Nicolino Ruperto’s research while affiliated with Università degli Studi di Milano-Bicocca and other places

Background To our knowledge, limited information is available about the differences in the characteristics of rheumatoid factor (RF)-negative polyarticular juvenile idiopathic arthritis (JIA) throughout the world. This study was aimed to compare the demographic and clinical features of patients with RF-negative polyarthritis across the world. Methods Patients were part of a multinational sample included in a study aimed to investigate the prevalence of disease categories, treatment regimens, and disease status in patients from different geographical areas (EPOCA Study). All patients underwent a retrospective assessment, based on the review of clinical chart, and a cross-sectional evaluation, which included assessment of physician- and parent-reported outcomes and collection of ongoing medications. Results Among the 9081 patients enrolled in the EPOCA study, 2141 patients (23.6%) with RF-negative polyarthritis were included in the present analysis. The prevalence of RF-negative polyarthritis was highest in North America and lowest in Southeast Asia (12.7%). The age at disease onset was lower in Northern and Southern Europe, where the highest prevalence of uveitis was found. Uveitis was rare in Southeast Asia, Africa & Middle East and Latin America. Patients from Eastern Europe, Latin America and Africa and Middle East presented with the highest prevalence of active joints at the visit. The combination of early onset, ANA positivity, and uveitis was observed mainly in Southern Europe (39%). Conclusions Our results confirm the wide heterogeneity of the clinical presentation and outcome of children with RF-negative polyarticular JIA throughout the world. In particular, relevant differences in the onset age were observed across geographic areas. The group of children with early onset polyarthritis, ANA positivity, and risk of uveitis is remarkably frequent in Southern Europe.

Objectives To confirm the presence of different disease phenotypes of pediatric SAPHO syndrome (pSAPHO) based on their skin manifestations in a large cohort of Italian patients. Methods pSAPHO were enrolled in the Eurofever Registry and the data retrospectively analysed. Patients were divided depending on their skin manifestations into an Acne-Hidradenitis suppurativa (HS) group and a Palmoplantar Pustulosis-Psoriasis Vulgaris (PPP-PV) group and were compared with patients without skin manifestations (chronic non-bacterial osteomyelitis, CNO). Comparison of frequencies between groups was performed by the means of χ2 test or by Fischer’s Exact test. Results 54 pSAPHO with skin manifestations (35 acne-HS, 19 PPP-PV) were enrolled and compared with 167 CRMO. In the Acne-HS, 82.9% were males, in the PPP-PV, 84.2% were females, while in the CNO group there were no gender differences (p< 0.0001). The 3 groups differed significantly for age at disease onset: acne-HS median 13.3 years, PPP-PV median 10.2 years, CNO median 9.5 years (p= 0.0001). An axial pattern was more frequent in acne-HS (91.4%) and PPP-PV group (89.4%) compared with CNO (46%) (p< 0.0001). Both acne-HS (82.9%), and PPP-PV (63.2%) required more frequently a biologic therapy than CNO (36.8%), but acne-HS presented a refractory skin disease requiring steroids and different lines of treatment, while PPP-PV responded well to biologics. Conclusions Our data have identified two different phenotypes of pSAPHO based on skin manifestations, with different sex, age and response to treatments. These two groups have peculiar clinical features different from the CNO group. A new classification encompassing these phenotypes is warranted.

Objective The Paediatric Rheumatology International Trials Organisation (PRINTO) recently undertook an effort to better harmonize the pediatric and adult arthritis criteria. These provisional criteria are being refined for optimal performance. We aimed to investigate differences between patients who did and did not fulfill these PRINTO criteria among youth diagnosed with juvenile spondyloarthritis (SpA) that met axial juvenile SpA (axJSpA) classification criteria. Methods This was a retrospective cross‐sectional sample of youth diagnosed with juvenile SpA who met the axJSpA classification criteria. Demographics, clinical manifestations, and physician and patient‐reported outcomes were abstracted from medical records. Magnetic resonance imaging (MRI) scans underwent central imaging review by at least two central raters. Differences between groups were compared using Wilcoxon signed‐rank test or chi‐square test, as appropriate. Results Of 158 patients who met axJSpA criteria, 107 patients (68%) met the PRINTO provisional criteria for enthesitis/spondylitis‐related arthritis. A total of 41 patients (26%) did not fulfill any of the three major PRINTO criteria due to lack of peripheral disease manifestations. Demographics, prevalence of inflammatory or structural lesions on MRI, family history of SpA, and duration of pain were not statistically different between those who did and did not meet PRINTO criteria. Those who fulfilled the PRINTO criteria had significantly more peripheral arthritis, enthesitis, and HLA‐B27 positivity but reported less sacral/buttock pain. Conclusion Phenotypic differences of children with axJSpA between those who were and were not classified by the PRINTO criteria were primarily due to peripheral disease manifestations and HLA‐B27 positivity. Modification of the PRINTO provisional criteria may facilitate capture of youth with primarily axial disease.

