p=0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p=0.0050) and tofacitinib (0.28 [0.14-0.57], p=0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p=0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p=0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p=0.017) and tofacitinib (0.23 [0.10-0.56], p=0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 (r=0.27; p=0.0004) and H1N1 (r=0.33; p<0.0001). CONCLUSIONS: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to Influenza/A, similar to COVID-19 vaccine-induced antibody responses.

Editorial Commentary: Meniscal Extrusion.

With the improved recognition of meniscal root tears over the past decade, it has become clear that root repairs are necessary in most patients indicated for a repair to prevent the further progression of osteoarthritis. Root repairs are cost beneficial to and prevent the early need for a total knee arthroplasty. As further postoperative follow-up occurs for root repairs, we have found that most patients have significantly improved patient-reported outcomes, while it is still clear that further clinical outcome study as well as further refinement of surgical technique is necessary. The next thing that we have to investigate is how to prevent recurrent meniscal extrusion after a root repair. Nonanatomic repair significantly alters tibiofemoral biomechanics and results in notably increased meniscal extrusion. In contrast, biomechanical studies show anatomic repair of the meniscus attachment within 1 cm of the meniscus attachment site restores joint loading close to normal.

Reference standards for stress radiography measurements in knee ligament injury and instability: a systematic review.

PURPOSE: Stress radiographs are an easily accessible, cost-effective tool in the evaluation of acute and chronic ligament knee injuries. Stress radiographs provide an objective, quantifiable, and functional assessment of the injured ligament and can be a useful adjunct when planning surgical management and to objectively assess postoperative outcomes. This study aimed to review the literature reporting on stress radiographic techniques in evaluating knee ligament injury and instability and propose thresholds for interpreting stress radiography techniques. METHODS: The following three databases, OVID MEDLINE, the EMBASE library, and the Cochrane Controlled Trials Register, were systematically searched on January 23, 2023, for studies published from January 1970 to January 2023. The search extended to the reference lists of all relevant studies and orthopedic journals. Included studies were those that described a stress technique for the diagnosis of knee ligament injury; studies that reported a description or comparison of the accuracy and/or reliability of one or several stress radiography techniques, or studies that reported a comparison with alternative diagnostic modalities. RESULTS: Sixteen stress radiography techniques were reported for assessing the ACL with stress applied in the anterior plane, 10 techniques for assessing the PCL with stress applied in the posterior plane, 3 techniques for valgus stress, and 4 techniques for varus stress. The Telos device was the most commonly used stress device in the ACL and PCL studies. There was no consensus on the accuracy and reliability of stress radiography techniques for the diagnosis of any knee ligament injury. Stress radiography techniques were compared with alternative diagnostic techniques including instrumented arthrometry, MRI, and physical examination in 18 studies, with variability in the advantages and disadvantages of stress radiography techniques and alternatives. Analysis of results pooled from different studies demonstrated average delta gapping in knees with a completely injured ligament compared to the normal contralateral knee as per the following: for the ACL 4.9 ± 1.4 mm; PCL 8.1 ± 2.5 mm; MCL 2.3 ± 0.05 mm; and the FCL 3.4 ± 0.2 mm. CONCLUSION: Despite heterogeneity in the available literature with regard to stress examination techniques and device utilization, the data support that stress radiography techniques were accurate and reliable when compared to numerous alternatives in the diagnosis of acute and chronic knee ligament injuries. The present study also provides average increased ipsilateral compartment gapping/translation for specific knee ligament injuries based on the best available data. These values provide a reference standard for the interpretation of stress radiography techniques, help to guide surgical decision-making, and provide benchmark values for future investigations. LEVEL OF EVIDENCE: III.

Knee extension contracture with fixed anterior tibia subluxation treated with PCL release and quadricepsplasty: a case report.

58-year-old male presented with knee extension contracture (25°) with iatrogenic fixed anterior tibial subluxation. Consecutive arthroscopic arthrolysis, manipulation under anesthesia, and quadriceps-Z-plasty during one surgery failed to restore flexion. Therefore, shortened posterior cruciate ligament was released, which eliminated subluxation and allowed 115° flexion. Despite physiotherapy, flexion progressively decreased to 70° postoperatively. Revision quadricepsplasty by transverse incisions restored 120° of flexion maintained at 31-months follow-up. International Knee Documentation Committee increased 4/87- > 50/87, Knee injury and Osteoarthritis Outcome 7/100- > 68/100 at follow-up. Posterior cruciate ligament release and repeated quadricepsplasty could be a viable salvage option in severe extension contracture with fixed anterior tibial subluxation.

Combined Rip-Stop and Transtibial Pull-out Technique for Lateral Meniscus Radial Repairs.

Radial tears of the meniscus disrupt circumferential fibers that allow for the dispersion of axial tibiofemoral forces. Both nonoperative treatment and meniscectomy carry increased risk of early-onset degeneration of the joint because of decreased contact surface area and increased point-loading of the chondral surfaces. Radial type tears are also notable for the relatively high failure rate associated with repair. The purpose of this technical note is to demonstrate our surgical technique for a radial lateral meniscus repair construct that allows for good apposition and anatomic reduction of the meniscus with less risk of residual postoperative extrusion through use of a combination inside-out rip-stop and transtibial pull-out suturing repair.

Concurrent Repair of Medial Meniscal Ramp Lesions and Lateral Meniscus Root Tears in Patients Undergoing Anterior Cruciate Ligament Reconstruction: The "New Terrible Triad".

Recent studies have suggested that up to 8% of patients with anterior cruciate ligament (ACL) tears can present with a combined medial meniscal ramp lesion (MMRL) and lateral meniscus root tear (LMRT). MMRLs and LMRTs often are missed preoperatively and can increase the risk of ACL graft failure if left untreated. Given the potential synergistic biomechanical consequences and challenging repair techniques used for treatment, our group commonly refers to this presentation (MMRL-LMRT-ACL) as the "new terrible triad" of ACL pathology. This Technical Note aims to describe a systematic approach for arthroscopic assessment and our preferred inside-out and transtibial pull-out repair techniques to efficiently diagnose and treat a combined MMRL and LMRT at the time of ACL reconstruction surgery.

ACL Mucoid Degeneration-Anterior and Posterior Arthroscopic Decompression for Combined Knee Flexion-Extension Deficit.

Mucoid degeneration of the ACL (MDACL, ACL ganglion cysts) is a disease involving ACL thickening due to accumulation of mucoid substance and fiber degeneration with possible formation of "ganglions". Clinically, it leads to anteroposterior impingement and painful limitation of knee range of motion due to impingement of the anterior portion of the thickened ACL with the intercondylar notch during knee extension and the thickened posterior part of the ligament with posterior structures of the knee in flexion. Different treatment methods have been described, including total or partial resection of the ACL degenerative fibers. However, these techniques do not allow for ACL preservation and are associated with a risk of postoperative instability. Also, most procedures treat anterior impingement only. Therefore, the aim of this technical note is to present an arthroscopic technique allowing for minimally invasive anteroposterior ACL decompression. The technique is focused on evacuation of the interfibrous mucoid substance, ganglions, and bony decompression, as well as maintenance of ligament integrity. Its greatest advantage is that it is safe and ACL-preserving yet allows for comprehensive treatment of all intra- and extra-ligamentous possible reasons of MDACL origin and promoting good healing conditions.