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# About the complexity of adult onset Still's disease... and advances still required for its management

Philippe Guilpain, Alain Le Quellec

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Philippe Guilpain, Alain Le Quellec. About the complexity of adult onset Still's disease... and advances still required for its management. BMC Medicine, 2017, 15 (1), pp.5. 10.1186/s12916-016-0769-1. hal-01792664

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# About the complexity of adult onset Still's disease... and advances still required for its management

Philippe Guilpain<fnref n="1" />,<fnref n="2" />,³* and Alain Le Quellec<fnref n="1" />,<fnref n="2" />

Abstract

Adult onset Still's disease (AOSD) is a rare inflammatory disorder that remains poorly understood. Its pathophysiology is yet to be completely elucidated, but is known to consist mainly on a cytokine cascade, responsible for the systemic manifestations. AOSD diagnosis is usually difficult and delayed, with physicians having to rule out several other conditions, including cancer or infectious diseases. Prognosis is heterogeneous and difficult to establish, ranging from benign outcome to chronic destructive polyarthritis and/or life-threatening events. In addition, treatment remains to be codified, especially considering the development of new drugs. In this commentary, we attempt to elucidate the complexity of AOSD and to highlight the need of working on prognostic tools for this disorder. We also discuss the numerous advances that would be useful for patients in the daily management of this disease.

Please see related article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0738-8.

**Keywords:** Adult onset Still's disease, Macrophage activation syndrome, Score, Diagnosis, Prognosis, Therapy, Cytokine, Inflammasome

Background

More than 100 years after its first clinical description, adult onset Still's disease (AOSD) remains challenging to diagnose and treat, and an understanding of its pathophysiology is far from being achieved [1]. Even if the road ahead remains long and difficult, the study conducted by Ruscitti et al. [2] on the prognostic tools of AOSD represents a new step towards the better management of the disease. Their study, one of the largest published to date, provides confirmation of the impact of Pouchot's 'systemic score' on AOSD prognosis. Indeed, these results are of significant importance considering that patient management is limited by disease complexity at the diagnosis, prognosis and therapeutic levels.

AOSD is a rare inflammatory disorder, the diagnosis of which is usually complex and delayed. Indeed, clinical

presentation is heterogeneous and the main clinical features (spiking fever, joint involvement, skin rash and blood neutrophilia), as well as other minor ones (pharyngitis, lymph node or spleen enlargement, seritis, myalgia, hepatitis and abdominal pain), are unspecific [1]. In addition, histological confirmation and relevant biomarkers are lacking in this entity (notably, determination of glycosylated ferritin level is deceiving). Therefore, diagnosis is based on criteria (Yamaguchi's or Fautrel's) developed for classification rather than daily practice [3, 4]. In fact, AOSD has a diagnosis of exclusion and physicians have to rule out several other striking conditions (autoimmune, infectious or malignant diseases) through a complex diagnosis procedure. Conversely, in some cases, malignancies or infections have also been reported as triggering factors for AOSD, making the understanding of clinical presentation even more complex [1]. Disease complexity also lies in the pathophysiological mechanisms leading to a cytokine cascade (typically Th1) through an abnormal response of

<footnote>* Correspondence: p-guilpain@chu-montpellier.fr</footnote>

<footnote n="1">¹Montpellier 1 University, Medical School, Montpellier F-34967, France</footnote>

<footnote n="2">²Department of Internal Medicine – Multiorganic Diseases, University of Montpellier, Local Referral Center for Auto-Immune Diseases, Saint-Eloi Hospital, Montpellier F-34295, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
innate immune cells (especially macrophages) following
the activation of Toll-like receptors [1].

Another complexity level is the highly variable prognosis,
which ranges from a limited and benign outcome to chronic
destructive polyarthritis and/or life-threatening involvement
such as visceral complications (heart, kidney, lung or central
nervous system), thrombotic microangiopathy or macro-
phage activation syndrome (MAS; also called reactive hemo-
phagocytic lymphohistiocytosis) [1, 5–8]. Although
exceptional, fatal events have been linked to AOSD-related
complications and infections. Additionally, current treat-
ments (i.e. NSAIDs, glucocorticoids and immunosuppressive
drugs and biotherapies, in some cases) may also be deleteri-
ous, particularly in the long-term. Of note, the classification
[5, 9, 10] distinguishing monocyclic, polycyclic and chronic
AOSD is not useful for patient management, since it does
not integrate severity and a functional and/or vital related
prognosis. More precisely, it remains difficult to predict out-
come at diagnosis and, consequently, drawing management
guidelines presents a major challenge.

Clearly, joint involvement at diagnosis may affect func-
tional prognosis through destructions resembling those
of rheumatoid arthritis [11], while systemic manifesta-
tions can impair vital prognosis [6] ('dichotomous view'
of AOSD [1]). A fever higher than 39.5 °C mainly occurs
in systemic AOSD, whereas a leukocyte count higher
than 30,000/mm³ and systemic inflammation markers
are correlated with relapses [12]. Increased serum fer-
ritin levels are associated with disease activity and
chronic or recurrent forms of AOSD [7, 12–14]. In
1991, from a study on 62 patients, Pouchot et al. [5] pro-
posed a 'systemic score' reaching up to 12 points, and
assigning one point to each of the following manifesta-
tions: fever, skin rash, pleuritis, pneumonia, pericarditis,
liver involvement, spleen involvement, lymphadenop-
athy, leucocytosis > 15,000/mm³, sore throat, myalgia,
and abdominal pain. This score is easy to calculate, but
remains to be validated in further studies.

