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The Journal of Dermatological Treatment Dec 2023Limited information exists on the risk of adverse events (AEs) attributed to methotrexate (MTX) and biologics for the treatment of psoriasis/psoriatic arthritis... (Observational Study)
Observational Study
Limited information exists on the risk of adverse events (AEs) attributed to methotrexate (MTX) and biologics for the treatment of psoriasis/psoriatic arthritis (PsA/PsO) in heterogeneous clinical practice and beyond the duration of clinical trials. An observational study of 6294 adults with incident PsA/PsO who initiated MTX or biologics in Stockholm from 2006-2021 was conducted. The risk of kidney, liver, hematological, serious infectious, and major gastrointestinal AEs was quantified and compared between therapies using incidence rates, absolute risks, and adjusted hazard ratios (HRs) from propensity-score weighted Cox regression. Median follow-up was 4.3 (2-7) years. Users of MTX had a higher risk of anemia (HR 1.79 [95% CI, 1.48-2.16]), particularly mild-moderate anemias (1.93;1.49-2.50), and mild (1.46;1.03-2.06) and moderate-severe liver AEs (2.22;1.19-4.15) compared to biologics. Chronic kidney disease incidence did not differ between therapies (affecting 1.5% of the population in 5 years; HR:1.03;0.48-2.22). Acute kidney injury, serious infections, and major gastrointestinal AEs showed low absolute risks and no clinically meaningful differences between both therapies. The use of MTX for psoriasis patients in routine care was associated with a higher risk of anemia and liver AEs than biologics, but similar risks of kidney, serious infections, and major gastrointestinal AEs.
Topics: Adult; Humans; Methotrexate; Biological Products; Arthritis, Psoriatic; Psoriasis; Cognition
PubMed: 37246910
DOI: 10.1080/09546634.2023.2215354 -
Journal Der Deutschen Dermatologischen... Apr 2024The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoS represents a spectrum of sclerotic skin diseases in which, depending...
The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoS represents a spectrum of sclerotic skin diseases in which, depending on the subtype and localisation, structures such as adipose tissue, muscles, joints, and bones may also be affected. Involvement of internal organs or progression to systemic sclerosis does not occur. LoS can be classified into four main forms: limited, generalized, linear, and mixed forms, with some additional subtypes. For cases of limited skin involvement, the guideline primarily recommends therapy with topical corticosteroids. UV therapy can also be recommended. In subtypes with severe skin or musculoskeletal involvement, systemic therapy with methotrexate is recommended. During the active phase of the disease, systemic glucocorticosteroids can be used additionally. In cases of methotrexate and steroid refractory courses, contraindications, or intolerance, mycophenolate mofetil, mycophenolic acid, or abatacept can be considered as second-line systemic therapies. In the case of linear LoS, autologous adipose-derived stem cell transplantation can also be performed for correcting soft tissue defects.
Topics: Humans; Methotrexate; Scleroderma, Localized; Skin; Dermatologic Agents; Mycophenolic Acid
PubMed: 38426689
DOI: 10.1111/ddg.15328 -
Advances in Rheumatology (London,... Jul 2023Our aim was to compare the efficacy of rituximab, tocilizumab, and abatacept in individuals with rheumatoid arthritis (RA) refractory to treatments with MTX or TNFi... (Meta-Analysis)
Meta-Analysis
Compared efficacy of rituximab, abatacept, and tocilizumab in patients with rheumatoid arthritis refractory to methotrexate or TNF inhibitors agents: a systematic review and network meta-analysis.
BACKGROUND
Our aim was to compare the efficacy of rituximab, tocilizumab, and abatacept in individuals with rheumatoid arthritis (RA) refractory to treatments with MTX or TNFi agents.
METHODS
We searched 6 databases until January 2023 for phase 2-4 RCTs evaluating patients with RA refractory to MTX or TNFi therapy treated with rituximab, abatacept, and tocilizumab (intervention arm) compared to controls. Study data were independently assessed by two investigators. The primary outcome was considered as achieving ACR70 response.
RESULTS
The meta-analysis included 19 RCTs, with 7,835 patients and a mean study duration of 1.2 years. Hazard ratios for achieving an ACR70 response at six months were not different among the bDMARDs, however, we found high heterogeneity. Three factors showing a critical imbalance among the bDMARD classes were identified: baseline HAQ score, study duration, and frequency of TNFi treatment in control arm. Multivariate meta-regression adjusted to these three factors were conducted for the relative risk (RR) for ACR70. Thus, heterogeneity was attenuated (I2 = 24%) and the explanatory power of the model increased (R2 = 85%). In this model, rituximab did not modify the chance of achieving an ACR70 response compared to abatacept (RR = 1.773, 95%CI 0.113-10.21, p = 0.765). In contrast, abatacept was associated with RR = 2.217 (95%CI 1.554-3.161, p < 0.001) for ACR70 compared to tocilizumab.
