High Titers Of Antinuclear Antibodies Research Articles

Double-negative T cells in pediatric rheumatic diseases.

Double-negative (CD4-CD8-) T (DNT) cells have been implicated in Autoimmune Lymphoproliferative Syndrome (ALPS), where their expansion inside the circulating pool of T cells represents a diagnostic criterion. Recent experimental evidence has supported the immunomodulatory roles of DNT cells, and studies in adult patients have suggested that they may be altered in some immune-mediated conditions. This study aimed to retrieve available data on circulating DNT cells in pediatric rheumatic disorders that do not arise in the context of ALPS through a systematic literature review of three scientific databases (PubMed, Scopus, and Web of Science). The final output of the systematic literature search consisted of eight manuscripts, including cross-sectional (n=6) and longitudinal (n=2) studies. Overall, the pooled population of patients includes children affected with pediatric Systemic Lupus Erythematosus (n=104), Juvenile Idiopathic Arthritis (n=92), Behçet's disease (n=15), mixed connective tissue disease (n=8), Juvenile Dermatomyositis (n=6), and Kawasaki disease/multisystem inflammatory disease in children (n=1 and n=14, respectively); moreover, one study also included 11 children with a high titer of antinuclear antibody but no diagnosis of rheumatic disease. All studies except one included a control group. The number of DNT cells were increased in most studies of children with rheumatic diseases. Even if such a limited number of studies and their great heterogeneity in several methodological aspects do not allow for reliable conclusions about the relevance of DNT cells in specific rheumatic conditions in children, this cell population deserves further investigation in this pathological setting through well-designed clinical studies.

High antinuclear antibody titer is associated with increased mortality risk in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a diagnosis of exclusion, requiring that potential etiologies of interstitial lung disease be ruled out. Antinuclear antibody (ANA) testing is commonly performed in individuals with IPF, but the clinical significance of ANA positivity remains uncertain. A retrospective search identified 161 patients diagnosed with IPF between May 2010 and January 2021. Data on ANA titers at the time of diagnosis were available in all cases. Mean age of the patients was 66.4 ± 9.6 years; 70.8% were male. ANA titers were high (≥ 1:160) in 25.4% of the cohort. Baseline characteristics were comparable between those with high and low ANA titers. During follow-up (median 28 months), 93 patients (57%) died. On Cox proportional-hazards analysis with lung transplantation entered as a competing risk and adjusting for potential confounders (age, sex, and baseline forced vital capacity and diffusing lung capacity for carbon monoxide), ANA ≥ 1:160, as a dichotomized variable, was significantly associated with case-specific mortality (HR 2.25, 95% CI 1.14−4.42, P = 0.02) and older age (for each 10-year increment, HR 1.55, 95% CI 1.07−2.25, P = 0.02). High ANA titers appear to be associated with increased mortality in IPF. This finding emphasizes the potential prognostic value of ANA testing. Further studies are needed to validate these findings and explore their implications for patient management.

P022 Unmasking the storm: hemophagocytic lymphohistiocytosis in systemic lupus erythematosus - a case series

