Background Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA). Methods This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intentionto-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or snore of study medication. This trial is registered with ClinicalTriats.gov, NCT02592434. Findings Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0.46, 95% CI 0.27-0.79; p=0.0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study. Interpretation The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Background: Tofacitinib is an oral JAK inhibitor that is being investigated for JIA. Objectives: To assess tofacitinib efficacy and safety in JIA patients (pts). Methods: This was a Phase 3, randomised, double-blind (DB), placebo (PBO)-controlled withdrawal study in pts aged 2−<18 years with polyarticular course JIA (pcJIA), PsA or ERA ( NCT02592434 ). In the 18-week open-label Part 1, pts received weight-based tofacitinib doses (5 mg BID or lower). Pts with ≥JIA ACR30 response at Week (W)18 were randomised 1:1 in the DB Part 2 (W18−44) to continue tofacitinib or switch to PBO. Primary endpoint: disease flare rate by W44. Key secondary endpoints: JIA ACR50/30/70 response rates; change from Part 2 baseline (Δ) in CHAQ-DI at W44. Other efficacy endpoints: time to disease flare in Part 2; JADAS27-CRP in Parts 1 and 2. PsA/ERA pts were excluded from these efficacy analyses. Safety was evaluated in all pts up to W44. Results: 225 enrolled pts with pcJIA (n=184), PsA (n=20) or ERA (n=21) received tofacitinib in Part 1. At W18, 173/225 (76.9%) pts entered Part 2 (pcJIA n=142, PsA n=15, ERA n=16). In pcJIA pts, disease flare rate in Part 2 was significantly lower with tofacitinib vs PBO by W44 (p=0.0031; Fig 1a). JIA ACR50/30/70 response rates (Fig 1b) and ΔCHAQ-DI (Fig 1c) at W44, and time to disease flare in Part 2 (Fig 2a), were improved with tofacitinib vs PBO. Tofacitinib reduced JADAS27-CRP in Part 1; this effect was sustained in Part 2 (Fig 2b). Overall, safety was similar with tofacitinib or PBO (Table): 77.3% and 74.1% had adverse events (AEs); 1.1% and 2.4% had serious AEs. In Part 1, 2 pts had herpes zoster (non-serious) and 3 pts had serious infections (SIs). In Part 2, SIs occurred in 1 tofacitinib pt and 1 PBO pt. No pts died. Conclusion: In pcJIA pts, tofacitinib vs PBO resulted in significantly fewer disease flares, and improved time to flare, disease activity and physical functioning. Tofacitinib safety was consistent with that in RA pts. Table. Safety in all pts Part 1 Part 2 Tofacitinib a N=225 Tofacitinib a N=88 PBO N=85 Pts with events, n (%) AEs 153 (68.0) 68 (77.3) 63 (74.1) SAEs 7 (3.1) 1 (1.1) 2 (2.4) Permanent discontinuations due to AEs 26 (11.6) 16 (18.2) 29 (34.1) AEs of special interest Death 0 0 0 Gastrointestinal perforation b 0 0 0 Hepatic event b 3 (1.3) 0 0 Herpes zoster (non-serious and serious) 2 (0.9) c 0 0 Interstitial lung disease b 0 0 0 Major adverse cardiovascular events b 0 0 0 Malignancy (including non-melanoma skin cancer) b 0 0 0 Macrophage activation syndrome b 0 0 0 Opportunistic infection b 0 0 0 SI 3 (1.3) 1 (1.1) d 1 (1.2) Thrombotic event (deep vein thrombosis, pulmonary embolism b or arterial thromboembolism) 0 0 0 Tuberculosis b 0 0 0 a 5 mg BID or equivalent weight-based lower dose in pts <40 kg b Adjudicated events c Both non-serious d One SAE of pilonidal cyst repair was coded to surgical procedures instead of infections, and was inadvertently not identified as an SI. Following adjudication, the SAE did not meet opportunistic infection criteria; it is also included in the table as an SI AE, adverse event; BID, twice daily; PBO, placebo; pts, patients; SAE, serious AE; SI, serious infection Acknowledgments: Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc. Disclosure of Interests: Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Olga Synoverska Speakers bureau: Sanofi, Tracy Ting: None declared, Carlos Abud-Mendoza Speakers bureau: Eli Lilly, Pfizer Inc, Alberto Spindler Speakers bureau: Eli Lilly, Yulia Vyzhga Grant/research support from: Pfizer Inc, Katherine Marzan Grant/research support from: Novartis, Vladimir Keltsev: None declared, Irit Tirosh: None declared, Lisa Imundo: None declared, Rita Jerath: None declared, Daniel Kingsbury: None declared, Betül Sözeri: None declared, Sheetal Vora: None declared, Sampath Prahalad Grant/research support from: Novartis, Elena Zholobova Grant/research support from: Novartis and Pfizer Inc, Speakers bureau: AbbVie, Novartis, Pfizer Inc and Roche, Yonatan Butbul Aviel: None declared, Vyacheslav Chasnyk: None declared, Melissa Lerman Grant/research support from: Amgen, Kabita Nanda Grant/research support from: Abbott, AbbVie, Amgen and Roche, Heinrike Schmeling Grant/research support from: Janssen, Pfizer Inc, Roche and USB Bioscience, Heather Tory: None declared, Yosef Uziel Speakers bureau: Pfizer Inc, Diego O Viola Grant/research support from: Bristol-Myers Squibb, GSK, Janssen and Pfizer Inc, Speakers bureau: AbbVie and Bristol-Myers Squibb, Holly Posner Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Keith Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ann Wouters Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cheng Chang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Richard Zhang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Irina Lazariciu Consultant of: Pfizer Inc, Employee of: IQVIA, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ricardo Suehiro Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Alberto Martini Consultant of: AbbVie, Eli Lily, EMD Serono, Janssen, Novartis, Pfizer, UCB, Daniel J Lovell Consultant of: Abbott (consulting and PI), AbbVie (PI), Amgen (consultant and DSMC Chairperson), AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (PI), Celgene, Forest Research (DSMB Chairman), GlaxoSmithKline, Hoffman-La Roche, Janssen (co-PI), Novartis (consultant and PI), Pfizer (consultant and PI), Roche (PI), Takeda, UBC (consultant and PI), Wyeth, Employee of: Cincinnati Children’s Hospital Medical Center, Speakers bureau: Wyeth, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis

