Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Protective Effects of Glatiramer Acetate Against Paclitaxel-Induced Peripheral Neuropathy in Rats: A Role for Inflammatory Cytokines and Oxidative Stress.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge for cancer patients who undergo chemotherapy with paclitaxel. Therefore, finding effective therapies for CIPN is crucial. Glatiramer acetate is used to treat multiple sclerosis that exerts neuroprotective properties in various studies. We hypothesized that glatiramer acetate could also improve the paclitaxel-induced peripheral neuropathy. We used a rat model of paclitaxel (2 mg/kg/every other day for 7 doses)-induced peripheral neuropathy. Rats were treated with either different doses of glatiramer acetate (1, 2, 4 mg/kg/day) or its vehicle for 14 days in separate groups. The mechanical and thermal sensitivity of the rats by using the Von Frey test and the Hot Plate test, respectively, were assessed during the study. The levels of oxidative stress (malondialdehyde and superoxide dismutase), inflammatory markers (TNF-α, IL-10, NF-kB), and nerve damage (H&E and S100B staining) in the sciatic nerves of the rats were also measured at the end of study. Glatiramer acetate (2 and 4 mg/kg) exerted beneficial effects on thermal and mechanical allodynia tests. It also modulated the inflammatory response by reducing TNF-α and NF-κB levels, enhancing IL-10 production, and improving the oxidative stress status by lowering malondialdehyde and increasing superoxide dismutase activity in the sciatic nerve of the rats. Furthermore, glatiramer acetate enhanced nerve conduction velocity in all treatment groups. Histological analysis revealed that glatiramer acetate (2 and 4 mg/kg) prevented paclitaxel-induced damage to the nerve structure. These results suggest that glatiramer acetate can alleviate the peripheral neuropathy induced by paclitaxel.

Anti-drug antibodies against anti-TNF in patients with inflammatory bowel disease: an evaluation of possible strategies.

OBJECTIVE: Immunogenicity against anti-TNF antibodies usually leads to loss of response. We aimed to evaluate the efficacy of clinical strategies to improve clinical remission and pharmacokinetics upon detection of anti-drug antibodies (ADA). METHODS: Inflammatory bowel disease (IBD) patients with ADA against infliximab or adalimumab were identified through a single centre database search covering 2004-2022. Criteria for successful intervention upon ADA detection (baseline) were clinical remission after 1 year without further change in strategy. RESULTS: Two-hundred-and-fifty-five IBD patients (206 Crohn's disease) were identified. At baseline, median ADA level was 77 AU/ml; 50.2% of patients were in clinical remission. Implemented strategies were: (1) 81/255 (32%) conservative management, (2) 102/255 (40%) anti-TNF optimisation, (3) 72/255 (28%) switch within or out of class. Switching was the most successful strategy for clinical remission (from 19% at baseline to 69% at 1 year, p < 0.001). Patients that continued the same dose anti-TNF or discontinued biological therapy were often in clinical remission, but deteriorated significantly (-22.7%, p = 0.004). Anti-TNF dose intensification with immunomodulator optimisation was the fastest (median 3.0 months, p = 0.009) and most effective (65% ADA suppression, p < 0.001) strategy to suppress ADA compared to solely anti-TNF or immunomodulator optimisation. CONCLUSIONS: Switching therapy, within or out of class, is the most successful strategy to regain and maintain clinical remission upon immunogenicity. When switching to another anti-TNF, concomitant immunomodulatory therapy should be started or continued to prevent repeated immunogenic loss of response. Anti-TNF dose escalation with concomitant immunomodulator optimisation is the fastest and most effective strategy to suppress ADA.

Immunogenicity against anti-TNF antibodies is associated with loss of response in patients with inflammatory bowel diseases and remains a clinical challenge. We investigated potential therapeutic strategies in a retrospective patient cohort focusing on clinical efficacy and pharmacokinetics.

Comorbidities in the Spondyloarthritis GISEA Cohort: an average treatment effect analysis on patients treated with bDMARDs.

