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Sulfasalazine (SULF), a sulfonamide antibiotic, has been utilized in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) since its discovery. However, its poor water solubility causes the high daily doses (1---3 g) for patients, which may lead to the intolerable toxic and side effects for their lifelong treatment for RA and IBD. In this work, two water-soluble natural anti-inflammatory alkaloids, matrine (MAR) and sophoridine (SPD), were employed to construct the co-amorphous systems of SULF for addressing its solubility issue. These newly obtained co-amorphous forms of SULF were comprehensively characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). We also investigated their dissolution behavior, including powder dissolution, in vitro release, and intrinsic dissolution rate. Both co-amorphous systems exhibited superior dissolution performance compared to crystalline SULF. The underlying mechanism responsible for the enhanced dissolution behaviors in co-amorphous systems were also elucidated. These mechanisms include the inhibition of nucleation, complexation, increased hydrophilicity, and robust intermolecular interactions in aqueous solutions. Importantly, these co-amorphous systems demonstrated satisfactory physical stability under various storage conditions. Network pharmacological analysis was utilized to investigate the potential therapeutic targets of both co-amorphous systems against RA, revealing similar yet distinct multi-target synergistic therapeutic mechanisms in the treatment of this condition. Our study suggests these drug-drug co-amorphous systems hold promise for optimizing SULF dosage in the future and providing a potential drug combination strategy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1 G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUC plasma ) of digoxin and sulfasalazine were not significantly different between SOD1 G93A and WT mice for both sexes. However, the AUC plasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1 G93A compared to WT mice, which was associated with lower AUC brain (female: 0.76-fold, male: 0.80-fold) and AUC spinal cord (female: 0.81-fold, male: 0.82-fold). The AUC stomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1 G93A compared to WT mice, suggesting reduced gastric emptying in SOD1 G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1 G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1 G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Ulcerative colitis is an inflammatory bowel disease (IBD) that involves inflammation of the colon lining and rectum. Although a definitive cure for IBD has not been identified, various therapeutic approaches have been proposed to mitigate the symptomatic presentation of this disease, primarily focusing on reducing inflammation. The aim of the present study was to evaluate the therapeutic potential of combining dental pulp stem cells (DPSCs) with sulfasalazine in an acetic acid-induced ulcerative colitis rat model and to assess the impact of this combination on the suppression of inflammatory cytokines and the regulation of oxidative stress in vivo., Methods: Ulcerative colitis was induced in rats through transrectal administration of 3% acetic acid. The therapeutic effect of combining DPSCs and sulfasalazine on UC was evaluated by measuring the colonic weight/length ratio and edema markers; performing histopathological investigations of colon tissue; performing immunohistochemical staining for NF-κB-P65 and IL-1β; and evaluating oxidative stress and antioxidant indices via ELISA. Moreover, the proinflammatory markers NF-κB-P65, TNF-α and TLR-4 were assessed in colon tissue via ELISA. Furthermore, qRT‒PCR was used to estimate the expression levels of the TLR-4, NF-κB-P65, and MYD88 genes in colon tissue., Results: The investigated macroscopic and microscopic signs of inflammation were markedly improved after the combined administration of sulfasalazine and DPSCs, where a noticeable improvement in histological structure, with an intact mucosal epithelium and mild inflammatory infiltration in the mucosa and submucosa, with slight hemorrhage. The administration of either DPSCs or sulfasalazine, either individually or in combination, significantly reduced ROS levels and significantly increased XOD activity. The immunohistochemical results demonstrated that the combined administration of DPSCs and sulfasalazine attenuated NFκB-p65 and IL-1β expression. Finally, the combined administration of DPSCs and sulfasalazine significantly downregulated MyD88, NF-κB and TLR4 gene expression., Conclusions: Cotreatment with DPSCs and sulfasalazine had synergistic effects on ulcerative colitis, and these effects were relieved., (© 2024. The Author(s).)

Chemodynamic therapy (CDT) is a promising strategy for cancer treatment, however, its application is restricted by low hydrogen peroxide (H 2 O 2 ) concentration, insufficient reactive oxygen species (ROS) generation, and high glutathione (GSH) levels. Here, we developed an injectable thermosensitive hydrogel (DSUC-Gel) based on "sea urchin-like" copper sulfide nanoparticles (UCuS) loaded with dihydroartemisinin (DHA) and sulfasalazine (SAS) to overcome these limitations of CDT. DSUC was cleaved to release DHA, SAS and Cu 2+ under acidic tumor microenvironment to enhance CDT. DHA with peroxide bridge responded to intracellular Fe 2+ to alleviate H 2 O 2 deficiency. SAS prevented GSH synthesis by targeting SLC7A11 and inhibited glutathione peroxidase (GPX4) activity to induce endogenous ferroptosis. ROS produced by Fenton-like reaction of Cu 2+ promoted lipid peroxidation (LPO) accumulation to promote ferroptosis. Enhanced CDT and ferroptosis induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration. As a result, DSUC-Gel significantly inhibited tumor growth both in vitro and in vivo. Our study provides a novel approach for enhancing anti-tumor efficacy by combining CDT, endogenous ferroptosis and ICD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We report a 9-year-old Japanese girl with chronic non-bacterial osteomyelitis (CNO) accompanied by recurrent erythema nodosum (EN) which was successfully treated with salazosulfapyridine (SASP). She was referred to our hospital because of recurrent erythema on her lower extremities and persistent knee and ankle arthralgia, which had been present for approximately 1 year. Although naproxen, a nonsteroidal anti-inflammatory drug, was initiated, her symptoms frequently recurred. Magnetic resonance imaging demonstrated multiple distinct high-intensity signals in the talus bones suggestive of multiple bone oedemas. Additionally, a histological examination of erythematous lesions was consistent with the histopathological findings of EN. She was diagnosed as having CNO complicated by EN, and received 250 mg/day of SASP as a second-line treatment, which showed partial response of both skin and bone lesions. Following increase in the dose of SASP to 500 mg/day resulted in complete remission of her skin and bone lesions. In conclusion, our findings suggest that SASP is effective not only for CNO bone lesions but also for EN. SASP could serve as a second-line therapeutic option at least for some cases of CNO complicated by EN refractory to nonsteroidal anti-inflammatory drugs., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objective: There are various combination conventional synthetic disease-modifying-antirheumatic drug (csDMARD) treatment strategies used in rheumatoid arthritis (RA). A commonly used csDMARD combination is triple therapy with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ). Another approach is double therapy with MTX and leflunomide (LEF). We compared the real-world retention of these two treatment combinations., Methods: Patients with RA from the Ontario Best Practices Research Initiative (OBRI) who received triple or double therapy on or after OBRI enrolment were included. Retention rates were compared between these two groups. We also analyzed which medication in the combination was discontinued and the reasons for treatment discontinuation. Disease activity was assessed at baseline, 6 and 12 months after treatment initiation as well as at time of discontinuation. Risk factors for treatment discontinuation were also examined., Results: Six hundred and ninety-two patients were included (258 triple and 434 double therapy). There were 175 (67.8%) discontinuations in the triple therapy group and 287 (66.1%) discontinuations in patients on double therapy. The median survival for triple therapy was longer (15.1 months; 95% CI: 11.2-21.2) compared to double therapy (9.6 months; 95%CI: 7.03-12.2). However, this was not statistically significant. Disease activity at 6 and 12 months, measured by 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) was lower with triple therapy (mean DAS28 at 6 months 3.4 vs. 3.9, P<0.0001 and at 12 months 3.2 vs. 3.5, P=0.0005)., Conclusion: Patients on triple therapy remained on treatment longer than patients on double therapy. However, this difference was not statistically significant., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sulfasalazine needs frequent daily dosing and the administration of numerous tablets per day pose challenges to patient compliance, contributing to increased adverse effects and difficulties in disease control. These inconveniences result in less effective treatment for arthritis associated with inflammatory bowel disease i.e. ulcerative colitis etc. To improve drug bioavailability, a delayed-release mechanism that releases the drug at the colon is necessary. To develop and optimize colon-targeted controlled release bilayer tablets coated with pH-dependent polymers. The bilayer tablets containing the immediate release part and sustained release part were developed. The tablets were coated with enteric-coated with Eudragit® S-100 and l-100 to achieve release in the colon. Granule properties and tablets were evaluated. The physicochemical parameters of the tablets were evaluated including, stability study, and drug release in 0.1 N HCl (pH 1.2), pH 6.8 phosphate buffer, pH 7.4 phosphate buffer for 2, 1, and up to 24 h respectively. Radiographic imaging and in vivo pharmacokinetic studies were also done in Rabbits. The bilayer tablets containing immediate and sustained release were successfully developed for the colon targeting. The granule properties were found within the acceptable range indicating good flow properties. The physicochemical properties of the tablets were also found acceptable. The tablets did not show release in 0.1 N HCl and 6.8 phosphate buffer but drug release was found under control in the 7.4 pH buffer. Sulfasalazine coated bilayer tablets were found stable and no significant changes were observed in the stability studies. Based on the X-ray studies, the formulated tablet remained discernible in the stomach, small intestine, and colon for a duration of up to 24 h. Finally, by the 32nd hour, the tablet was no longer visible in the X-ray examination, leading to the conclusion of complete drug release. The drug concentration in plasma remained within the therapeutic range for up to 24 h in vivo. These novel formulations present substantial advantages, providing prolonged targeted drug release and reducing systemic adverse effects. The results suggest promising potential for treating arthritis in Inflammatory bowel disease (IBD) patients, offering a solution to current delivery systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial., Methods: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m 2 /week., Results: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group., Conclusions: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety., Trial Registration: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 ., (© 2024. The Author(s).)

Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota., Competing Interests: Declaration of competing interest Abdul W. Basit is the inventor of the Phloral® Technology and holds its patent [US20070243253A1]. OPTICORE® is licensed by Tillots Pharma Ltd. as part of the Octasa® 1600 mg product., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This study aimed to investigate the protective effect of probiotics and synbiotics from traditional Thai fermented tea leaves (Miang) on dextran sulfate sodium (DSS)-induced colitis in mice, in comparison to sulfasalazine. C57BL/6 mice were treated with probiotics L. pentosus A14-6, CMY46 and synbiotics, L. pentosus A14-6 combined with XOS, and L. pentosus CMY46 combined with GOS for 21 days. Colitis was induced with 2% DSS administration for seven days during the last seven days of the experimental period. The positive group was treated with sulfasalazine. At the end of the experiment, clinical symptoms, pathohistological changes, intestinal barrier integrity, and inflammatory markers were analyzed. The probiotics and synbiotics from Miang ameliorated DSS-induced colitis by protecting body weight loss, decreasing disease activity index, restoring the colon length, and reducing pathohistological damages. Furthermore, treatment with probiotics and synbiotics improved intestinal barrier integrity, accompanied by lowing colonic and systemic inflammation. In addition, synbiotics CMY46 combined with GOS remarkedly elevated the expression of IL-10. These results suggested that synbiotics isolated from Miang had more effectiveness than sulfasalazine. Thereby, they could represent a novel potential natural agent against colonic inflammation.

Anaphylaxis is a life-threatening allergic reaction, for which the worldwide prevalence is rapidly increasing. The currently used synthetic antiallergic drugs have a high tendency to cause adverse effects, like gastric ulcers, in long-term use. Therefore, a great deal of attention has been given to develop new safer and more effective antiallergic agents from natural compounds that are chemically/enzymatically-modified. Here, we evaluated/compared the efficacy of two different doses (50 and 100 mg/kg body weight "b.w", given orally) of sodium R-lipoate (NaRLA) and enzymatically-modified isoquercitrin (EMIQ) in alleviating both local/systemic non-immunological anaphylactic reactions and stress-induced gastric ulceration in mice, in comparison with sulfasalazine (SSZ) as a reference drug. The results indicated that the pre-treatment of animals with NaRLA or EMIQ (especially at 100 mg/kg b.w) completely succeeded, as SSZ, in alleviating the hind paw edema induced by either histamine or compound 48/80 (Cpd 48/80). Furthermore, NaRLA and EMIQ prevented the mast cell degranulation and anaphylactic shock caused by Cpd 48/80 (in a dose-dependent manner) and reduced significantly (P < 0.001) the histamine release from the mouse peritoneal mast cells, like SSZ. Moreover, their use was associated with alleviating both gastric histopathological and biochemical alterations in the water-restraint stress (WRS) mice model towards the control values. They also decreased the percentage of degranulated mesenteric mast cells in the WRS mice model. In conclusion, our findings provide possibility that both NaRLA and EMIQ may serve as an effective therapeutic agents for mast cells-dependent anaphylactic reactions without risks of inducing gastric ulcers., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear., Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission., Design, Setting, and Participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019., Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80)., Main Outcomes and Measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin., Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred., Conclusions and Relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT01881308.

Microbial metabolites play a critical role in mucosal homeostasis by mediating physiological communication between the host and colonic microbes, whose perturbation may lead to gut inflammation. The microbial metabolite 3-indolepropionic acid (3-IPA) is one such communication mediator with potent antioxidative and anti-inflammatory activity. To apply the metabolite for the treatment of colitis, 3-IPA was coupled with acidic amino acids to yield colon-targeted 3-IPA, 3-IPA-aspartic acid (IPA-AA) and 3-IPA-glutamic acid (IPA-GA). Both conjugates were activated to 3-IPA in the cecal contents, which occurred faster for IPA-AA. Oral gavage of IPA-AA (oral IPA-AA) delivered a millimolar concentration of IPA-AA to the cecum, liberating 3-IPA. In a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model, oral IPA-AA ameliorated rat colitis and was less effective than sulfasalazine (SSZ), a current anti-inflammatory bowel disease drug. To enhance the anticolitic activity of 3-IPA, it was azo-linked with the GPR109 agonist 5-aminonicotinic acid (5-ANA) to yield IPA-azo-ANA, expecting a mutual anticolitic action. IPA-azo-ANA (activated to 5-ANA and 2-amino-3-IPA) exhibited colon specificity in in vitro and in vivo experiments. Oral IPA-azo-ANA mitigated colonic damage and inflammation and was more effective than SSZ. These results suggest that colon-targeted 3-IPA ameliorated rat colitis and its anticolitic activity could be enhanced by codelivery of the GPR109A agonist 5-ANA.

