Melatonin as an adjuvant therapy in patients with rheumatoid arthritis

Because of its antioxidant effects, Forrest et al. [1] used melatonin (10 mg daily for 6 months) as an add-on therapy to treat rheumatoid arthritis (RA) and showed that the indolamine had minor beneficial effects. Maestroni et al. [2], however, opposed using melatonin in RA patients. They claimed that melatonin should be referred as a chronological pacemaker and immune enhancer rather than a potent free radical scavenger. As a justification of this, they claimed that a search with the keywords ‘melatonin’ and ‘radical scavenger’ yielded 338 items including 69 reviews, and the keywords ‘melatonin’ and ‘immune’ resulted in 495 items, of which 157 were reviews. On this basis, they implied that melatonin is not an antioxidant. Pubmed searches, however, using the key words ‘melatonin’ and ‘antioxidant’ (or ‘melatonin’ and ‘free radical scavenger’), yielded >11 000 published papers, and since melatonin was discovered as an antioxidant in 1993, thousands of investigations have confirmed the antioxidative actions of melatonin. There is no doubt that not only melatonin itself but also several of its derivatives have strong free radical scavenging and antioxidative capacities [3]. Maestroni et al. [2] expected that melatonin would worsen the outcome of RA patients, but in fact it was not harmful; they actually seemed disappointed that melatonin treatment did not worsen RA. Consistently, published reports have documented that melatonin is an immune modulatory agent with multiple anti-inflammatory effects [4]. Maestroni et al. [2] referred to melatonin as a hormone. Although melatonin has hormonal properties, in many cases it functions in other capacities, e.g. as an autocoid, paracoid or direct free radical scavenger [5]. Also, whereas melatonin is produced in the pineal gland, the concentration of melatonin in the gut surpasses blood levels by 10–100 times and there is estimated to be at least 400× more melatonin in the gut than in the pineal gland. Thus, melatonin is not a conventional hormone, since it has both receptor-mediated and receptor-independent actions, and virtually all cells are its target whether or not they possess receptors for the indolamine. In relation to the high blood melatonin levels in RA patients as reported by Forrest et al. [1], the increased levels may have been a compensatory response to the inflammation of RA. Also, although the blood levels of melatonin reported by Forrest et al. [1] may seem high, they are comparable to the seemingly much higher levels of melatonin in cerebrospinal fluid [6] and its metabolites in patients with meningitis [7] and as shown in paediatric patients with epilepsy [8]. Forrest et al. [1] have performed a highly valuable study documenting that melatonin could be an effective add-on therapy in the treatment of RA. Melatonin is known to have substantial anti-inflammatory properties, which have been documented in studies using known inflammatory agents, e.g. zymosan, lipopolysaccharide and carrageenan [9]. Thus, Forrest et al. [1] were perfectly justified in performing this study. These authors should be encouraged concerning the emerging role of epigenetic dysregulation in the pathogenesis of RA [10], since nontoxic melatonin (maternal lowest observed adverse effect level 200 mg kg−1 day−1, developmental no observed adverse effect level ≥200 mg kg−1 day−1) [11] is a strong candidate for epigenetic regulation [12].