OBJECTIVES: We aimed to investigate the effectiveness of tumour necrosis factor inhibitors (TNFi), anti-interleukin-17 or interleukin-12/23 monoclonal antibodies (anti-IL) on comorbidities in a cohort of patients with spondyloarthritis (SpA), using an average treatment effect (ATE) analysis. METHODS: SpA patients from the multicentre Italian GISEA Registry were divided into groups according to pharmacological exposure: no treatment (G0), TNFi (G1) and non-responders to TNFi switched to anti-IL (G2). In each group, we recorded the prevalence and incidence of infectious, cardiopulmonary, endocrinological, gastrointestinal, oncologic, renal and neurologic comorbidities. Each comorbidity was then fitted for ATE and baseline features were evaluated for importance. RESULTS: The main findings of this study comprising 4458 SpA patients relate to cancer, other gastrointestinal diseases (OGID) and fibromyalgia. ATE showed no increased risk of solid cancer in G1 (0.42 95% CI 0.20-0.85) and G2 (0.26 95% CI 0.08-0.71) vs. G0, with significantly higher incidence in G0 (14.07/1000 patient-years, p=0.0001). Conversely, a significantly higher risk of OGID and fibromyalgia was found in G1 (1.56 95% CI 1.06-2.33; 1.69 95% CI 1.05-2.68, respectively) and G2 (1.91 95% CI 1.05-3.24; 2.13 95% CI 1.14-3.41, respectively) vs. G0. No treatment risk reduction was observed in haematological malignancies, cardiovascular events and endocrinological comorbidities. CONCLUSIONS: Overall, our study confirms the safety of TNFi and anti-IL in SpA patients, albeit with some caveats pertaining to solid cancers, OGID and fibromyalgia. Furthermore, taking into consideration causality with observational data may yield more reliable and relevant clinical information.

Protective effects of arbutin against doxorubicin-induced cardiac damage.

BACKGROUND: Doxorubicin is an effective antineoplastic agent but has limited clinical application because of its cumulative toxicities, including cardiotoxicity. Cardiotoxicity causes lipid peroxidation, genetic impairment, oxidative stress, inhibition of autophagy, and disruption of calcium homeostasis. Doxorubicin-induced cardiotoxicity is frequently tried to be mitigated by phytochemicals, which are derived from plants and possess antioxidant, anti-inflammatory, and anti-apoptotic properties. Arbutin, a natural antioxidant found in the leaves of the bearberry plant, has numerous pharmacological benefits, including antioxidant, anti-bacterial, anti-hyperglycemic, anti-inflammatory, and anti-tumor activity. METHODS AND RESULTS: The study involved male Wistar rats divided into three groups: a control group, a group treated with doxorubicin (20 mg/kg) to induce cardiac toxicity, a group treated with arbutin (100 mg/kg) daily for two weeks before doxorubicin administration. After treatment, plasma and heart tissue samples were collected for analysis. The samples were evaluated for oxidative stress parameters, including superoxide dismutase, malondialdehyde, and catalase, as well as for cardiac biomarkers, including CK, CK-MB, and LDH. The heart tissues were also analyzed using molecular (TNF-α, IL-1ß and Caspase 3), histopathological and immunohistochemical methods (8-OHDG, 4 Hydroxynonenal, and dityrosine). The results showed that arbutin treatment was protective against doxorubicin-induced oxidative damage by increasing SOD and CAT activity and decreasing MDA level. Arbutin treatment was similarly able to reverse the inflammatory response caused by doxorubicin by reducing TNF-α and IL-1ß levels and also reverse the apoptosis by decreasing caspase-3 levels. It was able to prevent doxorubicin-induced cardiac damage by reducing cardiac biomarkers CK, CK-MB and LDH levels. In addition to all these results, histopathological analyzes also show that arbutin may be beneficial against the damage caused by doxorubicin on heart tissue. CONCLUSION: The study suggests that arbutin has the potential to be used to mitigate doxorubicin-induced cardiotoxicity in cancer patients.

Tissue markers may predict treatment response to antitumor necrosis factor-α agents in children with Crohn's disease.

OBJECTIVES: Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. METHODS: Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. RESULTS: Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. CONCLUSIONS: Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.

Protective effects of esculetin against ovary ischemia-reperfusion injury model in rats.