Diurnal variations in pain hypersensitivity are common in chronic pain disorders. Temporal exacerbation of neuropathic pain hypersensitivity is dependent on diurnal variations in glucocorticoid secretion from the adrenal glands. We previously demonstrated that spinal expression of serum- and glucocorticoid-inducible kinase-1 (SGK-1) is associated with glucocorticoid- induced exacerbation of pain hypersensitivity, but there are no available strategies to inhibit SGK-1 in the spinal cord. By screening a clinically approved drug library (more than 1,200 drugs), we found that sulfasalazine (SSZ) has inhibitory effects on SGK-1. SSZ is a prodrug composed of 5-aminosalicylic acid and sulfapyridine linked by NN bond, which is therapeutically effective for inflammatory bowel diseases. However, the NN bond in SSZ was necessary for its inhibitory action against SGK-1. Although intrathecal injection of SSZ to nerve-injured mice significantly alleviated mechanical pain hypersensitivity, no significant anti- neuropathic pain effects of SSZ were detected after oral administration due to its low bioavailability and limited spinal distribution, which were associated with efflux by the xenobiotic transporter breast cancer resistance protein (BCRP). Concomitant oral administration of SSZ with febuxostat (FBX), which is an approved drug to inhibit BCRP, improved the distribution of SSZ to the spinal cord. The concomitant oral administration with FBX also increased the anti-neuropathic pain effects of SSZ. Our study revealed a previously unrecognized pharmacological effect of SSZ to alleviate SGK-1-induced painful peripheral neuropathy, and concomitant oral administration of SSZ with FBX may also be a preventative option for diurnal exacerbation of neuropathic pain hypersensitivity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aim: Although oral mesalamine is the first-choice drug for treating mild-to-moderate ulcerative colitis (UC), some patients show symptoms of intolerance, including exacerbation of diarrhea and abdominal pain. The present study clarified the current state and clinical courses of patients with mesalamine intolerance., Methods: Patients who were diagnosed with UC and administered oral mesalamine at eight hospitals in Japan with a follow-up period exceeding 1 year were analyzed., Results: Sixty-seven (11%) of 633 patients showed intolerance to at least one formulation of oral mesalamine. The frequency of mesalamine intolerance has increased in recent years, rising from 5.3% in 2007-2010 to 9.1% in 2011-2013 and 16.2% in 2014-2016. The most common complications were the exacerbation of diarrhea (n = 29), a fever (n = 25), and abdominal pain (n = 22). Readministration of mesalamine/sulfasalazine was attempted in 43 patients, mostly with other types of formulation of mesalamine, and more than half of these patients proved to be tolerant. The risk factors for mesalamine intolerance were female gender (odds ratio [OR] = 1.83; 95% confidence interval [CI], 1.08-3.12), age < 60 years old (OR = 2.82; CI, 1.19-8.33), and pancolitis (OR = 2.09; 95% CI, 1.23-3.60). There were no significant differences in the use of anti-tumor necrosis factor-α agents, colectomy, or steroid-free remission at the last visit between patients with and without mesalamine intolerance., Conclusions: Mesalamine intolerance is not rare, and its frequency has been increasing recently. The prognosis of patients with mesalamine intolerance did not differ significantly from that of those without intolerance., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Materials and Methods: The chemical compositions of EFH were identified using LC-ESI-MS. The mice with 3% DSS-induced UC were administered EFH (200, 400, and 800 mg/kg), sulfasalazine (SASP, 200 mg/kg), and azathioprine (AZA, 13 mg/kg) for 10 days via daily gavage. The colonic inflammation was evaluated by the disease activity index (DAI), colonic length, histological scores, and levels of inflammatory mediators. The gut microbiota was characterized by 16S rRNA gene sequencing and analysis., Results: LC-ESI-MS analysis showed that EFH was rich in alkaloids and flavones. The results indicated that EFH significantly improved the DAI score, relieved colon shortening, and repaired pathological colonic variations in colitis. In addition, proteins in the NF- κ B pathway were significantly inhibited by EFH. Furthermore, EFH recovered the diversity and balance of the gut microbiota., Conclusions: EFH has protective effects against DSS-induced colitis by keeping the balance of the gut microbiota and suppressing the NF- κ B pathway., Competing Interests: The authors declare that there is no conflict of interests with respect to this article., (Copyright © 2020 Guosheng Lin et al.)

