This study aimed to investigate biochemically and histopathologically the protective effect of adenosine triphosphate (ATP) and coenzyme Q10 (CoQ10) against potential hydroxychloroquine (HCQ)-induced retinal damage in rats. Twenty-four male albino Wistar-type rats were randomly separated into four groups: healthy (HG), receiving HCQ (HQG), receiving ATP + HCQ (AHQ), and receiving CoQ10 + HCQ (CoQHQ). ATP (4 mg/kg, intraperitoneal) was given to the AHQ, and CoQ10 (10 mg/kg, oral) to the CoQHQ. Rats in the HQG, AHQ, and CoQHQ were given HCQ (120 mg/kg, oral) 1 h after administering ATP and CoQ10. Treatments continued once a day for seven days. On the 8th day, the rats were sacrificed with 50 mg/kg sodium thiopental, and the eyes were removed. Malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT), and interleukin-6 (IL-6) levels were measured in the retrieved eye tissues and retinal tissues were assessed histopathologically. An increase in MDA and IL-6 levels and a decrease in tGSH, SOD, and CAT levels were detected in the eye tissues of the HQGcompared to the HG. HCQ-induced changes in oxidant and antioxidant levels were significantly suppressed by ATP and CoQ10 treatment. ATP was more successful than CoQ10 in this inhibition. Severe damage was observed in the eye tissues of the HQG group, whereas the damage was mild in the AHQ and moderate in the CoQHQ. Although both ATP and CoQ10 have the potential to be effective in the prevention of HCQ-induced retinal damage through antioxidative activity, ATP appears to be the more preferable treatment approach.

The application of swept-source optical coherence tomography angiography (SS-OCTA) technique is used to detect the effects of long-term use of hydroxychloroquine (HCQ) on retinal structure and microcirculation in patients with systemic lupus erythematosus (SLE) before visual dysfunction occurs.

Retrospective case-control study. A total of 73 SLE patients (73 eyes) who had taken HCQ regularly for a long period of time were included as the SLE patient group, while 21 healthy individuals (21 eyes) were included as the control group. Based on the duration of HCQ use (HCQ course), the SLE patient group was divided into baseline group (6 months ≤ medication time < 1 year), low-risk group ( 1 year ≤ medication time < 5 years), and high-risk group (medication time ≥ 5 years). All participants underwent bilateral SS-OCTA macular imaging (6 mm*6 mm), slit-lamp examination, non-contact tonometry, computerized visual field (30 - 2) test, and fundus autofluorescence imaging (FAF).

Compared among the groups, the full-layer retinal thickness and superficial blood vessel density of the fovea, below the inner circle, temporal side of the outer circle and above the outer circle decreased in the macular area (6 mm*6 mm) in high-risk group of SLE patients, while the area and circumference of FAZ increased (P < 0.0125). Correlation analysis suggested that the duration of SLE disease and HCQ cumulative dose were negatively correlated with superficial retinal capillary plexus vessel density (SCP-VD) in the three regions of inner retina, full-layer retinal thickness in the fovea, fovea, temporal side of the inner circle, and above the inner circle (r < 0,P < 0.05), and positively correlated with the area and circumference of FAZ (r > 0,P < 0.05).

Analysis by SS-OCTA examination showed that long-term HCQ treatment had adverse effects on the inner retina, SCP-VD and FAZ parameters in subclinical SLE patients without visual impairment.

