Background/Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous disease with substantial variability in clinical manifestations and outcomes, influenced by ethnic and geographical diversity. Remission is the optimal treatment target, while low lupus disease activity state is an accepted alternative goal. Although sustained remission has been associated with reduced organ damage, the impact of early attainment of treatment targets on subsequent damage accrual in SLE remains incompletely defined. To explore a potential window of opportunity, this study aimed to identify factors associated with achieving remission or low lupus disease activity state within the first year of SLE diagnosis and to examine their associations with organ damage. Methods: This retrospective study was conducted across 22 rheumatology centres in Malaysia and included patients with systemic lupus erythematosus (SLE) who had complete follow-up from diagnosis until attainment of treatment targets. Treatment targets were defined as achieving either early remission or a low disease activity state (LDAS). Given the retrospective nature of the study and the unavailability of complete Physician's Global Assessment data, the definitions of early remission and LDAS were modified by excluding this component. Accordingly, treatment targets were defined as attainment of a clinical SLE Disease Activity Index (cSLEDAI) score of 0 with oral prednisolone doses of ≤5 mg/day and ≤7.5 mg/day, respectively, within 12 months of SLE onset. Multivariable Cox proportional hazards regression and logistic regression analyses were performed to determine factors associated with early remission and organ damage, respectively. Results: A total of 1599 patients were included, the majority of whom were female (92.5%). The cohort was predominantly Malay (68.7%), followed by Chinese (17.4%), Indigenous groups (10.8%) and Indian (3.0%). Early attainment of treatment targets was achieved in 45.7% of patients, while 54.3% experienced delayed attainment. In the multivariable cox regression model, the Malay and Chinese ethnic group demonstrated a significantly lower likelihood of achieving early remission compared to the Indigenous ethnic group. Patients with longer SLE duration, low C4 levels, presence of haematological and renal manifestations at the initial presentation, were identified as additional adverse factors associated with lower likelihood of early remission. Overall, 16.9% of patients accrued organ damage. Independent factors associated with organ damage included Indian ethnicity [OR 5.75, 95% CI 1.39-23.81, p = 0.02], delayed remission [OR 2.97, 95% CI 1.51-5.83) and absence of baseline hydroxychloroquine therapy [OR 4.13, 95% CI 1.21-14.07; p = 0.020]. Conclusions: Ethnic disparities were observed in the early attainment of the treatment targets, as well as in organ damage accrual within the Malaysian multi-ethnic SLE cohort. The significant association between the delay in achieving the treatment targets and organ damage underscores the importance of adopting an early treat-to-target approach in SLE management.

In the original publication [...].

To evaluate retinal microvascular and structural changes in patients undergoing hydroxychloroquine (HCQ) therapy using optical coherence tomography angiography (OCTA) in patients without clinical retinopathy. This prospective cross-sectional study enrolled both eyes of 59 age-matched control cases (Group 1) with 118 eyes from 59 HCQ-treated patients (27 with < 60 months of treatment [Group 2], 32 with ≥ 60 months [Group 3]) at Farabi Hospital (2020-2022). All participants underwent a comprehensive ophthalmic evaluation, including spectral-domain OCTA (Optovue RTVue XR Avanti). The inner, mid- and outer retinal layer thicknesses (IRT, MRT, ORT) and superficial, deep retinal vascular densities and choroidal vascular densities (SVD, DVD, CVD) were analyzed using ETDRS grids. We employed generalized estimating equations with a Bonferroni correction to compare groups. The Group 3 (≥ 60-month consumption of HCQ) demonstrated significant reductions in foveal inner retinal thickness (IRT) (43.25 ± 7.07 vs. 48.84 ± 8.71 μm, p = 0.002) and parafoveal outer retinal thickness (ORT) (146.14 ± 6.77 vs. 151.8 ± 9.94 μm, p = 0.002) compared to controls. OCTA analysis showed that foveal DVD and CVD were lower in Group 3 compared with Group 1, whereas parafoveal DVD was increased in Group 3. Moreover, Group 2 cases indicated choroidal changes compared with the control group. Duration and cumulative dose of HCQ consumption negatively correlated with foveal SVD and IRT, alongside a positive correlation with parafoveal DVD and FAZ. GEE regression revealed that longer treatment duration and higher cumulative dose were independently associated with reduced foveal IRT (β=-0.002, p = 0.03; β=-0.013, p = 0.046), reduced foveal SVD (β=-0.002, p = 0.003; β=-0.014, p = 0.006), and an enlarged FAZ area (β = 0.161, p = 0.039). OCTA suggests possible progressive retinal microvascular attenuation in HCQ therapy, with alterations observed after 60 months of treatment despite normal functional testing. Parafoveal DVD seems to be a key feature, underscoring the potential for OCTA's utility in monitoring HCQ retinopathy.

