Autoimmune Retinopathy Complicating TLR7-related Monogenic Interferonopathy.

Objective: To identify the presence of Neuromyelitis optica (NMO) in juvenile SLE patients.Background: NMO is a rare autoimmune demyelinating disease of the central nervous system, manifesting with transverse myelitis involving three or more continuous spinal segments and optic neuritis in the presence of NMO-IgG antibodies.Methods: Retrospective study of SLE patients with CNS symptoms, diagnosed from 2000 to2010 and review of clinical data, laboratory and MRI findings.Setting: A tertiary referral centre for juvenile SLE.Results: A total of 210 SLE patients were indentified, 39 of which had manifestations of potential CNS involvement and underwent CNS imaging including the spinal cord. Three were indentified with probable NMO, which was confirmed in two (0.9%). Both patients were adolescent females of Caucasian origin. In one patient NMO was the first manifestation of SLE. In the other NMO developed three years following diagnosis of SLE. They both presented with deterioration of visual acuity, localized spinal tenderness and malaise. NMO was confirmed based on MRI findings and the presence of raised Aquaporin-4-IgG-antibodies. NMO had a relapsing course and interestingly NMO relapses coincided with SLE disease flare-up, both of which responded to treatment simultaneously.Discussion: SLE is a multisystemic autoimmune disease and 25% of patients develop CNS involvement. While NMO has been described in adult patients with SLE, these cases derive specifically from a paediatric population. We believe that SLE and NMO are parts of the same disease spectrum. When this condition is noticed in patients with refractory, long standing SLE, prognosis is guarded.

Neuromyelitis optica (NMO), also known as Devic's disease, is a rare inflammatory demyelinating disorder causing myelitis and optic neuritis. While there have been reports of systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (SS) occurring with NMO, a formal association is not established. We aimed to investigate the occurrence of NMO in SLE and SS patients and study the clinical characteristics and outcomes of NMO and SLE/SS hospitalizations utilizing the national inpatient sample (NIS) database. The NIS database from 2016 to 2019 was used to extract data. Adult hospitalizations with the principal or secondary diagnosis of NMO were included. We classified NMO patients with and without concomitant diagnosis of SLE or Sjogren's syndrome. We evaluated and compared the clinical characteristics and outcomes of NMO hospitalizations with and without SLE or Sjogren's syndrome. STATA17 was used for data analysis. We also calculated the odds ratio of NMO in SLE and Sjogren's syndrome. There were a total of 16,360 adult hospitalizations with the principal or secondary discharge diagnosis of NMO. Among all NMO hospitalizations, 1425 (8.71%) had the primary or secondary diagnosis of SLE or SS. The odds of NMO in SLE and Sjogren's syndrome were noted to be 12.29 and 5.56, respectively. NMO with SLE/SS group had higher proportion of females (89.82% vs 79%, P value < 0.001), African Americans (56.63% vs 38.28, P value < 0.001), and Asians (5.73% vs 3.25, P value 0.04). The Charlson comorbidity index was higher for NMO-SLE/SS overlap (2.44 vs 1.28, P value < 0.001). There was no significant difference in overall mortality rates of both groups (2.11% vs 1.2%, P value 0.197). There were significantly higher reported seizures (14.73% vs 6.05, P value < 0.001) and paraplegia (21.75% vs 13.93%, P value < 0.001) in NMO-SLE/SS patients. These patients also had a longer length of stay in comparison to the reference group (7 vs 5 days, P value < 0.001) as well as higher total charges. NMO patients had a 12-fold higher risk of SLE and 5-fold higher risk of Sjogren's disease when compared to general population. Patients with overlap of NMO and SLE or Sjogren's were predominantly women and were more likely to be African-American. Co-existence of these autoimmune disorders was associated with poor prognosis in terms of higher morbidity for patients and increased health care burden. Key Points • NMO is a rare autoimmune disease seen predominantly in women in the middle age group with low overall mortality. • SLE and Sjogren's have increased odds of NMO in comparison to general population. • NMO patients have high rates of several complications such as paraplegia, quadriplegia, seizures, blindness, sepsis, and respiratory failure with even higher rates of seizures and paraplegia in those with concomitant SLE or Sjogren's.

