An observational study to identify causative factors for not using hydroxychloroquine in systemic lupus erythematosus.

Hydroxychloroquine (HCQ) use is indicated for patients with systemic lupus erythematosus (SLE). Nevertheless, reports discussing the reasons for not prescribing HCQ are limited. We identified the factors that interfere with HCQ use in patients with SLE. This observational, single-center study included data from 265 patients with SLE in 2019. The patients were categorized into groups with and without a history of HCQ use. Between these groups, clinical characteristics were compared using univariate analysis and logistic regression models. Among the 265 patients, 133 (50.2%) had a history of HCQ use. Univariate analysis identified older age; longer disease duration; lower prednisolone dose, clinical SLE disease activity index 2000, and estimated glomerular filtration rate; higher C3 level; and lower anti-double-stranded DNA antibody concentration as HCQ non-use-related variables. Logistic regression models identified a positive association between HCQ non-use and longer disease duration (odds ratio [OR] 1.08), prednisolone dose ≤ 7.5 mg/day (OR 4.03), C3 level ≥ 73 mg/dL (OR 2.15), and attending physician having graduated > 10 years prior (OR 3.19). In conclusion, a longer disease duration, lower prednisolone dose, higher C3 level, and longer time since attending physicians' graduation correlated with HCQ non-use. Physicians and patients should be educated to facilitate HCQ use despite these factors.

A case report of Vancomycin in the treatment of Q fever endocarditis.

The patient, a 43-year-old male, was admitted to the hospital with gradually aggravated exertional palpitations and chest tightness over a 2-day period. Upon hospital admission, a cardiac ultrasound revealed aortic valve redundancy, however multiple blood culture investigations came back negative. Blood mNGS was perfected, revealing Coxiella burnetii, and the diagnosis of Q fever (query fever) was established. The temperature and inflammatory indices of the patient were all normal with the treatment of vancomycin before cardiac surgery. But for the potential liver damage of and the Coxiella burnetii was still positive in the anti-phase II IgG titer, the doxycycline and hydroxychloroquine instead of vancomycin were applied for the patient. Despite receiving standardized anti-infective therapy of doxycycline combined with hydroxychloroquine, this patient had fever and increased leukocytes following surgery. After the addition of vancomycin as an anti-infective treatment, the temperature and leukocytes improved quickly. During the treatment of vancomycin, a discovery of liver injury may have resulted. These findings provide new therapy options for future professionals.

Effect of hydroxychloroquine blood concentration on the efficacy and ocular toxicity of systemic lupus erythematosus.

In the absence of evidence-based guidance on the impact of hydroxychloroquine (HCQ) blood concentration on efficacy and ocular toxicity in systemic lupus erythematosus (SLE), the clinical monitoring of HCQ blood concentration is not yet widely performed, which raised concerns about the necessity of conducting HCQ blood concentration monitoring. In this retrospective study, we consecutively enrolled 135 patients with SLE who received HCQ treatment for more than 6 months from July 2022 to December 2022. Ocular toxicity was evaluated by collecting relevant retinal parameters using optical coherence tomography angiography (OCTA). Therapeutic efficacy was evaluated using the SLE disease activity index (SLEDAI) and relevant clinical parameters. HCQ blood concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Spearman correlation analysis revealed that the cumulative dose of HCQ was positively correlated with the foveal avascular zone (FAZ) perimeter and FAZ area (r = 0.734, P < 0.001; r = 0.784, P < 0.001). Meanwhile, the treatment duration of HCQ was positively correlated with FAZ perimeter and FAZ area (r = 0.761, P < 0.001; r = 0.882, P < 0.001). The univariate and multivariate logistic regression analyses indicated that HCQ blood concentration was associated with the disease activity of patients with SLE (odds ratio 0.994, 95% CI 0.990-0.999). HCQ blood concentration may be an important factor in assessing the therapeutic effectiveness of SLE patients. The HCQ-related ocular toxicity was a long-term effect related to long term exposure, rather than the blood concentration of HCQ at the time of testing. More importantly, when addressing HCQ-related ocular toxicity, it may be crucial to pay attention to the cumulative dose and treatment duration of HCQ.

[Low disease activity and remission status of systemic lupus erythematosus in a real-world study].

