Sjögren's syndrome with adult-onset Still's disease: an overlap syndrome?

Adult-onset Still's disease (AOSD) is a rare systemic auto-inflammatory disease that is an exclusive diagnosis that needs to previously exclude infections, tumors, and rheumatic diseases. There are few reports on AOSD overlapping with other rheumatic diseases. We reported a 55-year-old male who presented with a high, daily spiking fever associated with an evanescent salmon-pink rash, arthralgia, and sore throat. He had a history of dryness of the mouth and eyes for decades with no medical treatment. On admission, tests for antinuclear antibody (ANA) and anti-SSA/Ro-52 antibody were positive, and salivary gland biopsy showed focal lymphocytic sialadenitis with a focus score of ≥ 1 foci/4 mm2, which was consistent with a diagnosis of primary Sjögren's syndrome (SS). However, the disease activity of SS was low at the time of the report. Combined with significantly elevated acute phase reactants, the patient also met the classification criteria of both Yamakuchi and Futel for AOSD. His clinical symptoms were relieved quickly with glucocorticoid therapy. We also reviewed the literature on SS with AOSD and AOSD with other rheumatic diseases, and scattered case reports were retrieved. So we think that AOSD is not an absolutely exclusive diagnosis and can occur in patients with other rheumatic diseases. To our knowledge, this is the only literature review of a reported AOSD case in a SS patient.

Repurposing an orally available drug for the treatment of geographic atrophy.

PURPOSE: Chronic oxidative stress and subacute inflammation have been implicated as causes of age-related macular degeneration (AMD). In this study, we tested whether an orally available 5-OH-tryptamine (5HT) 1a receptor agonist, xaliproden, could protect against retinal pigment epithelium (RPE) cell damage in culture and in a mouse model of geographic atrophy. METHODS: Paraquat was used to create mitochondrial oxidative stress in ARPE-19 cells, and tumor necrosis factor-α (TNF-α) was used to stimulate the production of inflammatory cytokines in these cells. The production of antioxidant proteins, metallothionein, and inflammatory cytokines was assayed with quantitative real-time PCR. Cell survival was analyzed with microscopy and a cell titer assay. Integrity of the RPE monolayer was determined by measuring the transepithelial electrical resistance (TEER) and with immunocytochemistry with zona occludens protein 1 (ZO-1) antibody. RPE atrophy was studied in mice deleted for Sod2 (the gene for mitochondrial superoxide dismutase) specifically in the RPE. The mice were treated orally with daily doses of xaliproden at 0.5 and 3 mg/kg for 4 months. The retinal structure was analyzed with spectral domain optical coherence tomography (SD-OCT) and with light and electron microscopy. Retinal function was assessed with full-field electroretinography (ERG) and with optokinetic measurements. RESULTS: Xaliproden led to a dose-dependent increase in cell survival following treatment with paraquat. Synthesis of the antioxidant response genes NqO1, GSTM1, CAT, HO-1, and Nrf2 was increased in response to the drug, as was the zinc chaperone metallothionein. Treatment of cells with TNF-α led to increased production of IL-1ß, IL-6, chemokine (C-C motif) ligand 20 (CCL20), and vascular endothelial growth factor (VEGF) by ARPE-19 cells, and this response was attenuated by treatment with xaliproden. TNF-α also led to a decrease in the TEER that was prevented by treatment with the 5HT1a agonist. Daily gavage with xaliproden at either dose induced the production of protective enzymes in the mouse retina, and treatment of the Sod2-deleted mice with the drug showed improved thickness of the outer nuclear layer and improved visual acuity relative to the control-treated mice. There was no significant difference in full-field scotopic ERG among the treatment groups, however. Vacuolization of the RPE and disorganization of the photoreceptor outer segments were reduced at both dose levels of xaliproden. CONCLUSIONS: Xaliproden protected RPE cells from oxidative and inflammatory insults and protected the mouse RPE and retina from RPE atrophy in the face of excess mitochondrial oxidative stress. These results suggest that this drug, which had a reasonable safety profile in clinical trials, may be used to prevent the progression of geographic atrophy in humans.

