Systemic lupus erythematosus (SLE) is a classic systemic autoimmune disease characterized by the immune system’s production of antibodies against self-antigens. This process leads to the formation of immune complexes that are widely distributed and deposited in affected tissues, causing a diverse range of clinical and laboratory features [1,2]. Autoantibodies against several nuclear and cytoplasmic antigens, including antinuclear antibodies (ANA), anti-Smith antibodies, anti-double-stranded DNA (anti-dsDNA), anti–Sjögren's-syndrome-related antigen A (anti-SSA), and anti-Sjögren’s-syndrome-related antigen B (anti-SSB) antibodies, are the serological hallmarks of SLE [3]. Interestingly, autoantibodies have been found as clusters related with particular clinical manifestations of lupus [4-10]. SLE is often regarded as a polygenic, complex disease characterized by the interaction of numerous genes and epigenetic alterations, as well as environmental and hormonal factors. Interestingly, autoantibodies have been found as clusters related with particular clinical manifestations of lupus [4-10]. SLE is often regarded as a polygenic, complex disease characterized by the interaction of numerous genes and epigenetic alterations, as well as environmental and hormonal factors [11,12]. It is worth noting that there is a distinctive subset of patients who exhibit distinct lupus features that can be attributed to a single genetic variant, either through association or as a cause [13-15]. Accordingly, they are labeled as patients with monogenic lupus. Typically, individuals with monogenic lupus exhibit parental consanguinity and an early onset of devastatingly severe disease manifestations [13].

To the best of our knowledge, to date, there have been no reports thus far that identify an association between autoantibody clusters with clinical manifestations in monogenic lupus.

Our study aimed to report the frequency of selected autoantibodies and explore the associations of the identified autoantibody profile with clinical features, including the occurrence of major organ manifestations and prognosis, in a cohort of Arab children with monogenic lupus.

This is an observational retrospective cohort study that comprised all patients with monogenic lupus who were followed at childhood lupus clinic at King Faisal Specialist Hospital and Research Center (KFSHRC), Riyadh, from June 1997 to July 2022. To ensure that all children with monogenic lupus were included, we retrieved our pediatric rheumatology database, and coordinated with the medical records department. The included patients were younger than 14 years of age at diagnosis and fulfilled the EULAR/ACR 2019 classification criteria for SLE [16,17]. It is worth mentioning that our standard practice is to perform genetic testing on individuals who have high-risk criteria such as early onset of specific lupus features, a lupus family history, and paternal consanguinity. All enrolled patients were required to have a confirmed pathogenic gene variant and a complete autoantibody profile, which included anti-dsDNA, anti-Smith, anti-SSA, anti-SSB, and anti-phospholipid (APL) antibodies, including anticardiolipin and β2-glycoprotien. Furthermore, the disease activity and damage were calculated using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and the pediatric adaptation of the Systemic Lupus International Collaborating Clinics American College of Rheumatology Damage Index (pSDI) respectively [18,19].

For a patient to be considered positive in the autoantibody test, the test had to yield positive results on more than two separate occasions. All the tests were conducted following the standard protocol in the pathology and laboratory department at KFSHRC, Riyadh, Suadi Arabia.

All enrolled patients’ medical records were reviewed for demographic, clinical manifestations.

Of note, patients with familial SLE without proven genetic testing and patients with insufficient data were excluded from the analysis. Calculating the sample size was impossible due to the rarity of monogenic lupus.

This study was approved by the Ethics Committee of the Research Affairs Council at KFSHRC, Riyadh, under RAC# 2221105. All clinical and laboratory assessments were done as part of standard clinical practice. In addition, written consent was obtained from patients’ parents for genetic testing. All collected data analyzed under confidentiality practice and no personal identity was required. Thus, the Declaration of Helsinki (2013) principles were followed during the preparation of this study.

