Association of circulating leptin, growth hormone, and ghrelin with fibromyalgia: A meta-analysis.

OBJECTIVE: The aim of this study was to evaluate the relationship between levels of leptin, growth hormone (GH), and ghrelin in the bloodstream and fibromyalgia. METHODS: We conducted a meta-analysis to compare the serum/plasma levels of leptin, GH, and ghrelin in individuals with fibromyalgia, as compared to healthy controls. The analysis included sixteen articles, which provided data from 697 fibromyalgia patients and 560 controls. RESULTS: The meta-analysis found that there was no significant difference in leptin levels between fibromyalgia patients and controls overall (SMD = 0.324, 95% CI = -0.264 to 0.913, P = 0.281). However, when subgroup analysis was done based on geographically different populations, it showed a positive association between high leptin levels and fibromyalgia in European populations (SMD = 1.131, 95% CI = 0.197 to 2.064, P = 0.018), while no significant association was found in Latin American populations (SMD = -0.160, 95% CI = -0.847 to 0.528, P = 0.649). As for GH levels, there was no significant difference between fibromyalgia patients and controls overall (SMD = -0.903, 95% CI = -2.036 to 0.231, P = 0.119). However, when subgroup analysis was done based on geographically different populations, it revealed a significant decrease in GH levels in European populations with fibromyalgia (SMD = -2.341, 95% CI = -3.664 to -1.017, P = 0.001), while no significant association was found in North American populations. Lastly, the analysis of ghrelin levels showed no significant association with fibromyalgia overall (SMD = -0.661, 95% CI = -1.382 to 0.059, P = 0.072). CONCLUSION: This meta-analysis shows that patients with fibromyalgia in Europeans have significantly higher levels of circulating leptin and GH. However, no significant association was found between ghrelin levels and fibromyalgia.

All-cause and cause-specific mortality in rheumatoid arthritis: a meta-analysis.

OBJECTIVE: This study aimed to evaluate standardized mortality ratios (SMRs) for both all-cause and cause-specific mortality in patients with rheumatoid arthritis (RA). METHODS: We conducted an extensive search across the Medline, Embase, and Cochrane databases to identify studies investigating SMRs for all-cause and/or cause-specific mortality in individuals with RA compared to the general population. Subsequently, we performed a comprehensive meta-analysis, examining SMRs across various categories, including all-cause, sex-specific, ethnicity-specific, and cause-specific SMRs in RA patients. RESULTS: Seventeen studies involving 486,098 patients with RA and 63,988 deaths met the inclusion criteria. Patients with RA had a 1.522-fold increase in all-cause SMR (SMR 1.522, 95% CI 1.340-1.704, p < 0.001) compared to the general population. Stratification by ethnicity revealed that the all-cause SMR was 1.575 (95% CI 1.207-1.943) in Caucasians and 1.355 (95% CI 1.140-1.569) in Asians. The gender-specific meta-analysis revealed elevated SMR in both women and men. RA patients exhibited an increased risk of mortality attributed to cardiovascular disease (CVD), respiratory disease, infection, and cerebrovascular accidents (CVA). However, no significant increase in SMR was observed for mortality due to malignancy. CONCLUSION: This meta-analysis study highlights a 1.522-fold increase in SMR in patients with RA compared to that in the general population, irrespective of sex or region. Additionally, a notable increase in mortality associated with specific causes, including CVD, respiratory disease, infection, and CVA, underscores the critical need for targeted interventions to manage these heightened risks in patients with RA.

Mortality in patients with systemic lupus erythematosus: A meta-analysis of overall and cause-specific effects.