Systemic treatment with a 5HT1a agonist induces anti-oxidant protection and preserves the retina from mitochondrial oxidative stress.

Chronic oxidative stress contributes to age related diseases including age related macular degeneration (AMD). Earlier work showed that the 5-hydroxy-tryptamine 1a (5HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) protects retinal pigment epithelium (RPE) cells from hydrogen peroxide treatment and mouse retinas from oxidative insults including light injury. In our current experiments, RPE derived cells subjected to mitochondrial oxidative stress were protected from cell death by the up-regulation of anti-oxidant enzymes and of the metal ion chaperone metallothionein. Differentiated RPE cells were resistant to oxidative stress, and the expression of genes for protective proteins was highly increased by oxidative stress plus drug treatment. In mice treated with 8-OH-DPAT, the same genes (MT1, HO1, NqO1, Cat, Sod1) were induced in the neural retina, but the drug did not affect the expression of Sod2, the gene for manganese superoxide dismutase. We used a mouse strain deleted for Sod2 in the RPE to accelerate age-related oxidative stress in the retina and to test the impact of 8-OH-DPAT on the photoreceptor and RPE degeneration developed in these mice. Treatment of mice with daily injections of the drug led to increased electroretinogram (ERG) amplitudes in dark-adapted mice and to a slight improvement in visual acuity. Most strikingly, in mice treated with a high dose of the drug (5 mg/kg) the structure of the RPE and Bruch's membrane and the normal architecture of photoreceptor outer segments were preserved. These results suggest that systemic treatment with this class of drugs may be useful in preventing geographic atrophy, the advanced form of dry AMD, which is characterized by RPE degeneration.

IgG4-related disease presenting as severely symptomatic hypercalcemia: A case report and review of literature.

Immunoglobulin G4-related disease (IgG4-RD)-associated hypercalcemia has rarely been reported. We report a case of IgG4-RD that presented as severe symptomatic hypercalcemia. A 50-year-old woman with a history of sustained bilateral periorbital swelling and proptosis for more than 5 years presented to our hospital complaining of a 3-day history of significant and progressive nausea, vomiting, loss of appetite, fatigue, and pruritus. She denied a long history of medication. On admission, laboratory tests showed severe hypercalcemia with serum adjusted calcium elevated to 4.34 mmol/L and renal dysfunction with serum creatinine elevated to 206 µmol/L. Urinary calcium excretion was increased. The serum IgG4 subclass was markedly elevated to 22.4 g/L with polyclonal hypergammaglobulinemia. Tests of autoantibodies were all negative. Bone metabolism markers that reflect the activity of osteoblasts and osteoclasts were all significantly elevated. However, the levels of intact parathyroid hormone and 25(OH) vitamin D3 were decreased. B-ultrasonography showed chronic inflammation of bilateral submandibular glands. Neither bone marrow biopsy nor positron emission tomography - computed tomography examination showed evidence of neoplastic diseases. The patient was treated with intravenous saline infusion, loop diuretics, salmon calcitonin, glucocorticoids, and hemodialysis with a good response.

Risk of Hepatitis B Virus Reactivation in Patients with Resolved Infection on Therapy with Corticosteroids and Conventional Synthesis Immunosuppressants for Kidney Disease: A Single-Center Analysis of 258 Patients.