Cognitive impairment poses significant challenges for aging populations. Systemic inflammation, a hallmark of rheumatoid arthritis (RA), has been implicated in neurodegeneration through mechanisms including blood-brain barrier disruption, microglial activation, and cytokine-mediated neuronal damage. This review examines the potential impact of disease-modifying antirheumatic drugs (DMARDs) on cognitive function in RA, focusing on the inflammatory pathways linking systemic inflammation to neuroinflammation and cognitive decline. DMARDs, categorized into conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic (tsDMARDs) classes, modulate immune responses through distinct mechanisms. Evidence suggests that DMARDs, particularly bDMARDs targeting proinflammatory cytokines such as TNF-α and IL-6, may mitigate neuroinflammatory processes and preserve cognitive function. However, the cognitive impact of csDMARDs such as methotrexate is complex, with conflicting reports regarding its role in vascular dementia. Emerging therapies such as Janus kinase inhibitors (JAK-i) offer promise in modulating central inflammation, though clinical evidence remains limited. While some studies highlight protective effects of DMARDs against dementia, findings are inconsistent, hindered by heterogeneity in study design, patient demographics, and cognitive assessment methods. This review underscores the need for personalized treatment strategies, integrating RA management with cognitive health considerations. Future research should prioritize robust, prospective studies with long-term follow-up, incorporating neuroimaging and biomarker analysis to elucidate the mechanisms underpinning DMARD-associated cognitive outcomes. A better understanding of the involved inflammatory pathways in RA and the potential effects of DMARDs could lead to improved therapeutic approaches, enhancing quality of life for patients with RA and potentially benefiting broader strategies in preventing or treating dementia.

To assess changes in the thickness of macular sublayers in individuals taking hydroxychloroquine (HCQ) without any evident toxicity and to review the relevant literature.

This prospective case-control study examined 47 adults on HCQ without evident toxicity on spectral-domain optical coherence tomography (SD-OCT) and visual field tests, as well as 25 healthy controls. Macular thickness in different sublayers was measured using SD-OCT. The thickness of combination layers and the variability of sublayers were also recorded. Data were compared between the case and control groups, and the correlation between cumulative HCQ use and outcome measures was analysed.

The average age of participants in the case and control groups was 45.6 ± 9.3 and 46.8 ± 11.7 years, respectively (p = 0.831). The percentage of female participants was 91.5% in the case group and 84.0% in the control group (p = 0.927). In the case group, the average duration of HCQ use was 5.1 ± 5.2 years, with a mean cumulative dose of 301 ± 365 g. No significant differences were found in the visual field mean deviation or pattern standard deviation between patients with HCQ use of <5-years vs. ≥5-years. Additionally, there were no statistically significant differences in various retinal thickness measurements between the case and control groups. However, a significant association was observed between the cumulative dose of HCQ and the thickness of the outer retinal layer (ORL) in both the outer (r = 0.344; p = 0.032) and inner Early Treatment Diabetic Retinopathy Study (ETDRS) macular rings (r = 0.303; p = 0.061).

No significant difference in macular sublayer thickness was found between patients taking HCQ without evident toxicity and the control group. A weak direct association was observed between the cumulative dose of HCQ and the ORL thickness. These findings suggest that analysing macular sublayer thickness may not be useful in detecting the earliest signs of presumed HCQ toxicity in individuals without classical sign of toxicity on qualitative SD-OCT or visual field test.

The unique immunomodulatory properties of hydroxychloroquine (HCQ) have attracted considerable interest beyond its use for malaria and rheumatological diseases, including a variety of dermatological conditions. Over recent years, especially after the coronavirus disease 2019 (COVID-19) pandemic, the prescription of HCQ has also significantly expanded, sometimes inappropriately, thus posing additional challenges on its optimal use, due to emerging safety issues. In this review, we provide dermatologists with the latest advancements on selected clinically relevant toxicities, namely retinopathy, pro-arrhythmia, cutaneous reactions, and neuropsychiatric effects. It is hoped this update can assist dermatologists to identify high-risk patients for tailored monitoring, screening, and risk minimization strategies, thus supporting safer HCQ prescribing.

Potent inflammatory responses stemming from innate and T cell activation are initiated during acute human immunodeficiency virus infection. Suppression of the virus replication by antiretroviral therapy reduces but does not normalize immune activation. By now, it is clear that residual immune activation can persist even after years of antiretroviral therapy and associates with increased risks for co-morbidities, thereby raising interest for strategies that can resolve the residual immune activation in people with human immunodeficiency virus on antiretrovirals. This brief review reports the human studies with various drugs with anti-inflammatory properties and their effects on measures of systemic immune activation on people with human immunodeficiency virus. Along with the possible reasons for conflicting outcomes, considerations for ongoing and future approaches are outlined.