OBJECTIVES: Our objective was to assess the overall and cause-specific standardized mortality ratios (SMRs) among patients diagnosed with systemic lupus erythematosus (SLE). METHODS: An exhaustive systematic review was undertaken, encompassing studies that scrutinized SMRs, both overall and for specific causes, in patients diagnosed with SLE compared to the general populace. The databases of PUBMED, EMBASE, and Cochrane were meticulously searched to collate relevant literature. Following this comprehensive search, a meta-analysis was executed to methodically assess all-cause, sex-specific, ethnicity-specific, and cause-specific SMRs in individuals with SLE. RESULTS: The inclusion criteria were met by 29 studies encompassing 72,342 patients with SLE and documenting 7352 deaths. The meta-analysis disclosed a pronounced 2.87-fold elevation in the SMR for all-cause mortality in SLE patients relative to the general population (SMR, 2.866; 95% confidence interval [CI], 2.490-3.242; p < .001). Region-specific assessments showed variable all-cause SMRs, with Europe reporting 2.607 (95% CI, 1.939-3.275; p < .001), Asia revealing 3.043 (95% CI, 2.082-4.004; p < .001), and particularly high SMRs noted in North America and Oceania. Gender-focused analyses presented a pooled SMR of 3.261 (95% CI, 2.674-3.848; p < .001) for females, and 2.747 (95% CI, 2.190-3.304; p < .001) for males. Evaluations specific to cause of death illustrated notably elevated SMRs for renal disease (SMR, 4.486; 95% CI, 3.024-5.948; p < .001), infections (SMR, 4.946; 95% CI, 4.253-5.639; p < .001), cardiovascular diseases (CVD) (SMR, 2.931; 95% CI, 1.802-4.061; p < .001), cerebrovascular accidents (CVA) (SMR, 1.588; 95% CI, 0.647-2.528; p = .001), and cancer (SMR, 1.698; 95% CI, 0.871-2.525; p < .001). CONCLUSIONS: This meta-analysis underscores a significant 2.87-fold elevation in the SMR among patients with SLE compared to the general population, transcending differences in sex or geographical regions. Moreover, an appreciable increase in mortality due to specific causes, including renal disease, infection, CVD, CVA, malignancy, and neuropsychiatric SLE, accentuates the imperative for targeted interventions to mitigate these elevated risks in SLE patients.

Effect of Thrombin-Containing Local Hemostatics on Postoperative Spinal Epidural Hematoma in Biportal Endoscopic Spinal Surgery.

STUDY DESIGN: Retrospective case-control study. PURPOSE: This study aimed to investigate the preventive effect of thrombin-containing local hemostatics (TCLH) on postoperative spinal epidural hematoma (POSEH) in biportal endoscopic spinal surgery (BESS). This study compared the incidence of morphometric and symptomatic POSEH with or without TCLH in BESS. OVERVIEW OF LITERATURE: POSEH is reported not uncommon in BESS when compared with conventional spine surgery (CSS). TCLH achieves hemostasis with a high success rate in CSS. However, few studies have examined the effect of TCLH on BESS. METHODS: Patients with and without TCLH were assigned to groups A and B, respectively. POSEH between the two groups was compared morphometrically and symptomatically. The risk factors for symptomatic and morphometric POSEH in BESS were identified. RESULTS: The morphometric POSEH was greater in group B, and the difference was significant (p =0.019). The incidence of symptomatic POSEH was lower in group A with 4.6% (5/109) than in group B with 9.5% (9/95); however, the rate was not significantly different (p =0.136). The morphometric POSEH was classified into two small (hG1 and hG2) and large (hG3 and hG4) and were compared between groups A and B, and the difference was significant (p =0.02). In the multivariable logistic regression, nonuse of TCLH (p =0.004) and preoperative diagnosis of stenosis (p =0.016) were variables found to be significant risk factors of morphometric POSEH. CONCLUSIONS: Severe compression of the thecal sac by POSEH is more common in patients without TCLH. The risk of hematoma formation was higher when bilateral decompression was needed and the cut bone surface was more exposed.

Use of Three-Column Reconstruction and Free Vascularized Fibular Grafts for the Repair of Large Tibial Defects after Tumor Resection.