Objective Ultraviolet (UV) radiation is considered to be an important environmental factor in the clinical course of children with juvenile dermatomyositis (DM). We aimed to evaluate the association between UV radiation and severe disease outcomes in juvenile DM. Methods This is a cross-sectional study of patients with juvenile DM enrolled in the US multicenter Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry from 2010 to 2015. The mean UV index (UVI) in the calendar month prior to symptom onset in each subject's zip code was calculated from daily satellite solar noon measurements. Multivariable logistic regression was used to model the relationship between the mean UVI and calcinosis as well as other outcomes of severe disease. Covariates included sex, race, age, time to diagnosis, disease duration, and latitude. Results In a multivariable model, there was no association between the mean UVI and calcinosis. African American race was associated with a 3-fold greater odds of calcinosis. However, there was a significant statistical interaction between race and mean UVI. Accounting for this interaction, the odds of calcinosis markedly decreased in African American subjects and steadily increased in non-African American subjects over a range of increasing the mean UVI. Higher mean UVI was associated with decreased odds of using biologics or nonmethotrexate disease-modifying antirheumatic drugs and skin ulceration. Conclusion We described a novel association between UV radiation, calcinosis, and race in a large cohort of patients with juvenile DM. This study furthers our knowledge of the role of UV radiation in the clinical course of juvenile DM and highlights the complex interplay between genes and environment in the clinical phenotypes and development of calcinosis in children with juvenile DM.

Background Children and adolescents with juvenile-onset systemic lupus erythematosus (jSLE) face considerable morbidity due to sequelae of disease activity, comorbidities and adverse effects of treatment. In order to improve the management of these patients, it is essential to better understand the risk factors associated with the development of permanent damage. Objectives The main goals of this study were to determine the prevalence of organ damage among children with jSLE and to identify risk factors for damage. Methods This was a retrospective chart review of the clinical courses of jSLE patients followed at MSCHONY/CUMC, from the time of diagnosis or first encounter until December 2009 or loss to follow-up. All patients were diagnosed before the age of 18, had a disease duration ≥6 months and were followed during the period 2007-2009. Disease activity (SLEDAI) at diagnosis and Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI) at the conclusion of the study were evaluated. Major infections were identified, defined as those that required treatment with parenteral antimicrobial agents or necessitated a course of antibiotics for more than one week. Chi-square/Fisher’s exact test and t-test were used to analyze categorical and continuous data, respectively. Results There were 120 children and adolescents with SLE: 93 female/27 male (F/M: 3.4/1), 61 Hispanic (51%) and 34 African-American (28%). The majority (53%) were diagnosed between the ages of 10-15 years. Mean duration of follow-up was 4.7±3.2 years. Mean SLEDAI at diagnosis was 9.6±6.5. Lupus nephritis affected 59 patients (49%). Neuropsychiatric manifestations (NPSLE) occurred in 15 children (12%). Mycophenolate mofetil (MMF) was used in 56% of the patients, cyclophosphamide in 37% and rituximab in 6%. The mean cumulative prednisone dose was 12g. There were 101 major infections affecting 44 patients (37%), the most common being skin infections (19), pneumonias (17), urinary tract infections with fever (14), sepsis (9), and herpes zoster (8). During the study 2 patients died due to disease-associated comorbidities. Damage (SDI ≥1) was present in 33% (39/118) of the patients after a mean disease duration of 5.0±3.3 years. The median SDI score was 1 (range 0-6). Damage to the musculoskeletal system was observed most frequently (9%), followed by neuropsychiatric (7%), ocular (7%), skin (7%), pulmonary (5%) and renal (5%) systems. No malignancies were encountered. Damage was significantly more likely in patients who had experienced neuropsychiatric manifestations during the first year of disease, had major infections or were treated with cyclophosphamide, MMF or rituximab (p<0.05). There was no association of damage with gender, renal involvement or cumulative dose of prednisone. Conclusions In a large cohort of children with jSLE, damage was common, but less frequent than previously reported. Neuropsychiatric involvement during the first year of disease, major infections and immunosuppressive therapy with cyclophosphamide, MMF and rituximab were identified in this cohort as risk factors for damage. References Gutiérrez-Suárez R et al. Arthritis Rheum 2006. 54:2989-96. Ravelli A et al. Arthritis Rheum 2003. 49:501-7. Disclosure of Interest None Declared