AIMS: Ovarian ischemia-reperfusion (I/R) injury is a phenomenon that necessitates urgent intervention, which occurs as a result of ovarian torsion, and it is frequently seen in young women. A large amount of free radical and oxidative damage as a result of I/R plays a role in the cause of the incident. Antioxidant agents are thought to be beneficial in preventing this damage, and the potential protective effects of esculetin, which had not been tested previously, were investigated in this study. STUDY DESIGN: The rats in the study were divided into five groups at random: control, sham, esculetin, I/R, and treatment. Oxidative stress parameters, proinflammatory cytokines, nuclear factor erythroid 2-related factor 2 (Nrf-2)/nuclear factor-kß (NF-κß) pathway, and histopathological analyses were evaluated at the end of the study. KEY FINDINGS: After I/R, malondialdehyde levels, proinflammatory cytokines, tumor necrosis factor-α and interleukin-1ß levels and NF-κß expressions were increased, Nrf-2 expression and glutathione level decreased and the histopathologic picture deteriorated. However, as a result of the esculetin treatment, ameliorative effects in the aforementioned parameters were determined, and it was ensured that they returned to normal levels. CONCLUSION: According to these findings, esculetin has protective effects on I/R damage by lowering lipid peroxidation and having antioxidant and anti-inflammatory properties. SIGNIFICANCE: Our results proved the protective effect of esculetin against ovarian IR injury in rats and this may be attributed to Nrf-2/NF-κß axis which showed antioxidant and anti-inflammatory effects. Therefore, esculetin can be used in the future for preventive effects to ovarian IR injury.

Alleviation effects of epigallocatechin-3-gallate against acute kidney injury following severe burns.

BACKGROUND: Burn patients often face a high risk of acute kidney injury (AKI) after severe burn injuries, meanwhile epigallocatechin-3-gallate (EGCG) has been proven to be effective in alleviating organ injury. METHODS: This study used the classical burn model in rats. Thirty model rats were randomly divided into a Burn group, a Burn + placebo group, a Burn + EGCG (50 mg/kg) group, and ten non-model rats as Sham group. The urinary excretion of the rats was subsequently monitored for a period of 48 h. After 48 h of different treatments, rat serum and kidneys were taken for the further verification. The efficacy of EGCG was assessed in pathological sections, biochemical indexes, and at the molecular level. RESULTS: Pathological sections were compared between the Burn group and Burn + placebo group. The rats in the Burn + EGCG group had less kidney damage. Moreover, the EGCG group maintained significantly elevated urine volumes, biochemical indexes manifested that EGCG could reduce serum creatinine (Cr) and neutrophil gelatinase-associated lipocalin (NGAL) level and inhibit the oxidation-related enzyme malondialdehyde (MDA) level, meanwhile the superoxide dismutase (SOD) level was increased. The molecular level showed that EGCG significantly reduced the mRNA expression levels of the inflammation-related molecules interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). CONCLUSION: The research indicated that EGCG had an alleviating effect on kidney injury in severely burned rats, and its alleviating effects were related to improving kidney functions, alleviating oxidative stress, and inhibiting the expression of inflammatory factors.

Positive effects of low-dose S-ketamine on preventing myocardial injury after thoracoscopic lobectomy in patients aged 70 to 85.