Background: Oral 5-aminosalicylic acid (5-ASA; also known as mesalazine or mesalamine) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. In an earlier version of this review, we found that 5-ASA drugs were more effective than placebo for maintenance of remission of ulcerative colitis (UC), but had a significant therapeutic inferiority relative to SASP. In this version, we have rerun the search to bring the review up to date., Objectives: To assess the efficacy, dose-responsiveness, and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for maintenance of remission in quiescent UC and to compare the efficacy and safety of once-daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens., Search Methods: We performed a literature search for studies on 11 June 2019 using MEDLINE, Embase, and the Cochrane Library. In addition, we searched review articles and conference proceedings., Selection Criteria: We included randomized controlled trials with a minimum treatment duration of six months. We considered studies of oral 5-ASA therapy for treatment of participants with quiescent UC compared with placebo, SASP, or other 5-ASA formulations. We also included studies that compared once-daily 5-ASA treatment with conventional dosing of 5-ASA and 5-ASA dose-ranging studies., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes were adherence, adverse events (AE), serious adverse events (SAE), withdrawals due to AEs, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus SASP, once-daily dosing versus conventional dosing, 5-ASA (balsalazide, Pentasa, and olsalazine) versus comparator 5-ASA formulation (Asacol and Salofalk), and 5-ASA dose-ranging. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each outcome. We analyzed data on an intention-to-treat basis, and used GRADE to assess the overall certainty of the evidence., Main Results: The search identified 44 studies (9967 participants). Most studies were at low risk of bias. Ten studies were at high risk of bias. Seven of these studies were single-blind and three were open-label. 5-ASA is more effective than placebo for maintenance of clinical or endoscopic remission. About 37% (335/907) of 5-ASA participants relapsed at six to 12 months compared to 55% (355/648) of placebo participants (RR 0.68, 95% CI 0.61 to 0.76; 8 studies, 1555 participants; high-certainty evidence). Adherence to study medication was not reported for this comparison. SAEs were reported in 1% (6/550) of participants in the 5-ASA group compared to 2% (5/276) of participants in the placebo group at six to 12 months (RR 0.60, 95% CI 0.19 to 1.84; 3 studies, 826 participants; low-certainty evidence). There is probably little or no difference in AEs at six to 12 months' follow-up (RR 0.93, 95% CI 0.73 to 1.18; 5 studies, 1132 participants; moderate-certainty evidence). SASP is more effective than 5-ASA for maintenance of remission. About 48% (416/871) of 5-ASA participants relapsed at six to 18 months compared to 43% (336/784) of SASP participants (RR 1.14, 95% CI 1.03 to 1.27; 12 studies, 1655 participants; high-certainty evidence). Adherence to study medication and SAEs were not reported for this comparison. There is probably little or no difference in AEs at six to 12 months' follow-up (RR 1.07, 95% CI 0.82 to 1.40; 7 studies, 1138 participants; moderate-certainty evidence). There is little or no difference in clinical or endoscopic remission rates between once-daily and conventionally dosed 5-ASA. About 37% (717/1939) of once-daily participants relapsed over 12 months compared to 39% (770/1971) of conventional-dosing participants (RR 0.94, 95% CI 0.88 to 1.01; 10 studies, 3910 participants; high-certainty evidence). There is probably little or no difference in medication adherence rates. About 10% (106/1152) of participants in the once-daily group failed to adhere to their medication regimen compared to 8% (84/1154) of participants in the conventional-dosing group (RR 1.18, 95% CI 0.72 to 1.93; 9 studies, 2306 participants; moderate-certainty evidence). About 3% (41/1587) of participants in the once-daily group experienced a SAE compared to 2% (35/1609) of participants in the conventional-dose group at six to 12 months (RR 1.20, 95% CI 0.77 to 1.87; moderate-certainty evidence). There is little or no difference in the incidence of AEs at six to 13 months' follow-up (RR 0.98, 95% CI 0.92 to 1.04; 8 studies, 3497 participants; high-certainty evidence). There may be little or no difference in the efficacy of different 5-ASA formulations. About 44% (158/358) of participants in the 5-ASA group relapsed at six to 18 months compared to 41% (142/349) of participants in the 5-ASA comparator group (RR 1.08, 95% CI 0.91 to 1.28; 6 studies, 707 participants; low-certainty evidence)., Authors' Conclusions: There is high-certainty evidence that 5-ASA is superior to placebo for maintenance therapy in UC. There is high-certainty evidence that 5-ASA is inferior compared to SASP. There is probably little or no difference between 5-ASA and placebo, and 5-ASA and SASP in commonly reported AEs such as flatulence, abdominal pain, nausea, diarrhea, headache, and dyspepsia. Oral 5-ASA administered once daily has a similar benefit and harm profile as conventional dosing for maintenance of remission in quiescent UC., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. It was previously found that 5-ASA drugs in doses of at least 2 g/day were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis (UC). This review is an update of a previously published Cochrane Review., Objectives: To assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators (i.e. other formulations of 5-ASA) for induction of remission in active UC. A secondary objective was to compare the efficacy and safety of once-daily dosing of oral 5-ASA versus conventional dosing regimens (two or three times daily)., Search Methods: We searched MEDLINE, Embase and the Cochrane Library on 11 June 2019. We also searched references, conference proceedings and study registers to identify additional studies., Selection Criteria: We considered randomized controlled trials (RCTs) including adults (aged 18 years or more) with active UC for inclusion. We included studies that compared oral 5-ASA therapy with placebo, SASP, or other 5-ASA formulations. We also included studies that compared once-daily to conventional dosing as well as dose-ranging studies., Data Collection and Analysis: Outcomes include failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events (AEs), serious adverse events (SAEs), withdrawals due to AEs, and withdrawals or exclusions after entry. We analyzed five comparisons: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once-daily dosing versus conventional dosing, 5-ASA (e.g. MMX mesalamine, Ipocol, Balsalazide, Pentasa, Olsalazine and 5-ASA micropellets) versus comparator 5-ASA (e.g. Asacol, Claversal, Salofalk), and 5-ASA dose-ranging. We calculated the risk ratio (RR) and 95% confidence interval (95% CI) for each outcome. We analyzed data on an intention-to-treat basis, and used GRADE to assess the overall certainty of the evidence., Main Results: We include 54 studies (9612 participants). We rated most studies at low risk of bias. Seventy-one per cent (1107/1550) of 5-ASA participants failed to enter clinical remission compared to 83% (695/837) of placebo participants (RR 0.86, 95% CI 0.82 to 0.89; 2387 participants, 11 studies; high-certainty evidence). We also observed a dose-response trend for 5-ASA. There was no difference in clinical remission rates between 5-ASA and SASP. Fifty-four per cent (150/279) of 5-ASA participants failed to enter remission compared to 58% (144/247) of SASP participants (RR 0.90, 95% CI 0.77 to 1.04; 526 participants, 8 studies; moderate-certainty evidence). There was no difference in remission rates between once-daily dosing and conventional dosing. Sixty per cent (533/881) of once-daily participants failed to enter clinical remission compared to 61% (538/880) of conventionally-dosed participants (RR 0.99, 95% CI 0.93 to 1.06; 1761 participants, 5 studies; high-certainty evidence). Eight per cent (15/179) of participants dosed once daily failed to adhere to their medication regimen compared to 6% (11/179) of conventionally-dosed participants (RR 1.36, 95% CI 0.64 to 2.86; 358 participants, 2 studies; low-certainty evidence). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Fifty per cent (507/1022) of participants in the 5-ASA group failed to enter remission compared to 52% (491/946) of participants in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02; 1968 participants, 11 studies; moderate-certainty evidence). There was no evidence of a difference in the incidence of adverse events and serious adverse events between 5-ASA and placebo, once-daily and conventionally-dosed 5-ASA, and 5-ASA and comparator 5-ASA formulation studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening UC. SASP was not as well tolerated as 5-ASA. Twenty-nine per cent (118/411) of SASP participants experienced an AE compared to 15% (72/498) of 5-ASA participants (RR 0.48, 95% CI 0.36 to 0.63; 909 participants, 12 studies; moderate-certainty evidence)., Authors' Conclusions: There is high-certainty evidence that 5-ASA is superior to placebo, and moderate-certainty evidence that 5-ASA is not more effective than SASP. Considering relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. High-certainty evidence suggests 5-ASA dosed once daily appears to be as efficacious as conventionally-dosed 5-ASA. There may be little or no difference in efficacy or safety among the various 5-ASA formulations., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Osteoarticular tuberculosis can occur in patients with rheumatoid arthritis (RA) receiving immunosuppressive therapy. Here, we describe a case of tubercular osteomyelitis in an old fused hip of a patient with RA who received prednisolone, salazosulfapyridine (SASP), and low-dose methotrexate (MTX). A 77-year-old man with a 4-year history of RA was admitted with a complaint of general fatigue. His symptoms of RA had been well controlled with a combination of prednisolone, SASP, and low-dose MTX. Because the laboratory data showed an increase in serum C-reactive protein levels, we suspected pneumonia. There was expansion of a pre-existing consolidation in the right lower lobe of his lung on chest computed tomography, and the sputum culture was positive for Klebsiella oxytoca . His family physician prescribed empiric antibiotics for pneumonia. Although the QuantiFERON ® test result was positive, the acid-fast bacillus staining result was negative in the sputum. He started complaining of pain in his left hip, where arthrodesis was performed for an unknown reason at the age of 20 years. Sonographic examination of his left thigh revealed fluid collection. The aspiration culture of the fluid was positive for Mycobacterium tuberculosis . He was initiated on rifampicin, isoniazid, pyrazinamide, and ethambutol. Surgical debridement of the fused left hip was performed twice along with a removal of previously implanted materials. Although infrequent, osteoarticular tuberculosis can occur during immunosuppressive therapy, especially in elderly patients. Physicians should be aware of a history of possible tuberculosis infection, such as hip arthrodesis, when prescribing MTX along with SASP and corticosteroid in the elderly.

Objectives: To evaluate the cost-effectiveness of treat-to-target strategies among recently diagnosed patients with rheumatoid arthritis (RA) using methotrexate (MTX) and a step-down glucocorticoid (GC) scheme (COBRA Slim) compared with (1) this combination with either sulphasalazine (COBRA Classic) or leflunomide (COBRA Avant-Garde) in high-risk patients and (2) MTX without GCs (Tight-Step-Up, TSU) in low-risk patients., Methods: The incremental cost-utility was calculated from a healthcare perspective in the intention-to-treat population (n=379) of the 2-year open-label pragmatic randomised controlled Care in early RA trial. Healthcare costs were collected prospectively through electronic trial records. Quality-adjusted life years (QALYs) were estimated using mapping algorithms for EuroQoL-5 Dimension. Multiple imputation was used to handle missing data and bootstrapping to calculate CIs. Robustness was tested with biological disease-modifying antirheumatic drugs at biosimilar prices., Results: In the high-risk group, Classic (∆k€1.464, 95% CI -0.198 to 3.127) and Avant-Garde (∆k€0.636, 95% CI -0.987 to 2.258) were more expensive compared with Slim and QALYs were slightly worse for Classic (∆-0.002, 95% CI -0.086 to 0.082) and Avant-Garde (∆-0.009, 95% CI -0.102 to 0.084). This resulted in the domination of Classic and Avant-Garde by Slim. In the low-risk group, Slim was cheaper (∆k€-0.617, 95% CI -2.799 to 1.566) and QALYs were higher (∆0.141, 95% CI 0.008 to 0.274) compared with TSU, indicating Slim dominated. Results were robust against the price of biosimilars., Conclusions: The combination of MTX with a GC bridging scheme is less expensive with comparable health utility than more intensive step-down combination strategies or a conventional step-up approach 2 years after initial treatment., Trial Registration Number: NCT01172639., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammatory bowel disease (IBD) is a chronic and idiopathic disease with gastrointestinal dysfunction. Current therapeutic approaches in IBD have several limitations such as, harmful side effects and high price for biologic drugs. It sounds that finding of an effective, safe and inexpensive strategy to overcome IBD is critical. Platelet derivatives, as biological pool of wide range of growth factors and cytokines, are widely used in regenerative medicine for treatment of soft and hard tissue lesions. We sought to determine whether platelet lysate (PL) alone or in combination with sulfasalazine (reference drug) can be a valuable strategy for overcoming IBD. In the present study, we investigated and compared the daily and alternate-day administration of PL alone or combined with sulfasalazine for treating colitis in a rat model of IBD. Histological damage scores of TNBS-induced colitis were reduced by co-administration of every alternate day PL and sulfasalazine. Pro-inflammatory cytokines TNF-α, IL-1 and IL-6 were decreased and anti-inflammatory cytokines IL-10 and TGF-β were increased after treatment with PL compared to that in the TNBS group. Furthermore, combined treatment with PL and sulfasalazine decreased apoptosis and inhibited the NF-κB signaling pathway. In conclusion, the combined administration of PL with conventional IBD therapy is able to effectively ameliorate IBD through modulation of inflammatory status., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020. Published by Elsevier Masson SAS.)