To explore the inter-eye retinal microvascular density asymmetry of patients on hydroxychloroquine (HCQ) therapy through optical coherence tomography angiography (OCTA).

40 subjects were enrolled in this cross-sectional study, including 20 systemic lupus erythematasus patients currently treated with HCQ (40 eyes) and 20 age- and sex-matched normal controls (NCs, 40 eyes). OCTA images were obtained to measure macular and peripapillary mircrovasculatures and microstructures, including vessel density, retinal nerver fiber layer thickness, and peripapillary ganglion cell-inner plexiform layer thickness. The absolute values of the difference between right and left eyes were taken as a measure of inter-eye asymmetry.

Macular whole image vessel density (wiVD-M) and perifoveal vessel density (pfVD) of superficial capillary plexus (SCP) were notably reduced in both the right and left eyes of the HCQ treatment group compared with NCs. Specifically, SLE patients treated with HCQ have higher inter-eye asymmetry of wiVD-M of SCP (2.28 ± 1.03 vs 1.27 ± 0.79, p < 0.01) and pfVD of SCP (2.55 ± 1.26 vs 1.78 ± 1.06, p = 0.04) compared with NCs. There were no significant differences in inter-eye asymmetry of structure parameters. Inter-eye asymmetry of wiVD-M of SCP (AUC = 0.80, p < 0.01) and pfVD of SCP (AUC = 0.71, p = 0.02) exhibited greater discrimination power.

SLE Patients treated with HCQ exhibited a notably higher inter-eye vessel density asymmetry compared to that of NCs. Thus, inter-eye vessel density asymmetry could be used to screen for HCQ retinal toxicity.

Flaviviruses, which include globally impactful pathogens, such as West Nile virus, yellow fever virus, Zika virus, Japanese encephalitis virus, and dengue virus, contribute significantly to human infections. Despite the ongoing emergence and resurgence of flavivirus-mediated pathogenesis, the absence of specific therapeutic options remains a challenge in the prevention and treatment of flaviviral infections. Through the intricate processes of fusion, transcription, replication, and maturation, the complex interplay of viral and host metabolic interactions affects pathophysiology. Crucial interactions involve metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, each playing a pivotal role in the replication and maturation of flaviviruses. These viral-host metabolic molecular interactions hijack and modulate the molecular mechanisms of host metabolism. A comprehensive understanding of these intricate metabolic pathways offers valuable insights, potentially unveiling novel targets for therapeutic interventions against flaviviral pathogenesis. This review emphasizes promising avenues for the development of therapeutic agents that target specific metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, which interact with flavivirus replication and are closely linked to the modulation of host metabolism. The clinical limitations of current drugs have prompted the development of new inhibitory strategies for flaviviruses based on an understanding of the molecular interactions between the virus and the host.

In an age where there is a remarkable upsurge in developing precision medicines, antibody-drug conjugates (ADCs) have emerged as a progressive therapeutic strategy. ADCs typically consist of monoclonal antibodies (mAb) conjugated to the cytotoxic payloads by utilizing a linker, combining the benefits of definitive target specificity of mAbs and potent killing impact of payload to achieve precise and efficient elimination of target cells. In addition to their well-established role in oncology, ADCs are currently demonstrating encouraging potential in addressing the unmet requirements in the treatment of autoimmune conditions such as rheumatoid arthritis (RA). Prevalent long-term autoimmune disease RA costs billions of dollars annually but still, there is a lack of precision-targeted therapeutics with minimal side effects. This review provides an overview of the RA pathogenesis, pre-existing therapies, and their limitations, the introduction of ADCs in RA treatment, the mechanism of ADCs, and a summary of ADCs in preclinical and clinical trials. Based on the literature we also propose a strategy in ADC synthesis, which may increase the efficiency in targeting multifactorial diseases like RA. We propose to utilize DMARDs (Disease-modifying anti-rheumatic drugs), the first-line treatment for RA, as a payload for ADC synthesis. DMARDs are the only class of medication that limits the disease progression, but their efficacy is limited due to off-target toxicities. Hence, utilizing them as payload will help to deliver them directly at the targeted site, reducing their off-target toxicity, which in turn will increase their efficiency in targeting disease. Also, as mAbs are not sufficient to achieve remission, they are given in combinations with DMARDs. Hence, synthesizing ADCs may reduce the multiple and higher dosages given to patients, which in turn may enhance patient compliance.