Objective To evaluate the influence of pelvic magnetic resonance imaging (MRI) findings on axial disease assessment in juvenile spondyloarthritis (JSpA). Methods This was a cross-sectional study of patients with JSpA with suspected axial disease. Three experts reviewed each case and rated their confidence (–3 to +3) in the presence of axial disease, first with clinical data and second with clinical and MRI data. Agreement was defined as ≥ 2/3 clinical experts with a rating of ≤ –1 or ≥ 1, and high confidence agreement as ≤ –2 or ≥ 2. The association of clinical features and both global assessments was tested with modified Poisson regression models. Results Two hundred seventy-two of 303 cases (89.8%) achieved agreement with clinical data alone. Adding imaging data affected agreement in 38.9% (118/303) and directionality of agreement in 23.4% (71/303). Agreement was facilitated in 26/31 cases and lost in 21/272 cases. Of those 71 cases that changed directionality, 33 changed from axial disease being absent to present and 38 from present to absent. The final model had an area under the receiver-operating characteristic (AUROC) curve of 0.93 and 3 factors were independently associated with expert agreement (HLA-B27: relative risk [RR] 1.41, 95% CI 1.14-1.74; pain improvement with activity: RR 1.27, 95% CI 1.05-1.54; and bone marrow edema on MRI: RR 4.08, 95% CI 2.91-5.73). Conclusion The addition of imaging data affected directionality and improved high confidence agreement of expert assessment of axial disease. These results underscore the integral role of MRI in the determination of axial disease in JSpA.

Objective To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA). Methods Whole‐blood samples were collected from patients with JIA at baseline and after 18 weeks of open‐label tofacitinib treatment. Patients who achieved a JIA–American College of Rheumatology (ACR) response of 70% or above at week 18 were classified as treatment responders (TRs), whereas those with at most a JIA–ACR30 were classified as poor responders (PRs). Differential gene expression and gene ontology overrepresentation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline. Results Samples from 67 patients at baseline and 60 patients at week 18 were analyzed. After 18 weeks of tofacitinib treatment across all patients with JIA, 883 genes showed significant differential expression (week 18 to baseline). The most strongly down‐regulated genes were overrepresented within interleukin‐7 (IL‐7) and type I and type II interferon pathways, whereas up‐regulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PRs and TRs at baseline, 663 genes showed differential expression. Up‐regulated genes were overrepresented within ontologies including activation of MAPK activity (P = 9.40 × 10⁻⁵), myeloid cell development (P = 8.13 × 10⁻⁵), activation of GTPase activity (P = 0.00015), and organelle transport along microtubules (P = 0.00021). Conclusion Tofacitinib treatment in JIA down‐regulated genes in interferon and IL‐7 signaling pathways regardless of effectiveness. Furthermore, baseline up‐regulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.

Objective The physician global assessment of disease activity (PhGA) is a tool used nearly ubiquitously by pediatric rheumatologists for the assessment of patient disease activity status. However, this tool lacks standardization in its scoring. This survey aimed to identify score influencing factors, along with inclusion or exclusion of extra‐articular manifestations and imaging, when scoring the PhGA in juvenile idiopathic arthritis (JIA). Methods Electronic surveys were sent to Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Care and Outcomes Improvement Network members who completed a previous survey on scoring of the PhGA. Respondents were asked to rank their top seven factors for inclusion in the PhGA for nonsystemic JIA (nsJIA) and systemic JIA (sJIA), along with ranking extra‐articular manifestations and imaging for inclusion. Frequency and percentage of rank and Likert responses were analyzed, and geographic regions as well as level of experience were compared using the chi‐square test and Fisher's test. Results A total of 276 respondents from 54 countries and six continents participated. For nsJIA, factors selected by >50% included number of swollen joints, active uveitis, duration of morning stiffness, and number of tender joints. For sJIA, factors selected by >50% were presence and duration of fever, laboratory tests, number of swollen joints, serositis, rash, hepatomegaly, lung disease, and lymphadenopathy. Agreement on the inclusion of extra‐articular factors, such as uveitis, macrophage activation syndrome, and sJIA‐associated lung disease, had >70% moderate or strong agreement for inclusion, whereas psoriasis had only 50.5% agreement for inclusion and imaging had 64.7% agreement for inclusion. Variations in rank between different geographic regions or level of experience were minor. Conclusion This survey identifies factors that pediatric rheumatology providers find important for PhGA scoring of disease activity, documents varying agreement on inclusion of extra‐articular manifestations of disease, and lays the framework for further consensus work.