OBJECTIVE: To investigate the effects of low-dose S-ketamine on marker of myocardial injury (BNP, hs-cTnT and HFABP) after thoracoscopic lobectomy in patients aged 70 to 85. METHODS: One hundred patients (four cases excluded) aged 70-85 years, with body mass index 18-24 kg·m-2 and American Society of Anesthesiologists physical status II-III, scheduled for elective lobectomy from April 2022 to April 2023, were selected. The patients were divided into two groups by a random number table method, namely, the low-dose S-ketamine combined with GDFT group (group S) and the control group (group C), with 48 cases in each group. In group S, a low dose of S-ketamine (0.2 mg/kg) was given 1 min before intubation, and the maintenance dose was 0.12 mg·kg-1·h-1. Fluid therapy, guided by cardiac index (CI), changes in stroke volume (△SV), and other dynamic indicators, was used for rehydration during the operation. Group C was given the same amount of normal saline (0.2 mg/kg) 1 min before intubation, and the same rehydration therapy was adopted during the operation. The mean arterial pressure (MAP) and heart rate (HR) of the two groups were observed and recorded immediately after entering the operating room (T0), immediately after intubation (T1), immediately after the beginning of one-lung ventilation (OLV) (T2), immediately after the beginning of surgery (T3), immediately after the end of OLV (T4), and at the end of surgery (T5). The intraoperative fluid intake and output and the use of vasoactive drugs were recorded. The plasma levels of heart-type fatty acid-binding protein (HFABP), high-sensitivity troponin T (hs-cTnT), brain natriuretic peptide (BNP), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) were recorded 24 h before operation and 24 and 48 h after operation. Visual analogue scale (VAS) pain scores at rest were recorded at 2 (V1), 6 (V2), 12 (V3), 24 (V4), and 48 h (V5) after operation, and the occurrence of myocardial ischemia during hospitalization was noted. RESULTS: Compared with group C, MAP was significantly higher at T1-T5 in group S (P < 0.05), and the plasma concentrations of IL-6, IL-8, TNF-α, BNP, hs-cTnT, and HFABP were significantly lower at 24 and 48 h after operation (P < 0.05). The VAS pain scores at 2, 6, 12, 24, and 48 h after operation, the number of effective patient-controlled intravenous analgesia (PCIA) compressions, and the total number of PCIA compressions within 48 h after operation were significantly decreased (P < 0.05). Compared with group C, The hospitalization days, and the incidence of postoperative myocardial ischemia in group S were lower (P < 0.05). There were no significant intergroup differences in urine volume, extubation time, the incidence of postoperative atrial fibrillation, bleeding volume, colloid infusion volume, total fluid infusion volume, and the incidence of rescue analgesia. CONCLUSIONS: Low-dose S-ketamine can reduce the levels of hs-cTnT, HFABP, and BNP in older patients after pulmonary lobectomy, which has a positive effect on preventing myocardial injury. TRIAL REGISTRATION: This study was registered on CHICTR (registration No. ChiCTR2300074475). Date of registration: 08/08/2023.

In RA in remission for >1 y, tapering TNFi to discontinuation did not meet noninferiority criteria compared with stable TNFi for disease flare at 12 mo.

SOURCE CITATION: Lillegraven S, Paulshus Sundlisaeter N, Aga AB, et al. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial. Ann Rheum Dis. 2023;82:1394-1403. 37607809.

Changes in Inflammatory Cytokines in Responders and Non-Responders to TNFα Inhibitor and IL-17A Inhibitor: A Study Examining Psoriatic Arthritis Patients.

This study aimed to examine the changes in biomarker levels in responders and non-responders to tumor necrosis factor alpha inhibitor (TNFi) and interleukin-17A inhibitor (IL-17Ai) in psoriatic arthritis (PsA) patients over a 4-month period after treatment initiation. A total of 68 PsA patients initiating either TNFi, IL-17Ai, or methotrexate treatment were included. Blood plasma and clinical outcome measures were collected adjacent to treatment initiation and after four months. A commercially available multiplex immunoassay was included to evaluate 54 biomarkers. Mean changes were used to evaluate change over time. A statistically significant decrease in pro-inflammatory cytokines IL-6 (log-transformed mean change -0.97, 95%CI -4.30; 2.37, [p = 0.032]) and an increase in anti-inflammatory IL-10 (0.38, 95%CI 1.74; 2.50 [p = 0.010]) were seen in TNFi responders. Meanwhile, a statistically significant increase in the target cytokine IL-17A was seen in both IL-17Ai responders (2.49, 95%CI -1.84; 6.85 [p = 0.031]) and non-responders (2.48, 95%CI -1.46; 6.41 [p = 0.001]). This study demonstrated differing changes in cytokine levels when comparing treatment responders and non-responders, highlighting the need to improve the understanding of the different immune response mechanisms explaining different responses to medical treatment in PsA patients.

Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial.