Hydroxychloroquine (HCQ), a well-known antimalarial and anti-inflammatory drug, has demonstrated potential neuroprotective effects in ischemic stroke by inhibiting pyroptosis, a programmed cell death associated with inflammation. This study investigates the impact of HCQ on ischemic stroke pathology using both in vivo and in vitro models. In vivo, C57BL/6 mice subjected to middle cerebral artery occlusion (MCAO) were treated with HCQ. Neurological deficits, infarct volume, and the expression of pyroptosis markers were evaluated. The results demonstrated that HCQ significantly improved motor function and reduced infarct volume in the MCAO mouse model. In vitro, BV2 microglial cells exposed to lipopolysaccharide (LPS) and oxygen-glucose deprivation (OGD) were treated with HCQ. Western blot and immunofluorescence analyses revealed that HCQ effectively suppressed the expression of pyroptosis markers GSDMD and NLRP3 in both in vivo and in vitro models. These findings suggest that HCQ mitigates ischemic stroke damage by inhibiting pyroptosis, highlighting its potential as a therapeutic agent for ischemic stroke. This study provides novel insights into the molecular mechanisms by which HCQ exerts its neuroprotective effects, offering a promising new avenue for developing safe, cost-effective, and widely applicable stroke treatments. The potential of HCQ to modulate neuroinflammatory pathways presents a significant advancement in ischemic stroke therapy, emphasizing the importance of targeting pyroptosis in stroke management and the broader implications for treating neuroinflammatory conditions.Significance Statement Ischemic stroke remains a leading cause of disability and death globally, with limited effective treatments. This study reveals that HCQ significantly mitigates ischemic stroke damage by inhibiting pyroptosis, a form of programmed cell death. Using in vivo and in vitro models, HCQ was shown to improve motor function and reduce infarct volume, highlighting its potential as a neuroprotective agent. These findings offer a promising new therapeutic approach for ischemic stroke, emphasizing the importance of targeting pyroptosis in stroke treatment.

Chloroquine and hydroxychloroquine, while effective in rheumatology, pose risks of retinal toxicity, necessitating regular screening to prevent visual disability. The gold standard for screening includes retinal imaging and automated perimetry, with multifocal electroretinography (mfERG) being a recognized but less accessible method. This study explores the efficacy of Artificial Intelligence (AI) algorithms for detecting retinal damage in patients undergoing (hydroxy-)chloroquine therapy. We analyze the mfERG data, comparing the performance of AI models that utilize raw mfERG time-series signals against models using conventional waveform parameters. Our classification models aimed to identify maculopathy, and regression models were developed to predict perimetric sensitivity. The findings reveal that while regression models were more adept at predicting non-disease-related variation, AI-based models, particularly those utilizing full mfERG traces, demonstrated superior predictive power for disease-related changes compared to linear models. This indicates a significant potential to improve diagnostic capabilities, although the unbalanced nature of the dataset may limit some applications.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems. Ocular involvement is estimated to manifest in one-third of individuals with SLE, of which lupus retinopathy and choroidopathy represent the severe subtype accompanied by vision impairment. Advancements in multimodal ophthalmic imaging have allowed ophthalmologists to reveal subclinical microvascular and structural changes in fundus of patients with SLE without ocular manifestations. Both ocular manifestations and subclinical fundus damage have been shown to correlate with SLE disease activity and, in some patients, even precede other systemic injuries as the first presentation of SLE. Moreover, ocular fundus might serve as a window into the state of systemic vasculitis in patients with SLE. Given the similarities of the anatomy, physiological and pathological processes shared among ocular fundus, and other vital organ damage in SLE, such as kidney and brain, it is assumed that ocular fundus involvement has implications in the diagnosis and evaluation of other systemic impairments. Therefore, evaluating the fundus characteristics of patients with SLE not only contributes to the early diagnosis and intervention of potential vision damage, but also holds considerate significance for the evaluation of SLE vasculitis state and prediction of other systemic injuries.

