4. Discussion
rheumatoid arthritis, AMD, dry, dry AMD, retinal thinning, systemic lupus erythematosus, long-term damage, drusen, detachments of basal linear or laminar deposits, retinal nerve insult, RPE, non-exudative, Drusen, retinal toxicity, HIT
RHEUMATOID ARTHRITIS, ADVERSE EFFECTS, DISEASE, SYSTEMIC LUPUS ERYTHEMATOSUS, RETINA, DRUSEN, ADVERSE EFFECTS, DRUSEN
The HIT study is the first study to address the effect of HCQ on the clinical and imaging characteristics of AMD. The main finding of this double-blind randomized controlled trial was less visual acuity deterioration at one-year follow-up among participants treated with HCQ than those treated with a placebo. Moreover, compared to the control group, the mean number of drusen per eye was lower for ARDS2 in the study group. For the study group, compared to the control group, the proportion of eyes with increased drusen growth was less, for both ARDS2 and ARDS3 drusen, and the total drusen growth was less. Drusen volume growth, as calculated by the area and height measured with macular OCT, was also more reduced in the study than the control group. None of the participants showed HCQ toxicity or adverse effects.Currently, no treatment can reverse AMD, due to the nature of retinal nerve insult. Thus, a preventive treatment could change the entire natural course of this disease. The HIT study examined the possibility that HCQ could be such an agent.Previous studies have examined means of preventing the development of AMD. Some studies focused on the correlation of retinal thinning or thickness with the development and progression of non-exudative (dry) AMD [Thus, if HCQ affects the development of drusen, it could stop the deterioration of the disease without long-term damage. The rationale of the current study emerged from the work of McGeer and Sibley, who showed that patients with rheumatoid arthritis who were treated with HCQ were relatively protected from the development of AMD [The retina is generally considered one of the most oxygen-consuming tissues in the human body, consuming even more oxygen per weight than the brain [Soft or large drusen may form, consequent to the formation of localized detachments of basal linear or laminar deposits; both these deposits reflect granular material collecting between the RPE and its basement membrane or outside the RPE's basement membrane [The demographic and pre-study clinical characteristics were similar for the study and control groups, reflecting good randomization. Comparing the final examination results (at two years from the beginning of the study, which was 12 months after treatment cessation), the mean number of new drusen formations was less in the study group, and fewer drusen grew in size. At the two-year follow-up, there was no difference in metamorphopsia between the groups. In both groups, the central macular was somewhat thicker at two-year follow-up, more so in the control group, though the difference between the groups was not statistically significant. At the final follow-up, the most significant difference between the groups was in visual acuity. Though visual acuity decreased in both groups, in the control group, this reduction was significantly greater than in the study group, yet only by 0.04 logMar.As drusen are considered to predispose to AMD, the main objective of this study was to show that HCQ treatment may reduce drusen production. Our study suggests that HCQ may have a protective effect against the development of inactive AMD (dry AMD), and also active AMD (wet AMD). We could not distinguish whether this effect is due to increased thickening of the retina outer band (RPE and Bruch’s membrane), as we suggested in our previous study [The precise mechanism underlying the anti-inflammatory and immunomodulatory effects of HCQ remains unknown, even though the drug is effective in treating several autoimmune and inflammatory illnesses, including systemic lupus erythematosus and rheumatoid arthritis. Due to its hydrophilic nature, HCQ can pass through cell membranes easily and accumulates in intracellular vesicles, including lysosomes, endosomes and autophagosomes. Raising the pH in these acidic vesicles precludes proper functioning of vesicular enzymes (such as proteases) [A main concern when treating patients with HCQ is retinal toxicity [Further studies are needed to explain the impact of HCQ on the retina and its protective effect against AMD development, whether due to thickening of the retinal outer band, an anti-inflammatory effect or something else. This study was composed of a single institute and comprised a relatively small number of participants. Treatment with HCQ and follow-up periods were relatively short. Adverse effects of a continuous therapy may first present only several years after initiation of treatment.