miR-19b-3p and miR-20a-5p are associated with the levels of antiphospholipid antibodies in patients with antiphospholipid syndrome.

Monocytes play a key role in pathophysiology of antiphospholipid syndrome (APS), nevertheless it is unclear if microRNA expression is associated with particular APS features. Identify whether miR-19b-3p and miR-20a-5p expression in monocytes are associated with hallmarks of the APS. Fifty-seven APS patients and 18 healthy controls were studied. Expression of miR-19b-3p and miR-20a-5p was measured in monocytes by RT-qPCR. Both miR-19b-3p (AUC = 0.835, 95% CI 0.733-0.938; P < 0.001) and miR-20a-5p (AUC = 0.857, 0.757-0.957; P < 0.001) discriminated APS patients from healthy individuals. A cut-off point of 1.98 for miR-19-3p and 2.18 for miR-20a-5p showed that APS patients with low microRNA expression had higher levels of IgM and IgG anticardiolipin antibodies than patients with high microRNA expression. In addition, APS patients with low microRNA expression had higher IgG anti-ß2 glycoprotein I antibody levels than their counterparts with high microRNA expression. Finally, miR-19b-3p and miR-20a-5p expression levels were significantly higher in APS patients using oral anticoagulants. Monocyte expression of miR-19b-3p and miR-20a-5p is low in APS, and patients with the lowest microRNA expression presented the highest levels of antiphospholipid antibodies.

The presence of IFL3/4 rs12979860 C allele influences the in vitro IP-10 production by mononuclear cells from patients with systemic lupus erythematosus.

OBJECTIVE: To explore whether the IFNL3/4 rs12979860 genotype may influence serum levels or production of interferon-inducible protein-10 (IP-10) by peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE). METHODS: Sixty-six patients with SLE and 22 healthy blood donors (controls) were included. The IFNL3/4 rs12979860 polymorphism was genotyped by real-time polymerase chain reaction. IP-10 levels in sera supernatants of IFNα stimulated peripheral blood mononuclear cells were measured by enzime-linked immunosorbent assay. RESULTS: Allelic frequencies were CC (29%), CT (52%) and TT (20%) in SLE, and CC (32%), CT (41%) and TT (27%) in healthy controls. Median serum IP-10 levels were higher in SLE patients than in controls (190.8 versus 118.1 pg/ml; p < 0.001), particularly in those with high disease activity (278.5 versus 177.2 pg/ml; p = 0.037). However, serum IP-10 levels were not influenced by IFNL3/4 genotypes. Higher IP-10 production by peripheral blood mononuclear cells was found in both SLE patients (median 519.3 versus 207.6 pg/ml; p = 0.012) and controls (median 454.0 versus 201.7 pg/ml; p = 0.034) carrying the IFNL3/4 C allele compared with carriers of the T allele. CONCLUSIONS: Although IFNL3/4 rs12979860 allele C does not appear to influence serum IP-10 levels in SLE, it plays an important role in the production of IP-10 by peripheral blood mononuclear cells after IFNα stimulation.

Levels of anti-Müllerian hormone in premenopausal women with the antiphospholipid syndrome and its association with the risk of clinical complications.

OBJECTIVE: The study aims to investigate the ovarian reserve in premenopausal women with antiphospholipid syndrome (APS) and to evaluate whether it is associated with cumulative organ damage or the risk of clinical complications. METHODS: This single-center study was conducted in 23 premenopausal female patients (10 with primary APS and 13 with secondary APS) and 24 healthy volunteers. Serum anti-Müllerian hormone (AMH) levels were measured by enzyme-linked immunoassay. Disease-specific organ damage (DIAPS score) and the risk of clinical complications (aGAPSS score) were additionally evaluated in APS patients. RESULTS: Serum AMH levels were similar in APS patients (median 6.06, interquartile range 4.31-7.54 ng/ml) and in controls (4.87, 2.64-6.40 ng/ml; P = 0.116), and no differences were observed between the primary (6.60, 5.49-8.88 ng/ml) and secondary (6.06, 3.91-7.30 ng/ml; P = 0.532) forms of the syndrome. In individuals with APS, serum AMH levels correlated inversely with the aGAPSS score (rho-0.421, 95% confidence intervals -0.716 to -0.001; P = 0.045), while no associations were observed with the DIAPS score (rho-0.001, -0.423 to 0.422; P = 0.996). CONCLUSIONS: Ovarian reserve is not reduced in premenopausal women with APS. In addition, serum AMH levels may reflect the risk of APS-related clinical complications but not the burden of disease-specific organ damage.

