Retrospective, single-center analysis of autoimmune hepatitis in Jordanian children: clinical features, treatments, and outcomes.

OBJECTIVES: This study describes clinical, biochemical, and histological features and long-term outcomes in pediatric patients diagnosed with autoimmune hepatitis (AIH) at King Abdullah University Hospital, Jordan. DESIGN: Retrospective, single-center study. SETTING: King Abdullah University Hospital, Jordan. PARTICIPANTS: Inclusion of all pediatric patients with AIH diagnosed at our hospital from 2015 to 2023. Exclusion criteria was patients aged over 18 at time of diagnosis and those diagnosed elsewhere. OUTCOME MEASURES: Understanding clinical, biochemical, and histological AIH features in children, evaluating treatment responses, and reporting short- and long-term complications, including mortality. RESULTS: Sixteen pediatric cases were diagnosed, with an average age of 9.84 ± 4.13 years. Females comprised 75% of patients, and 31.3% presented with acute liver failure. Jaundice was the most common symptom, and hepatosplenomegaly was observed in 18% of cases. Most patients had elevated transaminase levels, along with positive anti-smooth muscle antibody (ASMA) and antinuclear antibodies (ANA). Common hematological abnormalities included anemia (56.3%) and thrombocytopenia (37.5%). All patients underwent liver biopsy, with interface hepatitis present in 81.3% of cases. Treatment mainly involved prednisone and azathioprine. Three patients died, one discontinued therapy, two patients were lost to follow-up, and 10 remained on treatment. CONCLUSION: Autoimmune hepatitis affects Jordanian children, primarily female children. Jaundice is the most common presenting symptoms. Only Type I AIH occurred in our cohort. Although of good response to conventional treatment with steroids and immunosuppression, mortality reached 18.8%.

Clinical significance of antinuclear antibody as prognostic marker for first-line pembrolizumab in advanced non-small cell lung cancer.

BACKGROUND: The relationship between antinuclear antibody (ANA) and the efficacy of programmed death-1 (PD-1) blockade remains controversial. Here, we investigated the prognostic significance of ANA titer in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab monotherapy as the first-line treatment, compared with that of platinum-based chemotherapy with PD-1 blockade. METHODS: Our clinical data based on the ANA titer (1:80) were retrospectively reviewed for patients with advanced NSCLC, who were treated with first-line pembrolizumab monotherapy and platinum-based chemotherapy with PD-1 blockade. Immunohistochemical staining for tumor-infiltrating lymphocytes such as CD4, CD8 and Foxp3 was performed. RESULTS: Among 106 patients treated with pembrolizumab, 19 (17.9%) tested high for ANA. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high ANA than in those with low ANA, and high ANA was identified as an independent prognostic predictor, particularly in the subgroup with programmed death ligand-1 (PD-L1) ≥ 50%. However, no statistically significant difference in PFS and OS based on the ANA titer was observed in 59 patients treated with combinational chemotherapy and immunotherapy. High numbers of intratumoral Foxp3 and stromal CD8 were significantly associated with low ANA. CONCLUSIONS: Assessment of preexisting ANA titers was useful to prognose PD-1 blockade as a first-line setting, particularly for the PD-L1 ≥ 50% subgroup, but not in the case of combined immunotherapy and chemotherapy.

Significance of co-positivity for anti-dsDNA, -nucleosome, and -histone antibodies in patients with lupus nephritis.

