key: cord-0832588-brr6g0od
authors: Naddei, Roberta; Alfani, Renata; Bove, Martina; Discepolo, Valentina; Mozzillo, Filomena; Guarino, Alfredo; Alessio, Maria
title: Increased relapse rate during COVID‐19 lockdown in an Italian cohort of children with juvenile idiopathic arthritis
date: 2021-08-16
journal: Arthritis Care Res (Hoboken)
DOI: 10.1002/acr.24768
sha: 89f78350c63654ce815bfd67e9fbaa02edb71f8a
doc_id: 832588
cord_uid: brr6g0od

OBJECTIVES: Changes of routine disease management associated with COVID‐19 lockdown might have potentially affected the clinical course of juvenile idiopathic arthritis (JIA). Aim of our study was to assess the rate of disease flare before and during COVID‐19 lockdown to investigate its impact on disease course in JIA children. METHODS: A single‐center retrospective study was conducted, including patients presenting inactive JIA between September 1(st), 2018 and March 9(th), 2019 (group A) and between September 1(st), 2019 and March 9(th), 2020 (group B). For each patient, demographic and clinical data were collected. The rate of JIA flare from March 10(th), 2019 to June 30(th), 2019 for group A and from March 10(th), 2020 to June 30(th), 2020 for group B was compared. RESULTS: Group A included 126 patients and group B 124 patients. Statistical analysis did not show significant differences among the two cohorts with respect to age, sex, age of JIA onset, JIA subtype, co‐occurrence of uveitis, ANA positivity and past or ongoing medications. The rate of disease flare during lockdown at time of first COVID‐19 pandemic wave, was significantly higher in comparison to the previous year (16.9% vs 6.3%, p=0.009). CONCLUSION: Our study showed that COVID‐19 lockdown was associated with a higher rate of joint inflammation in JIA children. This finding has a considerable clinical implication, since restrictive measures may be necessary in order to contain pandemics. Our data highlight the need for rearrangement in the home and healthcare management of JIA children during lockdowns.

The first European country affected by the Coronavirus Disease 2019 (COVID-19) pandemic was Italy, where the outbreak exploded in February 2020 having immediately far-reaching health and social implications. Since the beginning of COVID-19 outbreak, restrictive measures were implemented to prevent the spreading of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). During the so-called "phase 1" of the COVID-19 outbreak in Italy, starting on March 10 th , 2020, school's closure was a major component of social distancing along with the shutdown of all non-essential activities, including leisure and sport. During "phase 2", from May 4 th to June 15 th , 2020, there was a progressive easing of the containment measures although schools and gyms remained closed. While national and regional governments ordered the discontinuation of deferrable medical and surgical activities during phase 1, they were allowed in phase 2.

Children affected by juvenile idiopathic arthritis (JIA) might be considered a vulnerable population. In the first months of COVID-19 pandemic, JIA patients and their parents had to cope with major challenges in the routine disease management, such as limiting non-essential health care visits and physical activity due to home confinement and the concerns raised by the use of immunosuppressive medications, like conventional disease-modifying antirheumatic drugs (cDMARDs) and biologic disease-modifying drugs (bDMARDs) (1) . These factors might potentially contribute to disease worsening during the pandemic. Current findings on the course of inflammatory rheumatic diseases during lockdown mainly regard adult patients (2) (3) (4) , while physical effects of pandemic on pediatric chronic arthritis (5) have not been widely reported. Therefore, we investigated the rate of JIA flare before and during COVID-19 lockdown, in order to explore its impact on disease course in children with JIA.

A single-center retrospective study was conducted by reviewing medical records of JIA patients admitted at the Pediatric Rheumatology Unit of the University of Naples Federico II with a minimal follow-up duration of 6 months. All patients were diagnosed according to the International League of Associations for Rheumatology criteria (6) and were divided in two groups:

This article is protected by copyright. All rights reserved (V1) and then re-evaluated between March 10 th , 2020 and June 30 th , 2020 (V2).