An imbalance in the T-helper phenotypes displayed by senescent CD4+CD28null T cells is associated with erosive arthritis (rhupus syndrome) in systemic lupus erythematosus.

OBJECTIVE: The objective was to assess the proportion of Th1, Th2 and Th17 phenotypes in senescent CD4+CD28null cells from patients with systemic lupus erythematosus (SLE) and its association with the pattern of joint involvement. METHODS: This cross-sectional study was performed in SLE patients with erosive arthritis (rhupus) or nondeforming, nonerosive arthritis. Total CD4+CD28null cells as well as the proportion of these cells expressing T-bet, GATA3 or RORγt were analyzed by color-flow cytometry. Serum osteopontin levels were measured by ELISA. RESULTS: Eighteen SLE patients (nine with rhupus and nine with nonerosive arthritis) were studied. The percentage of CD4+CD28null/CD4+ cells (17.7%, 10.3-25.0% versus 9.4%, 8.1-22.4%; P = 0.386) as well as the osteopontin levels (5800, 5,134-5995 pg/ml versus 5578, 5171-5717 pg/ml; P > 0.05) were similar in both groups. A higher percentage of CD4+CD28nullT-bet+ cells (42.8%, 33.5-53.4% versus 30.0%, 23.3-34.2%) but a lower percentage of CD4+CD28nullGATA3+ cells (3.1%, 1.7-5.6% versus 6.2%, 2.6-18.4%) was observed in patients with rhupus than in their counterparts ( P = 0.016). The frequency of CD4+CD28nullRORγt+ cells was similar between groups. CONCLUSIONS: In patients with rhupus, senescent CD4+CD28null cells are preferentially polarized to a Th1 phenotype, whereas this is partial towards Th2 in lupus patients with a nonerosive arthritis pattern.

Levels of uric acid may predict the future development of pulmonary hypertension in systemic lupus erythematosus: a seven-year follow-up study.

OBJECTIVE: The objective of this paper is to assess whether pulmonary hypertension (PH) may be detected at one point in time or longitudinally predicted by serum uric acid (sUA) levels in systemic lupus erythematosus (SLE). METHODS: We conducted a post-hoc analysis of a long-term followed cohort of Mexican SLE patients. Echocardiography-based definitions of PH by the ESC/ERS/ISHLT and its associations with clinical and laboratory data on enrollment were studied. Especially, the impact that sUA levels at baseline may have on the future development of PH in patients with normal pulmonary artery systolic pressure (PASP) was explored. RESULTS: Out of the 156 SLE patients originally enrolled in the cohort, 44 met the inclusion criteria for the present study and were grouped as having (n =10) or not having (n = 34) PH. At baseline, sUA levels of 5.83 ± 1.79 and 5.82 ± 1.97 mg/dl (p = ns) were found in patients with and without PH, respectively. No association between PASP and other markers was found. In patients with normal PASP, the presence of sUA ≥ 7 mg/dl at baseline predicted future development of PH (relative risk 8.5, 1.0009 to 72; p = 0.04). CONCLUSION: In SLE, sUA levels at one point in time are useless to detect PH. However, steady hyperuricemia may predict the future development of PH in patients with normal PASP at baseline.

Antinuclear antibodies detected by Enzyme-Linked Immunosorbent Assay (ELISA) in severe COVID-19: clinical and laboratory associations.