OBJECTIVE: The aim of this study was to define the clinical, histopathologic, and prognostic features associated with simultaneous positivity for anti-dsDNA, -nucleosome, and -histone antibodies (3-pos) in Korean patients with biopsy-proven lupus nephritis (LN). METHODS: The 102 patients included in the study had undergone kidney biopsy prior to the start of induction treatment, were treated with immunosuppressives, and followed-up for >12 months. RESULTS: In total, 44 (43.1%) of the 102 LN patients were 3-pos. Patients with 3-pos had a higher SLEDAI-2K score (p = .002), lower lymphocyte count (p = .004), and higher rates of proteinuria > 3.5 g/24 h (p = .039) and positivity for urinary sediments (p = .005) at the time of renal biopsy than non-3-pos patients. 3-pos patients had a more proliferative form of LN (p = .045) in the renal histopathologic findings, and as co-positivity gradually increased from 0 to 3, the total activity score in the renal biopsy findings increased significantly (p = .033). In addition, 3-pos patients had a more rapid eGFR decline than non-3-pos patients after a follow-up of 83.2 months (p = .016). CONCLUSIONS: Our findings suggest that 3-pos is related to severe LN and that 3-pos patients are more likely to experience a rapid decline of renal function than non-3-pos patients.KEY MESSAGEPatients with co-positivity for anti-dsDNA, -nucleosome, and -histone antibodies (3-pos) had higher disease activity and a worse renal histopathology than those without co-positivity.3-pos patients had a more rapid decline of renal function than non-3-pos patients.

Severe Lupus Myocarditis Preceded by Mesalazine-induced Lupus.

In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A 41-year-old-woman with a history of ulcerative colitis presented with polyarthritis and myositis and was positive for anti-double stranded (ds) DNA IgG antibody. After discontinuation of mesalazine, the symptoms resolved, and the antibody titer decreased. The patient was diagnosed with DIL. Six months later, lupus myocarditis developed. After treatment with glucocorticoids, cyclophosphamide, intravenous immunoglobulin, and an intra-aortic balloon pump, she showed dramatic improvement. Patients with DIL and an immunological predisposition, such as anti-dsDNA antibodies, may have SLE and should be carefully monitored.

Torasemide-induced Vascular Purpura in the Course of Eosinophilic Granulomatosis with Polyangiitis.

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 µg per day, and ipratropium bromide 20 µg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a diagnosis of EGPA, which was later confirmed by a consultant in rheumatology. The patient was commenced on prednisone at a dose of 0.5 mg per kg of body weight daily and mycophenolate mofetil at a daily dose of 2 g. The antihypertensive therapy was modified, and torasemide was replaced by spironolactone 25 mg per day. The treatment resulted in a gradual regression of skin lesions within a few weeks. The first report of EGPA dates back to 1951. Its authors were Jacob Churg and Lotte Strauss. They described a case series of 13 patients who had severe asthma, fever, peripheral blood eosinophilia, and granulomatous vasculitis in microscopic evaluation of the skin. Three histopathological criteria were then proposed, and Churg-Strauss syndrome was recognized when eosinophilic infiltrates in the tissues, necrotizing inflammation of small and medium vessels, and the presence of extravascular granulomas were observed together in a patient (1). Only 17.4% of patients met all three histopathological criteria, and the diagnosis of the disease was frequently delayed despite of its overt clinical picture (2). In 1984, Lanham et al. proposed new diagnostic criteria which included the presence of bronchial asthma, eosinophilia in a peripheral blood smear >1.5 thousand per mm3, and signs of vasculitis involving at least two organs other than the lungs (3). Lanham's criteria could also delay the recognition of the syndrome before involvement of internal organs, and the American College of Rheumatology therefore established classification criteria in 1990. These included the presence of bronchial asthma, migratory infiltrates in the lungs as assessed by radiographs, the presence of abnormalities in the paranasal sinuses (polyps, allergic rhinitis, chronic inflammation), mono- or polyneuropathy, peripheral blood eosinophilia (>10% of leukocytes must be eosinophils), and extravascular eosinophilic infiltrates in a histopathological examination. Patients who met 4 out of 6 criteria were classified as having Churg-Strauss syndrome (4). The term EGPA was recommended to define patients with Churg-Strauss syndrome in 2012 (5). EGPA is a condition with low incidence (0.11-2.66 cases per million) and morbidity. It usually occurs in the fifth decade of life (6,7), although 65 cases reports of EGPA in people under 18 years of age could be found in the PubMed and Ovid Medline Database at the end of 2020 (8). The etiopathogenesis of the disease has not been fully explained so far. Approximately 40-60% of patients are positive to pANCA (9), but the role of these antibodies in the pathogenesis of EGPA remains unclear. They are suspected to mediate binding of the Fc receptor to MPO exposed on the surface of neutrophils. Subsequently, this may active neutrophils and contribute to a damage of the vascular endothelium (9,10). Glomerulonephritis, neuropathy, and vasculitis are more common in patients with EGPA who have detectable pANCA when compared with seronegative patients. There are at least several drugs which potentially may EGPA. The strongest association with the occurrence of EGPA was found with the use of leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast), although they are commonly used in the treatment of asthma, which is paradoxically one of the complications of the syndrome (13). Although no relationship has been demonstrated so far between the occurrence of EGPA and the intake of drugs from the groups used by the presented patient, a clear time relationship can be observed between the commencement of torasemide and the onset of symptoms in our patient. To date, only three cases of leukocytoclastic vasculitis have been reported after the administration of torasemide. Both of them developed cutaneous symptoms of the disease within 24 hours of the administration of torasemide in patients with no previous history of drug hypersensitivity, but they disappeared quickly within 8-15 days after drug discontinuation (14,15). The chemical structure of torasemide is similar to the molecule of sulfonamides which were previously found to be a triggering factors for EGPA (12). This drug belongs to the group of loop diuretics classified as sulfonamide derivatives. A comparison of the chemical structure of torasemide and sulphanilamide molecules is presented in Figure 1. The clear time relationship between starting the administration of torasemide and the occurrence of purpura-like lesions suggests that it was an aggravating factor for EGPA in our patient. A coexistence of several disorders (asthma, nasal polyps, symptoms of peripheral neuropathy) in our patient suggest EGPA could have developed in her years before oral intake of torasemide. The sudden onset of skin symptoms shows torasemide to be possible inducing factor for the development of vascular purpura in patients suffering from EGPA but without previous cutaneous involvement.

