Macrophage activation syndrome (MAS) is a subtype of haemophagocytic lymphohistiocytosis (HLH), and a well-described complication of systemic juvenile idiopathic arthritis (SJIA), triggered by disease onset or flare, infection, or some medications. Here, we report a 20-year-old man with previously well-controlled SJIA, who developed first time MAS after acute Epstein-Barr virus (EBV) infection, with MAS recurrence due to a drug reaction, '3-week sulfasalazine syndrome', secondary to prophylactic trimethoprim/sulfamethoxazole. Both episodes of MAS were minimally responsive to pulse corticosteroids. Initial EBV-driven MAS was treated with multiple doses of emapalumab prior to resolution, while MAS secondary to sulfasalazine-induced 3-week syndrome required the initiation of ruxolitinib. This case exhibits two rare but life-threatening causes of MAS/secondary HLH in a single patient and the difficulties in their diagnosis and management.

We designed colon-targeted trans-cinnamic acid (tCA) and synthesized its conjugates with glutamic acid (tCA-GA) and aspartic acid (tCA-AA). We evaluated the anti-colitic activity of colon-targeted tCA using a dinitrobenzenesulfonic acid-induced rat colitis model. The conjugates lowered the distribution coefficient and Caco-2 cell permeability of tCA and converted to tCA in the cecum, with higher rates and percentages with tCA-GA than with tCA-AA. Following oral gavage, tCA-GA delivered a higher amount of tCA to the cecum and exhibited better anti-colitic effects than tCA and sulfasalazine (SSZ), which is the current treatment for inflammatory bowel disease. In the cellular assay, tCA acted as a full agonist of GPR109A (EC50: 530 µM). The anti-colitic effects of tCA-GA were significantly compromised by the co-administration of the GPR109A antagonist, mepenzolate. Collectively, colon-targeted tCA potentiated the anti-colitic activity of tCA by effectively activating GPR109A in the inflamed colon, enabling tCA to elicit therapeutic superiority over SSZ.

Thyme (Thymus vulgaris L.) is an important medicinal and edible homologous plant, and the composition and bioactivity of its polyphenol extracts have attracted widespread attention from researchers. In this study, the polyphenols in thyme were separated and identified by UPLC/MS-MS and UPLC-DAD, and the intervention effect and mechanism of thyme polyphenols (TP) on ulcerative colitis (UC) were analyzed in combination with dextran sulfate sodium salt (DSS)-induced mice colitis model. It was found that the main substances of TP were scutellarin (160.68 ± 2.09 mg g-1), rosmarinic acid (80.33 ± 1.74 mg g-1), scutellarein (56.53 ± 1.32 mg g-1), apigenin-7-O-glucuronide (21.06 ± 0.68 mg g-1), gallic acid (13.80 ± 0.73 mg g-1), and ferulic acid (12.00 ± 0.20 mg g-1). TP and sulfasalazine, which were respectively supplemented to these experimental mice at 200 mg per kg bw and 100 mg per kg bw, showed similar effects on alleviating intestinal inflammation, as indicated by the consistency of the decreased NLRP3 and TLR4 proteins and inhibited pro-inflammatory cytokine secretion in NF-κB inflammatory signaling pathway. Furthermore, the treatment with TP at doses of 200 and 400 mg per kg bw both effectively upregulated tight junction protein expression and enhanced intestinal epithelial cell integrity. Consistently, the abundany of probiotics including Blautia, Bacteroides, Romboutsia, and Faecalibaculum associated with the synthesis of short chain fatty acids (SCFAs) were elevated, whereas harmful bacteria including Escherichia Shigella, Muribaculum, and Clostridium sensu stricto 1 associated with the inflammatory process were significantly inhibited. Notably, TP supplemented at the dose of 100 mg per kg bw showed weak mitigated effects on the above symptoms, while the other two TP experimental groups showed similar promising therapeutic potential, suggesting that such beneficial effects required a certain dose of TP to be achieved. These results indicated that TP could suppress the TLR4/NLRP3-NF-κB inflammasome pathways, protect the intestinal epithelial barrier, and remodel the disordered gut microbiota, which suggested that TP might be a promising dietary strategy for UC.