In their article recently published in *BMC Medicine*,
Ruscitti et al. [2] report that Pouchot's 'systemic score'
[5] successfully predicts a poor outcome in AOSD. More
precisely, a 'systemic score' higher than 6 (discriminating
cut-off ≥ 7) and the presence of any complication (MAS,
kidney failure or myocarditis) at diagnosis are associated
with mortality. Ruscitti et al. [2] observed MAS in 13
out of 100 patients recruited in the last 16 years, which
is consistent with values in previous studies (10–15%) [8,
15]. However, death occurred in 10 patients, which is ex-
tremely high and unexpected. In AOSD, MAS is clas-
sically associated with persistent and/or refractory
diseases and has been known to impair vital prognosis,
but not at this level. For example, a recent Korean study
identified 21 MAS among 109 AOSD patients and only
two patients died [15], which is consistent with other

published studies [8, 16]. In another recent study in
Japan, the MAS-related mortality rate was approximately
20% among AOSD patients [17]. Therefore, the high
mortality rate reported by Ruscitti et al. [2] undoubtedly
has an important weight on the results, especially for the
prognostic score, but also simply reflects on the poten-
tial severity of AOSD. Finally, since MAS is in reality a
life-threatening event, this should not modify our per-
ception of these findings.

Conclusions

We hope that physicians will now be interested in Pou-
chot's score and that further studies will simply confirm it
as a prognostic tool. The discriminating cut-off predictive
of death should also be evaluated and even precised. From
this point of view, the study by Ruscitti et al. [2] represents
an interesting step in the understanding of AOSD clinical
presentation. Interestingly, these findings are in line with
the 'dichotomous view' of AOSD [1] and could be helpful
for the therapeutic decision between glucocorticoids alone
or combined with immunosuppressive drugs/biologics as
first-line treatment.

The final issue raised by this study concerns the meth-
odology, whose improvement is crucial for clinical re-
search on AOSD in the near future. In this rare
inflammatory disorder, international or national (as that
by Ruscitti et al. [2]) collaborative studies would provide
the critical mass for pertinent statistical analyses and
validation through evidence-based medicine.

As often observed, prognostic and therapeutic ad-
vances will probably arise from a better understanding
of clinical phenotypes and pathophysiological mecha-
nisms, and from a 'dismemberment' of AOSD into sev-
eral entities, analogous to what ensued following the
discovery of biomarkers, such as anti-neutrophil cyto-
plasm antibodies, on the spectrum of 'polyarteritis
nodosa' and other vasculitides. The concept of AOSD as
a disorder clinically meeting Yamaguchi's criteria prob-
ably covers several entities with distinct pathophysi-
logical processes but certain common inflammatory
actors. Will the advances on inflammasome and cyto-
kines help during the following years? Since AOSD is at
the frontier of autoimmune and autoinflammatory disor-
ders, the answer is 'yes, probably'. In the end, what do
the two forms of AOSD, namely systemic monophasic
AOSD with high inflammation state at onset and
complete recovery after several months versus chronic
AOSD with systemic onset and chronic destructive sero-
negative polyarthritis, have in common? The answer re-
mains: 'only our perplexity and ignorance...'

Authors' contributions

PG analyzed and commented recent studies on the subject. PG and ALQ
equally contributed to the writing of this manuscript. Both authors read and
approved the final manuscript.
**Authors' information**

ALQ is MD, PhD, and Professor of Internal Medicine at Montpellier's University. ALQ is also the head of the department of "Internal Medicine - Multi-Organic Diseases" in Montpellier's teaching hospital. This department is a local referral centre for rare autoimmune diseases in adult patients. PG is MD, PhD, and Associate Professor in the same university and department. ALQ and PG are both working on autoimmune and/or inflammatory diseases, in particular systemic vasculitides, systemic sclerosis and adult-onset Still's disease.

**Competing interests**

PG is a medical expert for LFB (Laboratoire Français du Biofractionnement) and has received fees from Abbvie, Boehringr Ingelheim France, Pfizer, and Roche in the last five years. ALQ declares that they have no competing interest.

**Author details**

Received: 9 December 2016 Accepted: 9 December 2016

Published online: 06 January 2017

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<footnote n="1">¹Montpellier 1 University, Medical School, Montpellier F-34967, France.</footnote>

<footnote n="2">²Department of Internal Medicine - Multiorganic Diseases, University of Montpellier, Local Referral Center for Auto-Immune Diseases, Saint-Eloi Hospital, Montpellier F-34295, France. ³Inserm, U 1183, IRMB, Saint-Eloi Hospital, Montpellier F-34295, France.</footnote>