Juvenile Arthritis

We conducted a population-based study using both cohort design and nested case-control design in parallel, with the intention to preserve the advantages and complement the limitations of the other as we consider that cohort studies conventionally have a higher level of evidence, whereas case-control analysis was more appropriate for evaluating rare outcomes. The study period started in January 2014 and ended in December 2020. The cohort consisted of all incident patients aged above 10 years with diagnosis codes for depression (ICD-9-CM codes: 296.2, 296.3, 300.4, 311) between January 2014 and December 2016 without history of diagnosis for depression since 1993, when the database first became available. Patients were excluded if they had history of studied autoimmune diseases before onset of depression, or if they died immediately after cohort entry.
Throughout the study, patients were defined as treatment-resistant (exposed) if they had taken at least two antidepressant regimens of adequate duration (same antidepressant or combined therapy of at least 28 days with gaps of no longer than 14 days within regimens, whilst the 28-day duration was the minimum recommended duration to assess treatment responsiveness [26 ]) and had a third antidepressant regimen to confirm failure of the previous two trials. Patients who did not fulfil the criteria for TRD were considered as non-TRD (unexposed). Onset of outcome was confirmed on the date of the first autoimmune diagnosis in (1) organ-specific diseases including inflammatory bowel diseases, spondyloarthritis, psoriasis, insulin-dependent diabetes mellitus, Hashimoto’s thyroiditis, Graves’ disease, coeliac disease, vitiligo, alopecia areata, pemphigus vulgaris, dermatitis herpetiformis, pernicious anaemia, immune thrombocytopenic purpura, iridocyclitis and pemphigoid, and (2) systemic diseases including systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s disease, systemic sclerosis, polymyositis/dermatomyositis, multiple sclerosis and juvenile arthritis, captured across all settings including outpatient, inpatient and emergency services. List of ICD-9-CM codes to identify the cohort and outcomes is presented in Supplementary Table 1. Using the comorbidity rates reported from a previously similar population-based study, the sample sizes required for data collection were 5403 and 12545 for the analyses in systemic and organ-specific autoimmune diseases, respectively, to achieve an 80% statistical power in the cohort study [17 (link), 27 ].

The ethics committee approved this retrospective study at Keio University School of Medicine (#20,170,350). Informed consents were obtained from all the participants and their guardians through the website at Keio University School of Medicine by posting a detailed written guideline and ethical statement of the present study. This study followed the guidelines of the tenets of the Declaration of Helsinki. Ethical guidelines for clinical research from the Japanese Ministry of Health, Labor, and Welfare indicate the studies which do not involve biological tissue and include reviewing medical records retrospectively; researchers do not need to obtain written informed consent from patients and guardians. Following the guidelines of the ethics committees, we posted a detailed written guideline and ethical statement of the present study, including the background of the study, the purpose of the study, study design, privacy policy, freedom to withdraw, inclusion and exclusion criteria, the factors assessed in the medical records, advantage, and disadvantage of participating the study, disclosure of the data, presenting the data at a conference or in a journal, and contact information.
Since we considered patients equal to or older than 18 as adults, the medical records of consecutive patients less than 18 years of age who received allogeneic HSCT at Keio University Hospital from December 2004 to June 2017 were reviewed retrospectively. Ophthalmic examination for baseline screening is routinely performed before HSCT in our outpatient clinic. All patients underwent standardized clinical and ophthalmological evaluations as described below before HSCT and 3, 6, 9, 12, 18, 24, and 30 months after transplantation. Some patients had additional examinations as indicated according to our follow-up schedule. The inclusion criteria for the study were (1) cases with ophthalmic examinations before HSCT, (2) cases involving no ocular complications before HSCT, and (3) follow-up examinations during at least two years after HSCT. The exclusion criteria for all participants were as follows: (1) a history of previous treatment for ophthalmic diseases and (2) other types of severe DED, including Stevens-Johnson syndrome and ocular cicatricial pemphigoid. (3) Patients who had treatment for other inflammatory diseases, including Sjogren’s syndrome, systemic lupus erythematosus, systemic sclerosis, and juvenile rheumatoid arthritis, that require systemic immunosuppression.
In total, 28 patients met the inclusion criteria, and two patients were excluded according to the exclusion criteria. Twenty-six patients remained in our study, and 11 DED cases and 15 non-DED cases were ultimately included in the primary analysis. The patients were divided into these two groups based on the diagnosis of DED to describe the characteristics of pediatric GVHD-related DED.

The SLR was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines (Supplementary Table 1) [28 (link)]. The SLR protocol was registered in the PROSPERO database [29 ].
Relevant articles in English (with no limit on the date of publication) were identified via online searches of the Embase®, MEDLINE®, and PubMed® databases conducted on March 16, 2020, and subsequently updated on March 16, 2021. Relevant abstracts were also identified via online searches of congress websites and abstract supplements covering the most recent meetings (at the time of the search) of the ACR, Childhood Arthritis and Rheumatology Research Alliance, European League Against Rheumatism, and Paediatric Rheumatology European Society.
The searches applied population, intervention, comparator, outcomes, and study types criteria to identify relevant publications (Supplementary Table 2). The search strategies used for each of the online databases are shown in Supplementary Tables 3–5. In addition to online searches, the reference lists of relevant review articles and all publications included in the SLR were also searched by an analyst (C. Rolland) to identify any publications not indexed by the online databases.