Through their recognition of variousbacterial cell wallcomponents, TLR2 andTLR4 participate in the innate response and modulate the activation of adaptive immunity. Therefore, the genetic background of these receptors might play a crucial role in autoimmune diseases such as systemic lupus erythematosus(SLE).In this study, we investigated the possible association between polymorphisms within TLR2and TLR4 genes with SLE susceptibility. A total of 100 SLE patients and 200 unrelated healthy controls of the Tunisian population were enrolled in the study.TLR4rs4986790, TLR4rs4986791, and TLR2rs5743708 genotyping were performed using a polymerase chain reaction-restriction fragment length polymorphism method. The number of guanine-thymine (GT) repeat microsatellite in the intron 2 of TLR2 gene was analyzed by sequencing. We reported a lack of allelic and genotypic association between SNPs of TLR4 and TLR2 genes and SLE pathogenesis. No correlation was found with any SLE features. However, SLE susceptibility was associated with the GT repeat microsatellite polymorphism in the human TLR2 gene. Further subclassification of alleles into three subclasses revealed a significant association between the long-sized repeats ((GT)>23) and SLE. Though the results showed the absence of genetic association of TLR4 and TLR2 SNPs with the risk of developing SLE, we have identified a protective association between the microsatellite polymorphism in intron 2 of the TLR2 gene and SLE. Functionally, these (GT)n repeats may confer modifying effects or susceptibility to certain inflammatory conditions.

Excerpt During the last six years the author has had the opportunity personally to study and treat 175 patients with systemic lupus erythematosus. The purpose of this paper is to review the current...

Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis

Non-infectious myelitis in systemic lupus erythematosus (SLE) may be due to SLE myelitis, comorbid multiple sclerosis (MS), or neuromyelitis optica (NMO). We compared characteristics of these three conditions in SLE patients at a large academic institution. We searched for neurologic diagnoses of SLE myelitis, NMO myelitis, and MS myelitis among 2297 patients with at least four 1997 American College of Rheumatology revised criteria for SLE between 2000 and 2015. Each subject was reviewed by a neurologist to confirm the underlying neurologic diagnosis. Demographic, clinical, laboratory, and radiographic data were extracted and compared using Fisher's exact test, analysis of variance, and Wilcoxon rank-sum test. Fifteen of the 2297 subjects with SLE (0.7%) met criteria for a spinal cord syndrome: seven had SLE myelitis, three had AQP4 seropositive NMO, and five had MS. The median SLE Disease Activity Index 2000 score at time of neurologic syndrome presentation was higher in SLE myelitis subjects (8, interquartile range (IQR) 7-16) compared with subjects with NMO (6, IQR 0-14) or MS (2, IQR 0-4), p = 0.02. Subjects with SLE myelitis were also more likely to have elevated anti-dsDNA antibodies at presentation (86%) compared with subjects with NMO (33%) or MS (0%), p = 0.03. Myelitis occurs rarely among patients with SLE. Compared with subjects with SLE + NMO and subjects with SLE + MS, subjects with SLE myelitis had higher SLE disease activity at presentation.

