Introduction
Still's disease is a rare systemic inflammatory disorder of unknown etiology characterized by quotidian spiking fevers, evanescent rash, arthritis, and elevated acute-phase reactants in the serum linked to alterations in the production of proinflammatory cytokines. Treatment has been empirical, with data on treatment efficacy extrapolated from case reports and small scale retrospective studies. Non-steroidal anti-inflammatory drugs and corticosteroids have been a mainstay for decades in treating adults with Still's disease; however, resistance to treatment as well as drug-related complications have been observed [
1,
2]. Immunosuppressants, mainly methotrexate (MTX), used as steroid-sparing drugs, have shown modest efficacy across studies [
3,
4]. In recent years, advances in the understanding of the role of cytokines in the disease pathogenesis has led to the application of anticytokine agents, often in combination with traditional immunosuppressive drugs, which opened a new, promising horizon in the treatment of adult Still's disease. Hence, TNF-a inhibitors have been successfully employed in some cases unresponsive to conventional treatment [
5‐
10]. More recently, IL-1 activity has been linked to the pathogenesis of Still's disease as well as other systemic inflammatory diseases characterized in part by recurrent fevers, leucocytosis, anemia, and elevated acute-phase proteins, because rapid and sustained resolution of systemic and local inflammation is observed upon specific blockade of IL-1 receptors (IL-1R) [
11]. The application of biological therapy with the IL-1R inhibitor anakinra, a recombinant form of the human IL-1R antagonist that inhibits IL-1 binding on its receptor approved for use in rheumatoid arthritis, appears to be promising treatment in patietns with refractory Still's disease [
2,
12‐
19].
Discussion
In the present study we assessed the efficacy and safety of the IL-1R inhibitor anakinra in adult patients with refractory Still's disease. To our knowledge, this is the largest series reported in literature, because previous reports consist of smaller patient series as well as case reports [
2,
13‐
19,
22].
In agreement with previous data, we observed a rapid and sustained response to anakinra treatment in the majority of patients [
2,
13‐
19]. A dramatic improvement in all disease-related manifestations was evident from the first month of treatment. Complete resolution of clinical symptoms occurred within a few days after the initiation of treatment and was followed by normalization of acute-phase reactants, hematological parameters, and biochemical markers of systemic disease within the first three months. According to the already reported literature, the time to complete resolution of clinical activity varied from a few hours after the first injection up to two months of treatment, with most cases remitting within some days, while laboratory markers returned to normal subsequently within one week to two months [
13‐
19]. In the two largest already published series of 15 and 8 patients, respectively, disease activity completely resolved in 60% and 90% of patients, respectively, whereas no efficacy was reported in 13% of patients in the first study [
18,
19]. In accordance with our data, persisting clinical activity was expressed with arthralgias or fever. Elevated CRP, ESR, and ferritin levels were the abnormal laboratory markers in patients with residual serological activity. In line with our observations, Maier et al. reported anemia and high ferritin levels as disease markers that normalized at last [
17]. In our study, clinical activity resolved completely in 84% and laboratory parameters returned to normal in 80% of patients, while 4% did not show any response to treatment. In only two patients, anakinra was discontinued because of inadequate response. It is of note that three of four patients in partial response had a short follow-up time of 1.5 to 3 months because of an early drug withdrawal. Thus, a potential delayed response in those patients if they were treated for a longer time period cannot be excluded.
The great efficacy of the IL-1R inhibitor points toward the important role of IL-1 in the pathophysiological processes underlying Still's disease. Indeed, increased IL-1 levels have been detected in active untreated disease [
13,
15]. Kötter et al demonstrated high IL-1 and IL-18 in active disease, whereas moderately high TNF-a and IL-6 levels, that significantly fell following treatment with the IL-1R inhibitor [
15]. Similarly, Fitzgerald et al. demonstrated high IL-1a, IL-1b, IL-1RA, IL-6, and IL-18 serum levels prior to the first injection of anakinra, while a dramatic reduction in the levels of IL-6, IL-18, and IL-1RA accompanied the disease activity resolution upon treatment initiation [
13]. An increase in the serum proinflammatory cytokine levels was observed when therapy was stopped. However, the group of partial responders and non-responders might be suggestive of disease subtype heterogeneity and likely reflects different roles of cytokines and pathological processes in these patients [
23,
24]. In fact, one patient in the present study with prominent articular involvement without clinical signs of systemic disease, did not improve during anakinra treatment.
Relapses under anakinra are rarely reported [
13,
19]. However, studies with a large number of patients and a long period of follow up are still pending. In this report, the effects of anakinra treatment were sustained until the latest visit in all but one complete responder. This patient relapsed after reducing the frequency of drug injections. Two other patients who experienced a disease flare were in partial response.