Abstract Background/Aims Hemophagocytic lymphohistiocytosis (HLH), a critical illness of uncontrolled immunological activity and hyperinflammation, manifests as primary/familial or secondary form. Secondary HLH can be of multi-faceted etiology including infections, cancer, autoimmune and immunodeficiencies. HLH in context of systemic lupus erythematosus (SLE) is a rare entity and mirrors the clinical picture of SLE flare, adding to the diagnostic dilemma. Methods Our objective is to consider HLH as a key differential in unidentified autoimmune diseases. We present a trio of cases of undiagnosed SLE manifesting as HLH. Results A 13-year-old male presented with fever, rash, oral ulcers, and jaundice for a month with passage of dark coloured urine for last seven days. On examination, he had generalized lymphadenopathy, erythematous maculopapular rashes, palpable purpura, non-scarring alopecia, and hepatosplenomegaly. The labs revealed pancytopenia (Hb 9.8g/dL, WBC 2000/mm3, Platelets 23000/mm3), deranged creatinine (1.6mg/dL), transaminitis and hyperbilirubinemia, hyper-ferritinemia (2420µg/dL), hypertriglyceridemia (280mg/dL), hypofibrinogenemia (142mg/dL), and nephrotic range proteinuria (3.7g/24h). Diagnosis of SLE was confirmed by high titres of antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA) and anti-Smith positivity. Renal biopsy showed class II lupus nephritis and acute tubular necrosis. Bone marrow biopsy revealed hemophagocytosis and the diagnosis of SLE complicated by HLH was made. A 16-year-old girl presented with fever and headache for three weeks, worsening over last ten days with irritable behaviour for one day, and respiratory distress that necessitated endotracheal intubation. The presence of pancytopenia (9.1/1940/41000), transamintis, hyper-ferritinemia (4040µg/dL), hypertriglyceridemia (250mg/dL), and low fibrinogen (133mg/dL) in laboratory evaluation raised a compelling suspicion of HLH confirmed by hemophagocytosis on marrow biopsy. Cerebrospinal fluid analysis was unremarkable, however MRI detected features of vasculitis with vasculitic infarcts. Direct Coomb’s test was positive. Autoimmune profiling unveiled positive results for ANA, anti-dsDNA, and anti-Smith antibodies consistent with SLE. A 21-year-old female presented with fever and arthralgias for two months. Investigations were suggestive of pancytopenia (7/1050/36000), raised ESR (126mm/hr) and CRP (54 mg/dL), elevated ferritin (4320 µg/dL), lactate dehydrogenase (1068U/L) and triglycerides (439mg/dL). The marrow biopsy was negative for hemophagocytosis while her soluble interleukin - 2 receptor levels were elevated (2740 U/ml). ANA and dsDNA were positive in significant titres, complement levels were low and Coombs test was positive, thereby confirming the primary diagnosis of SLE. All patients received methylprednisolone pulse along with cyclophosphamide in case 1 and IVIG in case 2 and 3, resulting in remarkable improvement. Conclusion With a prevalence of 0.9-4.6%, HLH secondary to SLE is an uncommon entity. The diagnosis of HLH related to SLE is challenging since the symptoms overlap, however findings of hyperferritinemia, hypofibrinogenemia, and hypertriglyceridemia favour HLH over SLE. Once HLH is proven, immunological testing for SLE is warranted to prevent diagnostic delay. Early treatment is needed to combat such a fulminant life-threatening illness. Disclosure R. Mishra: None. A. Rohatgi: None. S. Anuradha: None. N. Kumar: None. S. Singhla: None. S.T. Mathews: None. S. Kumar: None. P. Gautam: None.

Machine learning approaches to identify systemic lupus erythematosus in anti-nuclear antibody-positive patients using genomic data and electronic health records

BackgroundAlthough the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE) has required at least a positive anti-nuclear antibody (ANA) titer (≥ 1:80), it remains challenging for clinicians to identify patients with SLE. This study aimed to develop a machine learning (ML) approach to assist in the detection of SLE patients using genomic data and electronic health records.MethodsParticipants with a positive ANA (≥ 1:80) were enrolled from the Taiwan Precision Medicine Initiative cohort. The Taiwan Biobank version 2 array was used to detect single nucleotide polymorphism (SNP) data. Six ML models, Logistic Regression, Random Forest (RF), Support Vector Machine, Light Gradient Boosting Machine, Gradient Tree Boosting, and Extreme Gradient Boosting (XGB), were used to identify SLE patients. The importance of the clinical and genetic features was determined by Shapley Additive Explanation (SHAP) values. A logistic regression model was applied to identify genetic variations associated with SLE in the subset of patients with an ANA equal to or exceeding 1:640.ResultsA total of 946 SLE and 1,892 non-SLE controls were included in this analysis. Among the six ML models, RF and XGB demonstrated superior performance in the differentiation of SLE from non-SLE. The leading features in the SHAP diagram were anti-double strand DNA antibodies, ANA titers, AC4 ANA pattern, polygenic risk scores, complement levels, and SNPs. Additionally, in the subgroup with a high ANA titer (≥ 1:640), six SNPs positively associated with SLE and five SNPs negatively correlated with SLE were discovered.ConclusionsML approaches offer the potential to assist in diagnosing SLE and uncovering novel SNPs in a group of patients with autoimmunity.