Objectives: We retrospectively evaluated the retention rate and clinical responses following treatment for rheumatoid arthritis (RA) with iguratimod (IGU) vs. salazosulfapyridine (SASP) as the first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD). Methods: We analyzed 197 RA patients who were treated with IGU or SASP as the initial treatment in the 3-year study period. The retention rate, clinical response, the dosage and percent user of prednisolone (PSL), and safety profiles were evaluated. Results: At month 36, the retention rates of the IGU and SASP groups were 52.4 vs. 32.1%. The rate of responders (good or moderate response) at month 36 was 85.8 vs. 65.2% in the IGU and SASP groups, respectively. At month 36 for the IGU and SASP groups, the percentages of PSL users were 16.7 vs. 46.7%, and the PSL dosage was 0.3 mg/d vs. 2.0 mg/d, respectively. The cumulative rates of any adverse event (AE) at month 36 were 19.8 vs. 29.2% in the IGU and SASP groups, respectively. Conclusion: IGU is a useful first-line csDMARD treatment for RA patients, showing a high retention rate and good efficacy without an increased risk of serious AEs, including serious infections. Our findings also indicate a PSL dose-sparing effect of IGU treatment.

Ulcerative colitis is a chronic auto-inflammatory disorder confined to the colorectal region. It is challenging to find an absolute treatment and current therapy aims to ameliorate symptoms, decrease relapses and prevent prognosis of colorectal cancer. In the present study, we investigated the possible action of xanthine oxidase inhibitors in murine colitis model by measuring different indicative parameters and comparing the results to those of the reference sulfasalazine. Also, we compared the effects of combining sulfasalazine and allopurinol to each drug alone. Dextran Sodium Sulfate (DSS) is used in this study to induce ulcerative colitis in male wistar rats as it is known to be the closest model that mimics human ulcerative colitis. Allopurinol was given prior to colitis induction by four days and febuxostat for six days before induction with DSS (5% w/v) and continue to give them concomitantly during the induction.Il-1β, malondialdehyde, reduced glutathione (GSH), xanthine oxidase, and superoxide dismutase were measured in colonic tissue. We also measured concentrations of IL-1β, Il-6 and uric acid in serum. Allopurinol dose-dependently ameliorated biochemical injuries. Febuxostat has shown better results than allopurinol and sulfasalazine, and this is the first study to demonstrate this., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The potential of probiotics for treating ulcerative colitis (UC) has attracted increasing attention. However, more studies are still needed to guide physicians on the proper selection and use of probiotics. Here, we propose that combination of multiple probiotics with different functions can reduce intestinal inflammation. In this study, the effects of probiotics (Lactobacillus reuteri, Bacillus coagulans, Bifidobacterium longum, and Clostridium butyricum) on the physiology and histopathology of colon were evaluated in a dextran sulfate sodium (DSS)-induced colitis mouse model. The combined species, as well as the species individually, were tested and compared with sulfasalazine (SASP) and two Chinese herbal therapies. Results show that the functions of the four probiotic strains were different in regulating intestinal immunity and barrier function. The four-species probiotic cocktail was more effective than the species individually and anti-inflammatory drugs in repairing the dysbiosis of mucosal microbial ecology and reducing intestinal inflammation. The multi-strain probiotic mixture increased the proportion of beneficial bacteria and decreased the proportion of pro-inflammatory bacteria in the colonic mucosa. In addition, probiotic mixture significantly enhanced the expression of IL-10 and intestinal barrier function. These results suggest that a combination of multiple probiotics with different functions has synergistic effects and can restore the balance of interactions between microorganisms and immunological niches.

Gastric chief cells differentiate from mucous neck cells and develop their mature state at the base of oxyntic glands with expression of secretory zymogen granules. After parietal cell loss, chief cells transdifferentiate into mucous cell metaplasia, designated spasmolytic polypeptide-expressing metaplasia (SPEM), which is considered a candidate precursor of gastric cancer. We examined the range of microRNA (miRNA) expression in chief cells and identified miRNAs involved in chief cell transdifferentiation into SPEM. Among them, miR-148a was strongly and specifically expressed in chief cells and significantly decreased during the process of chief cell transdifferentiation. Interestingly, suppression of miR-148a in a conditionally immortalized chief cell line induced up-regulation of CD44 variant 9 (CD44v9), one of the transcripts expressed at an early stage of SPEM development, and DNA methyltransferase 1 (Dnmt1), an established target of miR-148a. Immunostaining analyses showed that Dnmt1 was up-regulated in SPEM cells as well as in chief cells before the emergence of SPEM in mouse models of acute oxyntic atrophy using either DMP-777 or L635. In the cascade of events that leads to transdifferentiation, miR-148a was down-regulated after acute oxyntic atrophy either in xCT knockout mice or after sulfasalazine inhibition of xCT. These findings suggest that the alteration of miR-148a expression is an early event in the process of chief cell transdifferentiation into SPEM., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Juvenile Idiopathic Arthritis (JIA) may cause significant impairment in health-related quality of life (HrQoL), despite effective therapies. The aim of this study was to assess HrQoL during first-year treatment in patients with new-onset polyarticular JIA, and to compare treatment strategies., Methods: In ACUTE-JIA Study, 60 patients with new-onset JIA were randomized to receive either infliximab with methotrexate (IFX+MTX); a triple therapy of methotrexate, hydroxychloroquine, and sulfasalazine (Triple); or methotrexate monotherapy (MTX). Efficacy was measured with American College of Rheumatology pediatric (ACRp) score, and juvenile arthritis disease activity score (JADAS). HrQoL was evaluated with Child Health Questionnaire (CHQ), which includes physical and psychosocial summary scores (PhS and PsS). Linear mixed models were utilized to compare groups over time., Results: In the whole group of 60 patients, mean physical summary score (PhS) improved from 26.2 (SD 8.7) at week 0 to 49.7 (SD 13.2) at week 54 (p=0.046). Mean improvement of PhS was 20.3 (95% CI -15.5 to 56.2); 22.6 (-19.5 to 64.7); and 26.6 (-12.1 to 65.3) in IFX+MTX, Triple, and MTX, respectively. Changes in psychosocial summary score (PsS) were smaller: from 51.0 (SD 8.5) to 54.7 (6.3) (p=0.019) in all patients. No differences between the three treatment groups were detected in either of the measures. In multivariate analyses, Child Health Assessment Questionnaire (CHAQ), pain VAS, and time spent in inactive disease contributed to improvement in PhS; gender and CHAQ to PsS., Conclusions: HrQol improved during the first year on therapy for JIA irrespective of the treatment strategy. The timing of change in the different dimensions of HrQoL varied; improvement occurred earlier in physical than psychosocial domains of HrQol., Trial Registration: This study was registered within the Hospital District of Helsinki and Uusimaa (http://www.hus.fi) clinical trials, number 211864 in October 2002, and later on with ClinicalTrials.gov, number NCT01015547.