BackgroundRecent studies showed that dyslipidemia could be a critical factor in the progression of cardiovascular disease in systemic lupus erythematosus (SLE). The aim of the present study was to describe the relationship between serum lipid profile and SLE disease activity in young female adults with SLE.MethodsSeventy-one female subjects diagnosed with SLE aged 20~30 years were enrolled. Serum lipid profile including TC, TG, HDL-C, LDL-C, VLDL-C, Apo A, Apo B, and Apo E were evaluated between control and young female SLE patients. Univariate correlation analyses were performed to explore the correlation between serum lipid levels and SLE disease activity.ResultsOur results showed that TG and VLDL-C levels were significantly increased in young female SLE as compared to control, with TC, HDL-C, LDL-C, Apo A, and Apo B significantly reduced. Meanwhile, univariate correlation analyses showed negative correlations between SLE disease activity index and HDL-C, LDL-C, Apo A, and Apo B; with positive correlations between SLE disease activity index and TG and VLDL-C.ConclusionSerum lipid profile was significantly dysregulated in young female SLE patients. Moreover, SLE disease activity was correlated to the serum lipid levels, supporting the notion that the young patients with SLE might also have a higher risk of cardiovascular disease.

Background and Objectives: Rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriasis, and systemic lupus erythematosus (SLE), are characterized by chronic arthritis or spondyloarthritis, which can lead to joint and spine destruction. Our previous studies showed that the risk of common orthopedic surgeries, including total knee replacement (TKR), total hip replacement (THR), or spine surgery, was increased in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE. The aim of this review was to summarize the risk of TKR, THR, cervical spine, and lumbar spine surgery on the basis of studies conducted using data from Taiwan’s National Health Insurance Research Database (NHIRD). Materials and Methods: The risk of TKR, THR, cervical spine surgery, and lumbar spine surgery in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE was summarized from the results of our previous studies and unpublished findings based on NHIRD data. Results: Patients with rheumatoid arthritis and psoriasis and men with ankylosing spondylitis showed an increased risk of TKR. Patients with rheumatoid arthritis, ankylosing spondylitis, and women with SLE showed an increased risk of receiving THR. Only patients with ankylosing spondylitis had an increased risk of cervical spine surgery, and patients with rheumatoid arthritis or ankylosing spondylitis showed an increased risk of lumbar spine surgery. Although the risk of THR, TKR, or spine surgery in these patients has declined in the era of biologics use, direct evidence for the effects of biologics agents is not yet available. Conclusions: There was an increased risk of common orthopedic surgery in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE. Clinicians should be vigilant to reduce the increased risk of TKR and THR in young and middle-aged patients with rheumatoid arthritis, THR in young patients with ankylosing spondylitis, and young female patients with SLE, as well as cervical spine surgery in young patients with ankylosing spondylitis.

FRI0583 NEUROMYELITIS OPTICA OVERLAPS FREQUENTLY WITH SYSTEMIC RHEUMATIC DISEASES IN AFRICAN-AMERICANS: EXPERIENCE AT A LARGE US ACADEMIC MEDICAL CENTER

Variations in the TLR9 gene have been associated with several autoimmune disorders, but the relationship between TLR9 polymorphisms and systemic lupus erythematosus (SLE) remains controversial. This study aims to evaluate the potential association between three single-nucleotide polymorphisms (SNPs) within the TLR9 gene and susceptibility to SLE in the Han Chinese female population. A total of 150 SLE patients and 151 healthy controls of Han Chinese ethnicity were enrolled. Genotyping of TLR9 was performed using sequence-specific primer (SSP) polymerase chain reaction and validated by Sanger sequencing. Associations between the SNPs and SLE susceptibility were analyzed using the chi-square test or Fisher's exact test. Additionally, correlations between the SNPs and clinical manifestations of SLE were assessed. The TLR9 rs352139 polymorphism was significantly associated with increased SLE susceptibility in heterozygous (AG vs. AA, OR = 1.79, 95% CI [1.07-2.99], p= 0.025), homozygous (GG vs. AA, OR = 2.11, 95% CI [1.06-4.19], p= 0.033), dominant (GG+AG vs. AA, OR = 1.86, 95% CI [1.15-3.03], p= 0.012), and allele (G vs. A, OR = 1.49, 95% CI [1.07-2.06], p= 0.017) models. Similarly, rs352140 was significantly associated with SLE risk in homozygous (TT vs. CC, OR = 2.47, 95% CI [1.23-4.96], p= 0.010), recessive (TT vs. CC+CT, OR = 2.57, 95% CI [1.35-4.88], p= 0.003), and allele (T vs. C, OR = 1.43, 95% CI [1.03-1.99], p= 0.031) models. Haplotype analysis revealed that haplotype HT1 (C/A/T) had a protective effect against SLE (OR = 0.70, 95% CI [0.506-0.966], p= 0.030), while haplotype HT2 (T/G/T) was positively associated with increased susceptibility (OR = 1.505, 95% CI [1.068-2.121], p= 0.019). These findings suggest that the TLR9 rs352139 and rs352140 polymorphisms are significantly associated with increased susceptibility to SLE in the Han Chinese population, indicating a potential role of TLR9 in the pathogenesis of SLE.

