Background
Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. Its prevalence is less than 1/100,000 and it affects predominantly young people [
1]. AOSD typically presents with high-grade fever, evanescent rash, sore throat, arthromyalgia, arthritis, serositis, discrete lymphadenopathy, hepatosplenomegaly, neutrophilic leukocytosis, hepatic cytolysis, and high serum ferritin [
2,
3].
While differential diagnosis is broad (infection, malignancy, autoimmunity) there is no single biological nor pathological finding specific for AOSD [
2]. Thus it is an experience-based diagnosis. The long-term course may be monocyclic, polycyclic, and/or complicated by a chronic erosive polyarthritis [
2]. AOSD treatment relies on corticosteroids (CS) and immunosuppressive agents such as methotrexate or cyclosporin [
4‐
6]. Recently, biologics (off-label) targeting tumor necrosis factor alpha (TNF-α) [
7‐
10] and, more importantly, interleukin (IL)-1 (anakinra) [
11‐
14] or IL-6 (tocilizumab) [
7,
14,
15] have shown interesting efficacy in refractory chronic AOSD.
A few patients develop organ complications that can be life-threatening, including reactive hemophagocytic syndrome (RHS), cardiac failure, respiratory distress, coagulopathy, severe hepatitis, and multiple organ failure (MOF) [
16]. Data regarding these infrequent complications mainly arise from case reports or small series focusing on one manifestation such as RHS [
17‐
19] or myocarditis [
20]. Despite these patients posing important diagnostic and therapeutic dilemmas, little is known about life-threatening AOSD as a whole.
Our objectives were: (i) to describe the disease course and phenotype of life-threatening AOSD (i.e. cases with organ failure leading to ICU admission) (ii) to analyze the response to therapy and long-term outcome of these patients.
We report a multicenter case series of 20 intensive care unit (ICU) patients with life-threatening AOSD as well as a systematic literature review of organ manifestation of AOSD.
Discussion
Herein, we report on the first study focusing on AOSD patients requiring ICU admission due to AOSD-related organ failure. Our objectives were to describe the phenotypic spectrum, response to therapy and long-term outcome of this infrequent subgroup of patients with life-threatening AOSD.
Until now, most studies about AOSD have focused on the long-term risk of developing further systemic flare(s) and/or a chronic polyarthritis. Similarly, most data regarding therapeutics focuses on patients with refractory, chronic, and non-life-threatening disease [
1‐
15,
21,
22]. The fact that AOSD patients may develop severe organ manifestations is mentioned for decades, but this subset of patients has been seldom studied [
2]. The present work is the first attempt to study critically ill AOSD patients as a whole. The frequency of organ complications is difficult to estimate, but it may not be so rare. Among the last 38 patients with new-onset AOSD seen at our center (Nantes), five (13%) were diagnosed in the ICU. In a recent single-center series, 19 out of 57 patients (33%) developed one or more organ complications (with or without organ failure) [
3]. In the present study, we wanted to specifically focus on life-threatening AOSD, i.e. on ICU patients with overt organ failure. This stringent inclusion criterion explains the rather small size of this multicenter nationwide series.
Both in our series and in published cases, we found that three key AOSD organ manifestations can lead to ICU admission. The most frequent is respiratory failure due to lung damage and/or pleural effusion. The second is cardiocirculatory failure (non-cardiogenic shock, myocarditis, and/or cardiac tamponade). The third complication is hematologic disorders, including RHS and/or DIC. The majority of patients exhibit a combination of organ manifestations and one-third has MOF. These complications occurred mostly during the first flare. Expectedly, patients had usual signs of AOSD. Half of them exhibited the classic triad of high-grade fever with evanescent maculopapular rash and arthromyalgia [
2]. Other clues to the diagnosis, including sore throat, serositis, neutrophil leukocytosis, and hepatic cytolysis were highly prevalent. However, patients suffered significant diagnostic delay. Median time between fever onset and treatment was 3 weeks. Even once organ failure had occurred, therapeutic delay remained significant. The main issue was the difficulty to abandon the sepsis hypothesis, as reflected by the amount of antibiotics these patients received before AOSD diagnosis. High-grade fever, sore throat, lung infiltrates, hepatic cytolysis, and neutrophilic leukocytosis clearly misguided clinicians, along with the negativity of autoimmunity screening.
