Deranged Bioenergetics and Defective Redox Capacity in T Lymphocytes and Neutrophils Are Related to Cellular Dysfunction and Increased Oxidative Stress in Patients with Active Systemic Lupus Erythematosus

Urinary excretion of N-benzoyl-glycyl-Nε-(hexanonyl)lysine, a biomarker of oxidative stress, was higher in 26 patients with active systemic lupus erythematosus (SLE) than in 11 non-SLE patients with connective tissue diseases and in 14 healthy volunteers. We hypothesized that increased oxidative stress in active SLE might be attributable to deranged bioenergetics, defective reduction-oxidation (redox) capacity, or other factors. We demonstrated that, compared to normal cells, T lymphocytes (T) and polymorphonuclear neutrophils (PMN) of active SLE showed defective expression of facilitative glucose transporters GLUT-3 and GLUT-6, which led to increased intracellular basal lactate and decreased ATP production. In addition, the redox capacity, including intracellular GSH levels and the enzyme activity of glutathione peroxidase (GSH-Px) and γ-glutamyl-transpeptidase (GGT), was decreased in SLE-T. Compared to normal cells, SLE-PMN showed decreased intracellular GSH levels, and GGT enzyme activity was found in SLE-PMN and enhanced expression of CD53, a coprecipitating molecule for GGT. We conclude that deranged cellular bioenergetics and defective redox capacity in T and PMN are responsible for cellular immune dysfunction and are related to increased oxidative stress in active SLE patients

Urinary Neutrophil Gelatinase-Associated Lipocalin Is a Potential Biomarker for Renal Damage in Patients with Systemic Lupus Erythematosus

Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a novel biomarker in acute and chronic kidney disease. We hypothesized that 24-hour urinary NGAL excretion may be a predictor for renal damage in patients with systemic lupus erythematosus (SLE). Thirty-four SLE patients with renal involvement (SLE-renal group), 8 SLE patients without renal involvement (SLE-nonrenal group), 14 patients with non-SLE autoimmune diseases (disease control or DC group), and 12 healthy volunteers (normal control or NC group) were compared for 24-hour urinary excretion of NGAL and different cytokines. We found that the 24-hour urinary NGAL excretion in the SLE-renal group was higher than that in the SLE-non-renal, DC, and NC groups. However, the excretion of interleukin-10, transforming growth factor-β1, and tumor necrosis factor-α was not different between the SLE-renal and SLE-non-renal groups. Furthermore, NGAL excretion in the SLE-renal group was correlated with serum creatinine levels and creatinine clearance, but not with the SLE Disease Activity Index score. Multivariate logistic regression analysis and receiver operating characteristic curve analysis revealed that 24-hour urinary NGAL excretion is a potential biomarker for renal damage in SLE patients, with higher sensitivity and specificity than anti-dsDNA antibody titers

Hydrocephalus in an Elderly Man with Systemic Lupus Erythematosus

A 71-year-old man presented with quadriplegia, seizures, dysarthria, motor aphasia and urinary incontinence lasting for several years. The development of proteinuria and increased susceptibility to infections brought the physician's attention to possible underlying autoimmune diseases. Laboratory investigations revealed evidence for systemic lupus erythematosus (SLE) and antiphospholipid syndrome. Imaging studies showed obstructive hydrocephalus. Several courses of methylprednisolone therapies followed by maintenance therapy with low-dose steroid, ventriculoperitoneal shunt, and antihypertensives improved the proteinuria and dysarthria but not the urinary incontinence or dementia. A thromboembolic event in the central nervous system secondary to phospholipid antibodies or lupus activity may represent a pathogenetic basis for hydrocephalus. When encountering a patient with hydrocephalus but without apparent predisposing factors, it is always important to include SLE as a differential diagnosis

Tamm–Horsfall Protein is a Potent Immunomodulatory Molecule and a Disease Biomarker in the Urinary System

Tamm–Horsfall protein (THP), or uromodulin (UMOD), is an 80–90-kDa phosphatidylinositol-anchored glycoprotein produced exclusively by the renal tubular cells in the thick ascending limb of the loop of Henle. Physiologically, THP is implicated in renal countercurrent gradient formation, sodium homeostasis, blood pressure regulation, and a defense molecule against infections in the urinary system. Investigations have also revealed that THP is an effective binding ligand for serum albumin, immunoglobulin G light chains, complement components C1 and C1q, interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and interferon-γ through its carbohydrate side chains for maintaining circulatory and renal immune homeostasis. Thus, THP can be regarded as part of the innate immune system. UMOD mutations play crucial roles in congenital urolithiasis, hereditary hyperuricemia/gout, and medullary cystic kidney diseases. Recent investigations have focused on the immunomodulatory effects of THP on immune cells and on THP as a disease biomarker of acute and chronic kidney diseases. Our studies have suggested that normal urinary THP, through its epidermal growth factor (EGF)-like domains, binds to the surface-expressed EGF-like receptors, cathepsin G, or lactoferrin to enhance polymorphonuclear leukocyte phagocytosis, proinflammatory cytokine production by monocytes/macrophages, and lymphocyte proliferation by activating the Rho family and mitogen-activated protein kinase signaling pathways. Furthermore, our data support both an intact protein core structure and carbohydrate side chains are important for the different protein-binding capacities of THP. Prospectively, parts of the whole THP molecule may be used for anti-TNF-α therapy in inflammatory diseases, autoantibody-depleting therapy in autoimmune disorders, and immune intensification in immunocompromised hosts

Severe Vaso-occlusive Retinopathy as the Primary Manifestation in a Patient with Systemic Lupus Erythematosus