Pain is a common presenting complaint in the pediatrician’s office. As many as 30% of children and adolescents experience significant muscular fatigue and chronic or recurrent musculoskeletal pain. The symptoms have many causes and the differential in children includes infectious and metabolic conditions, growing pains, overuse injuries, hyperextensibility, orthopedic problems, arthritis, and genetic syndromes. Pain Amplification Syndromes are rarely recognized or diagnosed in a timely fashion by the primary care physician. These syndromes are characterized by a lack of physical or laboratory findings. Typically the child describes the pain as maximal (on a pain scale of 10/10). There is disability out of proportion to the physical findings, a sensation of pain to non-painful stimuli, psychological distress, an inappropriate indifferent affect (La Belle indifference), a significant family history of disability or chronic pain, and the presence of multiple somatic complaints. Indeed, the degree of pain and disability in these groups is strikingly high compared to children with Juvenile Idiopathic Arthritis or other classical rheumatic conditions where joint disease is readily demonstrable. Given the lack of a diagnostic test and variability of presentation, as well as a large number of potential etiologies, Pain Amplification Syndromes have been called by many synonyms, despite the possibility that they all represent variations of a common process. Generalized pain syndromes include fibromyalgia, fibrositis, myofascial pain syndrome, pain amplification syndrome, and diffuse wide spread myofascial pain, while localized pain syndromes have been called reflex sympathetic dystrophy, reflex neurovascular dystrophy, causalgia, and Sudeck’s atrophy. Some authors suggest that the precise classification in children with pain and fatigue is not necessary because overlap in clinical presentation is frequent and all children with pain syndromes respond to a similar treatment programs.

Results There were 120 children with SLE followed during the study period: 93 female (77.5%, M:F 3.4:1); 61 Hispanic (50.8%) and 34 African-American (28.3%). NPSLE affected 15 children (12.5%). Cognitive dysfunction was the most common manifestation, followed by significant headache, seizures, psychosis, and focal neurologic signs. NPSLE was diagnosed in the first year in 10/15 patients (67%). Abnormalities of brain magnetic resonance imaging were encountered in 10 patients (67%). Children with NPSLE had a significantly greater number of co-morbidities (end-stage renal disease, thrombocytopenia, and pancreatitis) than unaffected children with SLE (p<0.05). NPSLE was associated with a higher SLEDAI at diagnosis and the presence of anti-Smith antibodies (p<0.05). All patients received high-dose corticosteroid and cyclophosphamide. NPSLE was associated with the occurrence of major infections, as well as a higher SLICC damage index, and mortality (p<0.05). Conclusions In this cohort NPSLE was associated with co-morbidities, major infections, and higher damage scores.

Case report A 3 year old boy presented with 3 days of fever, rash, pharyngeal and gingival erythema, and swollen extremities. Laboratory investigations revealed leukocytosis, C– reactive protein 25.8 mg/dl, and erythrocyte sedimentation rate 100 mm/hr. Echocardiography disclosed diffuse dilatation of all proximal coronary arteries. The child received IVIG (2g/kg) and aspirin (100 mg/kg/d) with no response. IVIG was repeated, followed by methylprednisolone 30 mg/kg for 3 days, but the child remained febrile. Infliximab (5 mg/kg) was thereupon employed with prompt defervescence. Low-dose aspirin was continued, as well as clopidogrel. Echocardiographic findings remained stable. Six months after the initial episode, the child again presented with fever, irritability, sore throat and nuchal rigidity. Physical examination revealed cracked, swollen lips, oropharyngeal erythema, posterior cervical lymphadenopathy, and rash. Desquamation of the distal extremities was observed some days later. Aneurysms were detected, involving the left and right main coronary arteries, as well as the left anterior descending coronary. Magnetic resonance angiography of the chest and abdomen revealed no other involved vessels. The child again received IVIG, pulse methylprednisolone, and infliximab, but remained febrile and developed significant arthritis, requiring daily prednisolone. He is now asymptomatic.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Objective To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA).Methods Patients eligible for the open-label extension (OLE, weeks 52-204) received infliximab 3-6 mg/kg every 8 weeks plus methotrexate.Results Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively.Conclusions In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate.

A 16-year-old boy began having gum swelling and leg cramps 2 weeks before examination. Several days later, he noticed bruises on his lower legs and stiffness. In addition, he had hip, knee, calf, and pain in his left foot. He continued to notice new, large ecchymotic lesions on his lower extremities without any antecedent trauma.