Clinical characterisation of a multicentre nationwide cohort of patients with antisynthetase syndrome.

BACKGROUND: Antisynthetase syndrome (ASyS) is characterised by the association of inflammatory myopathy, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon (RP) or mechanic's hands (MH), with the presence of anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS). It has been suggested that different anti-ARS may be associated with distinct clinical pictures. OBJECTIVE: To characterise the clinical and immunological features of a multicentric nationwide cohort of ASyS patients. METHODS: This is a multicentre retrospective cohort study including patients with ASyS from nine Portuguese rheumatology centres. Data on patients' demographics, signs and symptoms, laboratory results, pulmonary imaging findings and treatment with immunomodulators were collected. Comparison between patients with different anti-ARS antibodies was made using the Chi-square test for categorical variables and Student's t-test or Man-Whitney test for continuous variables, considering anti-Jo1 positive patients as the reference group. RESULTS: Seventy patients were included (70% female) with a median age in years at disease onset of 52 (15-75) years and median follow-up time of 3 years (range 0-32). The three most common clinical manifestations were ILD (n=53, 75.7%), followed by arthritis (n=43, 61.4%) and myositis (n=37, 52.9%). Forty-three patients were positive for anti-Jo1 (61.4%), 11 for anti-PL12 (15.7%), 10 for anti-PL7 (14.3%), 4 for anti-EJ (5.7%), and 2 for anti-OJ (2.9%) antibodies. Antibody co-positivity with anti-Ro52 antibodies was found in 15 patients (21.4%) and was more prevalent in anti-Jo1 patients. ILD prevalence was similar in the different anti-ARS subgroups, without statistically significant differences. Patients positive for anti-PL7 antibodies had significantly lower risk of presenting arthritis (p =< 0.05) and those positive for anti-PL-12 antibodies had a significantly lower risk of presenting myositis than the reference group of anti-Jo1 positive patients (p =< 0.05). RP was more frequently found in patients positive for anti-PL-12 than in anti-Jo1-positive patients (p =< 0.05). Malignancies were reported in four (5.7%) patients, none of whom were anti-Ro52-positive, and one of such patients had a double malignancy. Only three deaths were reported. Corticosteroids were the most frequently prescribed therapy and the use of immunosuppressive drugs was decided according to the type of predominant clinical manifestation. CONCLUSION: The three most common clinical manifestations were ILD, followed by arthritis and myositis. Patients positive for anti-PL7 antibodies had significantly lower risk of presenting arthritis and those positive for anti-PL-12 antibodies had a significantly lower risk of presenting myositis than the reference group of anti-Jo1 positive patients. RP was more frequently found in patients positive for anti-PL-12 than in anti-Jo1-positive patients. Corticosteroids were the most frequently prescribed therapy. These results are generally concordant with data retrieved from international cohorts.

