2.3.2. Lupus Erythematosus
Systemic lupus erythematosus is a multisystemic autoimmune chronic inflammatory disorder that mainly involves joints, mucosae, skin, and endothelial vessels [90]. For a long time, HCQ has played a marginal role in the overall management of the disease. Since the 90s, the first evidence of HCQ effectiveness in controlling lupus erythematosus manifestations allowed its employment as a first-line medicament. Although it was not recommended in single therapy, the immunomodulating properties of HCQ seem to play an important role in the disease pathogenesis. It is associated with a decrement of exacerbation events, as well as protective effects towards vascular and thrombotic events [85]. Indeed, a 24-week randomized, double-blind placebo-controlled trial demonstrated that the discontinuing of HCQ treatment (100–400 mg/kg/day for at least six months) increased the risk of exacerbations by 2.5 times in patients with quiescent lupus. People who interrupted the therapy exhibited constitutional symptoms of the disease, as well as skin rashes, arthritis, and ulcers [83]. A long-term randomized study evaluated the withdrawal effects of HCQ on quiescent lupus erythematosus patients, revealing that a reduction by up to 57% is associated with HCQ maintaining treatment (272 mg/day) [84]. A case-control study was carried out in order to define the role of HCQ in the survival of individuals affected by lupus. The positive correlation between HCQ and survival led to the consideration of this drug as a great therapeutic option at the proper dose (6.5 mg/kg/bw) in lupus management [85]. If these clinical trials demonstrated the advantages of keeping up the therapy with HCQ in preventing disease exacerbations, doubts persisted about the efficacy of this treatment in the control of more severe clinical forms [83]. As the important role of the imbalance between immune cell populations, several preclinical and clinical studies have evaluated the role of HCQ in restoring this equilibrium. In particular, elevated levels of effector lymphocyte T (Th17) that mediate the autoimmune answer and decreased levels of regulatory lymphocyte T (Treg) that guarantees the immune homeostasis, may be observed in autoimmune diseases, in particular in lupus. Lately, autophagy had risen among the emerging strategies to reestablish the immune balance. As HCQ is a well-known autophagy inhibitor, An, N. et al. [86] evaluated the influence of HCQ intake (100 mg/kg/day) in MRL/lpr mice with the lupus-like disease. After four weeks of treatment, HCQ clearly restored the immune balance, by both inhibiting Th17 response and enhancing Treg immunosuppressive effects. The levels of autoantibodies and the expression of inflammatory cytokines, mainly in Th17 cells, were remarkably lowered, due to the inhibition of the activated autophagy, as demonstrated by the increase of autophagic flux marker expression in Th17 and Treg, compared with controls. This randomized trial further evidenced that HCQ treatment also remarkably attenuated kidney inflammation, by limiting the migration of lymphoplasmacytic cells into renal tissues [86]. Preclinical outcomes have been confirmed by a prospective cohort study, involving 41 patients with a diagnosis of lupus treated with 400 mg/day of HCQ. Dysregulated cytokine and autoantibody production, deriving from high autoreactivity that characterizes lupus disease, has been restored by two months of HCQ administration, demonstrating its ability in modulating inflammatory response, with normalized complement activity and reduced levels of pro-inflammatory cytokines, mainly IL-6 and TNF-α [87]. In a multiethnic US cohort on 35 lupus patients, HCQ treatment resulted in significant clinical benefits towards disease progression, probably due to the inhibition of toll-like receptor activation, resulting in down-regulation of IFN-α, which plays a pivotal role in lupus pathogenesis [88].
Infiltrating cells, most of all mast cells, could involve skin tissues, causing one of the most common signs of lupus, skin rashes. The consequences of HCQ intake on skin lesions have been investigated on a MRL/lpr murine model of lupus at low (4 mg/kg/day) and high (40 mg/kg/day) oral doses. The number of mast cells decreased with respect to the drinking-water control (from 81 to 50 in low-dose and 12 in high dose), while the mortality rate decreased by up to three times in both treated groups with respect to the control. These in vivo results, together with a significant histopathological alteration regression, suggest that HCQ is a good tool against skin injury in lupus erythematosus [89].
The chronic inflammatory status that features lupus erythematosus leads to a higher susceptibility to cardiovascular complications. Lupus, indeed, is often characterized by endothelial dysfunction, the earliest marker of cardiovascular disease, as well as hypertension and renal damage. In a NZB/W F1 mice model of lupus, oral HCQ gavage of 10 mg/kg/day for five weeks reduced the incidence of thromboembolic events. Moreover, improvements in hypertension, renal damage, and heart hypertrophy occurred, probably due to the normalized endothelium response and reduction of Reactive Oxygen Species (ROS) attributable to HCQ intake [90]. The same effect of normalizing nitric oxide and ROS production have been confirmed in a NZB/W F1 murine model at different times. HCQ at 3 mg/kg/day p.o. protected vascular endothelium, with a strong improvement of endothelial dysfunction [91]. The benefits on atherosclerosis also pass through the lipid-lowering power of HCQ. A clinical study on 155 autoimmune patients revealed a statistically significant association between HCQ (400 mg/day) and a lessening of triglyceride and cholesterol levels, mainly LDL, while no HDL changes were observed [92]. By contrast, HCQ in patients with a mild or inactive condition had no significant effects on lipid profile. A survey involving 65 Chinese lupus patients, treated with HCQ (244 ± 86 mg/day), demonstrated that only triglycerides tended to be lowered, while no statistically significant changes are observable in cholesterol levels [119]. The use of HCQ may be helpful in minimizing cardiovascular risk by improving glycemic homeostasis in lupus patients. A cross-sectional study performed between 2000 and 2005 on 149 nondiabetic women affected by lupus estimated that a mean dose of 400 mg of HCQ affects insulin sensitivity and resistance, as assessed by HOMA index, as well as fasting glucose levels [82].
HCQ remains a worthwhile primary or additional therapy in lupus patients, considering the low cost and its safety profile, also in pregnancy. A randomized double-blind study reported the safety of HCQ during pregnancy, correlating this drug with less disease activity and a lower required dose of prednisone [93]. A 5-year prospective study evaluated the effect of HCQ discontinuation on lupus progression in pregnant women. As it occurs in no pregnant people, interruption of HCQ treatment is linked to an exacerbation of the disease. Moreover, there are no statistically significant differences regarding pregnant complications with respect to the control, showing no fetal toxicity at a dose of 6.5 mg/kg/day in breast milk [94]. Fetal safety has been also assessed in women with lupus nephritis by a multicenter study, reporting a reduction of 85% of the possibility of having a small for gestational age baby in patients under HCQ. Moreover, it exerted protective effects on fetal growth [120].