Background: This study aimed to evaluate the clinical outcomes of three-column reconstruction of the lower leg using a single-barrel contralateral vascularized fibular graft (VFG), medial locking plate, and the ipsilateral fibula for the repair of large tibial defects after tumor resection. Methods: In this retrospective study, we reviewed 12 patients who underwent three-column reconstruction using a single-barrel contralateral VFG, medial locking plate, and the ipsilateral fibula between June 1996 and May 2020. These patients had large tibial bone defects following tumor resection. The mean age of the patients was 26.3 years (range, 11-63 years), and 7 of them were women. The mean follow-up period was 104.8 months (range, 26-284 months). The mean size of the tibial bone defect after tumor resection was 17.8 cm (range, 11-26.8 cm). The clinical and radiological outcomes were evaluated at the final follow-up. Results: All patients survived beyond the final follow-up without recurrence of the primary bone tumor. The mean time from reconstruction to bony union at both host-graft junctions was 12.9 months (range, 4-36 months). The mean Musculoskeletal Tumor Society score was 82.3% (range, 60%-97%). All tibial defects were reconstructed with adequate bone healing. There were 4 cases of stress fracture and graft failure; these were resolved by using longer plates and more screws. All patients were ambulatory without assistance and showed no permanent complications. Conclusions: Large tibial defects that occur after tumoral resection can be effectively reconstructed by three-column reconstruction using a medial locking plate, an inlay single-barrel VFG harvested from the contralateral side, and the intact ipsilateral fibula. This technique permits early weight-bearing before fibular hypertrophy and bony union.

Investigating the Cardiovascular Benefits of Dapagliflozin: Vasodilatory Effect on Isolated Rat Coronary Arteries.

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2-3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 µM), sGC inhibitor (ODQ, 5 µM), or COX inhibitor (indomethacin, 3 µM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca2+-activated K+ channel (KCa) blocker (TEA, 2 mM), voltage-dependent K+ channel (KV) blocker (4-AP, 2 mM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (3 µM), and inward-rectifier K+ channel (KIR) blocker (BaCl2, 30 µM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca2+ homeostasis via dapagliflozin administration.

Risk factors and clinical outcomes of cytomegalovirus diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation.

PURPOSE: This study aims to evaluate the risk factors and prognosis for CMV diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation (HSCT). METHODS: We performed a case-control study (1:2) between 2012 and 2022. Adults with pathologic-confirmed CMV diseases (n=60) among hematologic malignancy patients were matched and compared to whom without CMV disease. RESULTS: Lymphoma was the most common underlying malignancy, and gastrointestinal tract involvement was the most common CMV disease. In the case group, high-dose steroid administration and transfusion within one month before diagnosis were higher (p<0.001). Steroid administration (aOR=5.78; 95% confidence interval: 1.25-26.68, p=0.024), red blood cell transfusion within one month (aOR=14.63; 2.75-77.76, p=0.002), low BMI (aOR=13.46, 2.07-87.45, p=0.006), and hypoalbuminemia (aOR=26.48, 5.93-118.17, p<0.001) were independent risk factors associated with CMV disease. The 30-day mortality was higher in the case group and CMV disease was significantly associated with all-cause mortality (aOR=14.41, 3.23-64.31, p<0.001). CONCLUSION: In hematologic malignancy patients without HSCT, risk factors for CMV organ disease included high-dose steroid administration and RBC transfusion within one month, low BMI, and hypoalbuminemia. Overall mortality was significantly higher with CMV disease, and CMV disease occurrence was a significant risk factor for mortality.

The role of NLRP3 and CARD8 polymorphisms in the risk of rheumatoid arthritis: A meta-analysis of genetic association studies.

OBJECTIVE: To investigate the potential associations between rheumatoid arthritis (RA) and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) rs35829419, rs10754558, s4612666, and caspase recruitment domain family member 8 (CARD8) rs2043211 polymorphisms. METHODS: Relevant papers were searched for in MEDLINE, Embase, and Web of Science. Allele contrast, recessive, dominant, and homozygote contrast models were used to investigate the relationship between the NLRP3 rs35829419, rs10754558, and s4612666, and CARD8 rs2043211 polymorphisms and RA. This review was registered with PROSPERO (CRD42023451231). RESULTS: The meta-analysis included 11 comparative studies comprising 3789 patients with RA and 3956 controls. No significant association was found between NLRP3 rs35829419 C allele and RA in Europeans, Arabs, or Latinos. The NLRP3 rs10754558 G allele was not associated with RA in the Asian or Arab populations. However, a single study in Latin America discovered a link between RA and the NLRP3 rs10754558 G allele. The NLRP3 rs4612666 T allele was not associated with RA, according to the meta-analysis. When ethnicity was stratified, there was no association between the NLRP3 rs4612666 T allele and RA, except for a single study that found an association among Arabs. The CARD8 rs2043211 T allele did not seem to be associated with RA. According to an ethnic stratification study, the CARD8 rs2043211 T allele did not appear to be associated with RA in Europeans, Arabs, or Latinos. CONCLUSIONS: The meta-analysis indicated that the NLRP3 rs35829419, rs10754558, and s4612666 polymorphisms, as well as the CARD8 rs2043211 polymorphism, were not linked to RA susceptibility.