Association between thyroid autoimmunity and antinuclear antibody prevalence among pregnant women: a cross-sectional study in Qingdao, China.

To identify the relationship between thyroid autoimmunity and antinuclear antibody (ANA) prevalence in Chinese pregnant women. The study involved 1923 first-trimester women who were measured for thyroid stimulating hormone (TSH) level, thyroid autoantibodies (thyroperoxidase antibody [TPOAb] and thyroglobulin antibody [TgAb]) and ANA titer. Social demographic data were collected through standardized questionnaires. In this study, 23.3% of pregnant women tested positive for TPOAb and 9.9% tested positive for TgAb. Women with a positive ANA were more likely to be TPOAb-positive or TgAb-positive than women with a negative ANA (adjusted odds ratio [AOR] 1.96, 95% confidence interval [CI] 1.47-2.62 for TPOAb [+]; AOR 3.12, 95% CI 2.18-4.48 for TgAb[+]). In addition, ANA titers were closely associated with thyroid autoimmunity. Women with an ANA titer of >1:320 had a significant higher risk of being TPOAb positive or TgAb positive (AOR 4.49, 95% CI 1.48-13.66 for TPOAb [+]; AOR 5.51, 95% CI 1.65-18.49 for TgAb [+]). The higher the ANA titer, the greater the risk of developing thyroid autoimmunity, especially for those with a high ANA titer. ANA positivity is strongly correlated with thyroid autoimmunity. Further study is warranted to clarify the causal relationship between thyroid autoimmunity and ANA in pregnant women.This research is essential to evaluate and predict the risk of co-existing autoimmune disorders,leading to improved care for pregnancy and neonatal health.

Profiling of kidney involvement in systemic lupus erythematosus by deep learning using the National Database of Designated Incurable Diseases of Japan

BackgroundKidney involvement frequently occurs in systemic lupus erythematosus (SLE), and its clinical manifestations are complicated. We profiled kidney involvement in SLE patients using deep learning based on data from the National Database of Designated Incurable Diseases of Japan.MethodsWe analyzed the cross-sectional data of 1655 patients with SLE whose Personal Clinical Records were newly registered between 2015 and 2017. We trained an artificial neural network using clinical data, and the extracted characteristics were evaluated using an autoencoder. We tested the difference of population proportions to analyze the correlation between the presence or absence of kidney involvement and that of other clinical manifestations.ResultsData of patients with SLE were compressed in a feature space in which the anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody titer, antinuclear antibody titer, or white blood cell count contributed significantly to distinguishing patients. Many SLE manifestations were accompanied by kidney involvement, whereas in a subgroup of patients with high anti-dsDNA antibody titers and low antinuclear antibody titers, kidney involvement was positively and negatively correlated with hemolytic anemia and inflammatory manifestations, respectively.ConclusionAlthough there are various combinations of SLE manifestations, our study revealed that some of them are specific to kidney involvement. SLE profiles extracted from the objective analysis will be useful for categorizing SLE manifestations.

Concurrence of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura: a case report and review of the literature

BackgroundImmune thrombocytopenic purpura and thrombotic thrombocytopenic purpura are both causes of thrombocytopenia. Recognizing thrombotic thrombocytopenic purpura is crucial for subsequent treatment and prognosis. In clinical practice, corticosteroids and rituximab can be used to treat both immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura; plasma exchange therapy is the first-line treatment in thrombotic thrombocytopenic purpura, while corticosteroids are strongly recommended as first-line treatment in immune thrombocytopenic purpura. The differential diagnosis of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura is essential in clinical practice. However, case reports have suggested that immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura can occur concurrently.Case presentationWe report the case of a 32-year-old Asian female without previous disease who presented with pancytopenia, concurrent with immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura. The morphology of the megakaryocytes in the bone marrow indicated immune-mediated thrombocytopenia. The patient received glucocorticoid treatment, and her platelet count increased; however, schistocytes remained high during the course of the therapy. Further investigations revealed ADAMTS13 activity deficiency and positive ADAMTS13 antibodies. The high titer of antinuclear antibody and positive anti-U1-ribonucleoprotein/Smith antibody indicated a potential autoimmune disease. However, the patient did not fulfill the current criteria for systemic lupus erythematosus or mixed connective tissue disease. The patient responded well to plasma exchange therapy, and her platelet count remained normal on further follow-up.ConclusionsConcurrence of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura is rare, but clinicians should be aware of this entity to ensure prompt medical intervention. Most of the reported cases involve young women. Human immunodeficiency virus infection, pregnancy, and autoimmune disease are the most common underlying conditions.