Under a pH value lower than the pKa of adenine (3.5), adenine-rich sequences (A-strand) form a unique parallel A-motif duplex due to the protonation of A-strand. At a pH above 3.5, deprotonation of adenines leads to the dissolution of A-motif duplex to A-strand single coil. This pH-reconfigurable A-motif duplex has been developed as a novel pH-responsive DNA hydrogel, termed A-hydrogel. The hydrogel state is achieved at pH 1.2 by the A-motif duplex bridging units, which are cross-linked by both reverse Hoogsteen interaction and electrostatic attraction. Hydrogel-to-solution transition is triggered by pH 4.3 due to the deprotonation-induced separation of A-motif duplex. The A-hydrogel system undergoes reversible hydrogel-solution transitions by subjecting the system to cyclic pH shifts between 1.2 and 4.3. An anti-inflammatory medicine, sulfasalazine (SSZ), which intercalates into A-motif duplex, is loaded into A-hydrogel. Its pH-controlled release from A-hydrogel is successfully demonstrated. The strong acid-induced A-hydrogel may fill the gap that other mild acid-responsive DNA hydrogels cannot do, such as protection of orally delivered drug in hostile stomach environment against strong acid (pH ~ 1.2) and digestive enzymes.

The necessity of colon-specific drug delivery systems has been well recognized. Porous silica (PSi) coated with a pH-sensitive, biocompatible, and biodegradable polymer can be useful in colon delivery. In this study, porous silica was synthesized and sulfasalazine was loaded into it to investigate the release rate in a simulated intestinal media. The media was kept at 37 °C and pH 6.8 and 7.4, and subjected to continuous ultrasonic waves to simulate body fluid flow. Aqueous alginate and N, O-Carboxymethyl chitosan (NOCC) solutions, with a distinct composition (3% W/V) in different ratios, were prepared and coated on pressed porous silica disks. Porous silica (PSi) was also functionalized by aminopropyltrimethoxysilane grafting and was studied as a potential carrier for the controlled drug release of sulfasalazine. The release was studied in simulated gastric and intestinal media and results show that no burst release occurred in both coated and functionalized samples and the swelling degree of coats at basic and neutral media decreased by the presence of alginate in the network. It is concluded that the coat with a 50:50 ratio can release the colon drugs in 24 h at a suitable rate. It is also envisioned that functionalization was a factor boosting drug uptake, however, the release rate was lower in the functionalized samples. This study opens the gates to new ideas for the potential safe and localized delivery of sulfasalazine.

The reaction between hydroxyl radical (·OH) and cysteine (Cys) plays an important role in the redox balance of living cells. A deeper insight into this intracellular reaction modulation and process is necessary and draws great interest. A highly effective technique consists of the real-time visualization of the two bioactive species and the perception of their respective changes by using a fluorescent probe. In this study, a dual-site chemosensor SPI based on phenothiazine-cyanine was developed, which realized quantitative detection and real-time imaging of ·OH and Cys at their own fluorescence channels (·OH: λex = 485 nm, λem = 608 nm; Cys: λex = 426 nm, λem = 538 nm) without spectral crosstalk. The fluorescent sensor showed excellent anti-interference and selectivity for common biological substances, apart from the successful imaging of exogenous and endogenous ·OH and Cys. We further visualized the redox dynamic reaction and explored the correlation of ·OH and Cys generated by different inhibitors (sulfasalazine and (1S, 3R)-RSL3). Notably, the chemosensor also possesses the capacity to clearly monitor ·OH and Cys in living mice and zebrafish. This study reports on the first chemosensor to investigate the process of intracellular redox modulation and control between ·OH and Cys, which show potential to further explore some metabolic and physiological mechanisms.