OBJECTIVE: To investigate the rates of low disease activity and clinical remission in patients with systemic lupus erythematosus (SLE) in a real-world setting, and to analyze the related factors of low disease activity and clinical remission. METHODS: One thousand patients with SLE were enrolled from 11 teaching hospitals. Demographic, clinical and laboratory data, as well as treatment regimes were collec-ted by self-completed questionnaire. The rates of low disease activity and remission were calculated based on the lupus low disease activity state (LLDAS) and definitions of remission in SLE (DORIS). Charac-teristics of patients with LLDAS and DORIS were analyzed. Multivariate Logistic regression analysis was used to evaluate the related factors of LLDAS and DORIS remission. RESULTS: 20.7% of patients met the criteria of LLDAS, while 10.4% of patients achieved remission defined by DORIS. Patients who met LLDAS or DORIS remission had significantly higher proportion of patients with high income and longer disease duration, compared with non-remission group. Moreover, the rates of anemia, creatinine elevation, increased erythrocyte sedimentation rate (ESR) and hypoalbuminemia was significantly lower in the LLDAS or DORIS group than in the non-remission group. Patients who received hydroxychloroquine for more than 12 months or immunosuppressant therapy for no less than 6 months earned higher rates of LLDAS and DORIS remission. The results of Logistic regression analysis showed that increased ESR, positive anti-dsDNA antibodies, low level of complement (C3 and C4), proteinuria, low household income were negatively related with LLDAS and DORIS remission. However, hydroxychloroquine usage for longer than 12 months were positively related with LLDAS and DORIS remission. CONCLUSION: LLDAS and DORIS remission of SLE patients remain to be improved. Treatment-to-target strategy and standar-dized application of hydroxychloroquine and immunosuppressants in SLE are recommended.

Quality-by-design ecofriendly potentiometric sensor for rapid monitoring of hydroxychloroquine purity in the presence of toxic impurities.

Hydroxychloroquine (HCQ) is prescribed to treat malaria and certain autoimmune diseases. Recent studies questioned its efficiency in relieving COVID-19 symptoms and improving clinical outcomes. This work presents a quality-by-design approach to develop, optimize, and validate a potentiometric sensor for the selective analysis of HCQ in the presence of its toxic impurities (key starting materials), namely 4,7-Dichloroquinoline (DCQ) and hydroxynovaldiamine (HND). The study employed a custom experimental design of 16 sensors with different ion exchangers, plasticizers, and ionophores. We observed the Nernstian slopes, correlation coefficients, quantification limit, response time, and selectivity coefficient for DCQ and HND. The computer software constructed a prediction model for each response. The predicted responses strongly correlate to the experimental ones, indicating model fitness. The optimized sensor achieved 93.8% desirability. It proved a slope of 30.57 mV/decade, a correlation coefficient of 0.9931, a quantification limit of 1.07 × 10-6 M, a detection limit of 2.18 × 10-7 M, and a fast response of 6.5 s within the pH range of 2.5-8.5. The sensor was successfully used to determine HCQ purity in its raw material. The sensor represents a potential tool for rapid, sensitive, and selective monitoring of HCQ purity during industrial production from its starting materials.

Efficacy and safety of therapeutic strategies for human brucellosis: A systematic review and network meta-analysis.

BACKGROUND: Human brucellosis is a neglected, re-emerging, and endemic zoonosis in many countries. The debilitating and disabling potential of the disease is a warning about its morbidity, generating socioeconomic impact. This review aims to update the current evidence on the efficacy and safety of therapeutic options for human brucellosis using the network meta-analysis (NMA). METHODOLOGY: A systematic search was conducted in four different databases by independent reviewers to assess overall therapy failure, adverse events, and time to defervescence associated with different therapies. Randomized clinical trials (RCTs) evaluating any therapeutic drug intervention were selected, excluding non-original studies or studies related to localized forms of the disease or with less than 10 participants. Data were analyzed by frequentist statistics through NMA by random effects model. The risk of bias and certainty of evidence was assessed, this review was registered at PROSPERO. RESULTS: Thirty-one (31) RCTs involving 4167 patients were included. Three networks of evidence were identified to evaluate the outcomes of interest. Triple therapy with doxycycline + streptomycin + hydroxychloroquine for 42 days (RR: 0.08; CI 95% 0.01-0.76) had a lower failure risk than the doxycycline + streptomycin regimen. Doxycycline + rifampicin had a higher risk of failure than doxycycline + streptomycin (RR: 1.96; CI 95% 1.27-3.01). No significant difference was observed between the regimens when analyzing the incidence of adverse events and time to defervescence. In general, most studies had a high risk of bias, and the results had a very low certainty of evidence. CONCLUSIONS: This review confirmed the superiority of drugs already indicated for treating human brucellosis, such as the combination of doxycycline and aminoglycosides. The association of hydroxychloroquine to the dual regimen was identified as a potential strategy to prevent overall therapy failure, which is subject to confirmation in future studies.