OBJECTIVES: Many patients with rheumatoid arthritis (RA) require treatment with tumour necrosis factor inhibitor (TNFi) to reach remission. It is debated whether tapering of TNFi to discontinuation should be considered in sustained remission. The aim of ARCTIC REWIND TNFi was to assess the effect of tapering TNFi to withdrawal compared with stable treatment on the risk of disease activity flares in patients with RA in remission ≥1 year. METHODS: This randomised, open-label, non-inferiority trial was undertaken at nine Norwegian rheumatology departments. Patients with RA in remission ≥12 months on stable TNFi therapy were allocated by computer-based block-randomisation to tapering to discontinuation of TNFi or stable TNFi. Conventional synthetic disease-modifying antirheumatic co-medication was unchanged. The primary endpoint was disease flare during the 12-month study period (non-inferiority margin 20%), assessed in the per-protocol population. RESULTS: Between June 2013 and January 2019, 99 patients were enrolled and 92 received the allocated treatment strategy. Eighty-four patients were included in the per-protocol population. In the tapering TNFi group, 27/43 (63%) experienced a flare during 12 months, compared with 2/41 (5%) in the stable TNFi group; risk difference (95% CI) 58% (42% to 74%). The tapering strategy was not non-inferior to continued stable treatment. The number of total/serious adverse events was 49/3 in the tapering group, 57/2 in the stable group. CONCLUSION: In patients with RA in remission for more than 1 year while using TNFi, an increase in flare rate was reported in those who tapered TNFi to discontinuation. However, most regained remission after reinstatement of full-dose treatment. TRIAL REGISTRATION NUMBERS: EudraCT: 2012-005275-14 and clinicaltrials.gov: NCT01881308.

Pre-treatment calprotectin (MRP8/14) provides no added value to testing CRP alone in terms of predicting response to TNF inhibitors in rheumatoid arthritis in a post hoc analysis.

OBJECTIVES: The inflammatory protein calprotectin (MRP8/14) has been identified as a promising biomarker of treatment response in rheumatoid arthritis (RA). Our aim was to test MRP8/14 as a biomarker of response to tumour necrosis factor (TNF)-inhibitors in the largest RA cohort to date and to compare with C-reactive protein (CRP). METHODS: Serum MRP8/14 was measured in 470 patients with RA about to commence treatment with adalimumab (n=196) or etanercept (n=274). Additionally, MRP8/14 was measured in the 3-month sera of 179 adalimumab-treated patients. Response was determined using European League against Rheumatism (EULAR) response criteria calculated using the traditional 4-component (4C) DAS28-CRP and alternate validated versions using 3-component (3C) and 2-component (2C), clinical disease activity index (CDAI) improvement criteria and change in individual outcome measures. Logistic/linear regression models were fitted for response outcome. RESULTS: In the 3C and 2C models, patients with RA were 1.92 (CI: 1.04 to 3.54) and 2.03 (CI: 1.09 to 3.78) times more likely to be classified as EULAR responders if they had high (75th quartile) pre-treatment levels of MRP8/14 compared with low (25th quartile). No significant associations were observed for the 4C model. When only using CRP as a predictor, in the 3C and 2C analyses, patients above the 75th quartile were 3.79 (CI: 1.81 to 7.93) and 3.58 (CI: 1.74 to 7.35) times more likely to be EULAR responders and addition of MRP8/14 did not significantly improve model fit (p values=0.62 and 0.80, respectively). No significant associations were observed in the 4C analysis. Exclusion of CRP from the outcome measure (CDAI) did not result in any significant associations with MRP8/14 (OR 1.00 (CI: 0.99 to 1.01), suggesting that the associations were due to the correlation with CRP and that there is no additional utility of MRP8/14 beyond use of CRP in patients with RA starting TNFi therapy. CONCLUSION: Beyond correlation with CRP, we found no evidence to suggest that MRP8/14 explains additional variability in response to TNFi in patients with RA over and above CRP alone.

Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis.

OBJECTIVES: To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS: The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS: 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION: The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

Non-trough adalimumab and certolizumab drug levels associated with a therapeutic EULAR response in adherent patients with rheumatoid arthritis.