A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor-cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8 + T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate-cystine antiporter xc - , resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy. SIGNIFICANCE: This article describes ferroptosis as a previously unappreciated mechanism of action for radiotherapy. Further, it shows that ferroptosis is a novel point of synergy between immunotherapy and radiotherapy. Finally, it nominates SLC7A11, a critical regulator of ferroptosis, as a mechanistic determinant of synergy between radiotherapy and immunotherapy. This article is highlighted in the In This Issue feature, p. 1631 ., (©2019 American Association for Cancer Research.)

Objectives: To investigate whether MTX should be combined with an additional DMARD and bridging glucocorticoids as initial treatment for patients with early RA to induce an effective long-term response., Methods: The Care in early RA study is a two-year investigator-initiated pragmatic multicentre randomized trial. Early RA patients, naïve to DMARDs and glucocorticoids, were stratified based on prognostic factors. High-risk patients were randomized to COBRA-Classic (n = 98): MTX, sulfasalazine, prednisone step-down from 60 mg; COBRA-Slim (n = 98): MTX, prednisone step-down from 30 mg; or COBRA-Avant-Garde (n = 93): MTX, leflunomide, prednisone step-down from 30 mg. Low-risk patients were randomized to COBRA-Slim (n = 43); or Tight Step Up (TSU) (n = 47): MTX without prednisone. Clinical/radiological outcomes at year 2, sustainability of response, safety and treatment adaptations were assessed., Results: In the high-risk group 71/98 (72%) patients achieved a DAS28-CRP < 2.6 with COBRA-Slim compared with 64/98 (65%) with COBRA-Classic and 69/93 (74%) with COBRA-Avant-Garde (P = 1.00). Other clinical/radiological outcomes and sustainability of response were similar. COBRA-Slim treatment resulted in less therapy-related adverse events compared with COBRA-Classic (P = 0.02) or COBRA-Avant-Garde (P = 0.005). In the low-risk group, 29/43 (67%) patients on COBRA-Slim and 34/47 (72%) on TSU achieved a DAS28-CRP < 2.6 (P = 1.00). On COBRA-Slim, low-risk patients had lower longitudinal DAS28-CRP scores over 2 years, a lower need for glucocorticoid injections and a comparable safety profile compared with TSU., Conclusion: All regimens combining DMARDs with glucocorticoids were effective for patients with early RA up to 2 years. The COBRA-Slim regimen, MTX monotherapy with glucocorticoid bridging, provided the best balance between efficacy and safety, irrespective of patients' prognosis., Trial Registration: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01172639., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis.

Objective: Combination treatments for patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX) alone include the addition of a tumor necrosis factor inhibitor (TNFi) or the addition of sulfasalazine (SSZ) and hydroxychloroquine to MTX (triple therapy). We compared persistence and adherence rates between these 2 combination therapies in US veterans and report the reasons for discontinuation of combination treatment in these groups., Methods: Using Veteran's Affairs clinical and administrative data from 2006 to 2012, veterans with RA escalating treatment from MTX to MTX-TNFi or triple therapy were examined for a 12-month period after combination initiation. Persistence was defined as treatment without a ≥90-day gap in therapy. Adherence was calculated using the proportion of days covered ≥80% at 12 months. Matching weights-adjusted models were applied to more closely mimic randomization in this study. The reasons that patients discontinued their combination regimens were identified by chart abstraction., Results: Full persistence at 1 year was 45% in the MTX-TNFi patients (n = 2,125) and 18% in the triple therapy patients (n = 171) (P < 0.001). Adherence was higher for the MTX-TNFi group (26%) than the triple therapy group (11%) (P < 0.0001). The triple therapy group was associated with significantly more treatment discontinuation, which was most often due to adverse drug events from SSZ., Conclusion: Differences in persistence and adherence between the MTX-TNFi and triple therapy groups appear to be primarily related to adverse drug events that were most often attributed to SSZ., (© 2018, American College of Rheumatology.)

Objective: To retrospectively compare the long-term clinical, functional, and cost outcomes for early RA patients (symptoms < 1 year) who did or did not achieve early remission in a treat-to-target strategy., Method: Five-year data of 471 patients included in the DREAM remission induction cohort were used. Patients were treated according to a pre-specified 28-joint Disease Activity Score (DAS28) remission driven step-up treatment strategy starting with methotrexate, addition of sulfasalazine, and exchange of sulfasalazine for biological medication in case of failure. Two- and 3-year healthcare costs were available for selected subsamples of patients only., Results: DAS28 remission was achieved in 27.7%, 38.2%, and 51.6% of patients at 2, 3, and 6 months, respectively. Achieving DAS28 remission at 2, 3, or 6 months was consistently associated with significantly lower DAS28 and Health Assessment Questionnaire-Disability scores at 1, 3, and 5 years of follow-up (all P values < 0.02). Patients in remission at 2, 3, or 6 months also had significantly lower medication costs per patient over the first 2 and 3 years of treatment, mainly due to lower biologic use, but differences in total healthcare resource costs (hospital admissions plus consultations) were less pronounced. Mean total medication and total healthcare resource costs at 3 years were €1131 and €1757 for patients in remission at 6 months vs. €7533 (P < 0.01) and €2202 (P = 0.09) for those not in remission., Conclusion: Achieving early remission was associated with beneficial clinical outcomes for early RA patients and lower costs in the long term. Key Points • Previous studies in rheumatoid arthritis patients have demonstrated that early good response is associated with sustained remission and better long-term clinical outcomes. • This study extents these findings by examining the long-term benefits of achieving early remission on clinical, patient-reported, and economic outcomes in a real-world cohort of patients with very early rheumatoid arthritis treated according to treat-to-target principles. • The findings of this study clearly demonstrate that aiming for early remission in rheumatoid arthritis patients is beneficial in the long-term in terms of better clinical and functional outcomes and lower healthcare costs.

We investigated if the therapeutic switching of sofalcone (SFC), a gastroprotective agent, to an anticolitic agent is feasible using colon-targeted drug delivery. SFC can activate the anti-inflammatory nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-hemeoxygenase-1 (HO-1) pathway in human colon epithelial cells and murine macrophages. For the efficient treatment of colitis, SFC was coupled with acidic amino acids to yield SFC-aspartic acid (SFC-AA) and SFC-glutamic acid, and their colon targetability and therapeutic effects were assessed as an anticolitic agent in a 2,4-dinitrobenezenesulfonic acid-induced rat colitis model. The SFC derivatives were decoupled up to 72% in the cecal contents but remained stable in the small intestinal contents. Oral gavage of SFC-AA (oral SFC-AA, equivalent to 1.67 mg/kg of SFC) delivered SFC (maximal cecal concentration: 57.36 μM) to the cecum, while no SFC was detected with oral gavage of SFC (oral SFC, 1.67 mg/kg). Moreover, oral SFC-AA (equivalent to 10 mg/kg of SFC) did not afford detectable concentration of SFC in the blood but detected up to 4.64 μM with oral SFC (10 mg/kg), indicating efficient colonic delivery and limited systemic absorption of SFC upon oral SFC-AA. Oral SFC-AA ameliorated colonic damage and inflammation in rat colitis with elevating colonic levels of HO-1 and nuclear Nrf2 protein, and the anticolitic effects of SFC-AA were significantly undermined by an HO-1 inhibitor. At an equivalent dose of SFC, oral SFC-AA but not oral SFC increased colonic HO-1 and nuclear Nrf2 levels, and oral SFC-AA was more effective than oral SFC in treating rat colitis. Moreover, oral SFC-AA was as effective against colitis as oral sulfasalazine being used for the treatment of inflammatory bowel disease. In conclusion, colon-targeted delivery of SFC facilitated the therapeutic switching of the drug to an anticolitic drug via Nrf2 activation.