Acute Pericarditis with High Anti-Nuclear Antibody Titers Following BNT162b2 mRNA COVID-19 Vaccination.

Acute Pericarditis with High Anti-Nuclear Antibody Titers Following BNT162b2 mRNA COVID-19 Vaccination.

Standardized diagnosis and treatment of undifferentiated connective tissue disease and mixed connective tissue disease

Undifferentiated connective tissue disease (CTD) usually refers to patients who are presented with certain symptoms and signs related to CTD, and positive serological evidence of autoimmune diseases but don't fulfill any of the classification criteria for a certain CTD. Mixed CTD refers to patients who are presented with one or more clinical manifestations such as hand swelling, synovitis, myositis, Raynaud's phenomenon, and acrosclerosis. Patients with mixed CTD always have high-titer anti-nuclear antibodies (ANA) of speckled pattern and high-titer anti-U1 ribonuclear protein (RNP) antibody in serum, while with negative anti-Sm antibody. The update of diagnosis and treatment of undifferentiated CTD and mixed CTD lags behind other established CTD. There is a lack of evidence from randomized controlled trials or guidelines/recommendations on the treatment of undifferentiated CTD or mixed CTD. At present, the conventional therapy is mainly adopted according to the specific clinical manifestations of the disease. The standardized diagnosis and treatment of undifferentiated CTD and mixed CTD were drafted by the Chinese Rheumatology Association based on the previous guidelines and the progress of available evidence, so as to improve the management of these patients in China.

Predictors of relapse, death or heart transplantation in myocarditis before the introduction of immunosuppression: negative prognostic impact of female gender, fulminant onset, lower ejection fraction and serum autoantibodies.

Outcome predictors in myocarditis are not well defined; we aimed at identifying predictors of death, heart transplantation (HTx) and relapse before the introduction of immunosuppression. From 1992 to 2012, 466 consecutive patients (68% male, mean age 37 ± 17 years, single centre recruitment, median follow-up 50 months) were included, of whom 216 had clinically suspected and 250 biopsy-proven myocarditis. Serum anti-heart (AHA) and anti-intercalated disk (AIDA) autoantibodies were measured by indirect immunofluorescence. Univariable and multivariable analyses of clinical and diagnostic features at diagnosis were performed. Survival free from death or HTx at 10 years was 83% in the whole study population and was lower in biopsy-proven versus clinically suspected myocarditis (76% vs. 94%, p < 0.001). Female gender (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1-6.5), fulminant presentation (HR 13.77, 95% CI 9.7-261.73), high-titre organ-specific AHA (HR 4.2, 95% CI 1.2-14.7) and anti-nuclear antibodies (ANA) (HR 5.2, 95% CI 2.1-12.8) were independent predictors of death or HTx; higher echocardiographic left ventricular ejection fraction (LVEF) at diagnosis was protective, with a 0.93-fold risk reduction for each 1% LVEF increase (95% CI 0.89-0.96). History of myocarditis at diagnosis (HR 8.5, 95% CI 3.5-20.7) was an independent predictor of myocarditis relapse at follow-up; older age was protective (HR 0.95, 95% CI 0.91-0.99). Predictors of death, HTx and relapse did not differ in biopsy-proven versus clinically suspected myocarditis. Young age and a previous myocarditis were independent relapse predictors; female gender, fulminant onset, lower LVEF at presentation and high-titre organ-specific AHA and ANA were independent predictors of death and HTx, suggesting that autoimmune features predict worse prognosis.

