PMC:7696151 / 42913-47447 JSONTXT

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Rheumatoid Arthritis\nRheumatoid arthritis is a systemic autoimmune disease, characterized by chronic inflammation and damage to the joints. Immune dysregulation underlies the pathogenesis of rheumatoid arthritis, leading to uncontrolled production of antibodies, mainly rheumatoid factor and citrullinate, involved in the autoreactivity against cartilage and bone [117]. It is estimated that the prevalence of rheumatoid arthritis is around 1%, mainly in women [118]. The immunosuppressive effects of HCQ are due to the ability to modulate T-cell and B-cell hyperactivity, resulting in a reduction of pro-inflammatory cytokine gene expression. As the involvement of neutrophils in this disease, Jancinova, Pazourekova, Lucova, Perecko, Mihalova, Bauerova, Nosal and Drabikova [75] investigated the impact of oral HCQ administration on these cells, in rats with adjuvant arthritis. At doses of 40 mg/kg daily, per oral administration (p.o.), it strongly decreased the blood concentration of neutrophil-derived oxidants, involved in the tissue damage and the onset of chronic inflammation [75].\nA 36-week randomized, double-blind, placebo-controlled trial has evaluated the effect of the administration of HCQ in a dose of up to 7 mg/kg per day (maximum 400 mg/day) in patients with rheumatoid arthritis. Within 36 weeks and during the study, HCQ showed statistically significant benefits on physical function, mainly on synovitis and joint pain, without side effects with respect to the control. Moreover, HCQ was associated with a decrement of corticosteroid injections. By contrast, no improvements in psychological function have been demonstrated [76]. Two comparative double-blind, randomized trials, involving 60 patients each, with sulfasalazine and HCQ have demonstrated that HCQ showed no significant differences among overall clinical effects respect to sulfasalazine, but presented a later onset. In the first study, patients treated with HCQ (400 mg/day for 6 months and 200 mg/day for the next 6 months) experienced time-dependent statistically significant improvements in morning stiffness, pain, swollen joints, together with a decrease in blood levels of immunoglobulin M and erythrocyte sedimentation rate [77], while, in the second study, the same treatment was associated to no erosions in the 12% of the patients [78].\nIn patients with rheumatoid arthritis, the cardiovascular risk is more than doubled, compared to the healthy population. Chronic inflammatory status leads to an intensification of the atherosclerotic process, resulting in a higher susceptibility to hypertension, obesity, and metabolic syndrome. The overproduction of IL-6 is strictly related to lipid profile alterations, given its role in adipose tissue lipolysis. The inflammation and endothelial damage are exacerbated by leptin production. Batun-Garrido, Salas-Magana and Juarez-Rojop [79] found a significant correlation between HCQ treatment and lower IL-6 and leptin levels. The positive effect of HCQ on dyslipidemia was also confirmed by Morris, Wasko, Antohe, Sartorius, Kirchner, Dancea and Bili [80] in a cohort study involving 706 rheumatoid arthritis diagnosed patients, finding a significant and stable cholesterol-lowering, mainly Low-Density Lipoprotein (LDL), and triglyceride decrease associated with HCQ intake (6.5 mg/kg/day). A small but statistically significant amelioration in total cholesterol and LDL under HCQ treatment at the same dosage was also highlighted by a randomized, double-blind cross-over trial on patients with rheumatoid arthritis [81]. The correlation between HCQ and cardiovascular risk was also assessed in a cross-sectional observational study involving 177 women with rheumatoid arthritis. At doses of 200 mg/kg/day, HCQ usage led to lower fasting glucose in women, arising as a valuable tool to enhance glycemic control [82]. However, apparent different outcomes were derived from a randomized double-blind crossover trial, recruiting 23 non-diabetic subjects with stable rheumatoid arthritis to receive 6.5 mg/kg/day of HCQ for eight weeks. For these patients, no significant changes in insulin resistance were observable [81]. This study evaluated only insulin sensitivity, by Homeostatic Model Assessment (HOMA) index, without considering insulin metabolism. Thus, inconsistency should be explained by this factor, together with the short duration of treatment. The anti-diabetic properties of HCQ have been also assessed in patients without arthritis, as reported in the next paragraphs."}