Lemierre's syndrome is a rare postanginal septic thrombophlebitis involving the internal jugular vein in younger adults. Extension into the thoracic inlet and upper extremity venous system is uncommon, and the role of underlying autoimmune disease in amplifying thromboinflammatory responses remains poorly characterized. A 29-year-old man with systemic lupus erythematosus (SLE), intermittently compliant with hydroxychloroquine, presented with two weeks of progressive right-sided neck pain and swelling, meeting sepsis criteria on arrival with marked systemic inflammation, acute kidney injury, and proteinuria. Initial contrast-enhanced computed tomography demonstrated diffuse cervicothoracic cellulitis without abscess. Within 24 hours, he developed worsening neck pain, dysphagia, and right upper extremity swelling with C5-C8 distribution numbness, and hand weakness. Repeat imaging revealed extensive septic thrombophlebitis involving the right internal jugular, subclavian, brachiocephalic, axillary veins, and superior vena cava, producing thoracic outlet-like neurovascular compression. Blood cultures remained persistently negative. Autoimmune evaluation demonstrated high-titer antinuclear antibody, elevated anti-double-stranded DNA antibodies, positive anti-Smith and anti-SSA antibodies, and preserved complement levels. Coagulation studies confirmed lupus anticoagulant positivity and concurrent antiphospholipid syndrome. The patient was treated with broad-spectrum antibiotics, therapeutic anticoagulation, and corticosteroids, resulting in clinical improvement with C-reactive protein decline and resolution of upper extremity swelling. No surgical intervention was required. While anticoagulation remains debated in Lemierre's syndrome, therapeutic anticoagulation was strongly indicated given the multifactorial nature of presentation. The culture-negative presentation, absence of pharyngitis, potential environmental exposure, age, and suboptimally controlled SLE with active lupus nephritis distinguish this from classic Lemierre's syndrome and highlight diagnostic challenges in atypical presentations.

This study aimed to investigate the mechanism of ophiopogonin D (OD) in treating primary Sjögren's syndrome (pSS) through integrated analysis of gut microbiota and metabolomics. Non-obese diabetic/LtJ mice, a well-established pSS model, were used as the model group and treated with OD or hydroxychloroquine. Fecal and tissue samples were collected starting 4 weeks after administration. Basic pathological examination, 16S rRNA sequencing, and ultra-high-performance liquid chromatography-mass spectrometry were employed to assess changes in tissue function, inflammation levels, gut microbiota, and metabolite profiles across all groups. The results showed that OD reduced the expression levels of inflammatory factors, regulated immune balance, and ameliorated functional damage of the submandibular gland. It also modulated the abundance of Rikenella, Mycoplasmataceae, Mycoplasmatales, and Erysipelotrichales, thereby affecting glycerophospholipid metabolism and improving the disease phenotype in pSS mice. In conclusion, OD may treat pSS by lowering inflammation, restoring salivary gland function, and correcting gut microbiota and metabolic imbalances.

