Rheumatoid arthritis (RA), an autoimmune disease, is characterized by inflammatory cell infiltration that damages cartilage, disrupts bone, and impairs joint function. The therapeutic efficacy of RA treatments with the severely affected side remains unsatisfactory despite current treatment methods that primarily focus on anti-inflammatory activity, largely because of the complicatedly pathological mechanisms. A recently identified mechanism for RA development involves the interaction of RA autoantibodies with various proinflammatory cytokines to facilitate the formation of neutrophil extracellular traps (NETs), which increased inflammatory responses to express inflammatory cytokines and chemokines. Therefore, NETs architecture digestion may inhibit the positive-feedback inflammatory signal pathway and lessen joint damage in RA. In this work, deoxyribonuclease I (DNase) is connected to oxidized hyaluronic acid (OHA) via Schiff base reaction to extend the half-life of DNase. The modification does not influence the DNase activity for plasmid deoxyribonucleic acid hydrolysis and NETs' architecture disruption. Carboxymethyl chitosan is crosslinked with DNase-functionalised OHA (DHA) to form an injectable, degradable, and biocompatible hydrogel (DHY) to further strengthen the adhesive capability of DHA. Importantly, the collagen-induced arthritis model demonstrates that intra-articular injection of DHY can significantly reduce inflammatory cytokine expression and alleviate RA symptoms, which can be significantly improved by combining methotrexate. Here, a DNase-functionalised hydrogel has been developed for RA treatment by constantly degrading the novel drug target of NETs to decrease inflammatory response in RA.

Chemodynamic therapy (CDT) reflects a novel reactive oxygen species (ROS)-related cancer therapeutic approach. However, CDT monotherapy is often limited by weak efficacy and insufficient endogenous H2O2. Herein, a multifunctional combined bioreactor (MnFe-LDH/MTX@GOx@Ta, MMGT) relying on MnFe-layered double hydroxide (MnFe-LDH) loaded with methotrexate (MTX) and coated with glucose oxidase (GOx)/tannin acid (Ta) is established for applications in H2O2 self-supply and photothermal enhanced chemo/chemodynamic combined therapy along with photothermal (PT) /magnetic resonance (MR) dual-modality imaging ability for cancer treatment. Once internalized into tumor cells, MMGT achieves starvation therapy by catalyzing the oxidation of glucose with GOx, accompanied by the regeneration of H2O2, enabling a Fenton-like reaction to accomplish GOx catalytic amplified CDT. Moreover, MMGT manifests significant tumor-killing ability through improved CDT performance with outstanding photothermal conversion efficiency (η = 52.2%) under 808 nm laser irradiation. In addition, the release of Mn2+ from MnFe-LDH in a solid tumor can significantly enhance T1-contrast MR imaging signals. Combined with MnFe-LDH-induced PT imaging under 808 nm laser irradiation, a dual-modality imaging directed theranostic nanoplatform has been developed. The present study provides a new strategy to design H2O2 self-supply and ROS evolving NIR light-absorption theranostic nanoagent for highly efficient and combined chemo/chemodynamic cancer treatment.

This paper summarizes the case of a patient admitted to the hospital due to methotrexate-induced colitis in the setting of pancytopenia. Although methotrexate is commonly used for a variety of diseases, this medication can precipitate side effects in a subset of patients. This is an atypical case of chronic low-dose methotrexate use leading to colitis and pancytopenia. It is of utmost significance to monitor patients on methotrexate through routine laboratory checks such as complete blood counts and liver function tests to ensure safety and reduce mortality.

Nonsteroidal topicals and systemic therapies are often utilized for atopic dermatitis (AD) in children with inadequate response to topical corticosteroids. We sought to characterize patient factors associated with prescriptions for nonsteroidal topical (tacrolimus, pimecrolimus, crisaborole), systemic immunosuppressant (methotrexate, mycophenolate, cyclosporine, azathioprine), and systemic corticosteroid therapy among children with AD. In a cross-sectional study of patients <18 years old with AD seen at a large children's hospital between 2009 and 2017, we found that nonsteroidal topical and systemic medication prescriptions were associated with older age of the patient, male sex, comorbid atopy, greater healthcare utilization, specialist care, and race/ethnicity. Compared to White patients, Black and Hispanic patients were less likely to be prescribed nonsteroidal topicals and non-White patients were less likely to be prescribed systemic medications, suggesting that further examination of potential disparities in pediatric AD treatment is needed.