The description of neuromyelitis optica spectrum disorder: Patient registry in Yangtze River Delta area of China.

OBJECTIVE: To describe the clinical features of neuromyelitis optica spectrum disorder (NMOSD) through patient registry in Yangtze River Delta area of China. METHODS: A total of 502 consecutive patients diagnosed with aquaporin-4 antibody (AQP4-ab)-positive NMOSD were registered between December 2018 to January 2021 in multiple tertiary referral centers within the framework of Yangtze River Delta of China. Their baseline data were reviewed, and follow-up clinical information were collected prospectively. RESULTS: The mean age at onset was 37.3 (range 3-80 years) years and the female-to-male ratio was 8.1:1. The median disease duration was 47 months (interquartile range [IQR] 25-84 months). A total of 1372 attacks of the 502 patients were recorded till the last follow-up, with a median annualized relapse rate of 0.4 (IQR 0.3-0.6). Nearly one-fourth (24.5%, 336/1372) of the attacks had prodromic events, including upper respiratory tract infection (36.3%, 122/336), fever (20.2%, 68/336) and pregnancy-related issues (17.9%, 60/336), etc. Myelitis was the most common attack type throughout the disease course (51.4%, 705/1372), followed by optic neuritis (ON, 43.1%, 592/1372). As for onset phenotype, ON (37.3%, 187/502) prevailed over myelitis (28.3%, 142/502). The median time to first relapse was 12 months (IQR 5-25 months). Patients with brainstem encephalitis at onset were more likely to have other anatomical region involved in subsequent attacks (p < 0.001), compared to other onset type. The median serum AQP4-ab titer measured by cell-based assays was 1:100 (IQR 1:32-1:320, range 1:10-1:10,000). The baseline AQP4-ab titer in cerebrospinal fluid (r = 0.542, p <0.001), overall ARR (r = 0.232, p< 0.001) and the EDSS scores at last follow-up (r = 0.119, p = 0.022) significantly correlated with baseline serum AQP4-ab titer. Antinuclear antibodies (48.4%), thyroid peroxidase antibodies (30.7%), and anti-SSA antibodies (26.2%) represented the most frequent concomitant antibodies, while autoimmune thyroid disorders (13.1%, 66/502) and Sjogren's syndrome (10.8%, 54/502) were the most common accompanying autoimmune diseases. Till the last follow-up, 403 patients received preventive treatments. Azathioprine represented the most common initial treatment, mycophenolate mofetil and rituximab was the most common second and third-line treatment, respectively. The EDSS score at the last follow-up ranged from 0 to 8.5 with a median of 2 (IQR 1-3). CONCLUSIONS: A comprehensive clinical picture of patients with AQP4-ab-positive NMOSD in Yangtze River Delta area of China was presented. More information on disease tragedy and predictive prognostic factors could be generated through long-term observations.

Effect of antinuclear antibodies on pharmacokinetics of anti-TNF therapy in patients with inflammatory bowel disease.

