We aimed to review all full-text, peer-review publications reporting childhood Sjogren syndrome with kidney or nerve damage. Records were identified from the PubMed, EMBASE databases. The search terms were primary Sjogren syndrome, child, children, and childhood. Results were limited to case reports written in English. The search date was December 23, 2019.
The initial search yielded 511 articles, after excluding the duplicate articles and reading titles and abstracts, 61 papers were then read in detail. Finally, 20 case reports were included in the literature review after extracting and analyzing the data from the articles (Fig. 4). The information that was extracted from the papers were as follows: references and year, age and gender of patient, symptoms at onset, dry eyes or mouth, parotitis,neurologic manifestation, renal damage, elevated ANA, presence of anti-SSA and SSB antibodies, ESR, RF, hyperglobulinemic, schirmer test, CSF, renal and salivary gland biopsy and immunomodulatory therapy (Table 1)[2–21].
Primary Sjogren syndrome is an autoimmune disorder that causes inflammation and injury to the exocrine glands[22], predominantly the lacrimal and salivary glands, resulting in dry eyes and mouth (sicca syndrome). There are few reports on childhood primary Sjogren syndrome, because SS is more common in adults than in children. The female to male ratio in adults is 9:1, and joint problems were present in 30%-50%, while the incidence of kidney disease varies from 0.3% to up to 33.5%, depending on the study[23–27]. Other extraglandular diseases, such as cutaneous vasculitis, pulmonary manifestations, and peripheral nervous system manifestations occur in less than 10%[22]. In children, the sex ratio was 83-92.3% female[28, 29], and the most frequent symptom was parotid swelling,which was present in 42.3–53%, while central nervous system symptoms were present in 8.7%, and renal manifestations were present in 9.9%-11.5%. Central nervous system and renal damage is uncommon in pediatric cases. We report a case of childhood pSS presenting with interstitial nephritis and neurological disorders.
We reviewed all full-text articles on childhood primary Sjogren syndrome and focused on cases of pediatric pSS with kidney or nerve damage(Table 1). In the review, 20/22 children were female, and 10/22 children had neurologic manifestations, often prior to the diagnosis of pSS. We reported a case in a female pediatric patient that had fever and superficial sensation disorder in the limbs months after pSS was diagnosed. Neurologic disorders included the peripheral nervous system (PNS) and the central nervous system (CNS), and involved fever, headache, mental disorder, gaze deviation, lethargy, muscle weakness, urinary incontinence, hypalgesia, difficulty with ambulation, or ptosis. Until now, no studies have been performed on the epidemiology and characteristics of neurological damage in children with pSS. The prevalence of neurologic manifestations in adults ranges between 28% and 67.5% according to the different study populations and the definition or methods for the detection of neuropathy[30–32]. The studies showed that 46%-80% of adult patients with neurological symptoms developed such symptoms prior to the diagnosis of pSS[30, 31]. The frequency of constitutional symptoms and lung involvement was significantly higher in pSS with neurological involvement than in pSS without neurological involvement, and the articular symptoms were significantly less frequent in pSS with neurological involvement[33]. At present, the pathogenic mechanisms for most forms of neurological involvement in pSS have not been elucidated. However, several mechanisms have been considered to explain this involvement. In the development of PNS involvement in pSS patients, vascular or peripheral inflammatory infiltrates with or without necrosis may be found, and vasculitis of the vasa nervorum has also been proposed as a pathogenic mechanism[34–38]. These CNS disorders may be explained by three pathogenic factors. The first hypothesis involves the direct infiltration of the CNS by mononuclear cells[39]. The second hypothesis involves vascular injury that may be related to the presence of antineuronal antibodies and anti-Ro antibodies[40]. Finally, researchers[41–43] suggest that the underlying mechanism of CNS lesion development in pSS involves ischemia secondary to small vessel vasculitis.