Sjögren's syndrome is a long-standing autoimmune condition that predominantly affects the body's exocrine glands, most notably the eyes and mouth, leading to ocular and oral dryness. Neurological involvement, particularly affecting the central nervous system, is infrequently encountered, and the occurrence of stroke as an initial clinical manifestation remains exceptionally uncommon. We report a 42-year-old diabetic male who presented with an acute onset of right hemiplegia and aphasia, and was subsequently diagnosed with primary Sjögren's syndrome. Evaluation revealed multiple acute infarcts in the left middle cerebral artery territory with apical clot and ischemic heart disease. Positive antinuclear antibody by immunofluorescence, Ro-52 recombinant antibody positivity, and raised inflammatory markers suggested an autoimmune vasculitic process secondary to Sjögren's syndrome. The patient improved significantly after pulse methylprednisolone and hydroxychloroquine therapy. This case highlights the importance of considering autoimmune etiologies like Sjögren's syndrome in young stroke patients with systemic features.

SARS-CoV-2 vaccination or infection may not protect from future novel coronavirus outbreaks. Although several drugs targeting essential coronavirus proteins are broadly effective, the error-prone coronavirus RNA-dependent RNA polymerase and a rapid viral replication cycle mean that drug resistance will likely emerge. Small molecules that target sequence-stable host proteins could offer more durable pan-coronavirus activity. Here, we show that the well-tolerated and orally bioavailable small molecule SH-BC-893 protects from endosomal, but not plasma membrane, entry by diverse coronavirus strains. SH-BC-893 alters endolysosomal trafficking similar to PIKfyve inhibitors and, like hydroxychloroquine, reduces cathepsin L activity. While all three compounds block endosomal entry mediated by coronavirus spike proteins in vitro, PIKfyve inhibitors and chloroquine derivatives are ineffective or even increase viral titer in vivo. In contrast, SH-BC-893 reduced viral titer in the lungs of mice infected intranasally with the LD50 of the MHV-1 coronavirus by 3 logs. Thus, poor in vivo outcomes when using apilimod or chloroquine as anti-virals likely reflect pharmacologic limitations of these compounds rather than a flawed therapeutic strategy. We anticipate that SH-BC-893 or optimized analogs with similar tissue pharmacology could control infections by novel coronaviruses, particularly if given in combination with TMPRSS2 inhibitors to block entry at the plasma membrane, an obvious escape pathway. Because it targets host rather than viral proteins, SH-BC-893 might also block infection by many other viruses that enter via endosomal pathways: orthomyxoviruses (influenza), filoviruses (Ebola, Marburg), flaviviruses (Dengue, Zika, and West Nile), alphaviruses (Chikungunya) rhabdoviruses (rabies), and bunyaviruses (Hantaan or Sin Nombre). In sum, further evaluation of SH-BC-893 and/or optimized analogs as potential pan-antiviral agents is merited.

When estimating the effects of medical therapies from their use outside of randomized trials, researchers often rely on assumptions that are difficult to justify and typically impossible to verify. The resulting estimates may thus be far from their intended causal targets, potentially making a harmful treatment appear beneficial or vice versa. We review the stability-controlled quasi-experiment (SCQE), a method suited to settings where a treatment's prevalence changes sharply over a short period, and apply it to assess the effects of remdesivir, hydroxychloroquine, and dexamethasone on COVID-19 mortality. Rather than requiring debate about the absence (or limited strength) of unobserved confounding, about "parallel trends'', or other well-known strategies, the SCQE asks users to reason about a "baseline trend'' assumption. In this setting, this asks"How much could COVID-19 mortality have changed over a short period, absent the treatment change in question?'' Any plausible range for this assumption yields a corresponding range of plausible causal effect estimates. Conversely, SCQE clarifies what baseline trends must be defended or refuted in order to defend or refute a given conclusion about a treatment's efficacy or harm. Using data from two hospital systems early in the COVID-19 pandemic, we show that SCQE could have enabled safe yet informative inferences about treatment effects before clinical trial completion, producing conclusions consistent with eventual trial results.