There is no clear evidence whether the use of anakinra in combination with a DMARD, such as MTX, improves its efficacy. In our series, either the overall efficacy or the articular disease were both comparable between patients receiving anakinra as adjunct and those as monotherapy. Similarly, in the report by Lequerré et al, DMARD use was not particularly different in the complete response vs. the non-responder cohort [
18]. However, long-term data are missing. Our study provides evidence that anakinra monotherapy may be an effective therapeutic option in some patients, whereas combination with a DMARD may be necessary when residual or recurrent disease activity is present. In fact, recurrent disease in the form of arthralgias/arthritis, fever, rash, and acute inflammatory response was effectively controlled by the addition of MTX to anakinra treatment, as also previously reported [
13,
19].
Regarding concomitant oral corticosteroid usage, anakinra was shown to be an effective steroid-sparing agent. In agreement with the already reported literature, the use of anakinra allowed fast steroid tapering in responders and total discontinuation of steroid intake in approximately half of them [
13,
14,
17‐
19]. Moreover, four patients did not require any corticosteroid therapy during the whole follow up.
The optimal treatment duration with anakinra is unknown. An interesting issue is whether the number of anakinra injections per week can be decreased in responders. Gradual reduction of anakinra dosing after a median of 12 months on remission seemed to be safe in our series, because only one of seven patients under alternate day treatment relapsed. Safe increasing of the time interval between anakinra applications has been also reported by Maier et al., whereas Kötter et al. described recurrence of disease activity after reducing anakinra to alternate day dosing [
15,
17]. In responders, total drug discontinuation led to the recurrence of disease activity in two of eight of our patients, while the rest of patients remained in complete remission for a median time of 6.5 months. Thus, remission may be maintained in some patients after drug discontinuation. However, given the small number of patients and the relatively short follow up after drug withdrawal, any conclusions can only be interpreted with caution.
In regard to toxicity, anakinra was safe and well tolerated in all but three patients who discontinued therapy because of severe urticarial-like skin reactions and one patient with severe trachiobronchitis. Lequerré et al. reported anakinra withdrawal in two patients who developed skin rash at first and third month of treatment, whereas severe systemic inflammatory response syndrome has been also described as an IL-RA therapy complication [
18,
22]. Infections were not rare in our patients (28%). The observed rates were similar with those described previously [
18]. Finally, local pain or reactions to injections have been frequently reported in literature [
15,
16,
18,
19]. The rebound of disease activity following transient cessation of IL-1RA therapy due to opportunistic infections, was noticed in one of our patients as well as in other published cases; however, disease activity resolved after drug reinstitution in all of them [
13,
16,
19].
Compared with TNFa inhibitors or MTX monotherapy, anakinra seems to have a more rapid and efficient effect in adult patients with Still's disease. Response rates in the largest series using anti-TNFs and/or MTX were lower than in the present study ranging between 25% and 69%, whereas worsening of disease and/or exacerbations were also reported [
3‐
6]. Compared with anakinra, the response was delayed with most cases remitting after two weeks of treatment and up to 16 weeks. However, most promising results have been reported in smaller series [
9,
10]. At this point, it is worth presenting unpublished data on a historical control of adult patients with Still's disease followed up in our department and treated with TNF inhibitors (infliximab n = 4, etanercept n = 2, adalimumab n = 1), and (n = 5) or MTX (n = 6). In accordance with previously reported data, 54% of patients went into complete disease remission, whereas 43% of the responders relapsed. The median time to clinical response was four months (range 0.5 to 6 months), while laboratory parameters returned to normal after a median time of four months (range 0.5 to 10 months). Sequential treatment with different anti-TNFs in five of our patients did not change drug efficacy, whereas two of four patients who received anakinra due to unresponsiveness to anti-TNFs went into remission.
Finally, our results should be interpreted in the context of potential limitations. The present study was not prospectively designed. Therefore, detailed information on the drug use before the initiation of anakinra was not always available. Moreover, the relatively small number of patients limits the statistical power of the study. Thus, no definite conclusions can be drawn regarding the efficacy of anakinra as adjunct vs. monotherapy. Additionally, more than one third of our cohort had a duration of follow up shorter than one year. Nevertheless, the rapid clinical response as well as the long-lasting efficacy together with the steroid-sparing effect and the favorable safety profile in most of our patients encourages further use of anakinra in adults with Still's disease.
KL, MD: Resident in Rheumatology at the Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece
AGT, MD: Professor at the Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece
HMM, MD, FRCP, FACP, Master ACR: Professor at the Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
KL participated in the design of the study, collected the data, performed the statistical analysis and interpretation of data, and drafted the article. AGT participated in the design of the study and its coordination, helped in revising the article, and provided intellectual content of critical importance. HMM conceived of the study, and provided intellectual content of critical importance. All authors read and approved the final manuscript.