Colchicine is a historic treatment for gout that has been used for more than a millennium. It is the treatment of choice for Familial Mediterranean Fever and its associated complication, amyloidosis. The 2009 FDA approval of colchicine as a new drug had research consequences. Recent investigations utilizing large cohorts of gout patients who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology. Some emerging dermatologic uses include the treatment of epidermolysis bullosa acquisita, leukocytoclastic vasculitis, aphthous stomatitis and others. In this work we relate the history and the new horizon of this ancient medicine.

Colchicine is one of the oldest remedies still in use today. It is derived from the bulb-like corms of the Colchicum autumnale plant, also known as autumn crocus. Its history as an herbal remedy for joint pain goes back at least to the 1500 BCE Egyptian manuscript, the Ebers Papyrus (Figure 1). The active ingredient, colchicine (Figure 2), was isolated in the early 1800’s and remains in use today as a purified natural product. In view of the long history of colchicine’s use in medicine, it is perhaps surprising that it was not until 2009 that colchicine was approved by the U.S. Federal Drug Administration.

Figure 1 – The 1500 BCE Egyptian manuscript, the Ebers Papyrus

Figure 2 – Colchicine formula

Despite its use for thousands of years, colchicine’s exact mechanism of action is still being explored. In the 1950’s and 1960’s the microtubule (MT) was identified as the primary cellular target. MTs serve as a major part of our cellular cytoskeleton, and are essential to cellular functions such as mitosis, as well as intracellular organelle and vesicle trafficking. MT dynamics originate in a balance of polymer growth and shrinkage, mostly at the MT end that is distal to the nucleus. These dynamics allow changes in MT distribution and in overall cell shape. Structurally, MT are hollow cylinders composed of protofilaments, which in turn are made from αβ-tubulin heterodimers polymerized end to end. Colchicine binds to tubulin heterodimers and alters the tubulin conformation, allowing the tubulin dimer-colchicine complex to add to the growing end of a MT but preventing any further growth, thus poisoning the dynamics of that MT. The exact mechanism by which this colchicine induced MT destabilization leads to alteration of cell function remains unclear.

Colchicine impairs neutrophil function by impacting inflammatory pathways and mediators of neutrophil activation. The drug decreases neutrophil L-selectin expression and modulates E-selectin expression on the cell surface of endothelial cells, thereby impairing neutrophil recruitment. It further prevents neutrophil migration by decreasing the inducing effects of platelet activating factor and leukotriene-β4 on neutrophil adherence. Neutrophil function is additionally compromised by colchicine via suppression of neutrophil superoxide production, a key contributor to the inflammatory response seen in neutrophil activation.

By impairing vesicular trafficking, colchicine is able to both decrease TNF-α receptor expression on macrophages (preventing activation) and interrupt granule release in mast cells (preventing degranulation). In keeping with this effect on inflammatory modulators, in vivo and in vitro studies demonstrate decreased levels of the proinflammatory cytokines IL-1β, IFNγ, IL-18 and IL-6 with colchicine use. Given these extensive effects on inflammation, it is not surprising that the use of colchicine has been explored in a number of inflammatory conditions.

Colchicine has been known as a treatment for gout for several millenia. Inflammation in gout is mediated by a combination of neutrophil and macrophage activation, leukocyte adhesion molecules, inflammasome activation as well as IL-1β production. As noted above, all of these pathways are affected by colchicine.

BCE – before the Common Era