A 62-year-old White female individual who had never smoked and who had a diagnosis of idiopathic sclerosing mesenteritis in 2006 and antiphospholipid syndrome was referred to the interstitial lung disease clinic in January 2025 for evaluation of progressive dyspnea. In 2009, she experienced pericarditis that required a pericardial window. A PET/computerized tomography/CT scan that was performed at that time revealed diffuse low-grade metabolic activity that involve the mediastinum, abdomen, and pelvis. A bone biopsy from the left iliac crest showed scattered foamy macrophages. Based on a multidisciplinary discussion, she was initiated on mycophenolate mofetil and hydroxychloroquine. Her clinical course remained indolent until 2016, when she presented with new-onset tachypnea and tachycardia. CT chest scan and cardiac MRI raised concerns for constrictive pericarditis, but right heart catheterization revealed concordant ventricular pressures, which ruled out constriction. Her symptoms stabilized until May 2023, when she reported dyspnea. Diuretics provided relief at that time. However, in December 2024, she experienced worsening dyspnea. A cardiac MRI demonstrated evidence of biventricular reduced ejection fraction along with increased infiltration of both atrial walls and interatrial septum by abnormal soft tissue. Chest CT scanning revealed progressive interlobular septal thickening and worsening ground-glass opacities, which raised suspicion for pulmonary involvement. At the interstitial lung disease clinic, she reported modified Medical Research Council grade 2 dyspnea. She denied orthopnea, paroxysmal nocturnal dyspnea, and weight changes and had no relevant occupational or environmental exposures.

As a major challenge currently plaguing reproductive medicine, recurrent pregnancy loss(RPL) has a variety of causes. Thyroid autoimmunity(TAI) is a prevalent thyroid disorder among women of childbearing age, potentially impacting maternal physiological changes and the balance of the maternal-fetal interface during pregnancy through endocrine and autoimmune pathways, which can lead to abortion and RPL. The selection of therapeutic agents and the effectiveness of treatment for patients experiencing RPL with thyroid autoimmunity remain contentious. Current research have explored the efficacy of medications such as levothyroxine, immunoglobulins, glucocorticoids, cyclosporine, hydroxychloroquine, selenium, and vitamin D for these patients. This review summarizes the correlation between TAI and RPL, as well as the current status of its diagnosis and treatment, with the aim of providing new ideas for clinical diagnosis and treatment.

Triple-negative breast cancer (TNBC), a subtype of aggressive breast cancer, has limited treatment options. Recurrent disease caused by drug-tolerant persister cells (DTPs) that evade chemotherapeutic agents (e.g., doxorubicin hydrochloride (DOX) and paclitaxel (PTX)) is a significant challenge in treating TNBC. Recent studies highlight both autophagy and lysosomal function as key mechanisms supporting cancer cell survival; however, their precise roles in mediating drug tolerance in TNBC remain largely unexplored. This study aimed to elucidate the mechanisms by which autophagic and lysosomal activities support the survival of TNBC DTPs following exposure to DOX and PTX. Compared with parental cells in both 2D and 3D cellular topologies, our results showed that treatment with DOX and PTX produced a fraction of latent DTPs that exhibited increased autophagic induction and improved lysosomal protein expression. The results revealed that pharmacological inhibition of autophagy (hydroxychloroquine) or lysosomal activity (bafilomycin A1) compromised DTPs' survival. Similarly, disrupting lysosomal integrity with L-leucyl-L-leucine methyl ester (LLOME) decreased DTPs' viability. Additionally, knockdown of the lysosomal protein LAMP1 (lysosomal-associated membrane protein 1) significantly reduced persister cells' viability and enhanced the cytotoxic effects of DOX and PTX. In a xenograft model, depleting LAMP1 in TNBC cells slowed tumor proliferation and delayed tumor initiation. Our results demonstrated that increased autophagy-lysosomal process renders DTP cell survival in TNBC by maintaining mitochondrial reactive oxygen species (mROS) generation, which, in turn, contributes to chemotherapy resistance. A potential treatment strategy for eradicating DTP cells and preventing tumor recurrence in TNBC involves targeting these mechanisms.