BACKGROUND/AIMS: The risk of hepatitis B virus reactivation in patients with a previously resolved hepatitis B virus infection on therapy with corticosteroids and conventional synthesis immunosuppressants for kidney disease has not been well described. MATERIALS AND METHODS: We performed a retrospective study on the risk of hepatitis B virus reactivation in patients with a previously resolved hepatitis B virus infection on therapy with corticosteroids and conventional synthesis immunosuppressants for kidney disease between January 2012 and December 2021 in the Department of Nephrology at Ruijin Hospital. RESULTS: A total of 258 patients with a previously resolved hepatitis B virus infection [all treated with high-dose corticosteroids, of whom 192 were receiving corticosteroids combined with conventional synthesis immunosuppressant therapy, including cyclophosphamide (155), cyclosporine A (14), mycophenolate mofetil (14), and tacrolimus (9)] were enrolled. During a mean follow-up time of 21.66 months (range 9-70 months), hepatitis B virus reactivation was not observed in these patients. CONCLUSIONS: Among patients with a previously resolved hepatitis B virus infection on therapy with corticosteroids and conventional synthesis immunosuppressants for kidney disease, hepatitis B virus reactivation was not common and severe, suggesting that universal prophylaxis may not be justified or cost-effective in this clinical setting.

Integrating Landscape Ecological Risks and Ecosystem Service Values into the Ecological Security Pattern Identification of Wuhan Urban Agglomeration.

Urban agglomerations are the main form of China's future promotion of new urbanization development. Nevertheless, their accelerated expansion and development are increasingly threatening the security of regional ecosystems. The identification and optimization of ecological safety patterns (ESPs) is the fundamental spatial way to guarantee the ecological safety of urban circles and realize the sustainable development of the socio-economic and ecological environment. Nevertheless, from the perspective of urban green, low-carbon, and ecological restoration, regional safety evaluation still lacks a complete framework integrating ecological elements and social and natural indicators. Moreover, the evaluation method of ESPs also has a lack of judgment on the long-term change dynamics of regional landscape ecological risks and ecosystem service values. Thus, we proposed a new regional ecological security evaluation system based on ecosystem service value (ESV) and landscape ecological risk (LER), using the Wuhan urban agglomeration (WUA) as the research object. This study analyzed LER and ESV's spatial and temporal changes over nearly 40 years from 1980 to 2020. LER and LSV were used as ecological elements combined with natural and human-social elements to jointly model the resistance surface of the landscape pattern. Applying the minimum cumulative resistance model (MCR), we identified green ecological corridors, constructed the ESPs of WUA, and proposed optimization measures. Our results show that: (1) The proportion of higher- and high-ecological-risk areas in WUA has decreased from 19.30% to 13.51% over the past 40 years. Over time, a "low-high-low" hierarchical distribution characteristic centered on Wuhan city was gradually formed in the east, south, and north; the total value of ecosystem services increased from CNY1110.998 billion to CNY1160.698 billion. The ESV was higher in the northeastern, southern, and central parts of the area. (2) This study selected 30 ecological source areas with a total area of about 14,374 km2 and constructed and identified 24 ecological corridors and 42 ecological nodes, forming a multi-level ecological network optimization pattern with intertwined points, lines, and surfaces, increasing the connectivity of the ecological network and improving the ecological security level of the study area to a large extent, which is of great significance to promote the ecological priority and green-rise strategy of WUA and the high-quality development path of the green ecological shelter.

The value of the neutrophil to lymphocyte ratio and PLT count for the diagnosis and prediction of COVID-19 severity.