Redirection of CAR-T Cell Cytotoxicity Using Metabolic Glycan Labeling with Unnatural Sugars.

T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical efficacy in solid tumors with high antigen heterogeneity. To overcome this, we metabolically labeled the glycans on cancer cells to redirect CAR-T cell cytotoxicity regardless of the endogenous antigen expression status of the cancer cells. We found that modifying cancer cells with N-azidoacetylmannosamine and bicyclo[6.1.0]non-4-yne-fluorescein isothiocyanate can elicit selective and durable cytotoxicity of anti-FITC CAR-T cells. Furthermore, we demonstrated that dinitrophenyl-conjugated sialic acid (Sia-DNP) generated DNP-modified glycans on cancer cells in situ that could be effectively targeted by anti-DNP CAR-T cells to eradicate established tumors in xenograft models. Our study illustrates that metabolic glycan labeling using unnatural sugars can be combined with CAR-T cell therapy to provide novel cancer immunotherapy for solid tumors that lack viable target antigens.

Engineering second-generation TCR-T cells by site-specific integration of TRAF-binding motifs into the CD247 locus.

BACKGROUND: The incorporation of co-stimulatory signaling domains into second-generation chimeric antigen receptors (CARs) significantly enhances the proliferation and persistence of CAR-T cells in vivo, leading to successful clinical outcomes. METHODS: To achieve such functional enhancement in transgenic T-cell receptor-engineered T-cell (TCR-T) therapy, we designed a second-generation TCR-T cell in which CD3ζ genes modified to contain the intracellular domain (ICD) of the 4-1BB receptor were selectively inserted into the CD247 locus. RESULTS: This modification enabled the simultaneous recruitment of key adaptor molecules for signals 1 and 2 on TCR engagement. However, the addition of full-length 4-1BB ICD unexpectedly impaired the expression and signaling of TCRs, leading to suboptimal antitumor activity of the resulting TCR-T cells in vivo. We found that the basic-rich motif (BRM) in the 4-1BB ICD was responsible for the undesirable outcomes, and that fusion of minimal tumor necrosis factor receptor-associated factor (TRAF)-binding motifs at the C-terminus of CD3ζ (zBBΔBRM) was sufficient to recruit TRAF2, the key adaptor molecule in 4-1BB signaling, while retaining the expression and proximal signaling of the transgenic TCR. Consequently, TCR-T cells expressing zBBΔBRM exhibited improved persistence and expansion in vitro and in vivo, resulting in superior antitumor activity in a mouse xenograft model. CONCLUSIONS: Our findings offer a promising strategy for improving the intracellular signaling of TCR-T cells and their application in treating solid tumors.

Association between the functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsiveness to biologics in rheumatoid arthritis patients: A meta-analysis.

OBJECTIVES: This study aimed to investigate the association between functional Fc gamma receptor 3A (FCGR3A) V158F and FCGR2A R131H polymorphisms and biologic therapy in rheumatoid arthritis (RA) patients. METHODS: We searched Medline, Embase, and Cochran databases for available articles. This study is a meta-analysis of the association between the FCGR3A V158F and FCGR2A R131H polymorphisms and their responsiveness to biologics in RA patients. RESULTS: Seventeen studies involving RA patients with FCGR3A V158F (n = 1884) and FCGR2A R131H (n = 1118) polymorphisms were considered. This meta-analysis showed that the FCGR3A V allele was associated with responsiveness to rituximab (odds ratio [OR] = 1.431, 95% CI = 1.081-1.894, P = 0.012), but not with tumor necrosis factor (TNF) blockers, tocilizumab, or abatacept. A significant association was also found between the FCGR3A V158F polymorphism and responsiveness to biologics using the dominant-recessive model. Additionally, the FCGR3A V158F polymorphism was associated with responsiveness to TNF blockers in the homozygous contrast model. Meta-analysis revealed an association between the FCGR2A RR + RH genotype and responsiveness to biologics (OR = 1.385, 95% CI = 1.007-1.904, P = 0.045). CONCLUSIONS: This meta-analysis demonstrates that FCGR3A V allele carriers show better responsiveness to rituximab, and FCGR2A R allele carriers may show a better response to biologics in RA treatment. Genotyping of these polymorphisms could be a useful tool to find associations with the responsiveness of personalized medicine to biologics.