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Rheumatoid Arthritis\nRheumatoid arthritis is a systemic autoimmune disease, characterized by chronic inflammation and damage to the joints. Immune dysregulation underlies the pathogenesis of rheumatoid arthritis, leading to uncontrolled production of antibodies, mainly rheumatoid factor and citrullinate, involved in the autoreactivity against cartilage and bone [117]. It is estimated that the prevalence of rheumatoid arthritis is around 1%, mainly in women [118]. The immunosuppressive effects of HCQ are due to the ability to modulate T-cell and B-cell hyperactivity, resulting in a reduction of pro-inflammatory cytokine gene expression. As the involvement of neutrophils in this disease, Jancinova, Pazourekova, Lucova, Perecko, Mihalova, Bauerova, Nosal and Drabikova [75] investigated the impact of oral HCQ administration on these cells, in rats with adjuvant arthritis. At doses of 40 mg/kg daily, per oral administration (p.o.), it strongly decreased the blood concentration of neutrophil-derived oxidants, involved in the tissue damage and the onset of chronic inflammation [75].\nA 36-week randomized, double-blind, placebo-controlled trial has evaluated the effect of the administration of HCQ in a dose of up to 7 mg/kg per day (maximum 400 mg/day) in patients with rheumatoid arthritis. Within 36 weeks and during the study, HCQ showed statistically significant benefits on physical function, mainly on synovitis and joint pain, without side effects with respect to the control. Moreover, HCQ was associated with a decrement of corticosteroid injections. By contrast, no improvements in psychological function have been demonstrated [76]. Two comparative double-blind, randomized trials, involving 60 patients each, with sulfasalazine and HCQ have demonstrated that HCQ showed no significant differences among overall clinical effects respect to sulfasalazine, but presented a later onset. In the first study, patients treated with HCQ (400 mg/day for 6 months and 200 mg/day for the next 6 months) experienced time-dependent statistically significant improvements in morning stiffness, pain, swollen joints, together with a decrease in blood levels of immunoglobulin M and erythrocyte sedimentation rate [77], while, in the second study, the same treatment was associated to no erosions in the 12% of the patients [78].\nIn patients with rheumatoid arthritis, the cardiovascular risk is more than doubled, compared to the healthy population. Chronic inflammatory status leads to an intensification of the atherosclerotic process, resulting in a higher susceptibility to hypertension, obesity, and metabolic syndrome. The overproduction of IL-6 is strictly related to lipid profile alterations, given its role in adipose tissue lipolysis. The inflammation and endothelial damage are exacerbated by leptin production. Batun-Garrido, Salas-Magana and Juarez-Rojop [79] found a significant correlation between HCQ treatment and lower IL-6 and leptin levels. The positive effect of HCQ on dyslipidemia was also confirmed by Morris, Wasko, Antohe, Sartorius, Kirchner, Dancea and Bili [80] in a cohort study involving 706 rheumatoid arthritis diagnosed patients, finding a significant and stable cholesterol-lowering, mainly Low-Density Lipoprotein (LDL), and triglyceride decrease associated with HCQ intake (6.5 mg/kg/day). A small but statistically significant amelioration in total cholesterol and LDL under HCQ treatment at the same dosage was also highlighted by a randomized, double-blind cross-over trial on patients with rheumatoid arthritis [81]. The correlation between HCQ and cardiovascular risk was also assessed in a cross-sectional observational study involving 177 women with rheumatoid arthritis. At doses of 200 mg/kg/day, HCQ usage led to lower fasting glucose in women, arising as a valuable tool to enhance glycemic control [82]. However, apparent different outcomes were derived from a randomized double-blind crossover trial, recruiting 23 non-diabetic subjects with stable rheumatoid arthritis to receive 6.5 mg/kg/day of HCQ for eight weeks. For these patients, no significant changes in insulin resistance were observable [81]. This study evaluated only insulin sensitivity, by Homeostatic Model Assessment (HOMA) index, without considering insulin metabolism. Thus, inconsistency should be explained by this factor, together with the short duration of treatment. The anti-diabetic properties of HCQ have been also assessed in patients without arthritis, as reported in the next paragraphs."}