Rheumatoid arthritis is a progressive, chronic, immunological, and inflammatory disorder that is distinguished by joint inflammation, joint tenderness, and synovial joint destruction. The study aimed to fabricate sulfasalazine-loaded solid lipid nanoparticle (SLN)-based gels for rheumatoid arthritis management. The SLNs were fabricated with the melt emulsification technique by employing central composite design (CCD) for SLNs optimization. The optimized formulation of SLNs (FF-1) showed particle size and drug entrapment efficiency of 117.25 nm ± 1.67 and 94.05% ± 1.05, respectively. To scrutinize the outcome of the independent variable on responses; model graphs and the polynomial equation obtained from the Design-Expert were used. The surface morphology studies of SLNs revealed a smooth surface with a slightly asymmetric shape. In vitro drug release of the optimized formulation (FF1) had shown a maximum release of up to ~ 91.89% ± 2.12 over 24 h. The optimized FF1 formulation was subsequently gelled using 1% w/v Carbopol 934 and subjected to ex vivo permeation that displayed 8.01 mg/cm2 ± 0.24 and 7.49 mg/cm2 ± 0.86 amount of drug permeated up to 24 h and 10 h from SLNs gel and plain gel, respectively. In vivo studies manifested a considerable reduction in the paw thickness (*p < 0.0001) and an arthritic score (*p < 0.0001) of the sulfasalazine SLN gel as compared to plain gel. Further, pro-inflammatory cytokines, viz. TNF-α, IL-1, and IL-6 levels, were significantly inhibited (p < 0.0001) by sulfasalazine SLN-based gel that exhibited substantial anti-inflammatory effects. In conclusion, sulfasalazine-loaded SLN-based gel showed sustained release of drug for up to 24 h and can be considered suitable as a topical application for rheumatoid arthritis management.

A female 17-year-old diagnosed with seronegative spondyloarthritis (SpA) following the first jab of the BioNTech162b2 (BNT162b2) vaccine presented with recurrent swelling and painful knee accompanied by posterior heel tenderness over the past 1.5 months. Laboratory investigations revealed elevated serum erythrocyte sedimentation rate and C-reactive protein. Synovial aspiration yielded level 3 crystal-free, aseptic and inflammatory effusion. She tested positive for the human leukocyte antigen-B27 and was diagnosed with peripheral SpA. She received daily celecoxib (400 mg), methylprednisolone (8 mg), and sulfasalazine (2 g), but the effect was limited. Nonetheless, her symptoms improved significantly with weekly subcutaneous etanercept administration (50 mg). Four weeks later, her arthritis was completely resolved. To our knowledge, this is the first case report of newly diagnosed seronegative peripheral SpA in an autoimmunity-disease-free individual following messenger RNA BNT coronavirus disease 2019 vaccination.

Chronic kidney disease (CKD) affects kidney cancer patients' mortality. However, the underlying mechanism remains unknown. M2-like macrophages have pro-tumor functions, also exist in injured kidney, and promote kidney fibrosis. Thus, it is suspected that M2-like macrophages in injured kidney induce the pro-tumor microenvironment leading to kidney cancer progression. We found that M2-like macrophages present in the injured kidney promoted kidney cancer progression and induced resistance to anti-PD1 antibody through its pro-tumor function and inhibition of CD8+ T cell infiltration. RNA-seq revealed Slc7a11 was upregulated in M2-like macrophages. Inhibition of Slc7a11 with sulfasalazine inhibited the pro-tumor function of M2-like macrophages and synergized with anti-PD1 antibody. Moreover, SLC7A11-positive macrophages were associated with poor prognosis among kidney cancer patients. Collectively, this study dissects the characteristic microenvironment in the injured kidney that contributed to kidney cancer progression and anti-PD1 antibody resistance. This insight offers promising combination therapy with anti-PD1 antibody and macrophage targeted therapy.