OBJECTIVES: Interventions aimed at increasing TNF-α inhibitor serum drug levels (SDLs) may improve treatment response; however, previous studies suggesting SDL cut-offs have not accounted for treatment adherence. The aim of this study was to establish the relationship between adalimumab/certolizumab SDLs and EULAR good vs non-/moderate response and to define SDL cut-offs associated with good response in fully adherent patients. METHODS: In a prospective observational study, 475 patients with RA were treated with certolizumab (n = 192) or adalimumab (n = 283). At baseline and 3, 6 and 12 months, patients had 28-joint DAS, self-reported treatment adherence and SDLs measured. Fully adherent patients were analysed as a subgroup. Follow-up data at 3, 6 and 12 months were analysed separately. Median SDLs were compared in good vs non-/moderate response patients and receiver operating characteristics (ROC) curves were used to establish cut-off SDLs. RESULTS: Fully adherent good responders had significantly higher median adalimumab/certolizumab SDLs compared with non-/moderate responders (P = 0.04 and P = 0.0005, respectively). ROC analysis reported 3 month non-trough adalimumab SDLs discriminated good vs non-/moderate response with an area under the curve (AUC) of 0.63 (95% CI 0.52, 0.75), with a cut-off of 7.5 mg/l being 39.1% specific and 80.9% sensitive. Similarly, 3 month non-trough certolizumab SDLs discriminated good vs non-/moderate response with an AUC of 0.65 (95% CI 0.51, 0.78), with a cut-off of 26.0 mg/l being 43.9% specific and 77.8% sensitive. CONCLUSION: In fully adherent patients, higher SDLs are detected in good responders, suggesting that interventions to improve SDLs, such as encouraging adherence, could improve treatment response. The 3 month non-trough SDL cut-offs of 7.5 mg/l for adalimumab and 26.0 mg/l for certolizumab may be useful in clinical practice.

Characteristics of patients with difficult-to-treat rheumatoid arthritis in a French single-centre hospital.

OBJECTIVES: To compare the features of difficult-to-treat rheumatoid arthritis (D2TRA) patients using two different definitions according to the previous failure of targeted therapies. METHODS: We stratified consecutive RA patients treated at Cochin Hospital into two groups, a D2TRA group and a non-D2TRA group, according to two definitions of D2TRA. Both definitions defined D2TRA as RAs failing at least two targeted therapies, with a different mechanism of action for the EULAR-D2TRA definition or without prejudging the mechanism of action and for the Alternative D2TRA definition. RESULTS: We included 320 consecutive RA patients. We identified 76 EULAR-D2TRA and 244 non-DTRA patients, and 120 Alternative D2TRA and 200 non-DTRA patients. Compared with non-D2TRA, D2TRA patients from both definitions were more likely to have lower socioeconomic level, positive rheumatoid factor, interstitial lung disease, higher DAS28-CRP and were more likely to respond to rituximab and Janus kinase inhibitors. Although EULAR and Alternative D2TRA patients displayed similar clinical and biological features, they were characterized by different therapeutic profiles. We observed fewer patients receiving methotrexate in the Alternative D2TRA group (53% vs 64%, P = 0.046). Patients with Alternative D2TRA not fulfilling the EULAR definition (n = 44) had all received two successive first-line TNF inhibitors, a monoclonal antibody and a soluble receptor, and were comparable to EULAR-D2TRA patients with regards to all other characteristics. CONCLUSION: Low socioeconomic status, diabetes, interstitial lung disease and absence of combination with methotrexate allow identification of D2TRA. In addition, the inclusion as 'early-D2TRA' of patients failing two TNF inhibitors in the EULAR definition of D2TRA would facilitate the rapid identification of D2TRA patients.

Biologics with or without methotrexate in treatment of polyarticular juvenile idiopathic arthritis: effectiveness, safety and drug survival.

OBJECTIVE: To investigate the impact of additionally given MTX on biologic treatment of polyarticular JIA in terms of effectiveness, safety and drug survival. METHODS: Patients suffering from polyarticular JIA and treated with either monotherapy with a first biologic or a combination of a biologic and MTX were selected from the BIKER registry. The TNF-α inhibitors (TNFi) adalimumab, etanercept and golimumab and the IL-6 inhibitor tocilizumab were considered. Upon a non-randomized study design, we adjusted the different cohorts using propensity score matching to improve comparability. RESULTS: A total of 2148 patients entered the analysis, who were treated by either combination therapy (n = 1464) or monotherapy (n = 684). Disease activity declined significantly more in patients upon combination therapy than upon biologic monotherapy. Comparison of adjusted cohorts revealed that patients who received TNFi gained more benefit from additionally given MTX than patients treated with tocilizumab. Median survival time of therapy with biologics was significantly longer upon combination therapy (3.1 years) than with monotherapy (2.7 years), as demonstrated by a Kaplan-Meier analysis (log rank test: P = 0.002). The safety profile was moderately affected by additional MTX due to increased incidence of gastrointestinal and hepatic adverse events. Serious adverse events occurred at an equal rate of 3.6 events per 100 patient-years in both cohorts. CONCLUSION: Additionally given MTX improves the effectiveness of biologic treatment in polyarticular JIA without seriously compromising treatment safety. Especially TNFi benefit from combination, while no improvement in outcome has been observed by combining tocilizumab with MTX.