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Rheumatoid Arthritis\nRheumatoid arthritis is a systemic autoimmune disease, characterized by chronic inflammation and damage to the joints. Immune dysregulation underlies the pathogenesis of rheumatoid arthritis, leading to uncontrolled production of antibodies, mainly rheumatoid factor and citrullinate, involved in the autoreactivity against cartilage and bone [117]. It is estimated that the prevalence of rheumatoid arthritis is around 1%, mainly in women [118]. The immunosuppressive effects of HCQ are due to the ability to modulate T-cell and B-cell hyperactivity, resulting in a reduction of pro-inflammatory cytokine gene expression. As the involvement of neutrophils in this disease, Jancinova, Pazourekova, Lucova, Perecko, Mihalova, Bauerova, Nosal and Drabikova [75] investigated the impact of oral HCQ administration on these cells, in rats with adjuvant arthritis. At doses of 40 mg/kg daily, per oral administration (p.o.), it strongly decreased the blood concentration of neutrophil-derived oxidants, involved in the tissue damage and the onset of chronic inflammation [75].\nA 36-week randomized, double-blind, placebo-controlled trial has evaluated the effect of the administration of HCQ in a dose of up to 7 mg/kg per day (maximum 400 mg/day) in patients with rheumatoid arthritis. Within 36 weeks and during the study, HCQ showed statistically significant benefits on physical function, mainly on synovitis and joint pain, without side effects with respect to the control. Moreover, HCQ was associated with a decrement of corticosteroid injections. By contrast, no improvements in psychological function have been demonstrated [76]. Two comparative double-blind, randomized trials, involving 60 patients each, with sulfasalazine and HCQ have demonstrated that HCQ showed no significant differences among overall clinical effects respect to sulfasalazine, but presented a later onset. In the first study, patients treated with HCQ (400 mg/day for 6 months and 200 mg/day for the next 6 months) experienced time-dependent statistically significant improvements in morning stiffness, pain, swollen joints, together with a decrease in blood levels of immunoglobulin M and erythrocyte sedimentation rate [77], while, in the second study, the same treatment was associated to no erosions in the 12% of the patients [78].\nIn patients with rheumatoid arthritis, the cardiovascular risk is more than doubled, compared to the healthy population. Chronic inflammatory status leads to an intensification of the atherosclerotic process, resulting in a higher susceptibility to hypertension, obesity, and metabolic syndrome. The overproduction of IL-6 is strictly related to lipid profile alterations, given its role in adipose tissue lipolysis. The inflammation and endothelial damage are exacerbated by leptin production. Batun-Garrido, Salas-Magana and Juarez-Rojop [79] found a significant correlation between HCQ treatment and lower IL-6 and leptin levels. The positive effect of HCQ on dyslipidemia was also confirmed by Morris, Wasko, Antohe, Sartorius, Kirchner, Dancea and Bili [80] in a cohort study involving 706 rheumatoid arthritis diagnosed patients, finding a significant and stable cholesterol-lowering, mainly Low-Density Lipoprotein (LDL), and triglyceride decrease associated with HCQ intake (6.5 mg/kg/day). A small but statistically significant amelioration in total cholesterol and LDL under HCQ treatment at the same dosage was also highlighted by a randomized, double-blind cross-over trial on patients with rheumatoid arthritis [81]. The correlation between HCQ and cardiovascular risk was also assessed in a cross-sectional observational study involving 177 women with rheumatoid arthritis. At doses of 200 mg/kg/day, HCQ usage led to lower fasting glucose in women, arising as a valuable tool to enhance glycemic control [82]. However, apparent different outcomes were derived from a randomized double-blind crossover trial, recruiting 23 non-diabetic subjects with stable rheumatoid arthritis to receive 6.5 mg/kg/day of HCQ for eight weeks. For these patients, no significant changes in insulin resistance were observable [81]. This study evaluated only insulin sensitivity, by Homeostatic Model Assessment (HOMA) index, without considering insulin metabolism. Thus, inconsistency should be explained by this factor, together with the short duration of treatment. The anti-diabetic properties of HCQ have been also assessed in patients without arthritis, as reported in the next paragraphs."}