OBJECTIVE: Antinuclear antibodies (ANA) are detected in approximately a quarter of COVID-19 patients when assessed by indirect immunofluorescence. Since there is no information, our study investigated the presence of ANA detected by Enzyme-Linked Immunosorbent Assay (ELISA) and its clinical and laboratory associations. PATIENTS AND METHODS: A longitudinal study was conducted on 92 patients with severe COVID-19, 20 patients with acute myocardial infarction, and 25 healthy subjects. Blood samples were obtained at hospital admission. Commercial ELISA was used to detect ANA, while flow cytometry was used to measure serum interferons. RESULTS: ANAs were positive in 8.6% of COVID-19 patients, 10% of myocardial infarction patients, and 4% in healthy individuals (p=0.676). COVID-19 patients with ANA+ had less ferritin, troponin, and neutrophils but more albumin and lymphocytes than ANA- patients. Serum levels of type I, II, and III interferons were similar between groups. At follow-up, all ANA+ patients survived, while mortality was significant in ANA- patients (0 vs. 36%; p=0.048). CONCLUSIONS: ANA detection is not increased in severe cases of COVID-19 when assessed by ELISA. However, its presence appears to be associated with a less aggressive disease phenotype, regardless of circulating levels of interferons.

Enhanced survival from CLP-induced sepsis following late administration of low doses of anti-IFNγ F(ab')2 antibody fragments.

OBJECTIVE: To assess the impact of different doses of anti-interferon gamma (anti-IFNγ) F(ab')2 fragments, administered prophylactically, on survival and on serum concentration of cytokines in a murine model of sepsis induced by cecal ligation and puncture (CLP). We further explore the impact of therapeutic administration of the most protective dose on survival. SUBJECTS AND TREATMENT: Balb/c mice were prophylactically treated by the intraperitoneal route with anti-IFNγ initiated 2 h before CLP and every 24 h for a total of five times in each of the following doses: 0.01, 0.1, or 1 mg/kg. Sham and control groups received sterile saline solution in a similar scheme. METHODS: Serum tumor necrosis factor (TNF), interleukin (IL)-1ß, IL-6, IL-10 and IFNγ were measured at 3, 24 and 48 h after CLP by ELISA. Survival curves were compared using a Mantel-Haenzel method. RESULTS: Significant prophylactic protection was found only with 0.01 mg/kg, in association with regulation of IL-1ß and IL-10 concentrations. As therapy, anti-IFNγ fragments were protective only when initiated 24 h after CLP. CONCLUSIONS: Delicate modulation of IFNγ at the correct timing, even when the septic process has begun, is an exciting alternative to explore in the treatment of sepsis.

The potential role of microRNAs as biomarkers in atopic dermatitis: a systematic review.

OBJECTIVE: Reliable biomarkers are required for clinical use in atopic dermatitis (AD). MicroRNAs are mediators of post-transcriptional gene silencing, and specific expression patterns are being characterized in AD. To assess whether microRNAs could be useful biomarkers for clinical use in patients with AD. MATERIALS AND METHODS: Systematic review of all articles identified in SCOPUS and PubMed through the PRISMA statement. Literature was summarized in narrative form and results are presented per category. RESULTS: From a total of 118 identified references 11 manuscripts were included for qualitative analysis, after selecting them according to the eligibility criteria. An aberrant expression of microRNAs characterizes AD, which facilitates T cell polarization towards a Th17 phenotype, especially miR-155. There is also altered regulation of Th1/Th2 phenotypes by overexpression of miR-151a. The aberrant keratinocyte function observed in AD could also be due to altered expression of microRNAs, specifically miR-146a, miR-143 and miR-29. Finally, miR-203 may reflect the extent of inflammation in AD, in parallel with the tumor necrosis factor pathway and immunoglobulin E levels. CONCLUSIONS: MicroRNAs are easily identifiable molecules in a variety of cells and body fluids that may be useful as diagnostic (miR-155 and miR-146a) and disease severity (miR-203) biomarkers in patients with AD.

Potential usefulness of pentoxifylline, a non-specific phosphodiesterase inhibitor with anti-inflammatory, anti-thrombotic, antioxidant, and anti-fibrogenic properties, in the treatment of SARS-CoV-2.