The objective of the present work was to evaluate the anti-inflammatory effects of Vicenin-2 on dextran sulfate sodium (DSS)-induced colitis model. Colitis was induced in C57BL/6J mice by administration of 2% DSS in drinking water for 7 days. In addition to DSS, Vicenin-2 (50 mg kg -1 /day -1 ) was administrated orally to the test group. The ulceration extent and severity were assessed macroscopically, histopathologically, and by disease activity index. The Vicenin-2 treated group showed significant differences in physiological parameters including bodyweight, colon weight, and colon length, compared to DSS-induced colitis group. In addition, Vicenin-2 treatment effectively reduced stool consistency and bleeding scores. Myeloperoxidase (MPO) activity, expressions of pro-inflammatory cytokines, and specific key inflammatory markers (iNOS and COX-2) significantly increased in DSS-induced colitis colon tissues. However, administration of Vicenin-2 effectively reduced the MPO activity, attenuated the expression of pro-inflammatory cytokines and key inflammatory markers, in DSS-induced colitis mice. These results were comparable with sulfasalazine, an anti-inflammatory drug used routinely for ulcerative colitis (UC). These findings suggest that Vicenin-2 effectively suppresses DSS-induced colitis by attenuating expressions of key inflammatory mediators and found to be an attractive therapeutic drug for treating UC., (© 2019 Wiley Periodicals, Inc.)

Objective: To investigate the influences of probiotics combined with sulfasalazine (SASP) on the expression of the Wnt/β-catenin signaling pathway in rats with ulcerative colitis (UC)., Materials and Methods: A total of 60 clean level and healthy Sprague-Dawley (SD) rats were randomly divided into the normal group, model group, SASP group and combination therapy group, with 15 rats in each group. The rats in the normal group were given normal feeding, and those in the remaining three groups were subjected to the establishment of the UC model. During the modeling, the rats underwent daily gavage and were sacrificed after 4 weeks. Clinical symptoms and pathological changes in ulcer indexes and colon tissues were observed in each group. The expression levels of relative genes in the Wnt/β-catenin signaling pathway were detected by Polymerase Chain Reaction (PCR)., Results: Compared with those in the model group, the pathological sections of rats in the SASP group and combination therapy group showed significant improvement in the inflammatory response. The expression levels of relative genes in the Wnt/β-catenin signaling pathway were downregulated in rats of the SASP group and combination therapy group relative to those in the model group., Conclusions: SASP and probiotics alleviate UC by reducing inflammation by inhibiting the activation of the Wnt/β-catenin signaling pathway, thereby improving intestinal function and restoring the intestinal structure.

Objectives: Mortality in patients with rheumatoid arthritis (RA) is higher than in the general population. We investigated mortality in the COBRA-trial cohort after 23 years follow-up, compared with a reference sample of the Dutch population., Methods: The COBRA-trial randomised patients with early RA to sulfasalazine monotherapy (SSZ, n=79) or a combination of SSZ, low-dose methotrexate and initially high, step-down prednisolone (COBRA, n=76). We compared the mortality in the COBRA-trial up to 2017 to a reference sample of the general population in the Netherlands (standardised mortality ratio, SMR), and its relation to early prognostic factors through stepwise Cox regression., Results: Duration of follow-up in patients alive was mean 23 (range 22-24) years. In total, 44 patients died (28%, SMR=0.80 [95% CI 0.59 to 1.06]); 20 of 75 COBRA patients (27%, SMR 0.75 [0.47 to 1.14]) and 24 of 79 SSZ patients (30%, SMR 0.85 [0.56 to 1.25]); p=0.61). In the reference sample of the general population, 55 people (36%) died. 5 factors were significantly associated with increased mortality hazard: damage progression at 28 weeks; high Health Assessment Questionnaire (HAQ) score and absence of HLA-DR 2 or 3; disease duration from start of complaints was also significant, but showed an uninterpretable pattern., Conclusions: This prospective trial cohort study of early RA is one of the first to show similar mortality compared with the general population after 23 years of follow-up. It confirms that early, intensive treatment of RA has long-term benefits and suggests that treating to target is especially important for patients with poor prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

To test whether sulpiride (SP), an anti-psychotic and prokinetic drug, shows beneficial effects on experimental murine colitis, a colon-targeted prodrug of SP, 5-(aminoethanoylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide (glycylsulpiride (GSP)), was synthesized and its colonic delivery and therapeutic activity against 2,4-dinitrobenzenesulfonic acid (DNBS)-induced rat colitis were assessed. Synthesis of GSP was verified by infrared and proton nuclear magnetic resonance spectroscopy. GSP was converted to SP when incubated with the cecal contents but not when incubated with the small intestinal contents. The percent conversion was about 50.5% at 6 h and 67.7% at 10 h. Colonic delivery of GSP was examined by comparison with sulfasalazine (SSZ), a colon-specific prodrug of 5-aminosalicylic acid currently used for the treatment of inflammatory bowel disease. The two prodrugs accumulated similar concentrations of the corresponding parent drugs in the cecum at 2, 4, and 6 h after oral gavage. Although oral gavage of GSP released millimolar level of SP in the large intestine, SP was hardly detected in the blood. GSP improved colonic damage score and reduced myeloperoxidase activity up to 80.5% in the inflamed colon in a dose-dependent manner. Moreover, GSP was able to reduce the levels of inflammatory mediators in the inflamed colon. Overall, the anti-colitic effectiveness of GSP and SSZ was similar. In conclusion, colonic delivery of SP ameliorates DNBS-induced colitis in rats with no significant systemic absorption of SP. Thus, colon-targeted SP may be therapeutically switched to an anti-colitic drug.

Question: Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)?, Methods: In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease.After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events., Results: 94 children (67 % girls) aged median (IQR) 9.1 (4.6-12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5-12), limited joints 2.5 (1-4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6).After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3-15.0) months in arm 1, 9.0 (6.0-12.8) months in arm 2 and 9.0 (6.0-12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0-6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar., Conclusion: Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to-target is feasible., Trial Registration Number: 1574., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Autocrine and paracrine factors, including glutamate and epidermal growth factor (EGF), are potent inducers of brain tumor cell invasion, a pathological hallmark of malignant gliomas. System xc(-) consists of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. We previously showed that the EGF receptor (EGFR) interacts with xCT and thereby promotes the activity of system xc(-) in a kinase-independent manner, resulting in enhanced glutamate release in glioma cells. However, the molecular mechanism underlying EGFR-mediated glioma progression in a glutamate-rich microenvironment has remained unclear. Here we show that the GluN2B subunit of the N-methyl-d-aspartate-sensitive glutamate receptor (NMDAR) is a substrate of EGFR in glioma cells. In response to EGF stimulation, EGFR phosphorylated the COOH-terminal domain of GluN2B and thereby enhanced glutamate-NMDAR signaling and consequent cell migration in EGFR-overexpressing glioma cells. Treatment with the NMDAR inhibitor MK-801 or the system xc(-) inhibitor sulfasalazine suppressed EGF-elicited glioma cell migration. The administration of sulfasalazine and MK-801 also synergistically suppressed the growth of subcutaneous tumors formed by EGFR-overexpressing glioma cells. Furthermore, shRNA-mediated knockdown of xCT and GluN2B cooperatively prolonged the survival of mice injected intracerebrally with such glioma cells. Our findings thus establish a central role for EGFR in the signaling crosstalk between xCT and GluN2B-containing NMDAR in glioma cells., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The objective of this study was to investigate risk factors for cytopenia when a prophylactic dose of trimethoprim-sulfamethoxazole (TMP-SMX) was co-administered with methotrexate (MTX). Patients who received MTX with or without a prophylactic dose of TMP-SMX were included. Patients who received a therapeutic dose of TMP-SMX were excluded. The MTX-alone and MTX with TMP-SMX groups (MTX group and MTX + TMP-SMX group, respectively) were matched in a 4:1 ratio according to age, creatinine level, mean corpuscular volume and MTX dose. Cytopenia was defined as a haemoglobin level decrease by > 2 g/dl, platelet count of < 150,000/mm 3 or white blood cell count of < 3500/mm 3 . The Cox proportional hazards model was used to evaluate risk factors for cytopenia in patients administered with MTX. The incidence of cytopenia did not significantly differ between the MTX group and MTX + TMP-SMX group (5.0 vs 5.7%, p > 0.999). According to the Cox proportional hazards model, chronic liver disease (hazard ratio [HR] 5.829, 95% confidence interval [CI] 1.211-28.063, p = 0.028) was associated with an increased risk of cytopenia. However, the concomitant use of a prophylactic dose of TMP-SMX (HR 1.717, 95% CI 0.352-8.371, p = 0.504) was not significantly associated with an increased risk of cytopenia. Compared with the use of MTX alone, the concomitant use of MTX with a prophylactic dose of TMP-SMX was not significantly associated with an increased risk of cytopenia. Thus, a prophylactic dose of TMP-SMX can be safely used with MTX.