High titers of antinuclear antibody and the presence of multiple autoantibodies are highly suggestive of systemic lupus erythematosus

The aim of this study is to evaluate the relationship between antinuclear antibody (ANA) titer and specificity, as well as the relationship between the number of positive-autoantibodies (AAbs) in antinuclear antibodies (ANAs) and specificity for systemic lupus erythematosus (SLE), so as to explore their significance in the diagnosis of SLE. A total of 1297 patients with ANA results was enrolled in this study, including 148 patients with SLE patients. The sensitivity, specificity, sensitive likelihood ratio and specific likelihood ratio of indicators in SLE were determined by receiver–operator characteristic (ROC) curve after measurement of ANA and ANAs by indirect immunofluorescence (IIF) and immunoblotting, respectively. ROC analysis showed that the specificity of ANA titer ≥ 1 +, ≥ 2 + and ≥ 3 + for SLE was estimated to be 81.29%, 90.69% and 96.52% respectively, with a increased titer-specific likelihood ratio (5.16, 9.29 and 19.60, respectively). The specificity of the number of positive-AAbs ≥ 1, ≥ 2 and ≥ 3 in ANAs for SLE was estimated to be 80.42%, 94.95% and 99.3% respectively, with a increased number-specific likelihood ratio (4.8, 15.26 and 72.48, respectively). The estimated sensitivity of the number of positive-AAbs ≥ 3, AnuA and anti-rRNP was higher than that of anti-Sm (p < 0.01) (50.68%, 41.89% and 31.76% vs. 16.89%, respectively), while there was no significant difference in their specificity (99.3%, 99.74% and 99.56% vs. 99.74%, respectively) (p > 0.05). High titers of ANA and the presence of multiple AAbs in ANAs are highly specific for SLE and highly suggestive of SLE. The likelihood of SLE can be assessed by ANA titer and the number of positive-AAbs in ANAs.

A rare case of Interstitial lung disease complicated by overlapping syndrome with obstructive ventilatory dysfunction as the first symptom

Interstitial lung disease is often a serious complication of connective tissue disease（CTD）, representing the first cause of death in CTD. However, there are few reports of SSc-RA overlap-associated interstitial pneumonia. Respiratory dysfunction as the first clinical manifestation is even rarely reported. We herein described a case of a male patient who developed significant respiratory dysfunction as the principal clinical sign for the past 6 months, plus newly developed skin thickening in bilateral upper limbs and pain and swelling of multiple joints for the past 6 weeks. Extensive immunological screening showed high titer of antinuclear antibodies(ANA), rheumatoid factor(RF), anti-cyclic peptide containing citrulline (anti-CCP)，and positive anti-Scl-70 antibody. Chest high resolution computed tomography(HRCT) was performed and hence ILD was confirmed. Pulmonary function test (PFT) revealed obstructive ventilatory dysfunction rather than restrictive ventilatory dysfunction. So bronchodilation test was performed and asthma was considered. Finally, after a multidisciplinary team (MDT) discussion, the diagnosis of asthma and ILD associated with SSc-RA overlap was established. It is important to note that CTD associated pulmonary interstitial fibrosis must be considered as the differential diagnosis of any newly diagnosed interstitial pulmonary disease. In addition, if patient with dyspnea is highly suspicious of pulmonary interstitial fibrosis, bronchodilation test is still needed to exclude asthma in order to avoid misdiagnosis.