RHS is the most frequent AOSD complication [
3,
17‐
19]. Both entities share pathophysiologic pathways and clinicobiological features [
2,
17‐
19,
26‐
30]. As for RHS, hyperferritinemia is a useful diagnostic clue for AOSD [
2,
21,
22]. The sensitivity and specificity of > 1000 ng/ml hyperferritinemia are 67–80% and 36–41%, respectively, outside the ICU. In our series, all patients had > 2000 ng/mL and 17/20 (85%) reached 10,000 ng/ml. Two out of three patients without such a massive hyperferritinemia only suffered from cardiac tamponade. In recent AOSD series, the incidence of RHS is 15%. Its mortality rate is 10 to 15% [
3,
17‐
19], which is lower than in infection and/or malignancy-related RHS [
17‐
19]. No validated criteria are available for the diagnosis of AOSD-related RHS. We found that biological parameters that best correlated with bone marrow hemophagocytosis were thrombocytopenia and hepatic cytolysis. Paradoxically, other cytopenias and ferritin level had less predictive value, which emphasis the role of macrophage activation in AOSD, beyond hemophagocytosis. Recently, Bae et al. studied 109 AOSD patients including 21 with clinically defined RHS [
18]. They found that low platelet count, anemia, and hepatomegaly were significant predictors of clinically defined RHS, but that leukocyte count and ferritin level were not. A scoring system has recently been proposed to estimate the probability of RHS (H-score) of any cause [
26]. Missing data precluded its calculation in our patients. Interestingly, this has been found to predict survival in an Asian AOSD cohort [
27].
AOSD, RHS, and sepsis share pathophysiological aspects, including the prominent role of pro-inflammatory cytokines IL-1, IL-6, and IL-18 [
2,
28‐
33]. Interestingly, a recent study has shown that clinicobiological assessment is more reliable than cytokine profiling to distinguish AOSD from sepsis [
33]. As for RHS, a careful analysis of patients’ biological profile is an important step to suspect AOSD [
2,
32]. In the appropriate clinical setting, the combination of absolute or relative thrombocytopenia or hypofibrinogenemia, and massive hyperferritinemia should lead to consider the diagnosis of AOSD.
Our second objective was to assess the prognosis and response to therapy. Two patients of ours succumbed to AOSD (10%). Yet, mortality may be higher since some patients with fatal AOSD have certainly been missed. A significant proportion of patients experienced classical ICU complications and/or sequelae such as distal necrosis or neuropathy, but long-term prognosis was favorable.
Overall, only half the patients responded to CS. We found that these patients tend to have a less severe disease, and lower ferritin levels. IVIgs were frequently used as second-line therapy in patients who failed CS. Indeed, persisting or recurrent fever under CS in an ICU patient raises the issue of superimposed infection. In such circumstances IVIgs are an appealing therapy even if little data are available regarding their use in AOSD. Our study and literature data show that IVIgs are rarely effective, with an overall response rate of only 41%. By contrast, we found that IL-1-targeting therapy with anakinra was highly effective. In our series, five patients (25%) received anakinra in the ICU, with a response rate of 80%. One of the limitations of its use is the lack of data for patients with severe renal failure. Indeed, the only patient that did not fulfill our response criteria (i.e leaving ICU without further treatment) died after anakinra was stopped due to persistent fever, infections, and AKI requiring RRT. Twenty years ago, a phase III randomized controlled trial investigated the efficacy of anakinra in ICU patients with severe sepsis [
34]. In this trial, stopped for futility, 116 patients had received anakinra. Mortality rate was not different from the placebo group. Of note, a recently published post hoc analysis suggests that anakinra could be beneficial in sepsis patients with features of RHS [
35]. A significant proportion of our patients had persistent disease activity after ICU discharge. At 3 months, 16 out of 18 required additional treatment. At this time point, 11 patients had received anakinra, which was effective in ten cases (91%).
Our series have several limitations owing to its retrospective nature, limited size, and heterogeneity. However, retrospective studies are essential tools for the study of such rare diseases. They can also provide meaningful information regarding the efficacy and safety of therapeutic strategies in complex yet real-life situations.
Acknowledgments
The authors thank the members of the Société de Réanimation de Langue Française and the Société Nationale Française de Médecine Interne.
Contributors:
Ygal Benhamou (MD), Service de Médecine Interne, CHU Charles Nicolle, 76031 Rouen, France.
Odile Beyne-Rauzy (MD), Service de Médecine Interne, CHU Purpan, 31059 Toulouse, France.
Philippe De Faucal (MD), Service de Médecine Interne, CH Privé du Confluent, 44277 Nantes, France.
Christophe Guitton (MD), Service de Réanimation Médicale, CH Le Mans, 72037 Le Mans, France.
Patrick Jego (MD, PhD), Service de Médecine Interne, CHU de Rennes, 35033 Rennes, France.
Jean Reigner (MD, PhD), Service de Réanimation Médicale, PHU3, CHU de Nantes, 44093 Nantes, France.
Laurent Sailler (MD, PhD), Service de Médecine Interne, CHU Rangueil, 31059 Toulouse, France.