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Northern Clinics of Istanbul 2024To investigate the effects of both the Fc fragment in tumor necrosis factor (TNF) inhibitors and rheumatoid factor (RF) titers on treatment survival, disease activity,...
OBJECTIVE
To investigate the effects of both the Fc fragment in tumor necrosis factor (TNF) inhibitors and rheumatoid factor (RF) titers on treatment survival, disease activity, and laboratory parameters in patients with rheumatoid arthritis (RA).
METHODS
In this retrospective cohort study, patients with RA who had started any anti-TNF therapy between January 2017 and March 2020 and who had stayed on this treatment for at least six months were included. The data of the patients were compared separately according to continuation or discontinuation of treatment and the presence or absence of Fc portion in the structure of anti-TNFs. Patients who were taking certolizumab pegol (CZP) without the Fc fragment were placed in the "without Fc group" (wo/Fc), while patients who were taking other drugs (adalimumab, etanercept, golimumab, and infliximab) were placed in the "with Fc group" (w/Fc).
RESULTS
Among the 221 RA patients whose data were available, 52 patients met the inclusion criteria and were included in the study. There was a significant difference in the DAS28-CRP score between wo/Fc group and w/Fc group in the third month of treatment (p=0.012). However, this difference did not persist at the sixth month of treatment (p=0.384). According to the cox-regression results, RF titers were determined to have a significant impact on the drug survival of anti-TNF agents when adjustments were made for the effects of other candidate predictors (Hazard ratio: 1.007 (1.002-1.012), p=0.009).
CONCLUSION
Our results suggest that compared to the Fc fragment, RF titers were the more important risk factor in survival of anti-TNF drugs.
PubMed: 38757098
DOI: 10.14744/nci.2023.01643 -
Mediterranean Journal of Rheumatology Mar 2024Aberrant activation of the IL-23/IL-17 axis leads to inflammatory phenotypes with overlapping clinical characteristics. Inhibition of IL-17 has mostly an...
INTRODUCTION
Aberrant activation of the IL-23/IL-17 axis leads to inflammatory phenotypes with overlapping clinical characteristics. Inhibition of IL-17 has mostly an anti-inflammatory effect, but sporadic cases of new-onset IBD have been reported.
CASE DESCRIPTION
We present the case of a 65-year-old male patient with new-onset Crohn's-like disease after treatment with secukinumab for skin psoriasis. Discontinuation of the IL-17 inhibitor and high-dose corticosteroid treatment were efficient initially, but a relapse was noted during corticosteroid tapering. Administration of certolizumab pegol did partially relieve the patient, but disease remission was only achieved with subcutaneous risankizumab therapy.
DISCUSSION
Clinical trials and real-world data indicate sporadic cases of new-onset IBD in patients receiving IL-17 inhibitors. Interestingly, our case is a "treatment-resistant" one since treatment with a biologic disease-modifying drug (bDMARD) usually leads to disease remission. As such, it is crucial to investigate the special characteristics of this clinical entity.
PubMed: 38736963
DOI: 10.31138/mjr.030124.ntt -
RMD Open May 2024There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs of inflammation such as MRI or C-reactive protein (CRP) levels. This study reports clinical outcomes up to 3 years of the C-axSpAnd trial, including safety follow-up extension (SFE) from Weeks 52 to 156, stratified by patients' baseline MRI and CRP status.
METHODS
C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated certolizumab pegol (CZP) in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. In this post hoc analysis, efficacy outcomes are reported to Week 156 of C-axSpAnd for patients stratified according to their MRI and CRP status at Week 0 (MRI+/CRP-, MRI-/CRP+ and MRI+/CRP+).
RESULTS
Across all outcome measures, including major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) and Assessment of SpondyloArthritis international Society criteria ≥40% response (ASAS40), outcomes were generally sustained in SFE patients from Week 52 to Week 156. MRI+/CRP+ patients showed numerically higher or comparable responses relative to MRI-/CRP+ and MRI+/CRP- patients at Weeks 52 and 156; however, all three subgroups demonstrated substantial improvements from Week 0 (in CZP-randomised patients, ASDAS-MI at Week 156 [observed case]: MRI+/CRP+: 73.1%, MRI-/CRP+: 52.2%, MRI+/CRP-: 30.4%; ASAS40: MRI+/CRP+: 76.9%, MRI-/CRP+: 62.5%, MRI+/CRP-: 65.2%).
CONCLUSIONS
In patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI-/CRP+ and MRI+/CRP- subgroups.
Topics: Humans; Certolizumab Pegol; Magnetic Resonance Imaging; C-Reactive Protein; Male; Female; Adult; Treatment Outcome; Axial Spondyloarthritis; Middle Aged; Biomarkers; Severity of Illness Index
PubMed: 38724259
DOI: 10.1136/rmdopen-2023-003884 -
Clinical Pharmacokinetics May 2024Although little information is available on the pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy, multiple mAbs are being used during pregnancy for...
