Colchicine in association for phase 3 treatment
The CS influences the patients state of health and it makes the clinical picture severe. At this stage it is evident that the most important therapeutic strategy to be implemented is to slow down or block the uncontrolled inflammatory response.
Antiviral treatments continue to be important even if we remember that now there is still a big confusion in terms of the greatest effects that this class of drugs can have. However, since CS has proved to be common in phase 3, anti-inflammatory therapy can help prevent further complications, multi-organ dysfunction and patient death.
As we know, there is a variety of anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs, glucocorticoids, immunomodulators.
The use of glucocorticoids is still a matter of discussion, in particular the doses to be used and the time when can be used. In contrast, the use of cytokine inhibitors such as tocilizumab (IL-6 inhibitor) or anakinra (IL-1 receptor antagonist) has shown good efficacy, and several studies are underway to test them. However, as with glucocorticoids, there are still many open questions, when to use immunomodulators, what doses, to which patients? Only valid clinical trial protocols can answer these questions. All these questions are still the subject of intense debate and an uncommon answer in scientific opinion. The main concern, of course, is that immunomodulatory drugs can delay the elimination of the virus by the immune system and, worse still, increase the risk of secondary infections, especially of the respiratory tract. The biological agents that have shown good efficacy, and for which several trials are underway, are the inhibitors IL-6 tocilizumab and sarilumab, which are indicated for the treatment of rheumatoid arthritis. In addition, on August 30, 2017, Tocilizumab was approved in the United States for life-threatening cytokine release syndrome caused by chimeric T cell antigen receptor immunotherapy (CAR-T), and studies are now underway to evaluate its efficacy in the treatment of FMF and pericarditis, just like colchicine. At this stage 3, it may be useful to administer colchicine (0.5 mg once or twice daily), in monotherapy or in combination with IL6 inhibitors to control CS. The advantage of colchicine over IL-6 inhibitors is that it acts upstream of the cytokine cascade and not only on one cytokine in particular, it also appears to have a higher safety profile than immunomodulants and glucocorticoids. In addition, in the most critical phase a combination of colchicine and IL-6 inhibitors could be considered, which could show a pharmacological synergism, as shown in Figure 2. At this stage we could also consider a triple therapy hydroxychloroquine colchicine and IL-6 inhibitors to block the inflammatory cascade on multiple points.