2.4.1. Autoimmune Diseases
HCQ belongs to the group of the disease-modifying antirheumatic drug (DMARD), which comprises drugs that are not chemically relted, sharing the same efficacy in dampening the progression of rheumatoid arthritis [122]. It often occurs also that glucocorticoids or natural antioxidant substances are included in the coadjutant therapy of rheumatoid arthritis [123]. A multicenter, randomized clinical trial analyzed the tolerability and the efficacy of combined therapy, including HCQ, sulphasalazine, MXT, and PRD with respect to the use of a single antirheumatic drug in the caring of early rheumatoid arthritis for two years. A total of 195 patients were equally divided into two groups to follow the assigned therapeutic protocol. The primary aim of clinical remission was achieved after one year by 24 of the 97 patients under combinatory therapy, while only by 11 of 98 single-drug therapy users, but this trend was further confirmed during the second year. After one year, 75% of subjects under combinatory therapy and 60% of those under single-therapy reached clinical improvement, intended as 50% clinical response. In terms of tolerability, the cotreatment resulted not to be more dangerous with respect to the single drug [123]. In a prospective trial, patients with the diagnosis of rheumatoid arthritis were scheduled to receive cotreatment of sulphasalazine (1–3 g/day), MXT (7.5–15 mg/week), and HCQ (200 mg/day) for six months. Significant improvements in clinical parameters revealed the efficacy of the cotreatment in counteracting endothelial injury. Indeed, the blood concentrations of endothelial injury markers, mainly soluble E selectin and thrombomodulin, experienced a significant drop after the cotreatment [124]. Likewise, a single-blinded clinical trial on 281 patients confirmed the better therapeutic efficiency of cotreatment (25 mg/week MXT, 2 g/day of sulphasalazine, and 400 mg/day HCQ p.o. plus intramuscular injection (i.m.) doses of 120 mg of methylprednisolone or 80 mg of triamcinolone) with respect to single therapy after three months, without significant differences in side effects [125]. Proofs of the better antirheumatic potential of the combination of drugs with respect to single therapy derived from an observational study that evaluated the higher improvement of quality of patients’ life after one year of coadministration of MXT, HCQ, and corticosteroids with respect to single MXT, or HCQ, or their combination with corticosteroids [126]. Great insights in disease remission were provided by a clinical trial involving 17 patients with active rheumatoid arthritis where the chronic inflammatory status of joints was evaluated through the 18F-FDG PET method. It was found that cotreatment with 7.5–15 mg/week of MXT, 2 g/day of sulphasalazine, 5 mg/kg/day of HCQ and a low dose of oral PRD (under 10 mg/day) is associated with a reduction of 30% in 18F-FDG uptake measures on PET imaging in 81% of patients after four weeks [127]. Although HCQ is effective and well-tolerated, other therapeutic alternatives have emerged in recent years. Among them, monoclonal antibodies are the most promising. In a multicenter open-label clinical trial, performed on 60 patients with juvenile idiopathic arthritis for 54 weeks, the combination of infliximab monoclonal antibodies with a conventional antirheumatic drug provided the better response in terms of disease inactivation with respect to DMARD administration [128].
In addition to rheumatoid arthritis patients, HCQ is also used in lupus erythematosus, another autoimmune disease. Regarding lupus erythematosus, HCQ is widely used. In vivo studies on a NZB/W F1 murine model of lupus showed that HCQ in combination with PRD (2.5 mg/kg/day and 1 mg/kg/day p.o.) decreased autoantibody production, as well as being able to inhibit toll-like receptor activation, resulting in the down-regulation of type I interferon (IFN-α) which is deeply implicated in lupus pathogenesis. The efficacy of treatment is due to the ability of drugs to alter the expression of urinary and immune cell micro RNA that contribute to lupus progression by post-transcriptional modulation of genes involved in the immune response, pro-inflammatory cytokines production and toll-like receptor pathways [129]. In association with low-dose aspirin, HCQ is also indicated for thromboprophylaxis in patients with lupus. The occurrence of thrombotic events was recorded for 13 years in 189 patients, showing that the cardiovascular complications were more frequent in patients treated only with aspirin, while HCQ (up to 600 mg) was associated with a stronger thrombo-protective effect in patients with lupus [130].
Thanks to its immunomodulatory properties, HCQ (20 mg/kg) was revealed to be useful in graft-versus-host disease, in combination with cyclosporine A. They synergistically suppressed T cell response, allowing the reduction of the dose of drugs in mice [131].