BACKGROUND AND OBJECTIVE
Although little information is available on the pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy, multiple mAbs are being used during pregnancy for various indications. The aim of this systematic literature review was to characterize the PK of mAbs throughout pregnancy.
METHODS
A systematic literature search was carried out in PubMed and Embase on 21 April 2023. Articles were included when information on PK or exposure parameters of mAbs in pregnant women was available.
RESULTS
A total of 42 relevant articles were included, of which eight discussed adalimumab, three certolizumab pegol, five eculizumab, one golimumab, 12 infliximab (IFX), two natalizumab, one canakinumab, one omalizumab, five tocilizumab, eight ustekinumab, and five vedolizumab. One of the 42 studies reported information on clearance (CL) and volume of distribution (VD) of IFX; all other studies only reported on serum concentrations in the pre-pregnancy state, different trimesters, and the postpartum period. For all of the assessed mAbs except IFX, serum concentrations were similar to concentrations in the pre-pregnancy state or modestly decreased. In contrast, IFX trough concentrations generally increased in the second and third trimesters in comparison to the non-pregnant state.
CONCLUSION
Available information suggests that the anatomical and physiological changes throughout pregnancy may have meaningful effects on the PK of mAbs. For most mAbs (not IFX), modestly higher dosing (per mg) maybe needed during pregnancy to sustain a similar serum exposure compared to pre-pregnancy.
Topics: Humans; Pregnancy; Female; Antibodies, Monoclonal; Pregnancy Complications
PubMed: 38583128
DOI: 10.1007/s40262-024-01370-7 -
RMD Open Apr 2024This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA).
METHODS
This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI ≥30 kg/m. All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI.
RESULTS
Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms.
CONCLUSION
In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received.
TRIAL REGISTRATION NUMBER
NCT01491815.
Topics: Humans; Methotrexate; Treatment Outcome; Arthritis, Rheumatoid; Risk Factors; Obesity; C-Reactive Protein
PubMed: 38580350
DOI: 10.1136/rmdopen-2024-004227 -
ACG Case Reports Journal Apr 2024Idiopathic granulomatous hepatitis is a rare condition characterized by hepatic granulomas with constitutional symptoms such as recurrent fevers, myalgias, and...
Idiopathic granulomatous hepatitis is a rare condition characterized by hepatic granulomas with constitutional symptoms such as recurrent fevers, myalgias, and hepatosplenomegaly in the absence of infection or inflammatory disorder. Typical treatment and course of this disease consist of a course of steroids with rapid symptom resolution. However, symptoms may recur when steroids are tapered. In these circumstances, azathioprine, methotrexate, infliximab, and adalimumab have demonstrated good response. In this case, we present a patient who developed antidrug antibodies to infliximab and adalimumab and was the first documented case of this disease to be treated with certolizumab pegol. Our case highlights the novel efficacy of certolizumab pegol for idiopathic granulomatous hepatitis and its role in treating idiopathic granulomatous hepatitis with antidrug antibodies.
PubMed: 38560016
DOI: 10.14309/crj.0000000000001310 -
Annals of the Rheumatic Diseases May 2024To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA).
Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis.
OBJECTIVES
To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA).
METHODS
This systematic literature research (SLR) investigated the efficacy and safety of conventional synthetic (cs), biological (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) in patients with PsA. A systematic database search using Medline, EMBASE, Cochrane CENTRAL was conducted to identify relevant articles published since the previous update in 2019 until 28 December 2022. Efficacy was assessed in trials while for safety observational data were also considered. Adverse events of special interest were infections (including herpes zoster, influenza and tuberculosis), malignancies, major adverse cardiovascular events, venous thromboembolisms, liver disease, laboratory changes and psychiatric adverse events. No meta-analyses were performed.
RESULTS
For efficacy, of 3946 articles screened, 38 articles (30 trials) were analysed. The compounds investigated included csDMARDs (leflunomide, methotrexate), bDMARDs inhibiting IL17 (bimekizumab, brodalumab, ixekizumab, izokibep, secukinumab,), IL-23 (guselkumab, risankizumab, tildrakizumab), IL-12/23 (ustekinumab) as well as TNF (adalimumab, certolizumab-pegol, etanercept, infliximab, golimumab) and Janus Kinase inhibitors (JAKi) (brepocitinib, deucravacitinib, tofacitinib, upadacitinib). The compounds investigated were efficacious in improving signs and symptoms of PsA, improving physical functioning and quality of life. For safety, 2055 abstracts were screened, and 24 articles analysed: 15 observational studies and 9 long-term follow-ups of trials, assessing glucocorticoids, TNFi, IL-17i, JAKi, IL-12/23i and PDE4i (apremilast). Safety indicators were generally coherent with the previous SLR in 2019.
