Search Results (789)

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder primarily targeting joints, leading to pain, swelling, and stiffness. RA results from the body’s own immune system attacking its own tissues. Currently, there are various treatments available for RA including disease-modifying antirheumatic drugs (DMARDs) and NSAIDs. Leflunomide (LEF) is a USFDA-approved synthetic DMARD which is being widely prescribed for the management of RA; however, it faces several challenges such as prolonged drug elimination, hepatotoxicity, and others. LEF exerts its therapeutic effects by inhibiting dihydroorotate dehydrogenase (DHODH), thereby suppressing pyrimidine synthesis and modulating immune responses. Emerging nanotechnology-based therapies help in encountering the current challenges faced in LEF delivery to RA patients. This review enlists the LEF’s pharmacokinetics, mechanism of action, and clinical efficacy in RA management. A comparative analysis with methotrexate, biologics, and other targeted therapies, highlighting its role in monotherapy and combination regimens and the safety concerns, including hepatotoxicity, gastrointestinal effects, and teratogenicity, is discussed alongside recommended monitoring strategies. Additionally, emerging trends in novel formulations and drug delivery approaches are explored to enhance efficacy and minimize adverse effects. Overall, LEF remains a perfect remedy for RA patients, specifically individuals contraindicated with drugs like methotrexate. The therapeutic applicability of LEF could be enhanced by developing more customized treatments and advanced drug delivery approaches. Full article

Background/Objectives: Immune-mediated necrotizing myopathy (IMNM) is a severe inflammatory myopathy marked by proximal muscle weakness, elevated creatine kinase (CK), and the presence of anti-HMGCR antibodies. Statin exposure is a recognized trigger for anti-HMGCR-positive IMNM, which may persist despite statin withdrawal. This pilot case series explores, for the first time, the use of bempedoic acid—a liver-specific lipid-lowering agent with minimal muscle toxicity—as an alternative to statins in these patients. Methods: We report 10 anti-HMGCR-antibody-positive IMNM patients (6 females, 4 males) previously on statins for primary prevention (8 on atorvastatin, 2 on simvastatin) without prior cardiovascular events. Statins were discontinued at myositis onset. All patients received prednisone and immunosuppressants (methotrexate in 7, mycophenolate in 3), plus bempedoic acid. Anti-HMGCR antibodies were measured using a chemiluminescence method. Results: Their mean anti-HMGCR antibody levels decreased significantly from 390.93 ± 275.22 to 220.89 ± 113.37 CU/L (p = 0.027) after 6 months of treatment. Their CK levels dropped from 1278.9 ± 769.39 to 315.1 ± 157.72 IU/L (p = 0.001), and aldolase dropped from 11.63 ± 2.18 to 6.61 ± 1.22 U/L (p = 0.0001). The mean LDL-C value was 96.1 ± 8.16 mg/dL. No disease recurrence was observed. Autoimmune panels were negative for other myositis-associated and/or -specific antibodies. Conclusions: Bempedoic acid appears to be a safe, effective, and cost-efficient lipid-lowering alternative in statin-intolerant IMNM patients. Larger studies are warranted to confirm its efficacy across different subgroups and to optimize dyslipidemia management in this setting. Full article

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms. Full article

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice. Full article

Background: Methotrexate (MTX) remains the most commonly prescribed drug used to treat rheumatoid arthritis (RA). Polymorphisms in solute carrier organic anion transporter family member 1B3 (SLCO1B3) and SLCO1B1 may play a critical role in MTX pharmacokinetics and patient outcomes. However, research on these polymorphisms in Saudi Arabia remains limited. We evaluated the association of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms with MTX efficacy and safety in Saudi patients with RA. Methods: This multicenter, case-control study included patients diagnosed with RA in Jeddah and Taif. Demographic and clinical data were collected and analyzed. Genotyping of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms was performed using Sanger sequencing. Statistical analyses, including logistic regression and haplotype analysis, were conducted to evaluate associations between these polymorphisms, MTX efficacy, and toxicity. Results: The study cohort comprised 100 patients with RA, with 46 showing a good response to MTX and 54 showing a poor response. Clinical predictors of MTX response were significantly higher in patients with poor response. Both SLCO1B3 polymorphisms (rs4149117, rs7311358) were significantly associated with anemia. Significant associations were found between SLCO1B1 (rs2306283) and gastrointestinal disturbances and anemia. The GAAT haplotype was significantly more prevalent among good responders, while the TGGT haplotype was significantly associated with poor responders. Conclusions: These results highlight the importance of genetic testing in predicting MTX treatment outcomes and tailoring personalized treatment plans for patients with RA to improve efficacy and minimize adverse effects. Full article