New proposal for a multimodal imaging approach for the subclinical detection of hydroxychloroquine-induced retinal toxicity in patients with systemic lupus erythematosus.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

UCOMB-real life data: treatment strategies for chronic urticaria patients with comorbidities.

BACKGROUND: There is a lack of real-life safety data on treatment options for chronic urticaria in the presence of comedication and comorbidities. METHODS: We present a single-center UCARE pilot study of 212 outpatients with chronic urticaria. Patients were divided into three groups according to different CU therapies according to international guidelines. RESULTS: Of 212 patients, 108 (mean age 48.9 years, 71.3% female) had 59 comorbidities, including cardiovascular, autoimmune and malignant diseases. Patients were followed for a mean of 24.6 months (SD ± 21.3). Urticaria therapies were divided into three groups: A: 105 (97.2%) with omalizumab and 2nd generation antihistamines), B: 16 patients (14.8%): dual therapy with antihistamines and cyclosporine in 10 (9.3%), montelukast in five (4. 6%), dapsone in four (3.7%), hydroxychloroquine in one patient (0.9%), C: 12 (11.1%) patients received a third drug for 4.9 months (SD ± 3.2) and one quadruple therapy (2.1 months). 10 out of 12 (83.3%) patients received montelukast, two (16.7%) cyclosporine, two (16.7%) dapsone and one (8.3%) hydroxychloroquine as a third drug for chronic urticaria. CONCLUSIONS: Combining treatment modalities for chronic urticaria and comorbidities are available and feasible with a good safety profile.

Hydroxychloroquine had neutral effect on long-term risk of malignancy in rheumatoid arthritis patients: A population-based retrospective cohort study.

BACKGROUND: The cancer risk in rheumatoid arthritis (RA) patients has been discussed. Hydroxychloroquine (HCQ) may exert protective effects against malignancy. The study investigated the association between HCQ use and the risk of subsequent malignancy in RA patients. METHODS: Catastrophic illness certificated RA patients were extracted from the National Health Insurance Research Database. The index date was set 180 days after the RA diagnosis date to avoid immortal time bias. Two groups were matched in a 1-to-1 ratio by propensity score regarding age, gender, index date, relevant comorbidities, and comedication. HCQ users prior to the diagnosis of RA were exempted to ensure compliance with the new-user design. Cancers diagnosed before or less than 180 days after the index date were excluded to mitigate protopathic bias. The study adopted the Kaplan-Meier curve and Cox proportional hazards model to examine the association between HCQ use and cancer risk. The assumption of proportional hazard was also tested. RESULTS: Based on strict criteria, we included 492 eligible RA patients and divided them into study and control groups (N = 246 in each group). HCQ users exhibited a neutral risk of cancer relative to the controls (adjusted hazard ratio, 0.99; 95% CI, 0.44-2.21, p > .05). The assumption of proportional hazard was not violated. CONCLUSION: This study does not observe the effect of using HCQ as a primary regimen to prevent cancer in RA patients. We are assured that HCQ is not associated with an increased risk of subsequent malignancy in RA patients. Further mechanistic research is needed.

Risk of uveitis in autoimmune diseases patients treated with hydroxychloroquine: A population-based retrospective cohort study.