Lupus has a complex relationship between autoantibodies and clinical manifestations that can provide diagnostic and prognostic value. The presence of specific autoantibodies in patients, including children with lupus, has been associated with distinct clinical manifestations and disease outcomes; certain autoantibodies can also indicate an increased risk of specific complications [21-23]. Monogenic lupus is a distinctive subset of lupus; patients, typically exhibit features such as parental consanguinity and an early onset of distinct lupus features [15]. This study aimed to report the frequency of selected autoantibodies and explore the associations of the identified autoantibody profile with clinical features, major organ involvement, and prognosis in a large cohort of Arab children with monogenic lupus. Our patients had a high prevalence of consanguinity and a family history of lupus, as well as early onset of disease with a multisystem disease, which may be related to the underlying genetic variants. Our cohort exhibited a diverse range of underlying genetic variants, with complement deficiency being the most common, followed by DNase1L3 variant. Our findings revealed differences in the frequency of clinical manifestations compared to previous studies [24]. In comparison to pre-pubertal patients (those under the age of seven years at the onset of the disease) with sporadic lupus, our patients exhibited a higher prevalence of various clinical manifestations, including hematological, musculoskeletal, mucocutaneous, and gastrointestinal manifestations. However, the occurrence of renal involvement was comparable between the two groups. However, they showed comparable findings to those with early disease onset, particularly in the presence of genetic variants [25]. This observation might support the idea that monogenic lupus is a unique form of lupus. Furthermore, the frequency of the selected autoantibodies was similar to reported previously in patients with early disease onset [25]. In general, anti-dsDNA antibodies are the most studied and considered a diagnostic marker for sporadic lupus and have a pivotal role in lupus nephritis. The current study revealed an unexpected finding: anti-dsDNA showed a significant association with a higher prevalence of musculoskeletal involvement, while there was no significant association with nephritis [26]. The exact reason behind this observation remains uncertain, but one possibility that might be considered is the genetic factors contributing to the etiopathogenesis of monogenic lupus. The cluster of anti-Smith, anti-SSA, and APL antibodies was found to be more frequent in patients with facial rashes, particularly discoid lesions as noted by the univariate analysis; this result was like previous reports [22,25]. But this significance did not hold in the multivariable analysis. On the contrary, these autoantibodies did not show a significant association with neuropsychiatric manifestations, vasculopathy, or thrombosis. Anti-Smith autoantibodies might contribute to lupus nephritis and renal failure [27,28]. However, in this study, anti-Smith autoantibodies were associated with heavy proteinuria; but the multivariable analysis did not show significant association. Interestingly, there was an association with recurrent infections. It is difficult to draw a conclusion from the current study. However, it might be considered a paradoxical phenomenon, which means these autoantibodies can be detected in recurrent infections. Although the SLEDAI score was high in our patients, there was no significant association with any of the selected autoantibodies. Nevertheless, the cluster of anti-Smith and anti-SSB autoantibodies was associated with accrued disease damage.

The current study confirms previously reported associations between certain autoantibodies and clinical manifestations. However, it also shows unique and unexpected clinical and prognostic associations with certain autoantibodies. It is important to highlight that the prevalence and sensitivity of autoantibodies can vary among lupus patients of different ethnicities, specifically Caucasian, African American, and Asian individuals [26]. This aspect should be considered when dealing with lupus patients who have underlying genetic variants.

Our study’s main strength, to the best of our knowledge, is the first report of autoantibodies associations in a large cohort of patients with monogenic lupus from a high rate of consanguinity in the Arab population. Nevertheless, this study has several limitations that warrant cautious interpretation. It relied on the analysis of retrospectively collected data spanning a lengthy time frame. Moreover, the data originated from a solitary childhood lupus clinic, and all patients were of Arab descent from a community with a notable consanguinity rate. These factors may have introduced bias in patient selection, and the potential influence of ethnicity cannot be disregarded.

This study presents the first and largest data highlighting the clinical and prognostic associations with the selected autoantibodies in monogenic lupus. Distinct clinical manifestations and prognosis association with certain autoantibodies support the idea that monogenic lupus is a distinctive form of lupus; however, due to the rarity of monogenic lupus, thus, international collaboration is warranted in the future to shed light on a better understanding of the associations between a wide set of autoantibodies and clinical manifestations.