BACKGROUND: COVID-19 and influenza A can cause severe respiratory illness. Differentiating between the two diseases and identifying critically ill patients in times of epidemics become a challenge for frontline medical staff. We sought to investigate whether both diseases and their severity could be recognized by routine blood parameters. METHODS: Our retrospective study analysed the clinical data and first-time routine blood parameters of 80 influenza A patients and 123 COVID-19 patients. COVID-19 patients were divided into three groups according to treatment modalities and outcomes: outpatient group, inpatient without invasive mechanical ventilation (IMV) group, and inpatient with IMV group. We used the Mann-Whitney and Kruskal-Wallis tests to analyze the differences in routine blood parameters between the two or three groups. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to assess the diagnostic accuracy. RESULTS: Compared with outpatient influenza A patients, outpatient COVID-19 patients had a higher neutrophil to lymphocyte ratio (NLR) (6.63 vs 3.55). ROC analysis showed that the NLR had a high diagnostic value for differentiating COVID-19 from influenza A (AUC = 0.739). The best cut-off point of the NLR was 6.48, the diagnostic sensitivity was 0.523, and the specificity was 0.925. The median platelet (PLT) count in the different COVID-19 groups was as follows: outpatient group (189×109/L), inpatient without IMV group (161×109/L), and inpatient with IMV group (94×109/L). Multivariate logistic regression analysis found a significant association between PLT and treatment modality and outcome in COVID-19 patients (p<0.001). CONCLUSIONS: NLR can be used as a potential biological indicator to distinguish COVID-19 and influenza A. Decreased PLT predicts the critical condition of COVID-19 patients and helps stratify the treatment of COVID-19 patients.

Idiopathic multicentric Castleman disease with pulmonary and cutaneous lesions treated with tocilizumab: A case report.

BACKGROUND: Human herpes virus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder driven by proinflammatory cytokines, which is still poorly understood. Pulmonary parenchyma lesion is a rare condition in iMCD, which mainly manifests as lymphocytic interstitial pneumonia and is an indicator of severe iMCD. Cutaneous lesion is also very rare and mainly occurs in Asians. There have been few reports of iMCD patients with both skin and lung parenchyma involvement. CASE SUMMARY: We present a Chinese man who complained about a 3-year history of intermittent dry cough and a 2-year history of diffuse reddish-brown maculopapules. Laboratory examination revealed polyclonal hypergammaglobulinemia and hypercytokinemia including interleukin 6. Chest computed tomography revealed small patchy shadows with ground-glass nodules scattered in two lobes and mediastinal lymphadenopathy. The pathological result of the lymph node was consistent with the plasma cell type of Castleman disease. As serum human immunodeficiency virus test and HHV-8 staining of the lymph node were negative, the patient was finally diagnosed with HHV-8 negative iMCD. He was treated with tocilizumab at an intravenous (i.v.) dose of 8 mg/kg every 2 wk combined with methylprednisolone at an i.v. dose of 80 mg/d initially with gradual dose tapering. Partial remission was achieved 9 mo later. CONCLUSION: iMCD with lung parenchyma and skin involvement is a rare condition that requires clinicians' attention and awareness for early diagnosis.

A Cohort Study of Liver Involvement in Patients With Adult-Onset Still's Disease: Prevalence, Characteristics and Impact on Prognosis.

Objective: Adult-onset Still's disease (AOSD) is a systemic disorder commonly accompanied by liver involvement. This study aims to illustrate the detailed information of liver abnormalities in patients with AOSD and evaluate the impact on the prognosis. Methods: A total number of 128 hospitalized patients, who met the Yamaguchi criteria of AOSD in the Department of Rheumatology and Immunology, Ruijin Hospital from July 2016 to August 2019 were consecutively enrolled and followed up. The demographic characteristics, clinical features, laboratory tests, treatments and prognosis were recorded. Correlations of liver function tests (LFTs) with disease activity and laboratory parameters were analyzed by the Spearman test. Risk factors of the refractory AOSD were evaluated by multivariate logistic regression analysis. Results: Liver involvement was presented in 104 (81.3%) patients with AOSD. We observed that 34 (32.7%) patients were with mild elevation, 32 (30.8%) patients were with moderate elevation, and 38 (36.5%) patients were with severe elevation. The majority of elevated ALT, AST and ALP decreased to normal within the range of 2 months, except for GGT. Furthermore, the LFTs were found significantly correlated with disease activity. Besides, we found patients with higher levels of LFTs tended to require more intensive treatments and suffered from poorer prognosis. Multivariate logistic regression analysis showed ALP ≥ 141 IU/L and GGT ≥ 132 IU/L are independent risk factors of refractory AOSD. Conclusion: Liver involvement is common in patients with AOSD, the levels of LFTs are associated with disease activity and related to the treatment strategies and prognosis.

Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential.

PURPOSE: Safety and efficiency are critical for successful gene therapy. Adeno-associated viral (AAV) vectors are commonly used for gene transfer in both human and animal studies. However, administration of AAV vectors can lead to development of neutralizing antibodies against the vector capsid, thus decreasing the efficiency of therapeutic gene transfer and preventing effective vector readministration. We investigated immune responses to different routes of ocular administration and readministration of AAV vectors, and the effect of previous exposure of AAV vector in one eye on the transduction efficacy of subsequent intraocular AAV-mediated gene delivery to the partner eye. METHODS: We tested two vector systems. One contained a cDNA encoding a secreted pigment epithelial derived factor (PEDF) cDNA under the control of a Cytomegalovirus (CMV) enhancer and chicken beta-actin promoter (CBA; AAV2-CBA-PEDF) and was tested in a murine model of laser-induced choroidal neovascularization (CNV). The other vector contained a cDNA encoding the intracellular reporter green fluorescent protein (GFP) under the control of the same promoter (AAV2-CBA-GFP). Animals were divided into groups and received sequential injections at different combinations of either intravitreal or subretinal routes. CNV was evaluated by fluorescein angiographic choroidal flat-mount image analysis. The expression of GFP was analyzed in retinal sections by direct fluorescence imaging. Antibodies against AAV2 capsid and transgenes were analyzed by ELISA using serum samples collected before injection and different time points after the injection. Neutralizing antibodies were characterized by in vitro assays. RESULTS: Various ocular compartments responded to AAV administration differently. Intravitreal administration of AAV vectors, which resulted in transduction of inner retina (primarily retinal ganglion cells), generated a humoral immune response against AAV capsid that blocked vector expression upon readministration via the same route into the partner eye. In contrast, it had no effect on vector readministered into the subretinal space of the partner eye. Additionally, subretinal administration of vector did not trigger any humoral immune response against AAV capsid, and had no effect on subsequent administration of vector either intravitreally or subretinally into the partner eye. CONCLUSIONS: These findings have important clinical implications for the design of AAV-mediated ocular gene transfer for retinal diseases, particularly if both eyes require sequential treatment.

Daily zeaxanthin supplementation prevents atrophy of the retinal pigment epithelium (RPE) in a mouse model of mitochondrial oxidative stress.

Oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). The dry form of AMD (geographic atrophy) is characterized by loss of RPE, photoreceptors, and macular pigments. The cumulative effects of oxidative stress impact mitochondrial function in RPE. In Sod2flox/floxVMD2-cre mice, the RPE specific deletion of Sod2, the gene for mitochondrial manganese superoxide dismutase (MnSOD), leads to elevated oxidative stress in retina and RPE, and causes changes in the RPE and underlying Bruch's membrane that share some features of AMD. This study tested the hypothesis that zeaxanthin supplementation would reduce oxidative stress and preserve RPE structure and function in these mice. Zeaxanthin in retina/RPE/choroid and liver was quantified by LC/MS, retinal function and structure were evaluated by electroretinogram (ERG) and spectral domain optical coherence tomography (SD-OCT), and antioxidant gene expression was measured by RT-PCR. After one month of supplementation, zeaxanthin levels were 5-fold higher in the retina/RPE/choroid and 12-fold higher in liver than in unsupplemented control mice. After four months of supplementation, amplitudes of the ERG a-wave (function of rod photoreceptors) and b-wave (function of the inner retina) were not different in supplemented and control mice. In contrast, the c-wave amplitude (a measure of RPE function) was 28% higher in supplemented mice than in control mice. Higher RPE/choroid expression of antioxidant genes (Cat, Gstm1, Hmox1, Nqo1) and scaffolding protein Sqstm1 were found in supplemented mice than in unsupplemented controls. Reduced nitrotyrosine content in the RPE/choroid was demonstrated by ELISA. Preliminary assessment of retinal ultrastructure indicated that supplementation supported better preservation of RPE structure with more compact basal infoldings and intact mitochondria. We conclude that daily zeaxanthin supplementation protected RPE cells from mitochondrial oxidative stress associated with deficiency in the MnSOD and thereby improved RPE function early in the disease course.