PURPOSE: The detection of antinuclear antibodies (ANA) in serum of patients with inflammatory bowel disease (IBD) has been associated with a worse response to anti-TNF therapy and the development of cutaneous or arthritic manifestations. The aim of this study was to investigate a possible association of serum ANA with infliximab (IFX) and adalimumab (ADA) trough levels (TLs) and anti-drug antibodies in IBD patients treated with IFX or ADA. METHODS: Consecutive IBD patients under maintenance therapy with IFX or ADA in whom there was at least one available measurement of anti-TNF TLs, antibodies to IFX or ADA, and ANA in serum were included. The correlation of ANA positivity with demographics, clinical characteristics, treatment, TLs and anti-drug antibodies, of all patients was analyzed. RESULTS: One hundred two IBD patients under maintenance therapy with IFX or ADA were enrolled. Of these, 53 (52%) were ANA positive with 28 (27.5%) positive also to anti-ds-DNA in serum. In the univariate analysis ANA positivity was found to be correlated with age (P = 0.008), female gender (P = 0.03), duration of treatment (P = 0.06), arthralgias (P = 0.04) and TLs (P = 0.005). However, in multivariate logistic regression analysis only age and TLs remained significantly associated with the presence of ANA positivity (P = 0.04 and P = = 0.006, respectively). No significant association of ANA positivity with the development of cutaneous or rheumatological manifestations was found. CONCLUSIONS: In IBD patients under maintenance therapy with anti-TNF ANA positivity is associated with lower TLs. The clinical significance of this finding remains to be defined in future larger prospective studies.

APA scoring system: a novel predictive model based on risk factors of pregnancy loss for recurrent spontaneous abortion patients.

The aim of this study was to analyse the risk factors of pregnancy loss of patients with recurrent spontaneous abortion (RSA) and develop a scoring system to predict RSA. Clinical data of 242 cases, with RSA who were treated at Fujian Provincial Maternity and Children's Hospital, were selected. The factors of pregnancy loss for RSA patients were evaluated by univariate and multivariate analyses. There were 242 RSA patients, of whom 34 (14.0%) developed pregnancy loss. A multivariate analysis showed the following adverse risk factors for RSA: antinuclear antibody spectrum, protein s deficiency and antiphospholipid antibodies. The pregnancy loss rates of antinuclear antibody spectrum group, protein S deficiency group and antiphospholipid antibodies group were 25.0%, 22.5% and 19.4%, respectively. Each of these factors contributed 1 point to the risk score. The pregnancy loss rates were 6.3%, 24.6%, 50% for the low-, intermediate- and high-risk categories, respectively (p < .001). The area under the receiver operating characteristic curve for the score of RSA was .733. Our findings suggest that this validated and simple scoring system could accurately predict the risk of pregnancy loss of RSA patients. The score might be helpful in the selection of risk-adapted interventions to decrease the incidence. Impact StatementWhat is already known on this subject? The live birth rate increases to 80%-90% after anticoagulant and/or immunosuppressive treatment in patients with RSA. However, there is still a high rate of re-abortion even after active treatment.What do the results of this study add? Antinuclear antibody spectrum, protein s deficiency and antiphospholipid antibodies were independent risk factors for pregnancy loss. A novel predictive model based on these factors was then established and validated.What are the implications of these findings for clinical practice and/or further research? The newly developed score might be helpful in the selection of risk-adapted interventions to decrease the incidence. For patients in the intermediate-risk and high-risk groups, we should conduct more targeted studies and formulate corresponding therapies to improve the success rate of treatment.

Lupus-like nephritis with positive anti-neutrophil cytoplasmic antibodies and negative antinuclear antibodies.

Antineutrophil cytoplasmic antibodies (ANCAs) are associated with small vessel vasculitis but their prevalence is not rare in other immune diseases. In lupus nephritis (LN), their pathological role and clinical relevance have been the target of controversial views. We present a case of acute kidney injury and nephrotic syndrome in a young woman with diffuse global proliferative and membranous nephritis on her kidney biopsy, showing a full-house immunofluorescence pattern, very allusive of class IV + V LN, but lacking associated clinical criteria and laboratory findings to support the diagnosis of systemic lupus erythematosus (SLE). Furthermore, the patient presented with high titers of ANCA, steadily decreasing alongside the renal function and proteinuria improvements, with mycophenolate mofetil (MMF) and steroid treatment. The authors believe this is a case of lupus-like nephritis, in which ANCAs are immunological markers, although they are not directly involved in the pathogenesis.

ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody.