Background/Objectives: Intramural pregnancy (IMP) is a rare type of ectopic pregnancy where the embryo implants within the uterine myometrium. This condition carries a high risk of massive hemorrhage, uterine rupture, and potentially life-threatening complications. Methods: We present a case of a 35-year-old patient who underwent in vitro fertilization (IVF) and was diagnosed with an IMP located in the back-isthmian portion of the uterus by ultrasound scan. Results: We performed a conservative treatment approach based on the gestational sac location and the patient’s stable clinical condition and desire for future fertility. We first administered mifepristone 600 mg, followed by intracavitary methotrexate under ultrasound guidance. Although originally planned, a uterine artery embolization was not performed due to the evidence of bilateral anastomoses between the uterine and ovarian arteries. Progressive reabsorption of pregnancy was observed over the course of 8 months. Conclusions: Non-surgical management can be considered for IMP, thus allowing fertility preservation. Full article

Lung cancer is one of the most common and deadly forms of cancer worldwide, despite sustained efforts to encourage smoking cessation and raise awareness of the risk factors. In Romania, lung cancer is a significant health challenge, being the leading cause of death caused by cancer, especially amongst men. The incidence of lung cancer in connective tissue disease (CTD) varies in different studies from 4.5% in rheumatoid arthritis (RA), to 4.4% in polymyositis or dermatomyositis, and up to 11.1% in systemic sclerosis. However, older studies have shown an increased risk of cancer in patients with rheumatoid arthritis (RA), ranging from 10% to 30% compared to the general population, particularly in those undergoing methotrexate therapy. Rheumatoid arthritis affects approximately 40 per 100,000 people annually worldwide, with a three- to four-fold higher incidence in women. Non-small cell lung cancer (NSCLC), the most common lung cancer subtype, has been linked to RA, yet the association remains poorly defined, with limited insight into the underlying molecular mechanisms. We present the case of a 61-year-old male with a 49-pack-year smoking history and a known diagnosis of rheumatoid arthritis, currently managed with methotrexate therapy. He was admitted for evaluation due to a progressive decline in general condition, characterized by worsening dyspnea and chest pain, symptoms that had been longstanding but had markedly exacerbated over the past two weeks. Based on a chest CT performed prior to the patient’s admission to our clinic, subsequent diagnostic investigations established the diagnosis of pulmonary adenocarcinoma. The diagnostic process proved to be particularly challenging due to the presence of multiple comorbidities, which significantly impacted both the diagnostic approach and the overall clinical trajectory. Full article

Background: The European League Against Rheumatism (EULAR), in collaboration with the European Scleroderma Trial and Research group (EUSTAR), published the first set of treatment recommendations for systemic sclerosis (SSc) in 2009, with subsequent updates in 2016 and 2023. Objectives: This study aimed to evaluate how rheumatologists’ clinical approaches to the treatment of SSc evolved following the 2016 update of the clinical management guidelines. Methods: Medication use for SSc was analyzed in a cohort of 378 patients. The patients were stratified based on enrollment before (233 patients) and after (145 patients) the guideline update, and medication usage was compared between the two groups. Results: Although all patients presented with Raynaud’s phenomenon (RP), only 35% received calcium channel blockers. Medications such as iloprost, phosphodiesterase type 5 (PDE-5) inhibitors, fluoxetine, and bosentan, recommended for the treatment of RP and digital ulcers, were not approved for SSc by the Republic Health Insurance Fund. Treatment for pulmonary arterial hypertension (PAH) was administered to only 16 patients (4.2%), including 2 who received bosentan, 10 who received PDE-5 inhibitors, and 4 who were treated with riociguat. The use of PDE-5 inhibitors increased following the 2016 update of the guidelines. Cyclophosphamide was consistently prescribed for interstitial lung disease (ILD), with an increased frequency observed after the guideline update. No significant differences were observed in the use of methotrexate for skin involvement, ACE inhibitors for scleroderma renal crisis, or antibiotics for gastrointestinal symptoms. Proton pump inhibitors (PPIs) were prescribed to 87.3% of patients with gastrointestinal involvement, with an increase in use of both PPIs and prokinetic agents following the guideline update. Conclusions: Rheumatologists’ adherence to the EULAR/EUSTAR guidelines varied considerably, with 25% to 100% of eligible patients receiving the recommended treatments. Concordance improved in the management of PAH, ILD, and gastrointestinal involvement after the 2016 guideline update. Full article