TNFα-dependent mTOR activity is required for tenotomy-induced ectopic ossification in mice.

INTRODUCTION: Ectopic ossifications often occur in skeletal muscles or tendons following local trauma or internal hemorrhage, and occasionally cause severe pain that limits activities of daily living. However, mechanisms underlying their development remain unknown. MATERIALS AND METHODS: The right Achilles tendon in 8-week-old female or male mice was dissected. Some mice were injected intraperitoneally either with phosphate-buffered saline, dimethyl sulfoxide, cimetidine, rapamycin, celecoxib or loxoprofen for 10 weeks. One week after surgery, immunohistochemical analysis was performed for mTOR, TNFα or F4/80. Ten weeks after surgery, ectopic ossification at the tenotomy site was detected by 3D micro-CT. RESULTS: Ectopic ossification was seen at dissection sites in all wild-type mice by dissection of the Achilles tendon. mTOR activation was detected at dissection sites, and development of ectopic ossification was significantly inhibited by administration of rapamycin, an mTOR inhibitor, to wild-type mice. Moreover, administration of the histamine 2 blocker cimetidine, which reportedly inhibits ectopic ossification in tendons, was not effective in inhibiting ectopic ossification in our models. TNFα-expressing F4/80-positive macrophages accumulate at dissection sites and that ectopic ossification of the Achilles tendon dissection was significantly inhibited in TNFα-deficient mice in vivo. Ectopic ossification is significantly inhibited by administration of either celecoxib or loxoprofen, both anti-inflammatory agents, in wild-type mice. mTOR activation by Achilles tendon tenotomy is inhibited in TNFα-deficient mice. CONCLUSION: The TNFα-mTOR axis could be targeted therapeutically to prevent trauma-induced ectopic ossification in tendons.

Improved Sleep Affects Epigastric Pain in Functional Dyspepsia by Reducing the Levels of Inflammatory Mediators.

INTRODUCTION: The pathogenesis of epigastric pain in functional dyspepsia (FD) is complex. The study aims to explore the effect of sleep improvement on this symptom. METHODS: In total, 120 patients with FD-associated epigastric pain and insomnia were randomly divided into experimental and control groups using the envelope method. After applying the exclusion criteria, 107 patients were enrolled in the experimental (56 patients) and control (51 patients) groups. Insomnia was graded according to the Pittsburgh Sleep Quality Index (PSQI). In the experimental group, eszopiclone 3 mg, eszopiclone 3 mg + estazolam 1 mg, and eszopiclone 3 mg + estazolam 2 mg were given to patients with mild, moderate, and severe insomnia, respectively. In the control group, patients were given 1, 2, or 3 tablets of vitamin B complex. Patient sleep quality was monitored with Sleepthing. Epigastric pain was evaluated with a Numeric Rating Scale. The serum levels of IL-1ß, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. Pain scores, sleep parameters, and serum levels of inflammatory mediators were compared before and after treatment. RESULTS: After treatment, the pain scores, sleep parameters, and TNF-α and IL-6 levels in the experimental group were significantly lower than those in the control group (p < 0.05). PSQI insomnia scores were significantly associated with pain scores, IL-6, and TNF-α (p < 0.05) but not in IL-8 and IL-1ß levels (p > 0.05) among the three groups. CONCLUSIONS: Improving sleep with eszopiclone and/or estazolam alleviates FD-associated epigastric pain, possibly by inhibiting related downstream transmission pathways and reducing the release of inflammatory mediators.

Mood Disorder in Systemic Lupus Erythematosus Induced by Antiribosomal P Protein Antibodies Associated with Decreased Serum and Brain Tryptophan.

Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.