Although most patients with coronavirus disease 2019 (COVID-19) have a good prognosis, in some cases, the disease progresses rapidly, and the mortality rate is high. Some evidence suggests that infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produces a 'cytokine storm', which is related to acute respiratory distress syndrome or multi-organ dysfunction leading to physiological deterioration and death. It is important to highlight the state of hypercoagulability that can be triggered, involving microvascular thrombosis and vascular occlusive events, which are relevant to such poor outcomes. At present, no specific antiviral drug or vaccine is available for SARS-CoV-2 infection, and current research is aimed at preventing and mitigating damage to the target organs, mainly the lungs. In seeking therapies for patients with COVID-19, immunomodulators, cytokine antagonists and early anti-coagulation therapies have been tested in attempts to reduce the mortality rate. Pentoxifylline, a non-specific phosphodiesterase inhibitor widely used to improve the rheological properties of blood, has beneficial anti-inflammatory properties and can significantly reduce the serum levels of pro-inflammatory cytokines such as interleukin (IL)-6, IL-1, tumour necrosis factor-alpha, C-reactive protein and other immunoregulators. It has also been found to exert anti-thrombotic, antioxidant and anti-fibrogenic actions. These properties could help to prevent or mitigate the inflammatory response and hypercoagulability that develop with SARS-CoV-2 infection, decreasing multi-organ dysfunction manifesting primarily as acute lung injury.

Interleukin-17A enhances the production of CD147/extracellular matrix metalloproteinase inducer by monocytes from patients with psoriasis.

OBJECTIVE: CD147 is the main inducer of extracellular matrix metalloproteinases, which are critically involved in different inflammatory diseases. Our objective was to assess whether in vitro stimulation with Th1 and Th17 cytokines modulate CD147 production in monocytes from psoriasis patients. PATIENTS AND METHODS: Serum CD147 levels were measured in 60 psoriasis patients and 60 healthy controls. Furthermore, CD14+ monocytes were cultured and stimulated with TNF, IFN-g or IL-17A, and CD147 production was measured. RESULTS: Serum CD147 levels were higher in psoriasis patients (median 1866, IQR 1517-2355 pg/mL vs. 1686, 1382-1947 pg/mL; p=0.023), allowing to distinguish between patients and controls (AUC-ROC 0.632 ± 0.0509). Baseline CD147 production was similar in monocytes from patients and controls (1298, 769-1645 pg/mL vs. 1290, 1048-1976 pg/ml, respectively). Stimulation with IL-17A (1638, 1426-2027 pg/mL; p<0.001), but no other cytokine, was associated with increased production of CD147 in monocytes from psoriatic patients. In contrast, none of the cytokines increased CD147 production in monocytes from healthy controls. CONCLUSIONS: CD147 production by activated monocytes is a cytokine-dependent process, specifically by cytokines of the Th17 phenotype instead of those belonging to the Th1 phenotype. CD147 is a novel inflammatory mediator that could be a therapeutic target in psoriasis.

Comparison of the 1999 Sapporo and 2006 revised criteria for the classification of the antiphospholipid syndrome.

OBJECTIVES: The 2006 revised criteria for antiphospholipid syndrome (APS) provide a new classification challenge, and studies validating the updated criteria against the older ones are still scanty. We compared the 1999 preliminary with the 2006 revised classification criteria for APS, and evaluated if the revised criteria provide an added value over the original ones. METHODS: A laboratory-based registry population was obtained on the basis of the positivity of antiphospholipid (aPL) antibodies. Patients were analysed for fulfillment of the 1999 and 2006 classification criteria for APS, non-criteria features of APS, and autoantibody profile. RESULTS: Of 144 aPL-positive identified patients, 119 had at least 2 aPL tests on separated occasions, and were included in this study. According to the 1999 criteria, 23 patients had APS (15 had thrombosis alone, 4 pregnancy morbidity, and 4 both); while 26 fulfilled the 2006 revised criteria (15 had thrombosis alone, 5 pregnancy morbidity, and 6 both). One patient with isolated thrombosis who met 1999 criteria did not meet those of 2006 (aCL positivity but not >12 weeks apart). One patient with thrombosis, other with pregnancy morbidity, and 2 with both only fulfilled the 2006 criteria because they had isolated anti-Beta(2)GPI antibody-positivity. High concordance between criteria was found, with kappa index of 0.87 (95%; CI, 0.76-0.98). CONCLUSIONS: The 2006 revised criteria represent a step-forward since it allows the inclusion of patients with anti-Beta(2)GPI antibodies as an isolated serological feature. However, a wider time interval between serologic tests seems unlikely to make differences.