CONCLUSION
We found high heterogeneity among studies comparing rituximab, abatacept, and tocilizumab. On multivariate metaregressions, if the conditions of the RCTs were similar, we estimate that abatacept could increase the chance of reaching an ACR70 response by 2.2-fold compared to tocilizumab.
Topics: Humans; Abatacept; Rituximab; Methotrexate; Tumor Necrosis Factor Inhibitors; Antirheumatic Agents; Network Meta-Analysis; Arthritis, Rheumatoid
PubMed: 37415193
DOI: 10.1186/s42358-023-00298-z -
Journal of the European Academy of... Mar 2024Evidence on the (long-term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real-world data is sparse. (Observational Study)
Observational Study
Real-world reported adverse events related to systemic immunomodulating therapy in patients with atopic dermatitis: Results from the TREAT NL (TREatment of ATopic eczema, the Netherlands) registry.
BACKGROUND
Evidence on the (long-term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real-world data is sparse.
OBJECTIVES
To describe real-world reported adverse drug reactions (AEs) related to systemic immunomodulating therapy in patients with AD and to compare the incidence rates of AEs with the Summaries of Product Characteristics (SmPCs).
METHODS
We conducted an observational prospective multi-centre cohort study, using the TREAT NL registry. All severe AEs, AEs of special interest and serious AEs in adult and paediatric patients on systemic immunomodulating treatment (ciclosporin, methotrexate, azathioprine, mycophenolic acid, dupilumab, tralokinumab, baricitinib and upadacitinib) were assessed. Incidences rates of all (potentially) drug-related AEs were standardized in patient years and compared to the cumulative incidences in the associated SmPCs.
RESULTS
We collected 422 patient years of safety data from 266 patients, of whom 129 (48.5%) reported a total of 224 (potentially) drug-related AEs. Compared to dupilumab's SmPC, higher incidence rates were found for four AEs (reported ≥5 times): eosinophilia, blepharitis, dry eyes and head and neck erythema (i.e. dupilumab facial redness). A higher incidence rate of fatigue was found in patients on oral methotrexate in our cohort compared to the SmPC. Two new drug-related AEs (reported ≥5 times) were found in patients on dupilumab, including non-infectious conjunctivitis and meibomian gland dysfunction.
CONCLUSIONS
Real-world reported AEs captured in AD patient registries can add information on the estimated incidence of AEs and benefit clinical decision aids. Future studies using data derived from the TREAT NL registry combined with data from other registries within the TREAT Registry Taskforce will provide more information on (rare) AEs associated with immunomodulating therapy in AD patients.
Topics: Adult; Humans; Child; Netherlands; Cohort Studies; Dermatitis, Atopic; Methotrexate; Prospective Studies
PubMed: 38031478
DOI: 10.1111/jdv.19643 -
Clinical and Translational Science Nov 2023The MTXPK.org webtool was launched in December 2019 and was developed to facilitate model-informed supportive care and optimal use of glucarpidase following the...
The MTXPK.org webtool was launched in December 2019 and was developed to facilitate model-informed supportive care and optimal use of glucarpidase following the administration of high-dose methotrexate (HDMTX). One limitation identified during the original development of the MTXPK.org tool was the perceived generalizability because the modeled population comprised solely of Nordic pediatric patients receiving 24-h infusions for the treatment of acute lymphoblastic leukemia. The goal of our study is to describe the pharmacokinetics of HDMTX from a diverse patient population (e.g., races, ethnicity, indications for methotrexate, and variable infusion durations) and identify meaningful factors that account for methotrexate variability and improve the model's performance. To do this, retrospectively analyzed pharmacokinetic and toxicity data from pediatric and adolescent young adult patients who were receiving HDMTX (>0.5 g/m ) for the treatment of a cancer diagnosis from three pediatric medical centers. We performed population pharmacokinetic modeling referencing the original MTXPK.org NONMEM model (includes body surface area and serum creatinine as covariates) on 1668 patients, 7506 administrations of HDMTX, and 30,250 concentrations. Our results support the parameterizations of short infusion duration (<8 h) and the presence of Down syndrome on methotrexate clearance, the parameterization of severe hypoalbuminemia (<2.5 g/dL) on the intercompartmental clearance (Q2 and Q3), and the parameterization of pleural effusion on the volume of distribution (V1 and V2). These novel parameterizations will increase the generalizability of the MTXPK.org model once they are added to the webtool.