NO RHEUM FOR AIR: MIXED CONNECTIVE TISSUE DISEASE PRESENTING AS INTERSTITIAL LUNG FIBROSIS IN A YOUNG WOMAN

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Interstitial Lung Disease(ILD) is a serious complication of Mixed Connective Tissue Disorder(MTCD) associated with high morbidity and mortality. We describe an unusual case of a young patient presenting with advanced fibrosis at the time of initial diagnosis of MTCD. CASE PRESENTATION: A 39 year old female presented with dyspnea and dry cough of four months duration that progressively worsened requiring assistance for daily activities. She had associated weight loss, night sweats, diffuse arthralgia without any swelling and right hand stiffening. She denied any fevers, oral/nasal ulcers, vision changes, recent travel, tick bites, skin rash, smoking, household mold or pets. Physical examination revealed bibasilar crackles and mild dusky appearance of fingers. Laboratory investigations showed a normal blood count, elevated d-dimer and inflammatory markers. High Resolution Computerized Tomography(HRCT) Scan of the chest showed diffuse ground glass opacities, subpleural reticulation/scarring, traction bronchiectasis with multiple areas of honeycombing as well as extensive mediastinal lymphadenopathy. The serological panel was significant for high titers of Anti-Nuclear Antibodies(ANA) 1:1280 speckled pattern with low complement C3/C4 level, Rheumatoid Factor(RF) 138, Immunoglobulin G(IgG) 5000, anti-SSA and anti-ribonucleoprotein antibodies 133 and 148 respectively, elevated aldolase and creatinine kinase. Infectious workup was negative. The diffusely positive serology and lymphadenopathy was concerning for lymphoma. However, the excisional lymph node biopsy was negative for malignancy and showed changes consistent with autoimmune etiology. She was diagnosed with MTCD with features of lupus, sjogrens, rheumatoid arthritis, myositis presenting as ILD. Treatment with steroids and hydroxychloroquine was initiated with improvement in her respiratory symptoms. DISCUSSION: ILD in patients with MTCD ranges from being asymptomatic to advanced fibrosis with a high mortality rate.Typically, intial pulmonary function testing shows reduced diffusion capacity which progresses to restrictive pattern in the later stages along with HRCT changes. Our patient, although young, had rapid progression of pulmonary symptoms and was found to have advanced scarring on initial presentation. The diffusely positive serology can overlap with lymphoma and biopsy of lymph node/lung can give definite diagnosis. Since screening guidelines for MTCD-ILD are not clearly established any clinical symptoms should prompt further investigations. Treatment especially steroids during the acute inflammatory phase with ground glass opacities has good prognosis whereas the response is poor once signs of fibrosis develop. CONCLUSIONS: Advanced fibrosis ILD is an uncommon presentation of MTCD in a young patient. Early diagnosis and prompt initiation of therapy especially during the acute phase can prevent further progression of disease. REFERENCE #1: Narula N, Narula T, Mira-Avendano I, Wang B, Abril A. Interstitial lung disease in patients with mixed connective tissue disease: pilot study on predictors of lung involvement. Clin Exp Rheumatol. 2018 Jul-Aug;36(4):648-651. Epub 2018 May 8. PMID: 29745875 REFERENCE #2: Taha R, Feteih M. Pulmonary Manifestations of Connective Tissue Diseases. Skills in Rheumatology. 2020 Aug 29:139–75. doi: 10.1007/978-981-15-8323-0_7. PMCID: PMC7784640.? DISCLOSURES: No relevant relationships by Sana Hyder, source=Web Response No relevant relationships by Evan Nadler, source=Web Response No relevant relationships by Nikola Perosevic, source=Web Response No relevant relationships by Evan Wasserman, source=Web Response

A case of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) with a high antinuclear antibody titer

A case of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) with a high antinuclear antibody titer

Interpretation of Anti-Nuclear Antibody Tests

Anti-nuclear antibodies (ANAs) are autoantibodies against nuclear substances or other cellular components. ANA tests are used in the diagnostic process to screen patients with suspected rheumatic or autoimmune diseases. ANA-associated diseases are characterized by a high titer of antinuclear antibodies and include systemic lupus erythematosus, systemic sclerosis, and mixed connective tissue diseases. ANA test results must be cautiously interpreted as they can be positive not only in infections and oncological diseases but also for the healthy general population. The ANA test mainly uses the indirect immunofluorescence test, and the results are expressed in terms of the final titer and pattern. The ANA test can increase diagnostic value when used in conjunction with the evaluation of disease-related clinical symptoms.

