We identified a total of 2027 studies using the search strategy detailed above. After checking for duplicates (n=0), 1992 papers were excluded as they did not fulfil the selection criteria. The remaining 51 full-length articles were screened in detail and a final number of 16 papers were deemed appropriate to be included in the qualitative analysis (Figure 1). One out of 16 eligible papers reported both on the puberty impact on autoimmune rheumatic disease outcomes and ARD impact on puberty-related outcome measures. The papers were grouped in two tables to enable the separate exploration of the bidirectional relationship between puberty and ARDs.
After scrutinising the types of outcome measures reported in the eligible papers, we concluded that a quantitative analysis (meta-analysis) was impossible because of the high heterogeneity of the reported outcomes and subjects included in the various studies.
The papers reporting the impact of ARDs on puberty-related outcomes (n=9) mainly focused on patients with JIA or juvenile rheumatoid arthritis (JRA) (n=5) and (J)SLE patients (n=4) (Table 1). Of the 8 papers which reported puberty impact on ARD outcomes, 6 papers investigated (J)SLE patients and one paper investigated patients with juvenile idiopathic arthritis (JIA)-associated uveitis (Table 2). We found no eligible studies in patients with dermatomyositis, enthesitis-related arthritis scleroderma, chronic recurrent multifocal osteomyelitis (CRMO) or childhood granulomatosis with polyangiitis. One paper investigated the impact of puberty on the prevalence of ANA positivity and musculoskeletal symptoms, although there was no evidence that patients with these characteristics proceeded to develop an ARD (26). The papers were published between 1998 and 2019, and most studies were single-centre cohort studies, with limited data on cohort ethnicity; details about ethnicity were only provided in 10 out of 16 papers.
The Cohen’s Kappa Statistic value calculated for the agreement reached by the manual screening of the paper abstracts was 0.69 (95%CI 0.682-0.71), while the screening of the full-text papers reached an agreement of 0.81 (95%CI 0.79-0.82).
The quality assessment of the included studies according to the Newcastle-Ottawa Scale, assessing criteria such as selection, comparability and outcome, ranged from 4-9/9, showing a small to moderate risk of bias overall (Tables 1 and 2).
Impact of autoimmune rheumatic diseases on puberty-related outcomes
The disease outcome measures investigated in JIA/JRA studies included cumulative dose of steroids, disease duration, disease activity, height, weight and age (27), as well as diagnosis (27–30), type of JIA (systemic) (29) and age at disease onset (30). Studies investigating the impact of JSLE on puberty were exclusively focused on evaluating the impact of being diagnosed with JSLE on puberty-related outcomes (13,31,32). The following aspects of puberty were investigated: age at puberty onset; Tanner staging G2-5 of genital development (29); presence or absence of facial, pubic and axillary hair (29); age at menarche (30–32); menstrual abnormalities and length of menstrual cycles, follicular stimulating hormone (FSH) and luteinizing hormone (LH) levels (32).
All the studies investigating the impact of JIA/JSLE on puberty reported some extent of delayed puberty in children with these conditions compared to healthy controls. Aggarwal et al. reported earlier puberty onset (Tanner stage G2 and onset of pubic/facial/axillary hair) in boys with systemic JIA compared to oligo- and polyarticular JIA (29), although despite this, the completion of puberty (defined as Tanner stage G5 achievement) was delayed in all male JIA patients compared to healthy controls. One study investigated the impact of JRA diagnosis on BMI and height, and found both to be significantly lower in JRA patients compared to age-matched healthy controls (28). Although there is evidence of growth delay associated with JIA in both boys and girls, the JRA clinical phenotype had a differential impact on growth in peri-pubertal Indian boys: boys with polyarticular and systemic onset JRA were shorter than those with pauci-articular JRA, until 15 years and 12 years of age, respectively (41). Similarly, adolescent JSLE patients experienced delayed puberty and growth retardation when compared to healthy controls as reported in the literature, and both correlated with the disease duration (44). The impact of ARD-related treatment on puberty was sparsely evaluated: one study in JIA showed a significant association between both the dose and an earlier age at administration of corticosteroids with delayed puberty in boys (27), while an older study did not show any impact of steroid use in girls with JRA on age at menarche compared to healthy controls (30). One study investigated additional puberty-related outcomes, and found that menstrual and hormonal abnormalities were significantly more common in patients with JSLE than in healthy controls (32).
Impact of puberty on autoimmune rheumatic disease-related outcomes
The studies investigating the impact of puberty on autoimmune rheumatic disease manifestations and severity included the following puberty parameters: Tanner stages (33–37), age at menarche (31,38), female reproductive factors (38) and gonadal function (31). One study focused on patients with JIA-associated uveitis (34), all the remaining studies investigated patients with JSLE or healthy controls who developed adult-onset SLE.
The impact of age at onset and puberty on JSLE severity was consistent across studies, showing similar trends of more severe disease in patients with earlier onset (pre-pubertal) compared to post-pubertal patients, irrespective of outcome measures used (renal, cardiovascular, pulmonary and haematological involvement; paediatric intensive care unit [PICU] admissions; steroid and cyclophosphamide use; autoantibodies and complement C3 levels, and accrued lupus-related damage). Of note, none of the JSLE studies investigating the impact of puberty evaluated overlapping outcome measures to allow for cross-validation of findings. One study showed, through multivariate analysis, that an age of less than 10 years at menarche was associated with the risk of SLE development later in life (38). Another study (31) found that delayed onset of menarche related strongly with both JSLE disease duration and cumulative prednisolone dose pre-menarche. This may be because both chronic disease as well as chronic use of corticosteroids can suppress growth, which can delay menarche and slow down puberty progression.
We identified only one study investigating puberty-related outcomes in ARD patients stratified based on sex (34). This study found increased incidence of ocular hypotony during puberty in boys with JIA-associated uveitis, and also found that pubertal females more frequently required systemic treatment for uveitis compared to either sex pre-puberty. The same study observed a biphasic course in JIA-associated uveitis in both boys and girls: a high activity at diagnosis, followed by a reduction, and a new wave of activity during early teenage years (34). However, the second activity wave cannot be linked to pubertal changes directly, as the authors do not provide puberty measurements or stages.