Objective We examine levels of candidate blood‐based biomarkers (CBBs) in patients with juvenile idiopathic arthritis (JIA) treated with tofacitinib. Methods Patients with JIA who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBBs (S100A8/9, S100A12, interleukin‐18 [IL‐18], serum amyloid A, resistin, vascular endothelial growth factor, angiopoietin‐1, angiopoietin‐2, matrix metalloproteinase 8 [MMP8], MMP2, tissue inhibitor of metalloproteinases 1, leptin, chemokine [C‐X‐C motif] ligand 9, soluble IL‐2 receptor, intercellular adhesion molecule 1, soluble tumor necrosis factor receptor, IL‐6, IL‐23, monocyte chemotactic protein 1, chemokine [C‐C motif] ligand 18 [CCL18], and CCL20). Association of CBBs with JIA response to treatment from baseline to week 18 were assessed. Results This study included 166 patients with polyarticular‐course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. Thirty‐five percent (50 of 143) of patients had a JIA‐American College of Rheumatology 90 (JIA‐ACR90) level improvement, whereas 90, 121, and 137 (63%, 85%, and 96%) achieved JIA‐ACR70, 50, and 30 improvement at week 18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in Juvenile Arthritis Disease Activity Score (JADAS‐27) or JIA‐ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with week 18 improvement in JADAS‐27 and JIA‐ACR90 response after adjusting for age, sex, JIA disease duration, and baseline resistin (r² 0.79, SE 0.070, P < 0.01, and odds ratio [95% confidence interval] 1.134 [1.018–1.264]). HLA‐B27 positivity was significantly associated with not achieving a JIA‐ACR90 response at week 18 (P = 0.0097). Conclusion Among the CBBs included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA‐B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.

This is a summary of the original article ‘Ten-year safety and clinical benefit from open label etanercept treatment in children and young adults with juvenile idiopathic arthritis’. Juvenile idiopathic arthritis (JIA) usually appears before the age of 16. JIA causes pain, swelling, and stiffness in the joints. People with JIA receive treatment for several years until the disease goes into prolonged remission. Therefore, the long-term safety of these treatments is an important topic. Etanercept is a treatment for JIA, which acts on the body’s immune system to reduce arthritis. This summary of research article describes safety and how well etanercept works in children with JIA taking it for up to 10 years.

Objective The goal was to develop and validate classification criteria for axial juvenile spondyloarthritis (SpA; AxJSpA). Methods This international initiative consisted of four phases: (1) item generation, (2) item reduction, (3) criteria development, and (4) validation of the AxJSpA criteria by an independent team of experts in an internationally representative validation cohort. Results These criteria are intended to be used on youth with a physician diagnosis of juvenile SpA and for whom axial disease is suspected. Item generation consisted of a systematic literature review and a free‐listing exercise using input from international physicians, which collectively resulted in 108 items. After the item reduction exercise and expert panel input, 37 items remained for further consideration. The final AxJSpA criteria domains included the following: imaging of active inflammation, imaging of structural lesions, pain chronicity, pain pattern, pain location, stiffness, and genetics. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was deemed necessary, but not sufficient, to classify a youth with AxJSpA. The threshold for classification of AxJSpA was a score of ≥55 (out of 100). When tested in the validation data set, the final criteria had a specificity of 97.5% (95% confidence interval [CI] 91.4%–99.7%), sensitivity of 64.3% (95% CI 54.9%–73.1%), and area under the receiver operating characteristic curve of 0.81 (95% CI 0.76%–0.86%). Conclusion The new AxJSpA classification criteria require an entry criterion and a physician diagnosis of juvenile SpA and include seven weighted domains. The AxJSpA classification criteria are validated and designed to identify participants for research studies. image