OBJECTIVE: Uveitis is a common manifestation of various autoimmune diseases and can lead to severe visual impairment. Hydroxychloroquine (HCQ) is an antimalarial drug that is also used to treat autoimmune diseases. The aim of this study was to investigate the association between HCQ use and the incidence of uveitis in patients with autoimmune diseases, as well as to identify potential risk factors for the development of uveitis in this study. METHODS: We conducted a population-based cohort study using a nationwide database to investigate the incidence of uveitis in patients with autoimmune diseases who received HCQ treatment. We selected non-HCQ comparison cohort at a 1:1 ratio by propensity score matching on age, sex, index date, urbanization, income, comorbidities, and medications. The data were analyzed using Cox proportional hazards models, and propensity score matching (PSM) was used to reduce selection bias. RESULTS: Our study included 15 822 patients with autoimmune diseases. After 1:1 PSM, there were 4555 individuals in both the HCQ group (n = 4555) and the non-HCQ group (n = 4555). The multiple Cox proportional hazard regression analysis was used for the estimation of adjusted hazard ratios on uveitis. After PSM, the adjusted hazard ratio for the HCQ group was 0.74 (95% CI = 0.58-0.95). These findings suggest that HCQ may play a protective role in reducing the risk of uveitis in patients with autoimmune diseases, including rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus groups. The Kaplan-Meier survival curves also showed a significantly lower incidence of uveitis in the HCQ group (log-rank = 0.0229) after PSM. CONCLUSION: HCQ use is associated with a lower incidence of uveitis in patients with autoimmune diseases. Further studies are needed to confirm this association and to investigate the underlying mechanisms.

Evaluation of weak genotoxicity of hydroxychloroquine in human TK6 cells.

Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 µM with or without exogenous metabolic activation. Subsequently, we found that short-term (3-4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD50 values (BMDL50) for MN induction in TK6 cells were about 19.7 µM for CQ and 16.3 µM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs.

A Box-Behnken design-based chemometric approach to optimize the sono-photodegradation of hydroxychloroquine in water media using the Fe(0)/S2O82-/UV system.

The huge utilization of hydroxychloroquine in autoimmune infections led to an abnormal increment in its concentration in wastewater, which can pose a real risk to the environment, necessitating the development of a pretreatment technique. To do this, we are interested in researching how hydroxychloroquine degrades in contaminated water. The main goal of this investigation is to optimize the operating conditions for the sono-photodegradation of hydroxychloroquine in water using an ultrasound-assisted Fe(0)/ S 2 O 8 2 - /UV system. To get adequate removal of HCQ, a chemometric method based on the Box-Behnken design was applied to optimize the influence of the empirical parameters selected, including Fe(0) dose, S 2 O 8 2 - concentration, pH, and initial HCQ concentration. The quadratic regression model representing the HCQ removal rate (η(%)) was evolved and validated by ANOVA. The optimal conditions as a result of the above-mentioned trade-off between the four input variables, with η(%) as the dependent output variable, were captured using RSM methodology and the composite desirability function approach. For HCQ full decomposition, the optimal values of the operating factors are as follows: S 2 O 8 2 - dose, 194.309 mg/L; Fe(0) quantity, 198.83 mg/L; pH = 2.017, and HCQ initial dose of 296.406 mg/L. Under these conditions, the HCQ removal rate, achieved after 60 min of reaction, attained 98.95%.

Excellent response to treatment with hydroxychloroquine in pediatric patients with SLE-related immune thrombocytopenia.

BACKGROUND: Pediatric immune thrombocytopenia (ITP) may precede systemic autoimmune disorders. In adolescent patients with ITP, routine screening for systemic lupus erythematosus (SLE) may be performed by testing for antinuclear antibody (ANA) titer. Hydroxychloroquine (HCQ) is a safe and effective immunomodulatory drug in patients with SLE but rarely used in ITP. We analyzed the platelet count response and safety of HCQ in treating pediatric patients with SLE-related ITP. METHODS: A retrospective study including pediatric patients with ITP and definite or incomplete SLE, who were treated with HCQ during 2010-2021. SLE was defined by ANA titer ≥ 1:160 as measured by immunofluorescence and ≥10 points according to the 2019 EULAR/ACR 2019 classification criteria, while patients with incomplete SLE achieved a score < 10. Complete response (CR) of the platelet count was defined as platelet count > 100 × 109/L; partial response (PR) as platelet count 30-100 × 109/L and exceeding ≥ twice baseline counts. RESULTS: Of the 17 patients included (median age 15.5 years; IQR 3.6), 15 (88.2%) were female, 13 had definite SLE, and four had incomplete SLE. HCQ was initiated at a median of 17 months after ITP diagnosis with a median platelet count of 38 × 109/L (IQR 28). At 8 weeks, 8 (47.1%) patients responded, including 6 (35.3%) achieving CR. After one year, the overall response was 82.4%, with the remaining patients having stable platelet counts requiring no additional ITP therapy. The response was maintained at a median follow-up of 42 months. No adverse effects to HCQ were noted. CONCLUSION: Pediatric patients with SLE-related ITP may benefit from treatment with HCQ.