CONCLUSION
The results of this SLR informed the task force responsible for the 2023 update of the European Alliance of Associations for Rheumatology recommendations for pharmacological management of PsA.
Topics: Arthritis, Psoriatic; Humans; Antirheumatic Agents; Treatment Outcome; Practice Guidelines as Topic; Biological Products
PubMed: 38503473
DOI: 10.1136/ard-2024-225534 -
RMD Open Mar 2024To assess the risk of serious infection associated with different targeted therapies for psoriatic arthritis (PsA) in real-world settings.
Risk of serious infection associated with different classes of targeted therapies used in psoriatic arthritis: a nationwide cohort study from the French Health Insurance Database (SNDS).
OBJECTIVE
To assess the risk of serious infection associated with different targeted therapies for psoriatic arthritis (PsA) in real-world settings.
METHODS
This nationwide cohort study used the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database to identify all adults with PsA who were new users of targeted therapies (adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, secukinumab, ixekizumab, ustekinumab, and tofacitinib) from 1 January 2015 to 30 June 2021. The primary outcome was a serious infection (ie, requiring hospitalisation), in a time-to-event analysis using propensity score-weighted Cox models, with adalimumab as the comparator, estimating weighted HRs (wHRs) and their 95% CIs.
RESULTS
A total of 12 071 patients were included (mean age 48.7±12.7 years; 6965 (57.7%) women). We identified 367 serious infections (3.0% of patients), with a crude incidence rate of 17.0 per 1000 person-years (95% CI, 15.2 to 18.7). After inverse propensity score weighting and adjustment for time-dependent covariates and calendar year, risk of serious infection was significantly lower for new users of etanercept (wHR 0.72; 95% CI, 0.53 to 0.97) or ustekinumab (wHR, 0.57; 95% CI, 0.35 to 0.93) than adalimumab new users. This risk was not statistically modified with the other targeted therapies.
CONCLUSIONS
The incidence of serious infection was low for PsA patients who were new users of targeted therapies in real-world settings. Relative to adalimumab new users, this risk was lower among new users of etanercept and ustekinumab and unmodified for the other molecules.
Topics: Adult; Humans; Female; Middle Aged; Male; Arthritis, Psoriatic; Adalimumab; Etanercept; Ustekinumab; Cohort Studies; Insurance, Health
PubMed: 38485454
DOI: 10.1136/rmdopen-2023-003865 -
Arthritis Research & Therapy Mar 2024Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a... (Randomized Controlled Trial)
Randomized Controlled Trial
Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis.
BACKGROUND
Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy.
METHODS
This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B (TXBM), 2,3-dinor-6-keto prostaglandin F (PGIM), leukotriene E (LTE) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography-mass spectrometry (LC-MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes.
RESULTS
Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24.
CONCLUSIONS
Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.
Topics: Humans; Female; Prostaglandins; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Arthritis, Rheumatoid; Methotrexate; Certolizumab Pegol; Dimaprit
PubMed: 38444034
DOI: 10.1186/s13075-024-03295-9 -
Pharmaceuticals (Basel, Switzerland) Feb 2024Disease-modifying anti-rheumatic drugs (DMARDs) is a class of anti-rheumatic medicines that are frequently prescribed to patients suffering from rheumatoid arthritis... (Review)
Review
Disease-modifying anti-rheumatic drugs (DMARDs) is a class of anti-rheumatic medicines that are frequently prescribed to patients suffering from rheumatoid arthritis (RA). Methotrexate, sulfasalazine, hydroxychloroquine, and azathioprine are examples of non-biologic DMARDs that are being used for alleviating pain and preventing disease progression. Biologic DMARDs (bDMARDs) like infliximab, rituximab, etanercept, adalimumab, tocilizumab, certolizumab pegol, and abatacept have greater effectiveness with fewer adverse effects in comparison to non-biologic DMARDs. This review article delineates the classification of DMARDs and their characteristic attributes. The poor aqueous solubility or permeability causes the limited oral bioavailability of synthetic DMARDs, while the high molecular weights along with the bulky structures of bDMARDs have posed few obstacles in their drug delivery and need to be addressed through the development of nanoformulations like cubosomes, nanospheres, nanoemulsions, solid lipid nanoparticles, nanomicelles, liposome, niosomes, and nanostructured lipid carrier. The main focus of this review article is to highlight the potential role of nanotechnology in the drug delivery of DMARDs for increasing solubility, dissolution, and bioavailability for the improved management of RA. This article also focusses on the different aspects of nanoparticles like their applications in biologics, biocompatibility, body clearance, scalability, drug loading, and stability issues.
PubMed: 38399463
DOI: 10.3390/ph17020248