ID was defined, according to the Wallace criteria (7), as no joint with active arthritis, no systemic manifestations due to JIA, no active uveitis, normal acute-phase reactants, physician global assessment (PGA) indicating no disease activity (defined as score of 0 on a 0-10 visual analogue scale) and duration of morning stiffness <15 minutes. However, the full set of Wallace criteria could not be applied before 2020, due to the limitations in the direct medical visits which precluded PGA. In those circumstances, when the other Wallace criteria were met, the absence of disease activity was inferred through the review of the patient chart by consensus of three investigators (RN, RA and MA). Also, patients evaluated with telemedicine tools during COVID-19 lockdown and reporting no signs of active disease were included in group B (N=31). In fact, during COVID-19 lockdown, remote consultations (telephone or email interviews) were performed with patients' parents, investigating the occurrence of signs and symptoms consistent with JIA flare (morning stiffness, joint swelling and/or pain and/or limited range of motion). If any of those was present, in person consultation was ordered. Otherwise, the direct visit was deferred.

For the purpose of the analysis and in agreement with Beukelman et al. (8) , patients were grouped in the functional phenotypes of oligoarthritis (4 or fewer affected joints), polyarthritis (5 or more affected joints), systemic arthritis (sJIA), and enthesitis-related arthritis (ERA). Among patients with sJIA, only patients with a history of chronic arthritis that persisted in spite of inactive systemic features, were included. In order to investigate lockdown effects only on articular symptoms in JIA children, patients with active uveitis without active arthritis at V2 were excluded from the analysis. A subset of patients included in group A was also evaluated the following year in the same period and thus included also in group B (N=71).

For each patient, demographic data, JIA subtype, age at JIA onset, co-occurrence of uveitis, antinuclear antibody (ANA) positivity, disease duration and past therapeutic regimens were collected into a dedicated anonymized database. Date of disease onset was defined as the date when the first symptoms of arthritis were noted, as recorded in the clinical charts. For each consultation, PGA, presence of morning stiffness, presence of JIA flare including the number and type of active joints (swelling or both tenderness and limited range of motion), erythrocyte sedimentation rate, routine

This article is protected by copyright. All rights reserved out-of-school physical activity (defined as regular sport activity at least twice a week), ongoing medications and therapeutic decisions at the visit were also collected. Type of consultation (in person or remote), missed days of school and deferred medical visits were also recorded for patients undergoing V2 during COVID-19 pandemic. Medication adherence was assessed by parental report, including overall adherence (yes/no) and potential barriers. In flaring patients of group B, contact history with COVID-19 cases, suspected or confirmed COVID-19 diagnosis before JIA relapse and the results of SARS-CoV-2 serology, if available, were also investigated and collected.

The JIA relapse rate at V2 was measured and compared between patients of group A and group B.

Descriptive statistics were reported as median and interquartile range (IQR) for continuous variables and as percentages for categorical ones. The rate of disease flare was expressed with 95% confidence intervals (95% C.I.). Comparison of categorical variables between the two groups were performed by χ 2 test or Fisher's exact test in case of expected frequencies less than 5, whereas Mann-Whitney U test was used in order to compare continuous variables. All statistical tests were 2-sided and considered significant with a P-value lower than 0.05.

The study protocol was approved by the Ethical Committee of the University of Naples Federico II (protocol #440/20).

With regard to group A, 165 patients with JIA presented ID at V1, of those 134 underwent V2.

Eight subjects affected by sJIA without persistent arthritis were excluded, resulting in a cohort of 126 patients (figure 1). With regard to group B, 178 patients presented ID at V1, of those 137 underwent V2. One patient with active uveitis at V2 and 12 patients with sJIA without history of persistent arthritis were excluded, resulting in a cohort of 124 patients (figure 1).

Looking at patients' demographic and clinical data ( (table 1) . Altogether, these data suggest that clinical and demographic features at baseline did not differ between the two groups of patients.

Due to discontinuation of deferrable medical activities, 31/124 (25%) patients in group B were evaluated only through a remote consultation at V2, 31 (25%) had their appointment postponed for over a month. At V2, no significant difference was found with respect to the ongoing JIA treatment between the two cohorts (table 2). Temporary drug interruptions for greater than one week were reported in 5/81 (6.2%) in group B, four of which were unrelated to COVID-19. One patient delayed her monthly Tocilizumab infusions without medical advice, due to fear to be 

This article is protected by copyright. All rights reserved COVID-19 lockdown, 6 did not practice sport before COVID-19 pandemic. Of note, none of the flaring patients had neither suspected or confirmed COVID-19 diagnosis nor COVID-19 exposure and 5 of them had a negative SARS-CoV-2 serology in June 2020.