Primary Sjogren's Syndrome with Bicytopenia: A Case Report.

Sjogren's syndrome is a chronic multisystem autoimmune disease presenting a wide variety of clinical manifestations ranging from mild sicca symptoms to severe systemic symptoms involving pulmonary, renal, musculoskeletal, cutaneous, and haematological diseases. These symptomatic diversities can delay the correct diagnosis of Sjogren's Syndrome for a long time. Here, we report the case of a 59-year-old woman with fatigue and weakness in whom bicytopenia was documented. A thorough bicytopenia workup brought us to the final diagnosis of Sjogren's syndrome. Hydroxychloroquine was started which normalized the patient's blood parameters and clinical symptoms. The haematological alterations in Sjogren's syndrome are not pathognomonic. However, only bicytopenia can be the initial presentation of Sjogren's syndrome as in our patient. Therefore, inexplicable bicytopenia in a middle-aged female may alert the clinician about the possibility of Sjogren's syndrome. Keywords: autoimmune diseases; case reports; cytopenia; sjogren's syndrome.

Efficacy and Safety of Hydroxychloroquine in Patients with IgA Nephropathy: A Meta-Analysis.

AIM: The purpose of this study was to determine efficacy and safety of hydroxychloroquine (HCQ) for patients with IgA nephropathy (IgAN). METHODS: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, Wanfang database, Chinese National Knowledge Infrastructure and VIP database up to February 2023 were searched for associated studies comparing HCQ with any other nonHCQ for treating IgAN. The effects of proteinuria, a 50% decrease in proteinuria, estimated glomerular filtration rate (eGFR) and adverse events in patients with IgAN were examined in a meta-analysis. Data were extracted and pooled using RevMan 5.3. RESULTS: Three randomized controlled trials (RCTs), two retrospective and two prospective studies (675 patients) that matched our inclusion criteria were identified. Compared with a control group, HCQ significantly reduced proteinuria (mean difference (MD): -0.26, 95% confidence interval (CI): -0.44 to -0.08, p < 0.01). Patients receiving HCQ plus renin-angiotensin system inhibitors (RASSi) had a better efficacy in proteinuria alleviation and a 50% decrease in proteinuria compared with control groups (MD: -0.38, 95% CI: -0.50 to -0.25, p < 0.001 and relative risk (RR) = 3.31, 95% CI: 1.73 to 6.36, p < 0.001). No appreciable variations were observed in eGFR between HCQ groups and control groups in treating patients with IgAN (MD: -2.00, 95% CI: -4.36 to 0.36, p = 0.10). Moreover, no serious adverse events were observed during HCQ treatment. CONCLUSIONS: Our results indicate HCQ is an efficient, secure treatment for IgAN.

Drug upgrade: A complete methodology from old drug to new chemical entities using Nematic Protein Organization Technique.

Drug repurposing is used to propose new therapeutic perspectives. Here, we introduce "Drug Upgrade", that is, characterizing the mode of action of an old drug to generate new chemical entities and new therapeutics. We proposed a novel methodology covering target identification to pharmacology validation. As an old drug, we chose hydroxychloroquine (HCQ) for its well-documented clinical efficacy in lupus and its side effect, retinal toxicity. Using the Nematic Protein Organization Technique (NPOT®) followed by liquid chromatography-tandem mass spectrometry analyses, we identified myeloperoxidase (MPO) and alpha-crystallin ß chain (CRYAB) as primary and secondary targets to HCQ from lupus patients' peripheral blood mononuclear cells (PBMCs) and isolated human retinas. Surface plasmon resonance (SPR) and enzymatic assays confirmed the interaction of HCQ with MPO and CRYAB. We synthesized INS-072 a novel analog of HCQ that increased affinity for MPO and decreased binding to CRYAB compared to HCQ. INS-072 delayed cutaneous eruption significantly compared to HCQ in the murine MRL/lpr model of spontaneous lupus and prevents immune complex vasculitis in mice. In addition, long-term HCQ treatment caused retinal toxicity in mice, unlike INS-072. Our study illustrates a method of drug development, where new applications or improvements can be explored by fully characterizing the drug's mode of action.