Chemoradiotherapy is frequently used to treat cancer. Stereotactic body radiotherapy (SBRT) is a single high-dose radiotherapy used to treat a variety of cancers. The anticancer drug methotrexate (MTX) shows affinity for solute carrier (SLC) and ATP-binding cassette (ABC) transporters. This study investigated relationships between accumulation of methotrexate and gene expression levels of solute carrier and ATP-binding cassette transporters in cancer cells after a single and high-dose X-ray irradiation. Cancer cell lines were selected from lung and cervical cancer cell line that are commonly used for stereotactic body radiotherapy and effective with methotrexate. We examined expression levels of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP1B7, and organic anion transporter (OAT)1 as solute carrier transporters and multidrug resistance-associated protein (MRP)1 and MRP2 as ATP-binding cassette transporters, using real-time polymerase chain reaction and accumulation of 3H-MTX in cancer cells after 10-Gy irradiation, assuming stereotactic body radiotherapy. Cells were divided into three groups: Control without irradiation; 4 h after irradiation; and 24 h after irradiation. In control, gene expression levels of OAT1 in all cells was below the limit of measurement. After irradiation, gene expression levels of OATP1B1/1B3/1B7 showed changes in each cell line. Gene expression levels of MRP1/2 tended to increase after irradiation. Gene expression levels of OATP1B1/1B3/1B7 were much lower than those of MRP1/2. Accumulation of 3H-MTX tended to decrease over time after irradiation. Irradiation of cancer cells thus alters gene expression levels of both solute carrier transporters (OATP1B1/1B3/1B7) and ABC transporters (MRP1/2) and decreases accumulation of 3H-MTX in cancer cells over time due to elevated expression of MRP1/2.

Primary cranial vault lymphoma (PCVL) is a rare lymphoma involving the skull with or without extra- and intracranial extension. Most cases of PCVL are diffuse large B-cell lymphoma (DLBCL). We report a case of primary cranial vault diffuse large B-cell lymphoma (PCV-DLBCL) that was successfully treated with anthracycline-based chemoimmunotherapy (CIT) alternating with central nervous system (CNS)-directed CIT with high-dose methotrexate and high-dose cytarabine. CNS-centric therapy was given for suspected cerebral cortical involvement and presumed elevated risk of CNS recurrence. The patient has remained in complete remission for 4.25 years following treatment. We suggest that PCV-DLBCL is potentially curable with CNS-directed therapy. Additionally, we provide genomic profiling results indicating an indeterminate cell of origin and multiple genetic mutations which are not frequently seen in DLBCL.

Rectal Ectopic Pregnancy (REP) is one of the most extremely rare forms of ectopic pregnancy which strongly leads to maternal mortality higher than common types. An early diagnosis of unruptured REP remains a challenge and its management ought to be individualized depending on the clinical scenario. Currently, due to the paucity of data, there are no practical guidelines for an appropriate treatment until today. We hereby present a very unusual case at our maternity care center. A 30 year-old pregnant woman (G2P2) complained with abdominal pain and retard menstrual cycle. Following serum beta-human chorionic gonadotropin (β-hCG) levels and ultrasonic exams, a diagnosis of ovarian ectopic pregnancy was established. Thus, the patient underwent explanatory laparoscopy for confirming the diagnosis and for the treatment. However, on the 5th day-postoperative course, her β-hCG level continued to increase every 48 hours. By magnetic resonance imaging and pelvic ultrasonography, a gestational sac adherent to the rectal wall was clearly detected. After counselling with multidisciplinary team, a minimally invasive laparoscopy followed by a local injection of methotrexate under ultrasound guidance for gestational sac access and a systemic multidose methotrexate regimen were indicated. In result, her serum β-hCG declined substantially. Although it is very rare, extra-uterine pregnancy involving the rectum may be presented. Early diagnosis helps in avoiding the fatal complications and a proper management should be counseled carefully. Conservative treatment with minimally surgical intervention could be an alternative option in appropriate condition. Further data is required to summarize this occult entity.

A 79-year-old woman presented with vomiting after being prescribed amenamevir by her primary care physician. She had a medical history of rheumatoid arthritis and was administered prednisolone and methotrexate. She was finally diagnosed with herpes zoster ophthalmicus and aseptic meningitis, and intravenous antiviral therapy was initiated. However, the patient developed oculomotor nerve palsy on the 11th day of hospitalization. In this case, there was a time lag between the administration of antiviral drugs and clinical improvement. Our case suggests the necessity of selecting antivirals, especially in high-risk cases of CNS complications, to avoid the low intracerebral transferability of antiviral drugs, including amenamevir.

Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case control genome-wide association study to explore genetic risk factors associated with MTX DILI. Seven international groups contributed blood samples and data of rheumatoid arthritis patients who used MTX. MTX-induced DILI was defined as an ALT level of at least 3X the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above 2X ULN. Per study site, control and MTX DILI patients (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000Genomes reference panel. SNPs were analyzed using an additive genetic model, corrected for sex, country, and age. A p-value of ≤5x10-8 was considered significant, while a p-value of ≤5x10-6 was considered suggestive. A total of 104 MTX-induced DILI cases and 315 controls were included for association analysis. None of the SNPs were significantly associated with MTX DILI. However, we found seven suggestive genetic variants associated with MTX DILI (p-value 7.43*10-8 to 4.86*10-6). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133) and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, while suggestive SNPs need further investigation.