Intramedullary fixation of metacarpal and phalangeal bone fractures with bioabsorbable Mg K-wire in 20 cases.

PURPOSE: The treatment of irreducible or severely displaced metacarpal and phalangeal bone fractures is still much debated. The recent development of the bioabsorbable magnesium K-wire is thought to allow effective treatment upon insertion via intramedullary fixation by minimizing articular cartilage injuries without discomfort until pin removal and drawbacks, such as pin track infection and metal plate removal. Therefore, this study investigated and reported the effects of intramedullary fixation with the bioabsorbable magnesium K-wire in unstable metacarpal and phalangeal bone fractures. METHODS: This study included 19 patients admitted to our clinic for metacarpal or phalangeal bone fractures from May 2019 to July 2021. As a result, 20 cases were examined among these 19 patients. RESULTS: Bone union was observed in all 20 cases, with a mean bone union time of 10.5 (SD 3.4) weeks. Reduction loss was observed in six cases, all showing dorsal angulation with a mean angle of 6.6° (SD 3.5°) at 4.6 weeks as compared with that noted in the unaffected side. The gas cavity upon H2 gas formation was first observed approximately 2 weeks postoperatively. The mean DASH score was 33.5 for instrumental activity and 9.5 for work/task performance. No patient complained of notable discomfort after surgery. CONCLUSION: Intramedullary fixation with the bioabsorbable magnesium K-wire may be used for unstable metacarpal and phalanx bone fractures. This wire is expected to be a particularly favorable indication for shaft fractures, although care should be taken due to the possibility of complications related to rigidity and deformity.

Reconstruction of Small-Sized Complex Defect on the Foot Dorsum Without Microsurgery: Intrinsic Adipofascial Flap.

Dorsal foot defects are difficult to cover and often require major flap surgery by microsurgeons, even for defects of limited sizes. Intrinsic adipofascial flaps for small-sized complex defects are simple and do not require microsurgery; thus, a flap specialist is unnecessary. This study aimed to assess our institutional experience with this technique and define its role in dorsal foot reconstruction. Nine patients aged 48 to 86 years with soft tissue defects of the dorsal foot were treated with the intrinsic adipofascial flap by rotating the adjacent adipofascial tissues from May 2019 and January 2021 in our institution. Demographic, clinical, and followup data were evaluated. Primary outcomes include flap viability, flap bulkiness, ability to wear shoes, and donor site morbidity. The mean followup period was 24.5 months (range, 10-30 months) and the mean defect size was 6.4 cm2 (range, 3.0-9.0 cm2). Eight flaps survived providing an adequate contour and durable coverage with a thin flap. Among 8 cases of healed flaps, 6 required secondary skin grafts while the other 2 healed spontaneously without additional operation. One patient (defect size: 3.0 cm × 3.0 cm) with underlying diabetes mellitus and peripheral arterial occlusive disease encountered flap total necrosis. Revisional flap surgery was performed to cover the flap total necrosis. In conclusion, the intrinsic adipofascial flap is a relatively simple and suitable method for complex dorsal foot defect reconstruction because it provides minimal donor site morbidity. However, relatively large defect size and comorbidities, such as underlying diabetes mellitus and vascular occlusive disease could accompany a risk of flap necrosis.

Design and Evaluation of a Carrier-Free Prodrug-Based Palmitic-DEVD-Doxorubicin Conjugate for Targeted Cancer Therapy.