Acute pancreatitis (AP) is one of the most frequent gastroenterological emergencies worldwide, presenting an overall mortality around 5-10%. Systemic lupus erythematosus (SLE) is an autoimmune pathology that can affect any organ, being a rare etiology for AP. The diagnosis of lupus-related AP is usually made after assessing other causes such as obstructive ones or toxic-metabolic. Its etiopathogenesis remains unknown, but it is believed to be multifactorial, involving antibodies production and immune processes; retrospective reports show a female prevalence of 9:1, and mean age of 31.4 years, with abdominal pain as the main symptom. A previously healthy 22-years-old woman presented 1 month after a cesarean delivery with weakness, arthralgia in hands, elbows, and knees without morning stiffness, which improved with rest. She also reported a daily 38 °C fever in the evening, night sweats, diffuse abdominal pain, nausea, vomiting, and unintentional weight loss (5 kg). On admission exams, normocytic normochromic anemia was evident, along with elevated canalicular enzymes. Abdominal tomography revealed hepatosplenomegaly, diffuse pulmonary nodules, and multiple lymphadenopathies. Lymphoproliferative disorder was excluded after a biopsy of a left cervical lymph. After 5 days of hospitalization, the patient developed left hypochondrial pain and multiple episodes of nausea and vomiting, without urinary or bowel changes and no gynecological complaints. Laboratory tests showed leukocytosis, elevated amylase and lipase, and increased bilirubin, predominantly direct. All serologies were negative. Abdominal ultrasound revealed mild AP of unclear etiology. Treatment was carried out with fasting and vigorous hydration. Based on the criteria determined by the American College of Rheumatology, the following findings contributed to the hypothesis of SLE: fine speckled nuclear anti-nuclear antibody (1/80), autoimmune hemolytic anemia (positive direct coombs and eluate tests), proteinuria 4.12 g/24 h, and anti-Smith antibody reagent. The diagnosis of autoimmune AP due to SLE was established. Hydroxychloroquine and methylprednisolone were initiated, leading to significant improvement. She was discharged with plans for early follow-up in the rheumatology outpatient clinic. The patient presented AP caused by SLE, which is a rare manifestation of the disease, affecting approximately 0.9% to 5% of SLE patients. This case stands out the importance of considering this hypothesis in young female patients with abdominal pain who present clinical characteristics and corresponding laboratory findings, and the relevance of understanding this association and the management to be carried out, avoiding unfavorable outcomes, as it is found rare.