Mercaptopurine (6MP) and methotrexate are the cornerstones of maintenance therapy in pediatric patients with acute lymphoblastic leukemia. However, although bone marrow suppression and liver dysfunction are common side effects of these antimetabolites, 6MP-induced hypoglycemia during the maintenance phase is rare. Guidelines and international protocols are well established for the management of bone marrow suppression and liver dysfunction, but promptly identifying 6MP-induced hypoglycemia is the key to its control. Here we report 2 cases of leukemia that developed hypoglycemia during the maintenance phase. Both patients were boys younger than 6 years of age and both suffered symptomatic morning hypoglycemia induced by 6MP (which was diagnosed after excluding all other possible causes). Successful management included changing the time of 6MP administration from evening to morning. Other management options are also discussed.

A 73-year-old female patient, affected by mycosis fungoides (MF), discontinued mogamulizumab, after initial clinical benefit, due to the onset of generalized erythema. Follow-up positron emission computed tomography (PET/CTs) carried out at 3 weeks and 6 months after therapy discontinuation showed, with respect to baseline PET/CT scan, a progressively increasing number of hypermetabolic enlarged lymph nodes suspected for a neoplastic involvement, but with histology indicative of an inflammatory reaction. After sequential therapy with corticosteroids and methotrexate, a complete remission was registered at 18F-fluorodeoxyglucose ([18F]FDG) PET/CT performed at 12 months after mogamulizumab interruption. The case we describe highlights the usefulness of serial examinations with [18F]FDG PET/CT in an MF patient presenting an unusual adverse reaction to mogamulizumab.

Atopic dermatitis (AD) is an inflammatory disease affecting over 20% of the pediatric population, with 85% of cases presenting before the age of five. Recently, therapeutic options in pediatric patients have evolved rapidly, following extensive development in adult treatments.

Vogt-Koyanagi-Harada disease is a multisystem autoimmune inflammatory disorder that affects the eyes, ears, skin, and the nervous system. It is a rare disease that mainly affects Asian, Hispanic, and Middle Eastern populations. Systemic steroids and immunosuppressants are frequently used to treat autoimmune diseases like this. Despite the fact that they reduce morbidity, immunosuppressants can have a number of side effects and are difficult to use, particularly when treating uncommon autoimmune illnesses. We present a case of a 56-year-old man who visited our health facility complaining of increased tears in both eyes along with bilateral blurring of vision. He was subsequently identified as having Vogt-Koyanagi-Harada disease. After prednisolone and methotrexate failed to have the desired effect, he was treated with azathioprine, which caused pancytopenia, and manifested as fever with positive blood culture for a coagulase-negative staphylococcus infection.

BACKGROUND Amyloid light-chain (AL) amyloidosis is usually due to deposition of immunoglobulin lambda light chains from plasma cells in patients with multiple myeloma. AL amyloid may involve the salivary glands, gastrointestinal tract, peripheral nerves, and skin. However, musculoskeletal amyloid and amyloid arthropathy are rare. This report is of a woman with bilateral upper limb musculoskeletal amyloid and amyloid arthropathy associated with multiple myeloma, initially diagnosed and managed as a case of rheumatoid arthritis. CASE REPORT A 59-year-old woman who was initially diagnosed with rheumatoid arthritis presented with bilateral polyarthritis in the upper limbs. Despite treatment with corticosteroids, methotrexate, and hydroxychloroquine, her symptoms did not improve. After 4 months, she revisited our hospital with the appearance of swollen soft tissue in the upper right arm and numbness of the right hand. She had an arthroscopic synovectomy of the right shoulder joint, and the mass in the right elbow area was removed. These specimens were positive by Congo red stain and confirmed the deposition of light chain protein as amyloid. She was diagnosed with multiple myeloma according to International Myeloma Working Group criteria, including bone marrow plasma cells more the 10%, lytic lesions in bone, and anemia. CONCLUSIONS This report highlights the importance of imaging, biopsy, and laboratory investigations in patients with arthropathy and musculoskeletal disease. In this case, the patient was seronegative for rheumatoid arthritis, and the presentation with very thick and nodular synovium supported an alternative diagnosis. The identification of musculoskeletal amyloid and amyloid arthropathy confirmed underlying multiple myeloma.

The poor cancer immunotherapy outcome has been closely related to immunosuppressive tumor microenvironment (TME), which usually inactivates the antitumor immune cells and leads to immune tolerance. Metalloimmunotherapy by supplementing nutritional metal ions into TME has emerged as a potential strategy to activate the tumor-resident immune cells. Herein, we engineered a magnesium-contained nano-aluminum adjuvant (NanoAlum) through hydrolyzing a mixture of Mg(OH)2 and Al(OH)3, which has highly similar components to commercial Imject Alum. Peritumoral injection of NanoAlum effectively neutralized the acidic TME while releasing Mg2+ to activate the tumor-resident T cells. Meanwhile, NanoAlum also blocked the autophagy pathway in tumor cells and subsequently induced cell apoptosis. The in vivo studies showed that merely peritumoral injection of NanoAlum successfully inhibited the growth of solid tumors in mice. On this basis, NanoAlum combined with chemical drug methotrexate or immunomodulatory adjuvant CpG further induced potent antigen-specific antitumor immunity. Overall, our study first provides a rational design for engineering tumor-targeted nanomodulator from clinical adjuvants to achieve effective cancer metalloimmunotherapy against solid tumors.