Timing of Antioxidant Gene Therapy: Implications for Treating Dry AMD.

Purpose: To investigate whether antioxidant gene therapy protects the structure and function of retina in a murine model of RPE atrophy, and to determine whether antioxidant gene therapy can prevent degeneration once it has begun. Methods: We induced mitochondrial oxidative stress in RPE by conditional deletion of Sod2, the gene for manganese superoxide dismutase (MnSOD). These mice exhibited localized atrophy of the RPE and overlying photoreceptors. We restored Sod2 to the RPE of one eye using adeno-associated virus (AAV) by subretinal injection at an early (6 weeks) and a late stage (6 months), injecting the other eye with an AAV vector expressing green fluorescent protein (GFP). Retinal degeneration was monitored over a period of 9 months by electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT). Immunohistochemical and histologic analyses were conducted to measure oxidative stress markers and to visualize retinal structure. Results: One month after delivery, the AAV-Sod2 injection resulted in production of MnSod in the RPE and negligible expression in the neural retina. Electroretinography and OCT suggested no adverse effects due to increased expression of MnSOD or subretinal injection. Decrease in the ERG response and thinning retinal thickness was significantly delayed in eyes with early treatment with the Sod2 vector, but treatment at 6 months of age did not affect the ERG decline seen in these mice. Conclusions: We conclude that antioxidant gene therapy may be effective in preventing the detrimental effects of oxidative stress, but may not be beneficial once substantial tissue damage has occurred.

Diabetic eNOS-knockout mice develop accelerated retinopathy.

PURPOSE: Dysfunction of endothelial nitric oxide synthase (eNOS) has been implicated in the pathogenesis of diabetic vascular complications. This study was undertaken to determine the role of eNOS in the development of diabetic retinopathy (DR), by investigating the functional consequences of its deficiency in the diabetic state. METHODS: Diabetes was induced in eNOS-knockout (eNOS(-/-)) and C57B/6 mice by streptozotocin (STZ) injection. Retinal vasculature was evaluated by albumin extravasation, to quantitatively measure vascular permeability, and by trypsin-digested retinal vascular preparations, to quantify acellular capillaries. Gliosis was evaluated by immunofluorescent techniques. Retinal capillary basement membrane thickness was assessed by transmission electron microscopy. Total retinal nitric oxide level was assessed by measuring nitrate/nitrite using a fluorometric-based assay, iNOS expression was examined by real-time PCR. RESULTS: Diabetic eNOS(-/-) mice exhibit more severe retinal vascular permeability than age-matched diabetic C57BL/6 mice, detectable as early as 3 weeks after diabetes induction. Diabetic eNOS(-/-) mice also show earlier onset and an increased number of acellular capillaries, sustained gliosis, and increased capillary basement membrane thickness. Total nitric oxide (NO) level was also increased, concomitant with elevated iNOS expression in diabetic eNOS(-/-) retina. CONCLUSIONS: Diabetic eNOS(-/-) mice exhibit A significantly wider range of advanced retinal vascular complications than the age-matched diabetic C57BL/6 mice, supporting the notion that eNOS-derived NO plays an essential role in retinal vascular function. This mouse model also faithfully replicates many of the hallmarks of vascular changes associated with human retinopathy, thus providing a unique model to aid in understanding the pathologic mechanisms of and to develop effective therapeutic strategies for diabetic retinopathy.