Topics: Adolescent; Young Adult; Child; Humans; Methotrexate; Antimetabolites, Antineoplastic; Retrospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37503924
DOI: 10.1111/cts.13600 -
International Journal of Rheumatic... Dec 2023
Topics: Humans; Methotrexate
PubMed: 38041651
DOI: 10.1111/1756-185X.14879 -
Joint Bone Spine Sep 2023
Topics: Humans; Methotrexate; Dysbiosis; Arthritis, Rheumatoid; Microbiota
PubMed: 37352969
DOI: 10.1016/j.jbspin.2023.105602 -
Arthritis Research & Therapy Sep 2023While the availability of biological or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) has improved outcomes for rheumatoid arthritis (RA)...
BACKGROUND
While the availability of biological or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) has improved outcomes for rheumatoid arthritis (RA) patients, there remains a subset of individuals who fail to achieve low disease activity or remission despite multiple cycles of b/tsDMARDs. This state is referred to as 'difficult-to-treat (D2T)' RA.
METHODS
Data from the Korean College of Rheumatology Biologics registry were utilized to analyze patients with RA who were treated with b/tsDMARDs.
RESULTS
Among 2,321 RA patients with RA treated with b/tsDMARDs, 271 (11.7%) were diagnosed with D2T RA. Lower age (OR = 0.98, p < 0.001), longer disease duration (OR = 1.06, p < 0.001), lower patient global assessment (OR = 0.89, p = 0.045), higher SDAI (OR = 1.06, p = 0.014) and RAPID3 (OR = 1.06, p = 0.002), lower RF positivity (OR = 0.65, p = 0.04), and lower prior use of methotrexate (OR = 0.44, p = 0.008), sulfasalazine (OR = 0.59, p = 0.003), and leflunomide (OR = 0.67, p = 0.013) were associated with D2T RA. The drug survival rate of b/tsDMARDs did not differ between patients with D2T RA and non-D2T RA (p = 0.35). However, the drug survival of individual b/tsDMARD differed between patients with D2T RA and non-D2T RA after eight years. Patients with D2T RA withdrew from b/tsDMARDs due to inefficacy more frequently than those without D2T RA (p < 0.001).
CONCLUSIONS
D2T RA patients experienced higher disease activity despite maintaining b/tsDMARD therapy. Withdrawal rates due to inefficacy were higher in D2T RA. Effective therapeutic strategies are needed to improve disease control and treatment outcomes in this unique patient population.
Topics: Humans; Antirheumatic Agents; Arthritis, Rheumatoid; Methotrexate; Registries; Biological Products
PubMed: 37726808
DOI: 10.1186/s13075-023-03165-w -
Medicine Nov 2023Idiopathic granulomatous mastitis is a benign, inflammatory disease of breasts characterized by non-caseating granulomas. Our study aims to identify distinguishing...
Idiopathic granulomatous mastitis is a benign, inflammatory disease of breasts characterized by non-caseating granulomas. Our study aims to identify distinguishing clinical and histopathological features of relapsing disease compared to those in complete remission. We queried databases at our institution (1990-2021) to include females ≥18 years with biopsy-proven diagnosis of idiopathic granulomatous mastitis, excluding patients with breast cancer, lymphoproliferative disorders, solid organ malignancy, foreign body reaction in breast, plasma cell mastitis, and ductal ectasia. Remission was defined as a 3-month period without recurrence of symptoms or imaging findings. Relapse was defined as recurrence after 3 months of remission. Clinical and histopathological features were compared using 2-sample t tests and chi-squared tests. Of the 27 patients that met our inclusion criteria, the mean age at diagnosis was 35.8 years (± standard deviation 9.4 years) with a mean body mass index of 31.7 kg/m2 (± standard deviation 6.7 kg/m2). 11 (41%) were Hispanic, 25 (93%) had at least one previous full-term pregnancy prior to diagnosis and 8 (30%) were on oral contraceptives. Remission was seen in 18 patients (66%) and 9 (33%) had relapse. Six of these patients received steroids after antibiotics, while 5 patients received methotrexate. Three (33%) patients with relapse and 14 (77%) with remission, had abscess formation confirmed on histopathology (P = .04). Patients with remission had a higher number of abscesses on histopathology and history of oral contraceptive use was associated with more relapse. By identifying key clinical and histopathological findings in this population may guide prognosis and treatment of these patients.
Topics: Female; Humans; Granulomatous Mastitis; Neoplasm Recurrence, Local; Breast; Methotrexate; Breast Neoplasms; Chronic Disease
PubMed: 37933043
DOI: 10.1097/MD.0000000000035679 -
International Journal of Nanomedicine 2024Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and...
BACKGROUND
Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events.
METHODS
We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA.
RESULTS
Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations.
CONCLUSION
Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.
Topics: Humans; Rats; Animals; Methotrexate; Rats, Wistar; Arthritis, Rheumatoid; Nanoparticles; Inflammation; Arthritis, Experimental; Lipids; Diclofenac
PubMed: 38482519
DOI: 10.2147/IJN.S439359