Atypical case of primary sjögren’s syndrome with psychiatric disorder

Primary Sjögren’s Syndrome (PSS) is a systemic autoimmune disorder characterized by chronic inflammation of exocrine glands. Neurological manifestations are sometimes found in patients with PSS, and both the Central Nervous System (CNS) and Peripheral Nervous System (PNS) can be involved. Psychiatric disorder is a rare manifestation caused by PSS. Herein, we report a 67-year-old woman admitted from the department of neurology for further investigations of progressive psychiatric abnormalities. High titers (1:320) of Antinuclear Antibodies (ANA) and antibodies against SSA and Rheumatoid Factor (RF) were detected. Rheumatology review revealed a history of Sicca symptoms and her Schirmer’s test was positive. This lead to the diagnosis of CNS complications associated with PSS. She had an excellent response to intravenous methylprednisolone followed by oral prednisolone and intravenous immunoglobulin infusions. This case highlights that CNS involvement can precede the diagnosis of PSS. For a patient with psychiatric disorder, attention should be paid to screening for accompanying PSS, especially in female patients. Keywords: Primary Sjögren syndrome; Autoimmune disease; Neurological involvement; Central nervous system; Psychiatric disorder.

Systemic Lupus Erythematosus Manifested as Pancytopenia during Tuberculosis Treatment

A 49-year-old Chinese woman presented to Ilsan Paik Hospital emergency department with fever and general weakness. Chest computed tomography revealed cavity and peribronchial nodules and consolidation in the right upper lobe. A diagnosis of suspected active tuberculosis was made. A review of the patient’s medication prescribed at another hospital indicated that she had been taking antituberculosis medication for several months. Initially, the patient had anemia and mild thrombocytopenia. In addition, she developed leukopenia and her thrombocytopenia worsened. After discontinuing the antituberculosis medication, her pancytopenia initially improved, but was aggravated again after starting on antituberculosis drugs. Despite discontinuing the antituberculosis medication again, her pancytopenia progressed. As she had a high anti-nuclear antibody titer, another systemic disease was suspected. She was diagnosed with systemic lupus erythematosus and her leukopenia and thrombocytopenia improved after initiation of treatment with systemic steroids and antimalarial drugs.

Efficacy and Feasibility of Programmed Death-1/Programmed Death Ligand-1 Blockade Therapy in Non-Small Cell Lung Cancer Patients With High Antinuclear Antibody Titers.

BackgroundImmune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce.MethodsThis study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed.ResultsOne hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39–84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups.ConclusionThe administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.

A novel mouse model for checkpoint inhibitor-induced adverse events.

Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of a variety of cancers, however their therapeutic potential is limited by abstruse immune related adverse events. Currently, no robust animal model exists of checkpoint inhibitor-induced adverse events. Establishing such a model will improve our mechanistic understanding of this process, which in turn will inform design of improved therapies. We developed a mouse model to determine inflammatory toxicities in response to dual checkpoint blockade in the presence of syngeneic tumors. Mice from susceptible genetic backgrounds received intraperitoneal injections of anti-mouse PD-1 and CTLA-4 antibodies. The mice were monitored for weight loss and histologic evidence of inflammation. Blood was collected for basic metabolic panels and titers of anti-nuclear antibodies. In parallel, mice were also treated with prednisolone, which is commonly used to treat immune related adverse events among cancer patients. Among all the genetic backgrounds, B6/lpr mice treated with anti-CTLA-4 and anti-PD-1 antibodies developed more substantial hepatitis, pancreatitis, colitis, and pneumonitis characterized by organ infiltration of immune cells. Mice that developed tissue infiltration demonstrated high serum levels of glucose and high titers of anti-nuclear antibodies. Finally, while administration of prednisolone prevented the development of the inflammatory adverse events, it also abrogated the protective anti-tumor effect of the checkout inhibitors. Genetic background and treatment modalities jointly modified the inflammatory adverse events in tumor bearing mice, suggesting a complex mechanism for checkpoint inhibitor-related inflammation. Future studies will assess additional genetic susceptibility factors and will examine possible contributions from the administration of other anti-inflammatory drugs.

Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis

This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.