Purpose: To report four patients with unusually severe acute keratitis sicca secondary to lacrimal tissue and ocular surface inflammation who eventually required systemic immunosuppressive therapy. Methods: Observational case series of four patients with extremely severe acute dry eye syndrome who were profoundly disabled by pain and photophobia (to the extent of staying in dark rooms) despite aggressive conventional therapy. Clinical data including visual acuities, other treatments administered for dry eye, systemic medical conditions, Schirmer and rose bengal staining results, degree of conjunctival injection, and medications were recorded. All four patients were treated with systemic immunomodulatory therapy. Results: All four patients were female with a mean age at presentation of 40 years (range 22–58 years), and all had systemic autoimmune diseases: systemic lupus erythematosus (SLE) and Sjogren's syndrome (n = 2), Sjogren's syndrome (n = 1), rheumatoid arthritis (RA) and psoriasis (n = 1). Schirmer test values at onset ranged from 0 to 2 mm. All patients had failed aggressive lubrication, topical cyclosporine, lid care, and punctual plugs. In two patients, serum tears and hyphrecation punctal occlusion were tried without success. Various systemic immunosuppressive agents were used to control inflammation of the lacrimal glands: methotrexate and cyclosporine A (patient 1), cyclosporine A (patient 2), prednisone (patient 3), and methotrexate and infliximab (patient 4). Treatment with systemic immunomodulatory agents resulted in resolution of the acute inflammatory assault on the lacrimal glands and control of signs and symptoms of keratoconjunctivitis sicca in all four patients, and visual acuities improved in all of them. Post-treatment Schirmer values ranged from 7 to 10 mm. Conclusion: Systemic immunosuppressive agents may be required in the treatment of recalcitrant primary and secondary Sjogren's syndrome caused by systemic autoimmune conditions. We show that systemic immunomodulatory therapy leads to significantly improved tear production and resolution of the keratoconjunctivitis in these rare but severe cases.

Neuromyelitis optica (NMO) is usually a relapsing demyelinating disease of the central nervous system associated with optic neuritis, transverse myelitis involving three or more contiguous spinal cord segments, and seropositivity for NMO-IgG antibody. NMO is often mistaken for multiple sclerosis and there are relatively sporadic publications about NMO and overlapping systemic or organ-specific autoimmune diseases, such as systemic lupus erythematosus (SLE). We described a unique case of a 25-year-old Arab young woman who was diagnosed with SLE, depending on clinical, laboratory investigations and after she had fulfilled the diagnostic criteria for SLE and had presented the following findings: constitutional findings (fatigue, fever, and arthralgia); dermatologic finding (photosensitivity and butterfly rash); chronic renal failure (proteinuria up to 400 mg in 24 hours); hematologic and antinuclear antibodies (positivity for antinuclear factor (ANF), anti-double-stranded DNA antibodies, direct Coombs, ANA and anti-DNA, low C4 and C3, aCL by IgG and IgM). Recently, she presented with several episodes of transverse myelitis and optic neuritis. Clinical, radiological, and laboratory findings especially seropositivity for NMO-IgG were compatible with NMO. Accurate diagnosis is critical to facilitate initiation of immunosuppressive therapy for attack prevention. This case illustrates that NMO may be associated with SLE.

Patients with systemic lupus erythematosus (SLE) are at increased risk of coronary heart disease (CHD). Even though the absolute risk of cardiovascular disease (CVD) among SLE patients increases with advancing age, younger female patients are at the greatest risk of developing acute myocardial infarction (AMI). These young patients are not considered to be at high risk for CVD using traditional risk assessment tools. Also, subclinical atherosclerosis is less common among young lupus patients. AMI could present with or without significant obstruction in coronary arteries in younger patients. There are no guidelines on appropriate cardiac screening of younger lupus patients, often without chest pain or who present with non-specific complaints. In recent years, the incidence of acute coronary syndrome (ACS) and ST-segment elevation AMI has decreased in the general population and in older lupus patients. Why has a similar decline in cardiovascular (CV) events not been seen in younger lupus patients? Since the issue of CVD in younger lupus patients is under-researched, a narrative review, rather than a systematic literature review was performed, based on the selected articles and points of view relevant to the topic. The aim of this review is to raise awareness of the relationship between SLE and CVD in younger ages, discuss possible non-atherosclerotic mechanisms of obstructive and non-obstructive CHD in lupus, elaborate on acute coronary syndromes unique for young patients, point out current challenges in identifiing at-risk patients for ACS, potential for new imaging techniques, the need for individualised treatment, with or without coronary stenting in ACS, and to underscore the relevance of CVD studies in young patients with SLE.

Type I Interferon in Systemic Lupus Erythematosus and Other Autoimmune Diseases