In the development of new drugs, typical polymer- or macromolecule-based nanocarriers suffer from manufacturing process complexity, unwanted systematic toxicity, and low loading capacity. However, carrier-free nanomedicines have made outstanding progress in drug delivery and pharmacokinetics, demonstrating most of the advantages associated with nanoparticles when applied in targeted anticancer therapy. Here, to overcome the problems of nanocarriers and conventional cytotoxic drugs, we developed a novel, carrier-free, self-assembled prodrug consisting of a hydrophobic palmitic (16-carbon chain n-hexadecane chain) moiety and hydrophilic group (or moiety) which is included in a caspase-3-specific cleavable peptide (Asp-Glu-Val-Asp, DEVD) and a cytotoxic drug (doxorubicin, DOX). The amphiphilic conjugate, the palmitic-DEVD-DOX, has the ability to self-assemble into nanoparticles in saline without the need for any carriers or nanoformulations. Additionally, the inclusion of doxorubicin is in its prodrug form and the apoptosis-specific DEVD peptide lead to the reduced side effects of doxorubicin in normal tissue. Furthermore, the carrier-free palmitic-DEVD-DOX nanoparticles could passively accumulate in the tumor tissues of tumor-bearing mice due to an enhanced permeation and retention (EPR) effect. As a result, the palmitic-DEVD-DOX conjugate showed an enhanced therapeutic effect compared with the unmodified DEVD-DOX conjugate. Therefore, this carrier-free palmitic-DEVD-DOX prodrug has great therapeutic potential to treat solid tumors, overcoming the problems of conventional chemotherapy and nanoparticles.

Proteolysis-driven proliferation and rigidification of pepsin-resistant amyloid fibrils.

Proteolysis of amyloids is related to prevention and treatment of amyloidosis. What if the conditions for proteolysis were the same to those for amyloid formation? For example, pepsin, a gastric protease is activated in an acidic environment, which, interestingly, is also a condition that induces the amyloid formation. Here, we investigate the competition reactions between proteolysis and synthesis of amyloid under pepsin-activated conditions. The changes in the quantities and nanomechanical properties of amyloids after pepsin treatment were examined by fluorescence assay, circular dichroism and atomic force microscopy. We found that, in the case of pepsin-resistant amyloid, a secondary reaction can be accelerated, thereby proliferating amyloids. Moreover, after this reaction, the amyloid became 32.4 % thicker and 24.2 % stiffer than the original one. Our results suggest a new insight into the proteolysis-driven proliferation and rigidification of pepsin-resistant amyloids.

Placebo and nocebo responses in randomized controlled trials of non-tumor necrosis factor biologics and Janus kinase inhibitors in patients with active rheumatoid arthritis showing insufficient response to tumor necrosis factor inhibitors: A meta-analysis.

OBJECTIVE: This study evaluated the frequency and magnitude of placebo and nocebo responses in placebo-controlled RCTs of non-tumor necrosis factor (TNF) biologics and Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) patients with insufficient response to TNF inhibitors. METHODS: A meta-analysis on rates of placebo response, adverse effects (AEs), severe AEs (SAEs), and withdrawal due to AEs in placebo-controlled RCTs of non-TNF biologics and JAK inhibitors in patients with RA and an insufficient response to TNF inhibitors was conducted. RESULTS: In 9 RCTs containing 3442 patients the pooled incidence of ACR20 response rate in placebo-treated patients was 22.1 (95% CI 16.4-29.1%) and 27.9% (95% CI 24.5-31.6%) in RCTs of non-TNF and JAK inhibitors, respectively. Strong negative correlation was observed between ACR20 response and AE rates in the placebo arm, indicating that the greater the placebo response, the weaker the nocebo response (r = -0.762, P = 0.017). Strong positive correlation was observed between ACR20 response in the placebo and active comparator arms, indicating that the greater the placebo response, the greater the treatment response (r = 0.737, P = 0.003). The pooled estimate in placebo-treated patients with ≥1 AE was 71.8 (95% CI 57.4-82.7%) and 58.7% (95% CI 52.8-64.3%) in RCTs of non-TNF and JAK inhibitors, respectively. The pooled estimate in placebo-treated patients withdrawing due to an AE was 3.8 (95% CI 2.7-5.3%) and 4.0% (95% CI 2.7-6.0%) in RCTs of non-TNF and JAK inhibitors, respectively. Strong positive correlation was observed between AE rates in the placebo and active arms, indicating that the greater the nocebo response, the stronger the AE rate in the active arm (r = 0.855, P = 0.003). CONCLUSION: There were higher placebo and less nocebo effects of JAK vs. non-TNF inhibitors in RA patients with an insufficient response to TNF inhibitors, and the greater the placebo response, the weaker the nocebo response and the greater the efficacy.