Severe vaso-occlusive retinopathy as the initial manifestation of systemic lupus erythematosus (SLE) is rare. We report a 16-year-old female who developed bilateral visual impairment. Fundus examinations showed bilateral “cherry-red spot” appearance, multiple confluent cotton wool spots, and widespread arterial occlusion. Laboratory studies showed leukopenia, antinuclear antibody (+), and anti-double-stranded DNA antibody (+). Malar rashes, oral ulcers, and bilateral knee joint tenderness were noted during physical examination. SLE was diagnosed and pulse therapy started immediately. Best corrected visual acuity of the left eye improved to 6/10 after treatment. However, there was no visual improvement in the right eye. Four months later, bilateral panretinal laser photocoagulation was performed due to retinal neovascularization. However, tractional retinal detachment of the right eye and vitreous hemorrhage of the left eye still occurred. After undergoing cryoretinopexy of the right eye and intravitreous tissue plasminogen activator injection of the left eye, the visual acuity of the patient's right eye remained hand movement only at 10 cm, but that of the left eye returned to 6/10. The ocular and systemic conditions were stable in the follow-up period of more than 2 years. This case demonstrates that in patients with severe vaso-occlusive retinopathy, a generalized immunological disorder, like SLE, should be suspected

Semaphorin 3A in Ankylosing Spondylitis

Background/Purpose: To determine serum semaphorin 3A (Sema 3A) levels in ankylosing spondylitis (AS). Methods: Serum Sema 3A was measured in 46 AS patients and 30 healthy controls (HCs). For the patients, we recorded demographic data, disease activity, functional index & global assessment, detected human leukocyte antigen-B27 (HLA-B27), and measured erythrocyte sedimentation rate (ESR) & C-reactive protein (CRP). Results: Sema 3A was higher in AS patients than in HCs (3.98 ± 2.57 vs. 1.34 ± 0.48 ng/ml, p = 0.013). Area under the curve (AUC) of standard receiver operating characteristic (ROC) has suggested that Sema 3A > 2 ng/ml is better to predict the higher Bath Ankylosing Spondylitis Disease Activity Index (BASDAI, > 4) than ESR or CRP. There were good correlations between higher Sema 3A and uveitis, Schöber's test, as well as interstitial lung disease. AS patients undergoing anti-tumor necrosis factor therapies for 3 months exhibited a positive correlation of change in Sema 3A (ΔSema 3A) with disease activity fluctuation [ΔBASDAI, ΔBath Ankylosing Spondylitis Functional Index (BASFI) and ΔBath Ankylosing Spondylitis - Global score (BAS-G)]. Conclusion: Serum Sema 3A level was increased in AS patients and was inversely correlated to Schöber's test. Serum Sema 3A is better as a bio-marker than ESR or CRP to correlate with high disease activity in AS patients, and it is also a good indicator for monitoring disease activity and functional status during anti-TNF treatment. Also, Sema 3A may be taken as a predictor for extra-articular presentations in AS, but this needs further study to elucidate. Keywords: Ankylosing spondylitis, Semaphorin 3A, Osteoimmunology, Bone remodeling, Biomarke

Improvement of Active Rheumatoid Arthritis After Etanercept Injection: A Single-center Experience

To study the clinical effectiveness and adverse reactions of etanercept in patients with active rheumatoid arthritis (RA), in whom combination therapies with disease-modifying antirheumatic drugs (DMARDs) had failed. Methods: One hundred and thirty-three patients with active RA who had been treated without satisfactory effect with DMARDs were entitled, by the Taiwan Bureau of National Health Insurance, to undergo etanercept injection (25 mg subcutaneously, twice weekly) along with oral methotrexate (15 mg weekly) in Taipei Veterans General Hospital. The disease activity score in 28 swollen and 28 tender joints (DAS28), erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), rheumatoid factors (RFs), tender joint count (TJC), and swollen joint count (SJC) were recorded at the beginning, 3, 6, 9, and 12 months after treatment. Any adverse event, relevant or irrelevant to the therapy, was recorded throughout the whole course of treatment. Results: Ninety-four patients completed the 1-year therapeutic program. There were significant improvements in all parameters (DAS28, ESR, CRP, TJC and SJC), which approached satisfactory values at the end of the first 3 months and which were sustained thereafter in most patients. Patients also tolerated the treatment protocol well, with adverse events occurring sporadically. Significant clinical response occurred as early as 3 months after the start and might last beyond 1 year in some patients. Adverse effects such as injection site reaction or infections rarely occurred. Conclusion: Combination therapy with etanercept and DMARDs seemed to be effective at improving the aching symptoms associated with rheumatoid activity and was well tolerated in this cohort study. It was generally safe, though a small number of non-fatal infections were observed

Efficacy of isoniazid salvage therapy for latent tuberculosis infection in patients with immune-mediated inflammatory disorders – A retrospective cohort study in Taiwan

Background: Active tuberculosis (TB) in patients with latent tuberculosis infection (LTBI) was associated with use of biological agents for immune-mediated inflammatory disorders (IMIDs). For decreasing active TB, isoniazid prophylaxis therapy was administered before biologic therapy among IMID patients with LTBI. However, for patients who had been received biologics for a long time with unknown status of LTBI or exposure history of active TB, the prevalence of LTBI and efficacy of isoniazid therapy were unclear. Method: A retrospective cohort study was conducted during 2012–2014 in a tertiary medical center in Taiwan, and the incidence case of active TB was identified by the national TB registration system on October 1, 2015. Results: All 382 patients with 1532 person-years were followed up, the initial prevalence of LTBI by positive interferon-gamma releasing assay (IGRA+) was 17.5%. The prevalence of LTBI was increased in elder age (>20%, p  0.05). Conclusion: Isoniazid therapy can prevent active TB from LTBI despite of the timing of biologics administration. Keywords: DMARD, Isoniazid, Tuberculosi