Linear IgA bullous disease (LABD) is a rare, acquired, autoimmune, pruritic, and blistering skin condition. Dapsone is a first line treatment option, however, there are limited options if this fails, or if contraindicated. We present a case of successful management of LABD with sulfasalazine. A 46-year-old Caucasian female with LABD was commenced on high dose corticosteroids. She failed to wean, and dapsone was contraindicated due to a history of primary sclerosing cholangitis and risk of hepatitis. Following the failure of mycophenolate mofetil, sulfasalazine was trialed and successfully controlled both this patient&rsquo;s LABD and ulcerative colitis. There is little literature on the use of sulfasalazine in dermatological conditions. We present sulfasalazine as an option for patients who are unable to use classically used treatments for LABD, or in those who have a dual diagnosis, as in this case, allowing for one agent to manage both conditions. Furthermore, The National Institute for Health and Care Excellence guidance mentions sulfasalazine as one of the few drugs that can be continued during the COVID-19 pandemic, and its use spared this patient from the significant immunosuppression associated with other treatment modalities.J Drugs Dermatol. 2022;21(12): doi:10.36849/JDD.6717.

The impact of the COVID-19 pandemic on the incidence and management of inflammatory arthritis is not understood. Routinely captured data in secure platforms, such as OpenSAFELY, offer unique opportunities to understand how care for patients with inflammatory arthritis was impacted upon by the pandemic. Our objective was to use OpenSAFELY to assess the effects of the pandemic on diagnostic incidence and care delivery for inflammatory arthritis in England and to replicate key metrics from the National Early Inflammatory Arthritis Audit.

Sulfasalazine and its active metabolite mesalamine are poorly excreted into breastmilk. However, rather high levels of the mesalamine metabolite N-acetyl-5-ASA appear in breastmilk and its effects on breastfed infants are unknown. Another sulfasalazine metabolite, sulfapyridine, also appears in milk and infant serum and might cause hemolysis, especially in newborn infants and in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The time of greatest risk for hemolysis in fullterm newborns without G6PD deficiency might be as short as 8 days after birth.[1] Bloody diarrhea has occurred in an infant whose mother was taking sulfasalazine and a few cases of diarrhea have been reported in infants exposed to mesalamine in breastmilk, although the rate is not high. Most experts consider mesalamine derivatives to be safe during breastfeeding.[2-7] If sulfasalazine is required by the mother, it is not a reason to discontinue breastfeeding, but carefully observe breastfed infants for diarrhea. Other mesalamine derivatives that do not contain a sulfonamide are preferred.

Glioma is the most common primary brain tumor, with a high rate of recurrence and treatment resistance. Glioblastoma is highly invasive, infiltrating surrounding brain parenchyma, and is known to cause intracranial metastasis resulting in a dismal prognosis. Hypoxia contributes significantly to chemo- and radiotherapy resistance in cancer. Ferroptosis is a nonapoptotic oxidative cell death that has been identified as a potential anticancer mechanism. Sulfasalazine (SAS) activates ferroptosis and plays a potential role in tumor treatment. However, the relationship between hypoxia and SAS resistance has not been elucidated. This study is aimed at investigating the role of hypoxia in SAS-induced ferroptosis and the underlying mechanisms. Here, we found that hypoxia significantly suppressed SAS-induced ferroptosis by upregulating SLC7A11 expression in the U87 and U251 glioma cell lines. Hypoxia promotes SLC7A11 expression by enhancing the PI3K/AKT/HIF-1α pathway. The AKT inhibitor MK-2206 and HIF-1α inhibitor PX-478 significantly reversed this effect. In addition, under normoxia, PX-478 induced a higher lipid peroxidation level by decreasing SLC7A11 expression in the U87 and U251 cells but could not induce cell death directly; it could significantly enhance the tumor cell killing effect of SAS. In vivo, the combination of PX-478 and SAS had a coordinated synergistic effect on anticancer activity, as revealed by subcutaneous and orthotopic xenograft mouse models. In conclusion, hypoxia enhanced glioma resistance to SAS-induced ferroptosis by upregulating SLC7A11 via activating the PI3K/AKT/HIF-1α axis. Combination therapy with PX-478 and SAS may be a potential strategy against glioma.