Relative efficacy and safety of Janus kinase inhibitors for the treatment of active psoriatic arthritis: a network meta-analysis.

OBJECTIVE: To determine the relative effectiveness and safety of Janus kinase (JAK) inhibitors in active psoriatic arthritis (PsA) patients. MATERIALS AND METHODS: A Bayesian network meta-analysis was performed using data from randomized controlled trials (RCTs) to evaluate the effectiveness and safety of upadacitinib 30 mg, upadacitinib 15 mg, tofacitinib 10 mg, tofacitinib 5 mg, and filgotinib 200 mg in active PsA patients. RESULTS: Five RCTs including 2539 patients fulfilled the inclusion criteria. The surface under the cumulative ranking curve (SUCRA) revealed that filgotinib 200 mg had the highest probability of reaching a 20% American College of Rheumatology (ACR20) response rate, followed by upadacitinib 30 mg, upadacitinib 15 mg, tofacitinib 10 mg, tofacitinib 5 mg, and placebo. Upadacitinib 30 mg had the highest probability of achieving the ACR50 and ACR70 response rates, followed by upadacitinib 15 mg, filgotinib 200 mg, tofacitinib 10 mg, tofacitinib 5 mg, and placebo. The SUCRA rating based on the Psoriasis Area and Severity Index response rate of at least 75% (PASI75) showed that tofacitinib 10 mg had the highest probability of achieving this response, followed by upadacitinib 15 mg, filgotinib 200 mg, tofacitinib 5 mg, and placebo. Safety analyses evaluated adverse events (AEs) and serious adverse events (SAEs), but no statistically relevant differences were found. CONCLUSION: Based on the ACR response rates, filgotinib 200 mg and upadacitinib 30 mg were the most effective, whereas tofacitinib 10 mg was the most effective treatment for PsA based on PASI75. However, treatment options were similar with regard to AEs and SAEs.

The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis: a meta-analysis.

OBJECTIVE: The goal of this study was to assess the impact of negative expectations associated with receiving a placebo (the lessebo effect) on efficacy outcomes in randomized clinical trials (RCTs) of rituximab in patients with rheumatoid arthritis (RA). METHODS: We performed a meta-analysis on the American College of Rheumatology 20%, 50%, and 70% (ACR20, 50, 70) response rates in the placebo and active (biosimilar)-controlled groups (reference-pbo and reference-bs) of rituximab showing an insufficient response to methotrexate or tumor necrosis factor. We evaluated the difference in ACR20, 50, 70 response rates between the two groups (reference-bs vs. reference-pbo). RESULTS: Nine RCTs included a total of 2734 patients with RA. The pooled incidence of ACR20 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 53.1% (95% confidence interval [CI] 49.9-56.3%) and 75.0% (95% CI 71.2-78.4%), respectively. The difference in the ACR20 response rate between the placebo- and active-controlled groups was -20.9% (95% CI -26.9 to 61.9%, p < 0.001). The pooled incidence of ACR50 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 29.0% (95% CI 26.2-32.0%) and 47.4% (95% CI 43.2-51.6%), respectively. The ACR50 response rates were significantly higher in the active-controlled groups than in the placebo-controlled groups (-18.4%; 95% CI -18.4 to -13.4%, p < 0.001). The difference in the ACR70 response rate between the placebo- and active-controlled groups was -14.9% (95% CI -22.2 to -7.6%, p < 0.001). The ACR20, 50, 70 response rates were significantly higher in the active-controlled groups than in the placebo-controlled group. CONCLUSION: This study shows that the use of a placebo can be associated with a clinically significant reduction in the magnitude of change of the ACR20, 50, 70 response rates in rituximab RCTs for RA. The lessebo effect has potential implications for the development of new treatments and appraisal of current treatment options for RA.