The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response. We found that DX1 penetrated brain endothelial cells and crossed the BBB, and mechanistic studies identify ENT2 as the key transporter. In efficacy studies, DX1 crosses the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases. ENT2-linked transport of autoantibodies across the BBB has potential to be exploited in brain tumor immunotherapy, and its discovery raises hypotheses on actionable mechanisms of CNS penetration by neurotoxic autoantibodies in CNS lupus.

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies.

Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.

Reversible Cognitive Dysfunction in Elderly-onset Systemic Lupus Erythematosus, Successfully Treated with Aggressive Immunosuppressive Therapy.

A 70-year-old Japanese woman presented to our hospital with gait disturbance and cognitive dysfunction. Since she had arthritis, lymphopenia, hypocomplementemia, and anti-nuclear and anti-double-stranded DNA antibodies, she was diagnosed with systemic lupus erythematosus (SLE). T2-weighted magnetic resonance imaging revealed bilateral hyperintensities in the putamen. Based on her cognitive impairment, muscle rigidity, and high levels of interleukin-6 in the cerebrospinal fluid, we believed she had developed a complication of a neuropsychiatric disease and administered corticosteroids and intravenous cyclophosphamide therapy. Her cognitive function fully recovered, and her gait disturbance improved. Attending to cognitive impairment in elderly SLE patients is necessary.

Re-engineering and evaluation of anti-DNA autoantibody 3E10 for therapeutic applications.

A key challenge in the development of novel chemotherapeutics is the design of molecules capable of selective toxicity to cancer cells. Antibodies have greater target specificity compared to small molecule drugs, but most are unable to penetrate cells, and predominantly target extracellular antigens. A nuclear-penetrating anti-DNA autoantibody isolated from the MRL/lpr lupus mouse model, 3E10, preferentially localizes to tumors, inhibits DNA repair, and selectively kills cancer cells with defects in DNA repair. A murine divalent single chain variable fragment of 3E10 with mutations for improved DNA binding affinity, 3E10 (D31N) di-scFv, has previously been produced in P. pastoris and yielded promising pre-clinical findings, but is unsuitable for clinical testing. The present study reports the design, expression and testing of a panel of humanized 3E10 (D31N) di-scFvs, some of which contain CDR substitution. These variants were expressed in a modified CHO system and evaluated for their physicochemical attributes and ability to penetrate nuclei to selectively cause DNA damage accumulation in and kill cancer cells with DNA repair defects. Secondary structure was conserved and most variants retained the key characteristics of the murine 3E10 (D31N) di-scFv produced in P. pastoris. Moreover, several variants with CDR substitutions outperformed the murine prototype. In conclusion, we have designed several humanized variants of 3E10 (D31N) di-scFv that have potential for application as monotherapy or conjugates for targeted nuclear drug delivery.

Lupus Pleuritis with Silicotic Nodules in the Parietal Pleura.

A 63-year-old man with occupational exposure to silica presented with cutaneous ulcer, pleuritic pain, and a fever. Laboratory data showed lymphopenia and positive serum antinuclear and anti-DNA antibodies. Computed tomography of the chest showed egg shell-like calcification of the hilar and mediastinal lymph nodes without pulmonary parenchymal involvement of silicosis. A surgical biopsy showed silicotic nodules with surrounding infiltration of lymphocytes and plasma cells in the parietal pleura. With a diagnosis of systemic lupus erythematosus (SLE), systemic corticosteroid therapy was given, which led to the resolution of symptoms and laboratory abnormalities. We discuss the relationship between silica exposure and the development of SLE.

Antinuclear antibodies and mortality in the National Health and Nutrition Examination Survey (1999-2004).

