Adding colchicine to immunosuppressive treatments; a potential option for biologics-refractory adult-onset Still’s disease

Adult onset Still’s disease (AOSD) is a rare chronic inflammatory disorder that usually accompanied with high spiking fever, arthritis and salmon pink skin rash [1]. The wide range of disease manifestations and course suggest heterogeneity of the disease entity [2]. Macrophage activation and subsequent overproduction of cytokines are involved in the pathogenesis of AOSD [3]. Therefore, cytokine-directed therapies have the potential to target macrophage-activation seen in AOSD [4]. Also, recent insights into autoinflammatory disorders have indicated that interleukin (IL)-1 blockers may be effective against steroid-refractory or immunosuppressant-refractory AOSD [5]. To treat steroid-resistant AOSD, previous reports have suggested the use of immunosuppressants such as methotrexate and cyclosporine A [6]. Additionally, anti-cytokine treatments including TNF or IL-6 blockers appear to be an efficient well-tolerated, steroid-sparing treatment against immunosuppressants-refractory AOSD [7]. The application of these biologics may provide clinicians with useful tools for the management of refractory AOSD. While targeting these cytokines has shown promising effects [7], there remain AOSD patients who do not respond to these biologics [8] and they are associated with potential severe side effects. This is the first report on the successful induction of remission with colchicine in biologics-refractory AOSD.

Our patient is the first to be reported for effectiveness of colchicine in AOSD. The patient was treated with colchicine, and showed improvement of their clinical manifestations, such as fever and arthropathy, and normalization of their serum levels of CRP and ferritin. Although the data available to date remain limited because of the rarity of the disease, it seems clear that use of colchicine represents a good alternative to biologics therapies, which can potentially cause adverse events including infections.

The first-line therapy in AOSD is based on corticosteroid, but has various side effects [6]. Thus, immunosuppressants, such as methotrexate and cyclosporin A, have been used [10]. Recent studies demonstrated that tocilizumab treatment resulted in clinical and laboratory improvements in patients with AOSD refractory to treatment with other biologics [11]. However, in the present report, our patient was refractory to IL-6 or tumor necrosis factor (TNF)-α blockade treatments. Whereas the administration of colchicine resulted in long-term clinical remission in this case. It should be debated whether steroid pulse therapy may result in the clinical resolution of AOSD in this case. However, the effectiveness of colchicine in preventing febrile attacks was demonstrated even under the minimum dose steroid (PSL 8 mg/day) and one-course of steroid pulse therapy may not result in long-term of clinical remission of AOSD in this patient.

It could be also argued that the switch from TAC to CyA silenced the AOSD manifestations in this case. Mitamura et al., reported that CyA administration improved AOSD [12]. In contrast, Nakamura et al. reported that TAC, a calcineurin inhibitor similar to CyA, could be one of the useful option for refractory AOSD [13]. Murakami et al. reported a patient with AOSD successfully treated with TAC, while CyA was not effective [14]. Although there is no clear evidence that CyA, may be superior to TAC in the effectiveness of AOSD treatments, CyA should be comparable to TAC for treating AOSD.

Autoinflammatory diseases affect the innate immune system, and some of them are characterized by inflammasome activation and subsequent IL-1β production [15]. The clinical manifestations of autoinflammatory diseases are similar to those of AOSD, and a dramatic response to IL-1β blockade was reported in Western countries [16]. Nevertheless, IL-1β blockade treatment is not available for Japanese patients with AOSD. The finding that colchicine was effective in AOSD refractory to TNF-α or IL-6 blockade is interesting. Patients with heterozygous MEFV mutations with low penetrance were reported to present with clinical manifestations resembling familial Mediterranean fever (FMF) [17]. These reports indicate that the MEFV gene is not only associated with a single disease, FMF, but also linked to additional clinical presentations of autoinflammatory diseases [18]. The mutation analysis in our patient demonstrated no abnormalities in the MEFV gene. Therefore, the current case report suggests that colchicine is effective for non-FMF or non-MEFV gene-associated entities, because MEFV mutations typical to FMF were not demonstrated. Colchicine is widely used in rheumatology therapy for gout, FMF, and Bechet’s disease [19]. Its mode of action includes chemokines, and inhibition of neutrophils and endothelial cell adhesion molecules [20]. A recent investigation demonstrated that colchicine inhibits the assembly of the inflammasome complex by affecting the transport of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), an adaptor protein [21]. These findings suggest that colchicine may modulate the inflammasome-mediated proinflammatory cascades and that the broad concept of colchicine-responsive inflammatory conditions can be reconsidered. Our case report indicated that colchicine may be one of treatment options for refractory AOSD.

This is the first case report in which colchicine has been used to treat AOSD refractory to biologics treatment. Colchicine treatment resulted in clinical remission of refractory AOSD and allowed a large reduction of steroid doses in this case. Colchicine should be considered as one of the therapeutic options for AOSD refractory to anti-cytokines treatment.