To compare multimodal structural and functional diagnostic methods in patients with systemic lupus erythematosus (SLE) treated with hydroxychloroquine, to identify the best complementary approach for detecting subclinical retinal toxicity.

A cross-sectional, unicentric study was conducted on patients with SLE treated with hydroxychloroquine. Each patient underwent a comprehensive ophthalmic evaluation, comprising structural tests (spectral-domain optical coherence tomography (SD-OCT), en face OCT, en face OCT angiography (OCTA), fundus autofluorescence (FAF)) and functional tests (automated perimetry for visual field (VF) testing, multifocal electroretinography (mfERG)). A diagnosis of macular toxicity required the presence of abnormalities in at least one structural and functional test. The Kappa Concordance Index was used to assess the concordance among the different tests in detecting potential macular toxicity-associated alterations.

Sixty-six patients with SLE (132 eyes) were consecutively enrolled. Four (6.1%) patients developed subclinical hydroxychloroquine-induced retinal toxicity without visual acuity impairment. The proportion of abnormal results was 24% for both en face OCT and en face OCTA. Regarding functional analysis, VF was less specific than mfERG in detecting subclinical retinal toxicity (VF specificity 47.5%). En face OCT and en face OCTA structural findings showed better concordance, with a kappa index >0.8, and both identified the same cases of toxicity as FAF.

Although structural OCT and VF are frequently used to screen for hydroxychloroquine-induced retinal toxicity, our findings suggest that a combination of mfERG, en face OCT and en face OCTA could improve the diagnostic accuracy for subclinical retinal damage. This study emphasises the importance of a multimodal imaging strategy to promptly detect signs of hydroxychloroquine-induced retinal toxicity.

Hydroxychloroquine sulfate (Plaquenil®) is a disease-modifying anti-rheumatic drug (DMARD) utilized in the management of autoimmune diseases. While its immunomodulatory actions offer therapeutic benefits, a rare complication, hydroxychloroquine-induced retinal toxicity, poses a significant concern. We present the case of an 83-year-old patient with cutaneous lupus undergoing periodic hydroxychloroquine screening for eight years. Visual field changes consistent with retinal toxicity were observed. Chart review revealed subtle visual field depression two years prior. This highlights the importance of vigilance toward unexplained visual changes and subtle changes on ophthalmologic examination in hydroxychloroquine-treated patients. Our findings underscore the necessity of baseline and periodic ophthalmologic examinations with particular attention paid to visual field depression or deficit that might occur without macular changes. Additionally, we address the choice between red and white visual field testing. This case contributes to the understanding of hydroxychloroquine-induced retinal toxicity, emphasizing the importance of comprehensive ophthalmologic surveillance in long-term users.

Innate immune responses may be involved in the earliest phases of type 1 diabetes (T1D).

To test whether blocking innate immaune cells modulated progression of the disease, we randomly assigned 273 individuals with stage 1 T1D to treatment with hydroxychloroquine (n = 183; 5 mg/kg per day to a maximum of 400 mg) or placebo (n = 90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e., two or more islet autoantibodies with abnormal glucose tolerance).

After a median follow-up of 23.3 months, the trial was stopped prematurely by the data safety monitoring board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic examinations. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and reduced titers of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (P = 0.032).

We conclude that hydroxychloroquine does not delay progression to stage 2 T1D in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.