Background: Leprosy, caused by Mycobacterium leprae, presents on a spectrum ranging from tuberculoid to lepromatous disease. Borderline lepromatous leprosy represents an unstable immunological state that predisposes patients to immune-mediated reactions, including erythema nodosum leprosum (ENL), a severe inflammatory complication. Case Presentation: We report a case of a 62-year-old female with borderline lepromatous leprosy who presented with recurrent facial cellulitis and later developed disseminated ENL. She was initially diagnosed following a series of facial infections and confirmatory skin biopsy. Months later, she developed systemic inflammatory lesions consistent with ENL, requiring hospitalization. She was treated with high-dose corticosteroids for ENL and methotrexate to treat type 1 reaction and continued multidrug therapy (MDT) with minocycline, rifampin, and clarithromycin for leprosy, which led to significant clinical improvement. Conclusion: This case highlights the diagnostic challenges of leprosy in the United States and the importance of recognizing ENL as a severe immunologic complication requiring prompt intervention. A multidisciplinary approach is essential for optimal patient outcomes. Full article

Pancreatic cancer is one of the most lethal malignancies, in part due to its profound metabolic adaptability, which underlies drug resistance and therapeutic failure. This study explores the metabolic rewiring associated with resistance to treatment using a systems metabolomics approach. Exposure to the redox-disrupting agent erastin revealed key metabolic vulnerabilities but failed to produce lasting growth suppression. Combinatorial treatments with methotrexate or alpelisib significantly impaired proliferation and triggered marked metabolic shifts. Systems-level analyses identified serine metabolism as a central adaptive pathway in resilient cells. Metabolic tracing and gene expression profiling showed increased de novo serine biosynthesis and uptake, supporting redox homeostasis, biosynthetic activity, and epigenetic regulation. Notably, cells that resumed growth after drug withdrawal exhibited transcriptional reprogramming involving serine-driven pathways, along with elevated expression of genes linked to survival, proliferation, and migration. These findings establish serine metabolism as a functional biomarker of metabolic plasticity and adaptive resilience in pancreatic cancer, suggesting that targeting this adaptive axis may enhance therapeutic efficacy. Full article

Primary Sjögren’s syndrome (pSS) exhibits considerable clinical and immunological heterogeneity, complicating personalized management. We aimed to delineate the demographic, functional, serological, histopathological, and therapeutic features of a Romanian pSS cohort and to identify biomarker–treatment correlations that could inform patient-oriented strategies. Thirty-two patients meeting the 2016 ACR/EULAR classification criteria for pSS were retrospectively analyzed. Data collected included demographics, autoantibody profiles (Anti-Ro/SSA, Anti-La/SSB, ANA, RF, Anti-CCP), immunoglobulin levels, complement consumption (C3/C4), minor salivary gland biopsy (focus score), salivary flow tests, and systemic inflammation markers (CRP). Pearson correlation matrices were constructed to explore the associations between serological markers and prescribed therapies. The cohort was predominantly female (87.5%) with a mean age of 52.8 ± 9.9 years. Seropositivity rates were 50% for Anti-Ro/SSA, 77% for Anti-La/SSB, and 40% for ANA. Clinically significant glandular dysfunction was evident in 65% of patients (unstimulated flow ≤ 0.1 mL/min), and all biopsies demonstrated focus scores > 1. Methotrexate use correlated strongly with Anti-Ro/SSA and Anti-La/SSB positivity (p ≤ 0.05), indicating its targeted application in seropositive sub-phenotypes. Conclusion: These findings underscore the immunologic and clinical diversity of pSS and support a biomarker-driven, multidisciplinary framework for personalized treatment. Larger prospective and multicenter studies are warranted to validate these correlations and to refine precision medicine approaches in pSS. Full article

Background: Urticarial vasculitis (UV) is a rare form of small-vessel vasculitis characterized by persistent urticarial lesions and systemic manifestations. It differs from chronic spontaneous urticaria (CSU) both clinically and pathogenetically, often requiring systemic therapy. Despite its complexity, no standardized treatment algorithm exists. Methods: We conducted a retrospective, monocentric, observational study on 11 patients diagnosed with UV at the Dermatology Unit of Tor Vergata University Hospital (Rome) between 2014 and 2024. Demographic, clinical, serological, and therapeutic data were collected from medical records. The therapeutic response was assessed using the Urticaria Control Test (UCT) score. Results: The cohort comprised predominantly women (91%), with a mean age at diagnosis of 52.8 years. Autoimmune thyroiditis was the most frequent comorbidity (64%). Hypocomplementemia was detected in only one patient (9%), who also had systemic lupus erythematosus. Antihistamines, while usually prescribed, showed limited efficacy since none of the patients achieved complete remission with monotherapy. Systemic corticosteroids demonstrated rapid and effective control in acute phases. Omalizumab produced variable responses, with two patients achieving a high response (HR) and one reaching complete remission (CR). Methotrexate and cyclosporine yielded inconsistent outcomes. Due to the heterogeneity and limited sample size, statistical analyses were not performed. Conclusions: UV presents with diverse clinical profiles and therapeutic responses. No treatment proved universally efficacious, but corticosteroids and omalizumab were effective in an acute and maintenance phase, respectively. Our findings underscore the importance of individualized treatment plans and the need for further studies to define predictive biomarkers and therapeutic strategies in UV. Full article

