Systemic juvenile idiopathic arthritis and adult-onset Still's disease are the same disease: evidence from systematic reviews and meta-analyses informing the 2023 EULAR/PReS recommendations for the diagnosis and management of Still's disease

Abstract

Objectives: To analyse the similarity in clinical manifestations and laboratory findings between systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD).

Methods: Three systematic reviews (SR) were performed. One included cohort studies comparing sJIA versus AOSD that described clinical and biological manifestations with at least 20 patients in each group (SR1). The second identified studies of biomarkers in both diseases and their diagnostic performance (SR2). The last focused on diagnostic biomarkers for macrophage activation syndrome (MAS, SR3). Medline (PubMed), Embase and Cochrane Library were systematically searched. The risk of bias was assessed with an adapted form of the Hoy scale for prevalence studies in SR1 and the Quality Assessment of Diagnostic Accuracy Studies-2 in SR2 and SR3. We performed meta-analyses of proportions for the qualitative descriptors.

Results: Eight studies were included in SR1 (n=1010 participants), 33 in SR2 and 10 in SR3. The pooled prevalence of clinical manifestations did not differ between sJIA and AOSD, except for myalgia, sore throat and weight loss, which were more frequent in AOSD than sJIA because they are likely ascertained incompletely in sJIA, especially in young children. Except for AA amyloidosis, more frequent in sJIA than AOSD, the prevalence of complications did not differ, nor did the prevalence of biological findings. Ferritin, S100 proteins and interleukin-18 (IL-18) were the most frequently used diagnostic biomarkers, with similar diagnostic performance. For MAS diagnosis, novel biomarkers such as IL-18, C-X-C motif ligand 9, adenosine deaminase 2 activity and activated T cells seemed promising.

Conclusion: Our results argue for a continuum between sJIA and AOSD.

Prospero registration number: CRD42022374240 and CRD42024534021.

Keywords: Arthritis, Juvenile; Macrophage Activation Syndrome; Still's Disease, Adult-Onset.

Figure 1. Prevalence (pooled estimates) of clinical manifestations in patients with sJIA and AOSD (SR1: prevalence of manifestations). Values are pooled estimates of prevalence (95% CI). For each parameter, prevalence is represented in black for sJIA and grey for AOSD. ¹Heterogenity is summarised visually by asterisks: *low heterogeneity (I²<50%); **moderate heterogeneity (50<I²<75%); ***high heterogeneity (I²>75%). For details of the I² and p values of each group, please refer to the online supplemental material. ²Heterogeneity between groups is statistically different at p<0.05. For details of p values, please refer to the online supplemental material. The line "arthritis bis" gives the arthritis pooled estimate prevalence without the study by Inoue et al because it had a very low rate of arthritis in both age groups, accounting for the large part of variability when taken into account. sJIA, systemic juvenile idiopathic arthritis; AOSD, adult-onset Still’s disease.

Figure 2. Prevalence (pooled estimates) of modified biological features in sJIA and AOSD (SR1: prevalence of manifestations). Values are pooled estimates of prevalence (95% CI). For each parameter, prevalence is represented in black for sJIA and grey for AOSD. ¹Heterogenity is summarised visually by asterisks: *low heterogeneity (I²<50%); **moderate heterogeneity (50<I²<75%; there were no studies with moderate heterogeneity in this figure); ***high heterogeneity (I²>75%). For details of the I² and p values of each group, please refer to the online supplemental material. ²Heterogeneity between groups is statistically different at p<0.05. For details of p values, please refer to the online supplemental material. ANA, antinuclear antibody; AOSD, adult-onset Still’s disease; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; Hb, haemoglobin; RF, rheumatoid factor; sJIA, systemic juvenile idiopathic arthritis.

Figure 3. Prevalence (pooled estimates) of complications in patients with sJIA and AOSD (SR1: prevalence of manifestations). Values are pooled estimates of prevalence (95% CI). For each parameter, prevalence is represented in black for sJIA and grey for AOSD. ¹In Neau et al, the details of macrophage activation syndrome (MAS), thrombotic microangiopathy, tamponade, myocarditis and interstitial lung disease for each group (sJIA and AOSD) were obtained directly from the authors (not published data). ²Heterogenity is summarised visually by asterisks: *low heterogeneity (I²<50%); **moderate heterogeneity (50<I²<75%); ***high heterogeneity (I²>75%). For details of the I² and p values of each group, please refer to the online supplemental material. ³Heterogeneity between groups is statistically different at p<0.05. For details of p values, please refer to the online supplemental material. ⁴Note that for Neau et al [29], the authors reported a total n=26 in the published data, but in their Excel file n=24 (12 in sJIA group, 12 in AOSD group), so we considered n=24 for our meta-analysis. ⁵Only one study reported on the frequency of thrombotic microangiopathy, tamponade, myocarditis or pulmonary hypertension, and so meta-analysis was not performed for these complications. AOSD, adult-onset Still’s disease; sJIA, systemic juvenile idiopathic arthritis.