pharmaceutics Review Chronobiology and Chronotherapy in Inflammatory Joint Diseases Francesco Ursini 1,† , Alfredo De Giorgi 2,† , Martina D’Onghia 1 , Roberto De Giorgio 3 , Fabio Fabbian 2, * and Roberto Manfredini 2, *   Citation: Ursini, F.; De Giorgi, A.; D’Onghia, M.; De Giorgio, R.; Fabbian, F.; Manfredini, R. Chronobiology and Chronotherapy in Inflammatory Joint Diseases. Pharmaceutics 2021, 13, 1832. https://doi.org/10.3390/ pharmaceutics13111832 Academic Editors: Gus R. Rosania, Annabelle Ballesta and Joana Bicker Received: 9 August 2021 Accepted: 27 October 2021 Published: 2 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Medicine & Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; francesco.ursini2@unibo.it (F.U.); martina.donghia@gmail.com (M.D.) 2 Clinica Medica Unit, Department of Medical Sciences, University of Ferrara, Via L. Borsari 47, 44121 Ferrara, Italy; degiorgialfredo@libero.it 3 Internal Medicine II Unit, Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; dgrrrt@unife.it * Correspondence: f.fabbian@ospfe.it (F.F.); roberto.manfredini@unife.it (R.M.) † Francesco Ursini and Alfredo De Giorgi contributed equally as first authors. Abstract: Circadian rhythm perturbations can impact the evolution of different conditions, including autoimmune diseases. This narrative review summarizes the current understanding of circadian biology in inflammatory joint diseases and discusses the potential application of chronotherapy. Proinflammatory cytokines are key players in the development and progression of rheumatoid arthritis (RA), regulating cell survival/apoptosis, differentiation, and proliferation. The produc- tion and secretion of inflammatory cytokines show a dependence on the human day–night cycle, resulting in changing cytokine plasma levels over 24 h. Moreover, beyond the circadian rhythm of cytokine secretion, disturbances in timekeeping mechanisms have been proposed in RA. Taking into consideration chronotherapy concepts, modified-release (MR) prednisone tablets have been introduced to counteract the negative effects of night-time peaks of proinflammatory cytokines. Low-dose MR prednisone seems to be able to improve the course of RA, reduce morning stiffness and morning serum levels of IL-6, and induce significant clinical benefits. Additionally, methotrexate (MTX) chronotherapy has been reported to be associated with a significant improvement in RA activity score. Similar effects have been described for polymyalgia rheumatica and gout, although the available literature is still limited. Growing knowledge of chronobiology applied to inflammatory joint diseases could stimulate the development of new drug strategies to treat patients in accordance with biological rhythms and minimize side effects. Keywords: chronobiology; inflammatory joint diseases; chronotherapy 1. Introduction Circadian rhythms are genetically encoded, near 24 h oscillations found in essen- tially every physiological process in the human brain and body [1] and reflect behavioral, metabolomic, proteomic, transcriptomic, acetylomic, and methylomic dynamics [2]. Cir- cadian clocks are cell-autonomous, transcriptionally based, molecular mechanisms that enable organisms to prepare for changes in their physical environments and respond to environmental factors in a temporally appropriate manner [3]. The mammalian circa- dian timing system consists of three basic components: (i) input signals (environmental cues), (ii) a circadian oscillator as an intrinsic rhythm generator, and (iii) output rhythms. The suprachiasmatic nucleus (SCN), located in the anterior hypothalamus, consists of ap-proximately 20,000 neurons distributed across the SCN core and shell regions. The SCN receives environmental photic information by visual and nonvisual photoreceptors of the retina, reaches the SCN via the retinohypothalamic tract (RHT), and then synchro- nizes peripheral tissue clocks [4]. Such a self-sustaining nature requires the presence of a genetic mechanism known as the molecular circadian clockwork, and clock genes are required for generating and maintaining the circadian rhythm at either the organism or Pharmaceutics 2021, 13, 1832. https://doi.org/10.3390/pharmaceutics13111832 https://www.mdpi.com/journal/pharmaceutics