This study describes the synthesis of a series of dideaza analogs of methotrexate and their preliminary pharmacological and metabolic evaluation. The 5,8-dideazamethotrexate was efficiently obtained in five steps using a new synthetic route. Oxygenated and thiolated analogs of dideazamethotrexate were prepared following the devised pathway. Their cytotoxicity was studied in the A549 lung cancer cell line, as well as their DHFR dihydrofolate reductase inhibition activity and in vitro metabolism. The two new analogs showed strong activity on cancer cells and the enzymatic target. These compounds were not metabolized, a clear advantage over methotrexate, which is rapidly converted to the toxic metabolite 7-hydroxymethotrexate. Full article

Background/Objectives: Intrachromosomal amplification of chromosome 21 (iAMP21) represents a rare and heterogeneous distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (ALL) initially associated with a poor prognosis. Treatment intensification with additional doses of methotrexate and asparaginase was associated with better treatment outcomes. Methods: In this retrospective single-center study, we evaluated the impact of iAMP21 on treatment outcome in a cohort of pediatric patients treated with an intensified asparaginase regimen and describe the genomic landscape of four patients with iAMP21. Results: Four out of 89 patients > 1 year old were classified as iAMP21 positive. Five-year event-free survival (EFS) was inferior in the iAMP21-positive group: 25% versus 85.6% (p = 0.001). The cumulative incidence of relapse and treatment-related mortality were 50% vs. 9.9% and 0% vs. 2.38%, respectively, in the iAMP21-positive and non-iAMP21 groups (p = 0.02 and 0.76, respectively). These results did not translate into a significant difference in overall survival: 100% vs. 93.7% (p = 0.6). The presence of iAMP21 (HR 7.68, 95% CI 2.04–29.05; p = 0.002) and a measurable residual disease ≥1% after induction on day +33 (HR 8.82, 95% CI 2.6–29.91; p = 0.001) retained significant negative impact on EFS in multivariate analysis. Conclusions: We found an independent significant prognostic impact of iAMP21 on EFS among pediatric patients with ALL, and clinical presentation and early treatment response did not classify these patients as HR. Diverse genetic backgrounds among iAMP21-positive patients might influence the treatment response and outcome of this heterogeneous disease. Full article

Background: Reports of primary cutaneous lymphomas (CLs) following COVID-19 vaccines are extremely rare. Nevertheless, clinicians should be aware of a potential association between these events. Here, we report a case of the development and rapid progression of mycosis fungoides (MF) with lymph node involvement after COVID-19 vaccination. Case presentation: A 75-year-old female developed disseminated plaques and patches shortly after receiving the first dose of the SARS-CoV-2 mRNA vaccine. Within one month following the second dose of the mRNA vaccine, she additionally experienced rapid progression, leading to the development of tumors and inguinal lymphadenopathy. Blood and visceral involvement were excluded. The clinicopathological findings were consistent with the diagnosis of MF, and systemic methotrexate with topical treatment was implemented, resulting in remission of the lesions. Conclusions: The presented case of the development and rapid progression of MF after the SARS-CoV-2 mRNA vaccine raises the question of the possible immunomodulatory or oncomodulatory effects of mRNA vaccines. It prompted us to conduct a review outlining the mechanisms potentially causing the mRNA vaccine-associated CLs. We have performed an extensive literature search to determine an explanation for the observed phenomenon. Accumulated evidence suggests a link between CL occurrence and immunization with an mRNA vaccine. The proposed hypothesis revolves around shared signaling pathways that are enhanced by SARS-CoV-2 mRNA vaccines, thus driving the pathogenesis of MF. We want to raise clinicians’ attention to the rare side effects of COVID-19 vaccines and emphasize the need for thorough monitoring of patients with altered immunity in the course of various lymphoproliferative disorders. Full article