When comparing relapsed patients among the two groups, no differences in demographic and clinical features at V2 were found (supplementary table S1). Notably, ankle arthritis was slightly more frequent in group B (38% vs 0%, p=0.066).

To our knowledge, this study presented the largest pediatric JIA cohort in which the effects of COVID-19 lockdown on disease course were investigated. Our data showed that more JIA patients experienced a disease flare during home confinement due to SARS-CoV-2 pandemic compared to the same period of the previous year, supporting our hypothesis that containment measures during COVID-19 lockdown negatively impacted disease activity. compliance. Yet, a role of decreased drug adherence on disease activity during lockdown could not be entirely excluded, as it was not measured through a validated tool.

This article is protected by copyright. All rights reserved During COVID-19 lockdown, children spent less time engaged in physical activity, with a parallel increase in sleeping and TV or video watching/playing time (11, 12) . These lifestyle modifications may impact on daily life of patients with chronic diseases (13), and possibly contribute to a higher flare rate in JIA children. As expected, in our population the proportion of patients performing regular physical activity was significantly lower during COVID-19 pandemic compared to the previous year. In addition, our kids with JIA had not been attending school for about 3 months at the time of consultation. It is well-known that arthritis symptoms worsen in the morning or after prolonged rest (14) and that physical therapy may lead to pain reduction and increased range of motion in JIA patients (15) . Indeed, along with medications, exercise is recommended as a therapeutic tool to children and adolescent with JIA in order to counteract the disease-related inflammation and improve clinical symptoms (16) . Besides, it has been shown that peripheral blood lymphocytes of less active children present a proinflammatory profile, suggesting that physical activity may decrease systemic inflammatory responses (17) . Therefore, the physical inactivity associated to home confinement could be a possible explanation for clinical worsening in our patients. On this basis, we believe that prescription of home-based exercise programs by a physical therapist should be promoted to implement JIA management in case of public lockdowns.

The temporary interruption of non-essential healthcare in person consultations during the "phase 1" of COVID-19 pandemic might have led to delays in patients' management, however the proportion of delayed face-to-face visits was the same in patients with or without arthritis relapse, suggesting that the limitations in the outpatient rheumatology medical service was not a main contributor to the JIA worsening in our cohort. As a matter of fact, outpatient in person visits were postponed only if parents reported no signs or symptoms consistent with JIA relapse at the telemedicine call. Even though recent data suggest that telemedicine alone may be insufficient to guide a treat-to-target strategy (18), the use of telehealth tools might have limited the impact of the partial closure of ambulatory services on disease management, according to other reports (19).

From this point of view, the development of validated telemedicine models for JIA may be critical to guarantee an effective management of JIA in case of confinement measures and to monitor disease activity at home.

Our findings should be interpreted within the limitations of the study, which are mainly inherent to its observational and retrospective nature. Besides, our results reflect a single tertiary care center experience, so they may not be extended to other clinical settings. Since our study was not randomized and observational, we cannot exclude that patients in group B presented a more

This article is protected by copyright. All rights reserved aggressive disease than those in group A. Likewise, the slightly higher number of patients offtherapy in group B may represent a possible confounding factor in our analysis. Nevertheless, the comparison of the two cohorts showed homogeneity in regard to demographic and clinical features. Finally, since subtle signs of active arthritis might have been underrecognized and not reported at telemedicine, the relapse rate during lockdown could be even potentially higher than observed.

In conclusion, this study provides new evidence that COVID-19 lockdown was associated with a higher rate of relapse in JIA children, even in the absence of reduced drug adherence. This finding has considerable clinical implications, since restrictive measures are still occurring in several countries as the pandemic evolves. Our data highlight the need for implementing healthcare management of patients with JIA, including personalized at-home-exercise-programs, in case of new lockdowns. 

This article is protected by copyright. All rights reserved 

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Impact of home confinement during the COVID-19 pandemic on medication use and disease activity in spondyloarthritis patients

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