OBJECTIVE: Recent studies suggest antinuclear antibodies (ANA) may be related to mortality risk, but evidence is sparse and inconclusive. Thus, we investigated ANA associations with all-cause and cause-specific mortality in U.S. adults. METHODS: Our sample included 3357 adults (ages ≥20 years) from the 1999-2004 National Health and Nutrition Examination Survey with ANA measurements (1:80 dilution) and mortality data through 2011 (median follow-up: 9.4 years). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) via weighted Cox regression to assess ANA associations with mortality from all causes, cardiovascular disease (CVD), and cancer. Models adjusted for age, sex, race/ethnicity, education, and obesity. Analyses examined mortality in the full sample and in subgroups based on self-reported histories of CVD and cancer, both overall and stratified by sex and age at enrollment. RESULTS: Overall, ANA were not strongly associated with death from all causes (HR: 1.13; CI: 0.79, 1.60), from CVD (HR: 1.60; CI: 0.80, 3.20), or from cancer (HR: 1.58; CI: 0.75, 3.33), though all three HR estimates exceeded 1. In the subgroup with a history of cancer, ANA were associated with elevated all-cause mortality in men (HR: 2.28; CI: 1.01, 5.14) and in participants who enrolled at age ≥75 years (HR: 1.99; CI: 1.04, 3.80). CONCLUSION: These findings suggest that ANA are not strongly associated with mortality in the general population. Longitudinal studies with repeated assessments are needed to understand the temporal relationship between ANA, aging-associated diseases, and mortality.

The Diagnosis and Treatment of Sjögren's Syndrome.

BACKGROUND: Sjögren's syndrome is one of the more common inflammatory rheumatological diseases, with a prevalence of at least 0.4% in Germany. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed. Special attention is drawn to updated classification criteria and current treatment recommendations. RESULTS: Sjögren's syndrome has a wide variety of presentations, ranging from the local involvement of exocrine glands with keratoconjunctivitis sicca and xerostomia (the leading signs of the disease) to the systemic, extraglandular involvement of multiple organs. Fatigue also markedly worsens the patients' quality of life. Serologic testing reveals antinuclear auto-antibodies (anti-Ro/ SSA and anti-La/SSB) as well as rheumatoid factors. The histological hallmark of the disease is focal lymphocytic infiltration in otherwise normal-appearing glandular acini. The disease also markedly elevates the risk of non-Hodgkin lymphoma of the B-cell series, which arises in about 5% of patients. Primary Sjögren's syndrome (pSS) differs from the secondary form (sSS), which appears in the setting of another autoimmune disease, particularly systemic lupus erythematosus (15-36%), rheumatoid arthritis (20-32%), and limited or progressive systemic sclerosis (11-24%). Disease-modifying therapy is reserved for patients with systemic involvement; there is limited evidence for its efficacy. Because of the complexity of this disease, some of its clinical manifestations may require interdisciplinary treatment. CONCLUSION: The main considerations in the interdisciplinary care of patients with Sjögren's disease are measures to improve quality of life, pharmacological and non-pharmacological treatments to keep disease activity in check, and management of the risk of lymphoma. Future therapeutic approaches must take the heterogeneity of the disease into account.

A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors.

Strategies to target nanoparticles to tumors that rely on surface modification with ligands that bind molecules overexpressed on cancer cells or the tumor neovasculature suffer from a major limitation: with delivery of toxic agents the amount of molecules available for targeting decreases with time; consequently, the efficiency of nanoparticle delivery is reduced. To overcome this limitation, here we propose an autocatalytic tumor-targeting mechanism based on targeting extracellular DNA (exDNA). exDNA is enriched in the tumor microenviroment and increases with treatment with cytotoxic agents, such as doxorubicin (DOX), due to release of DNA by dying tumor cells. We tested this approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface-conjugated with fragments of 3E10 (3E10EN), a lupus anti-DNA autoantibody. We demonstrated that 3E10EN-conjugated nanoparticles bound to DNA and preferentially localized to tumors in vivo. The efficiency of tumor localization of 3E10EN-conjugated, DOX-loaded nanoparticles increased with time and subsequent treatments, demonstrating an autocatalytic effect. 3E10EN-conjugated DOX-loaded nanoparticles exhibited a significant anti-tumor effect that was superior to all controls. This work demonstrates the promise of autocatalytic drug delivery mechanisms and establishes proof of concept for a new anti-DNA autoantibody-based approach for enhancing delivery of nanoparticles to tumors.