In renal manifestations, the main damage in childhood pSS is tubulointerstitial nephritis(TIN), and the clinical features of renal involvement are proteinuria, hematuria, glucoseuria, or alkalineurine. A literature review of pediatric pSS showed that renal manifestations were present in 9.9%, including renal tubular acidosis (RTA), membranous glomerulonephritis(MGN), hypokalemia, and interstitial nephritis[28]. Glomerular damage is rare, and we only found three cases,one report a case of pSS with mesangial proliferative glomerulonephritis and IgA deposits[8], another report a girl with pSS complicated by MGN[15], the last one reported a case of pauci-immune crescentic glomerulonephritis[12]. It has been proposed that the course of renal impairment might be shorter in the interstitial nephritis group, and the incidence of cryoglobulinemia and low C4 might be higher in the glomerulonephritis(GN) group[9]. The prevalence of renal involvement in adult pSS has been reported to range from 1% in some large retrospective registries, to 5–14% in most European studies, and > 30% in a cohort of 573 Chinese patients[44]. Unlike children, the renal damage in adults is manifested by overt or latent distal RTA, nephrogenic diabetes insipidus, and rarely, proximal RTA[27, 44, 45].The frequency of GN in adults varies from 16.6 to 58.2% depending on race, center, and number of cases[23, 24, 46–48]. In renal biopsies of GN, membranoproliferative glomerulonephritis(MPGN) secondary to cryoglobulinaemia is the most common type, and other pathological types include membranous nephropathy, IgA nephropathy, focal segmental glomerulosclerosis, minimal change disease, unspecified proliferative glomerulonephritis, crescentic glomerulonephritis, and global glomerulosclerosis[44]. A large cohort of adult pSS patients revealed that patients with TIN have a better prognosis and clinical outcome, while patients with GN have a less favorable prognosis and a higher risk of developing lymphoma, which is related to cryoglobulinemia .
From the review, except the girl we reported, 20 of 21 children were positive for ANA and anti-SSA, while, 8 out of 20 were anti-SSB negative. This result is consistent with previous observations that the positive rate of ANA and anti-SSA is higher than anti-SSB in adults and children[32, 49, 50]. From a systematic review of primary Sjogren syndrome in pediatric populations, the presence of anti-SSA (Ro), anti-SSB (La), and anti-nuclear antibodies (ANA) was positive in 36.4–84.6%, 27.3–65.4%, and 63.6–96.2%, respectively[50]. New research showed that patients positive for both anti-SSA and anti-SSB had a substantially higher risk of cerebral infarction and venous thromboembolism than the general population[51].
Meanwhile, we also found an interesting phenomenon, hyperglobulinemia presented in 12 cases, and 11/12 were IgG, only 3 cases were IgA. High IgG levels are a common feature of SS and might reflect greater B cell activation[52]. Research showed that patients with high IgG levels had a higher prevalence of purpura and immunological markers (ANA, RF, anti-SSA, and anti-SSB)[53]. All of the 3 cases with high IgA had renal damage, so we speculated whether IgA participated the pSS and kidney disease at the same time. Plasma cells producing IgA rather than IgG or IgM are dominantly observed in the salivary glands of SS patients [54]. Enrichment of anti-SS-B IgA antibodies in the saliva of patients with SS may suggest enhanced local synthesis of anti-SS-B IgA [55]. The presence of IgA autoantibodies against M3 muscarinic acetylcholine receptors is also considered to be a pathophysiological factor of primary SS[56]. These findings suggest that abnormal immunity of IgA production may attributable to SS, but unfortunately immunofluorescent findings of the 3 children indicated no deposition of IgA. More extensive investigations will be needed to support the hypothesis.
All the patients in our report received immunomodulatory therapy including glucocorticoid, azathioprine, rituximab, hydroxychloroquine, cyclophosphamide, mycophenolate mofetil, and methotrexate. At present, the treatment of childhood pSS presenting with renal and nerve damage lacks large-scale evidence-based medicine and is mostly based on clinical experience. Although the long-term outcome of renal damage in pediatric pSS is usually good, glucocorticoids were often used in pediatric cases with RTA and TIN, and chronic immunosuppression is needed for the glomerular involvement often associated with a progressive course[5, 7, 57]. Long term outcomes may be related to the improvement in overall survival rate, renal survival rate, and complete remission rate of renal disease in childhood pSS treated with immunosuppressive therapy. From our review, steroids (1 mg/kg/day) were often used as the initial immunosuppressive treatment in pediatric pSS patients with TIN or GN. However, the outcome of children presenting with neurological diseases in the review is relatively less favorable. All the cases here reported residual neurologic manifestations, even though these children received steroids (1–2 mg/kg/day) or other immunosuppressive therapies. Kornitze[3] reviewed reported cases of childhood Sjogren syndrome with CNS complications in which 10 of 10 cases received steroid therapy and 7 of 10 patients had residual neurological deficits at follow-up. The effectiveness of glucocorticoids combined with other immunosuppressants in children still requires further study.
The frequency of renal damage and neurologic involvement in childhood pSS is much lower than in adults, and the clinical symptoms may be significantly different than what is seen in adults. If children present with unexplained renal diseases, neurological abnormalities, and unexplained fever, pSS should be considered. Special serological screening tests should be added to routine laboratory tests, while kidney biopsy may contribute to assessing the extent of renal damage and the need for immunomodulatory therapy. Early recognition and the appropriate treatment of renal damage and neurologic involvement would improve prognosis and prevent complications. Long term follow-up is essential for these children due to the possibility of rapid progression.