We aimed to investigate the efficacy and safety of Pidotimod, administered at high doses, in treating patients affected by PFAPA syndrome. To achieve this goal a preliminary, prospective, controlled, open, cross-over study was performed.
Currently, the treatment of PFAPA syndrome is primarily targeted to the resolution of acute inflammatory episodes, although there is no consensus concerning the best remedy for this disease. The available therapies are essentially symptomatic and prednisone (1–2 mg/kg) or betamethasone (0.1–0.2 mg/kg) are the most common treatments used in managing PFAPA symptoms. However, this therapeutic approach does not prevent the recurrence of febrile episodes rather it seems to short intervals between fever flare-ups in most PFAPA patients [4]. Moreover, the routine corticosteroid use to abort episodes of PFAPA is not widely supported because of concern for side effects associated with a frequent use [12]. Therefore, because of the limitation of this treatment as well as the nature of an acute inflammatory response occurring in PFAPA syndrome, authors aimed at assessing immunological mechanisms behind this condition to identify immune mediators that, associated pathogenetically with PFAPA, can be new potential therapeutic target. In this regard, colchicine, cimetidine, thalidomide, IL-1 blockers have been widely investigated but studies supporting the efficacy of different therapeutic strategies in PFAPA patients are sparse and based mostly on small cohorts of patients, also providing moderate-to-low quality of evidence [13]. Among the molecules capable of interfering in the innate and adaptive immune response, Pidotimod, an immunomodulatory agent able in increasing antigen presentation and promoting adaptive Th1-mediated immunity, showed good efficacy and safety when administered in, addition to a bacterial lysate, in children aged 3–12 years with PFAPA [11]. In their study, authors administered Pidotimod 200 mg/daily for 20 days for a minimum of 6 consecutive months and up to 36 months with a summer break of 4 to 6 months [10]; and reported that the healing rate of PFAPA symptoms was 68% (n = 25 patients), with 11% (n = 4 cases) in complete remission at the end of the second year of follow-up. Overall, 78% children (n = 29) experienced a marked decrease in the incidence of fever, a reduced antipyretic drugs and antibiotics use, a markedly improved quality of life as assessed by a decreased time lost from school for the children and work for the parents. Interestingly, a significant reduction of surgical tonsillectomy was also observed [11]. Similarly, our study also revealed that all patients receiving Pidotimod showed a significant reduction in frequency of fevers, number of episodes of tonsillitis, and aphthous stomatitis when compared to patients receiving only betamethasone. Moreover, whether Buongiorno et al. [11] reported a reduced antipyretic drugs and antibiotics use, herein, we noted a significant decrease in betamethasone use on need in all patients receiving Pidotimod compared to patients not receiving Pidotimod. Thus, our findings not only confirmed the efficacy of Pidotimod use in PFAPA syndrome but also firstly provided the evidence that Pidotimod, decreasing the routine corticosteroid use, is also able to prevent indirectly both the shortening intervals between fever flare-ups and the side effects associated with a frequent corticosteroid use. Moreover, differently to Buongiorno et al. [11], we wanted to test the Pidotimod use at higher doses (2 vials of 400 mg daily) for a shorter period (up to 3 months). By adopting this treatment regimen we not only have achieved the therapeutic efficacy but also, by reducing the treatment period, we reduced the stress of the patients related to long-term treatment. The compliance to the therapeutic regimen was good and all enrolled children completed the study, and any mild-to-serious adverse event was recorded in the treated groups. However, we cannot assess the long-term Pidotimod efficacy as, when comparing the two groups not receiving Pidotimod (group B in phase 1 and group A in phase 2) no significant differences in terms of clinical symptoms were recorded. On the other hand, the behaviour of the Pidotimod as symptomatic drug is in line with its properties; in fact, acting as an immunomodulator agent, Pidotimod is able to modify the immune response until it is administered, and, although it cannot change the natural history of disease, it can decrease the severity disease resulting in a potential pharmacological strategy in control of PFAPA attacks, without the side effects of corticosteroids used on a long-term.
Moreover, we believe that an additional follow-up study could be started to learn about longer term effects of Pidotimod and observe potential changes in the natural course of the disease by adopting, in addition to higher dosage, also a longer duration of Pidotimod treatment.