The aim of this study, was to determine the effect of sulfasalazine for different periods of time reduces disseminated intravascular coagulation, inflammation and organ damages by inhibiting the nuclear factor kappa beta pathway. The study was performed with 30 Wistar albino rats and the groups were established as Control group, LPS group; endotoxemia was induced with LPS, SL5 group: sulfasalazine (300 mg/kg, single dose daily) was administered for 5 days before the LPS-induced endotoxemia, and LS group: sulfasalazine (300 mg/kg, single dose) was administered similtenously with LPS. Hemogram, biochemical, cytokine (IL-1β, IL-6, IL-10, TNF-α) and acute phase proteins (HPT, SAA, PGE2) analyzes and oxidative status values were measured from blood samples at 3 and 6 h after the last applications in the all groups. The rats were euthanized at 6 h and mRNA levels of BCL2 and BAX genes were examined from liver and brain tissues. Sulfasalazine reduced the increased IL-1β, IL-6, TNF-α and PGE 2 levels and significantly increased anti-inflammatory cytokine IL-10 levels. In addition, decreasing of ATIII level was prevented in the SL5 group, and decreasing of fibrinogen levels were prevented in the LS and SL5 groups within first 3 h. In LPS group, leukocyte and thrombocyte levels were decreased, however sulfasalazine application inhibited decreases of leukocyte levels in LS and SL5 groups. In addition, sulfasalazine inhibited the decrease of total antioxidant capacity and unchanged apoptosis in brain and liver. In conclusion, the use of sulfasalazine in different durations reduce the excessive inflammation of endotoxemia cases.

Background/aim: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance., Materials and Methods: The human gastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding human CD44 or CD44v9, which were used for in vitro and in vivo experiments., Results: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells., Conclusion: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To investigate the effect of methotrexate (MTX) or sulfasalazine (SSZ) on the course of HLA-B27-positive, remitting acute anterior uveitis (AAU)., Methods: Forty-six patients with HLA-B27-positive AAU with or without associated systemic rheumatic disease either receiving MTX (n = 20), SSZ (n = 13), or no systemic immunomodulating treatment (Ctrl; n = 13) were studied retrospectively. Best-corrected visual acuity (BCVA), AAU relapse rate, and occurrence of uveitis-related ocular complications were analyzed at baseline (BL) and at 12-month follow-up (FU)., Results: Groups did not differ regarding age, gender, and presence of associated systemic diseases. BCVA at baseline was significantly worse in patients receiving MTX (logMAR 0.39 ± 0.4) than in those treated with SSZ (0.17 ± 0.2; P = 0.05) or in controls (Ctrl; 0.14 ± 0.2; P = 0.009). At the 12-month endpoint, MTX treatment was associated with significantly improved BCVA (0.18 ± 0.4 logMAR; P = 0.004). In contrast, BCVA did not significantly change in patients treated with SSZ (0.17 ± 0.3 logMAR) or in the controls (0.11 ± 0.2 logMAR). The annual uveitis relapse rate significantly decreased with MTX (BL 3.6 ± 2.4 relapses to FU 0.7 ± 0.8; P = 0.0001) and SSZ (BL 3.6 ± 1.9 to FU 1.8 ± 2.4, P < 0.01), but not in the controls (BL 1.9 ± 1.4 vs 1.9 ± 1.7 FU). The complication rate was slightly reduced with MTX (BL 1.75 ± 1.2 complications present versus FU 1.3 ± 1.2, P = 0.09) but not with SSZ (BL 0.9 ± 0.8 to FU 1.3 ± 1.4; P = 0.4) or in the controls (BL and FU 1.0 ± 0.95; P = 0.7)., Conclusions: MTX and SSZ reduced the uveitis relapse rate in HLA-B27-positive AAU patients, with MTX showing a beneficial effect on AAU-related macular edema.

In this study, promising approaches of dual-targeted micelles and drug-polymer conjugation were combined to enable injection of poorly soluble anticancer drugs together with site-specific drug release. Ursodeoxycholic acid (UDCA) as a hepatoprotective agent was grafted to maltodextrin (MD) via carbodiimide coupling to develop amphiphilic maltodextrin-ursodeoxycholic acid (MDCA)-based micelles. Sulfasalazine (SSZ), as a novel anticancer agent, was conjugated via a tumor-cleavable ester bond to MD backbone to obtain tumor-specific release, whereas resveratrol (RSV) was physically entrapped within the hydrophobic micellar core. For maximal tumor-targeting, both folic acid (FA) and lactobionic acid (LA) were coupled to the surface of micelles to obtain dual-targeted micelles. The decrease of critical micelle concentration (CMC) from 0.012 to 0.006 mg/mL declares the significance of a dual hydrophobicized core of micelles by both UDCA and SSZ. The dual-targeted micelles showed a great hemocompatibility, as well as enhanced cytotoxicity and internalization into HepG-2 liver cancer cells via binding to overexpressed folate and asialoglycoprotein receptors. In vivo, the micelles demonstrated superior antitumor effects revealed as reduction in the liver/body weight ratio, inhibition of angiogenesis, and enhanced apoptosis. Overall, combined strategies of dual active targeted micelles with bioresponsive drug conjugation could be utilized as a promising approach for tumor-targeted drug delivery.

Aim: To investigate the effects of hydroxychloroquine, sulfasalazine and methotrexate on ischemic stroke in patients with rheumatoid arthritis (RA)., Methods: This population-based retrospective cohort study included 7904 RA patients and 15 808 non-RA patients between 2000 and 2010. All of the participants were sampled from the National Health Insurance Research Database (NHIRD) of Taiwan. Using univariate analyses, these two groups of patients were compared to evaluate the differences in disease-modifying anti-rheumatic drugs usage and demographic variables. Cox proportional hazard models and Schoenfeld residuals test were performed to estimate the hazard ratios for ischemic stroke and proportional hazard assumptions of these drugs, respectively., Results: The mean age of participants was about 53 years old, and about 70% of RA patients were women. The hazard ratio for ischemic stroke was 1.21 (95% CI: 1.10-1.34; P < 0.01) in the case group compared with the control group, and this significant difference persisted throughout the 10-year period. With respect to RA patients, while hydroxychloroquine showed an insignificant protective effect on ischemic stroke, sulfasalazine and methotrexate were found out to have inconsistent effects during these 10 years. The proportional hazard assumption test of methotrexate at > 0.5 defined daily dose (8.75 mg/week) was violated at a significant level after adjustment (P = 0.0002)., Conclusions: At a dosage of > 0.5 defined daily dose, short-term methotrexate might decrease ischemic stroke risk in RA patients, while hydroxychloroquine and sulfasalazine were neutral., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Competing Interests: Competing interests: None declared.

Competing Interests: Competing interests: None declared.