Worldwide evaluation of Clinical Practice Strategies (CliPS) for lung involvement in Still’s disease within the JIR-CliPS network: a COST action

Dear Editor, Still’s disease is a rare autoinflammatory condition encompassing systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD). Still’s disease can be complicated by lung inflammation (LD), which appears to be more prevalent than previously recognized. Reports indicate that 6.8% of children with sJIA develop LD within 2 years of onset, with an initial mortality rate as high as 68% [1–3]. In adults, 5–12% of Still’s disease patients develop LD, with similarly high mortality rates [4, 5]. Recent findings from the AIDA Network registry published in your journal have provided new insights into the extent and characteristics of LD-Still’s disease [6]. In this cohort of 90 adult and pediatric patients, parenchymal lung involvement was observed in 34.4% and pulmonary arterial hypertension in 2.3% [6]. The latest EULAR/PReS guidelines have provided specific recommendations for the management of LD in Still’s disease [7]. While progress has been made in understanding these complications, significant gaps persist in clinical practice worldwide.

To evaluate global clinical approaches to LD in Still’s disease, the Juvenile Inflammatory Rheumatism Network conducted an international survey under Clinical Practice Strategy (CliPS) initiative. This survey has been distributed since September 2022 and targeted clinicians from diverse healthcare settings and experience levels (Supplementary Table S1, available at Rheumatology Advances in Practice online), collecting data on demographic characteristics, diagnostic methodologies, and therapeutic strategies. The responses were analyzed in September 2024, before the publication of EULAR/PReS recommendations, and stratified by pediatric and adult specialists, considering that clinical practices remain heterogeneous between these groups.

Among 372 clinicians from five continents (Supplementary Fig. S1, available at Rheumatology Advances in Practice online), who participated in the survey, 69 respondents (18.5%)—57 paediatricians and 12 adult specialists—reported experience in managing LD in Still’s disease. The survey results are detailed in Table 1.

Table 1.

Diagnostic investigations from paediatricians for lung involvement in Still’s disease

Investigation/action	Always (%)	Sometimes (%)	Never (%)	Number of participants (n)	Non respondent
Chest radiography	94	6	0	50/57 (88%)	n = 7/57
Chest CT scan	79	21	0	53/57 (93%)	n = 4/57
Echocardiography (for pulmonary hypertension)	82	18	0	50/57 (88%)	n = 7/57
Bronchoalveolar lavage (BAL)	24	63	13	46/57 (80%)	n = 11/57
Lung biopsies	2	72	26	43/57 (75%)	n = 10/57
Cytokine assays	19.2	53.8	26.9	41/57 (72%)	n = 16/57
IFN signature	15	42	43	40/57 (70%)	n = 17/57
Whole-exome sequencing	5	62	33	40/57 (70%)	n = 17/57
IL-18 measurements (for follow-up in LD-Still’s Disease)	Yes: 28	–	No: 71		n = 32/32 (100%)
HLADRB1*15 as a supplementary argument for lung involvement	40	16	44		n = 32/32 (100%)
Change in therapeutic approach if HLADRB1*15 allele is identified	29	23	48		n = 31/32 (96,8%)

A total of 79% and 82% of paediatricians reported routinely using chest CT scans and echocardiography for pulmonary assessment, respectively. The use of biomarkers such as IL-18 is not yet standard practice, with only 28% of paediatricians reporting its use. The interferon signature, while not yet universally adopted, is gaining recognition, with 57% of paediatricians incorporating it into clinical practice.

Genetic testing for HLA-DRB1*15, a potential risk factor for drug-induced reactions [1], is inconsistently performed, with 56% of paediatricians utilizing it, showing significant regional variation (Supplementary Table S2, available at Rheumatology Advances in Practice online). However, the clinical significance of HLA typing remains controversial in the literature [3, 7] and raises concerns among most practitioners.

Regarding treatment, most paediatricians (n = 38/46, 83%) opted not to discontinue IL-1 or IL-6 inhibitors if LD developed. Of these, 56% (n = 26/46) reported switching biologics if the treatment was ineffective in controlling disease activity, while the remaining continued the same biologic with the addition of other therapeutics. A significant proportion of paediatricians have integrated JAK inhibitors into their clinical practice for the treatment of LD, with 38.8% of participants selecting this option, followed by T cell-targeted therapies such as ciclosporin or mycophenolate mofetil (Supplementary Figs S2 and S3, available at Rheumatology Advances in Practice online). Hematopoietic stem cell transplantation remains a last-resort option, with 82% of surveyed paediatricians considering it a viable approach for refractory cases.

The survey results, which focused on a pediatric point of view due to the low participation of adult specialists, revealed substantial global variation. The asymptomatic development of these conditions often complicates early detection [8]. Chest CT scans, radiography and echocardiography appear to be standard tools for early detection, aligning with EULAR/PReS recommendations. Pulmonary biopsies, though informative, seem to be infrequently performed due to their invasive nature. We suggest that this procedure could be reserved for complex cases.

A notable finding is the disparity in the use of IL-18, which is less frequently performed in emerging countries, likely due to cost and accessibility constraints. The interferon signature, although not officially recognized as a biomarker in EULAR/PReS guidelines [7] or registry data [6], appears to be increasingly used in clinical practice, particularly with the growing adoption of JAK inhibitors, which directly target interferon signalling pathways.

Despite concerns that biologics might have exacerbated LD [8], most paediatricians continued their use in alignment with EULAR/PReS guidelines. Notably, data from the AIDA registry found no significant association between IL-1 or IL-6 inhibitors and the development of LD [6]. Our study also highlights the increasing incorporation of T cell-targeted therapies in cases of LD-associated Still’s disease, suggesting a growing emphasis on combination therapy as recommended by the EULAR/PreS.

Moreover, adult specialists were underrepresented in our study, suggesting they may be less familiar with LD in Still’s disease compared with paediatric rheumatologists. This result is opposed to the AIDA registry data collecting mostly adult patients (86.7%).

In conclusion, this study highlights gaps between registry data, recent guidelines and real-world clinical practices in managing LD associated with Still’s disease. Bridging these gaps will require targeted strategies to enhance clinician awareness, improve access to diagnostic tools and validate treatment recommendations across diverse healthcare settings.

Supplementary material

Supplementary material is available at Rheumatology Advances in Practice online.

Data availability

The data underlying this article cannot be shared publicly due to the privacy protection of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.

Funding

Clinical Practice Strategy (CliPS) initiative is funded by the COST-EU action CA21168.

Disclosure statement: The authors have declared no conflicts of interest.

Ethical approval and patient consent statement: In accordance with Article 2(1) of the Swiss Human Research Act (HRA), the Act applies only to research involving health-related personal data or interventions on humans. As this study collects identifiable data from physicians but does not involve any health-related personal data or patient-specific information, it falls outside the scope of the HRA and is thus not subject to ethical approval.