Associations between the interleukin-6 rs1800795 G/C and interleukin-6 receptor rs12083537 A/G polymorphisms and response to disease-modifying antirheumatic drugs in rheumatoid arthritis: A meta-analysis.

OBJECTIVE: We aimed to investigate the association between interleukin-6 (IL-6) rs1800795 G/C, IL-6 receptor (IL-6R) rs12083537 A/G, and rs4329505 T/C polymorphisms and responsiveness to disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). METHODS: We searched Medline, Embase, and Web of Science databases. We conducted a meta-analysis of studies on the association between the IL-6 rs1800795 G/C, IL-6R rs12083537 A/G and rs4329505 T/C polymorphisms and responsiveness to DMARDs in RA patients. RESULTS: Fourteen studies from eight published articles involving 982 patients were included in this meta-analysis. The meta-analysis showed a significant association between the IL-6 rs1800795 G allele and response to DMARDs in RA (P = 0.008). Stratification by DMARD class showed that the IL-6 rs1800795 G allele was significantly associated with responsiveness to biological DMARDs (bDMARDs) (P = 0.022), but not conventional synthetic DMARDs (P = 0.145). A significant association was also found between the IL-6 rs1800795 G/C polymorphism and response to DMARDs. The meta-analysis revealed a significant association between the IL-6R rs12083537 A allele and response to tocilizumab in RA patients (P = 0.001). A significant association was also found between the IL-6R rs12083537 AA genotype and response to tocilizumab in RA patients (P = 0.001). However, no association was found between the IL-6R rs4329505 T/C polymorphism and response to tocilizumab. CONCLUSIONS: This meta-analysis revealed associations between treatment response to bDMARDs and the IL-6 rs1800795 G/C polymorphism, and between response to tocilizumab and the IL-6R rs12083537 A/G polymorphism in RA.

Associations between TNFAIP3 Polymorphisms and Rheumatoid Arthritis: A Systematic Review and Meta-Analysis Update with Trial Sequential Analysis.

INTRODUCTION: The tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene produces ubiquitin-editing protein A20, which inhibits nuclear factor-κB (NF-κB) activation in a variety of signaling pathways. We examined the association between TNFAIP3 polymorphisms and rheumatoid arthritis (RA) susceptibility. METHODS: MEDLINE, Embase, Scopus, and Web of Science were searched for available articles on TNFAIP3 polymorphisms in RA patients from inception until July 11, 2022. We included case-control studies on the association between rs2230926 and rs5029937 polymorphisms of TNFAIP3 and RA, and we excluded studies that contained overlapping data. We scored the quality of each study included based on the Newcastle-Ottawa Scale. Meta-analyses evaluated the association between TNFAIP3 polymorphisms and RA susceptibility in diverse ethnic populations and was verified through trial sequential analysis (TSA). This meta-analysis was registered in the PROSPERO register (number: CRD42022345160). There was no funding source. RESULTS: Seventeen studies were chosen for meta-analysis. Ten studies for rs2230926, and seven for rs5029937. An association was noted between TNFAIP3 rs2230926 G allele and RA in all subjects (odds ratio [OR] = 1.389; 95% confidence interval [CI] = 1.161-1.662; p < 0.001). Ethnicity-specific analysis showed significant association of rs2230926 G allele with RA in Europeans and Asians (OR = 1.642; 95% CI = 1.099-2.452; p = 0.015; OR = 1.404; 95% CI = 1.262-1.562; p < 0.001). An association was also noted between TNFAIP3 rs5029937 T allele and RA in all subjects (OR = 1.389; 95% CI = 1.207-1.785; p < 0.001). An ethnicity-specific meta-analysis revealed a significant association of the rs5029937 T allele with RA in Europeans and Asians. Dominant model analysis showed the same pattern for TNFAIP3 rs2230926 G and rs5029937 T alleles in Europeans and Asians, suggesting an association between rs2230926 G and rs5029937. TSA indicated a robust association between the TNFAIP3 polymorphisms and the risk of RA. CONCLUSION: TNFAIP3 rs2230926 and rs5029937 polymorphisms are associated with RA susceptibility in European and Asian populations. However, the data were not stratified by parameters such as rheumatoid factor status, disease activity, or environmental variables.