Erosive arthritis in systemic lupus erythematosus is associated with high serum C-reactive protein and anti-cyclic citrullinated peptide antibodies.

Predictors for erosive arthritis in systemic lupus erythematosus (SLE) are poorly understood. We performed a pilot, descriptive case-series study to identify whether different biomarkers differentiate SLE patients from those additionally developing erosive arthritis. Median C-reactive protein (CRP) concentration in erosive arthritis was 14.5 mg/L (IQR, 6.6-19.4), but only 0.8 (0.45-7.37, p = 0.01) in non-erosive. Anti-cyclic citrullinated peptide antibodies (anti- CCP) were also associated with erosive arthritis (60 vs. 0% , p = 0.02; OR = 18.2, 0.66-495). Serum IL-6, IFNgamma, IL-4 and IL-10 tended to be higher in erosive arthritis, although none attained statistical significance. A negative correlation between IL-6 and CRP was found in non-erosive arthritis ( r-0.60). High CRP and anti-CCP may be useful serological markers for an erosive arthritis pattern among SLE patients.

Kidney involvement in Takayasu arteritis.

OBJECTIVE: To evaluate whether the presence of glomerulonephritis is or is not associated with the extent of arterial wall inflammatory cell infiltrate in Takayasu arthritis (TA). METHODS: Retrospective chart and pathology review of large artery and kidney specimens of TA autopsy cases. Kidney specimens were classified, according to their histopathological findings, in those with specific glomerular entities and those with non-specific, ischemic and/or hypertensive, glomerular changes. A control group of autopsy kidney specimens was utilized for comparison. Morphometric analysis was used to assess the extent of the arterial inflammatory infiltrates; results were compared among the different groups with kidney lesions. RESULTS: We included 25 kidney specimens from 25 autopsies. Specific glomerular entities were present in 14 specimens; 10 (40%) were classified as diffuse mesangial proliferative glomerulonephritis (DMPG [Group A]), and 4 (16%) as other associated glomerulopathies (Group B). Non-specific changes were observed in 11 (44%) specimens (Group C). The arterial inflammatory infiltrate proportion was 9.4 % for group A, 1.4% for group B, and 2.7% for group C. Furthermore, a larger proportion of vascular inflammation was confirmed for group A when compared with the other groups (p<0.05). Group A patients were younger than those in groups B and C (p<0.005) and exhibited shorter disease duration. CONCLUSION: The presence of DMPG was associated with a larger extent of vascular inflammatory cell infiltrate, suggesting a relationship between both phenomena.

Osteopoikilosis in an ancient skeleton: more than a medical curiosity.

We describe the palaeopathologic and radiographic findings of the human skeletal remains that belonged to a female who lived in Mexico's viceroyship period (seventeenth and eighteenth centuries A.D.). Radiographic studies showed numerous, radiodense, ovoid, small and well-defined foci in the long tubular bones, sacrum, scapulae and iliac bones. Computed tomography (CT) examination revealed multiple hyperdense foci located in the central marrow portion of the bones. Measurements of attenuation coefficient revealed +1548 HU. The findings are consistent with osteopoikilosis, an uncommon, benign sclerosing bone dysplasia transmitted in an autosomal dominant fashion, which in the clinical setting is important to set apart from different bone pathologies to avoid unnecessary interventions and treatments. To the best of our knowledge, this is the first report of osteopoikilosis in ancient human remains.

LPS pretreatment by the oral route protects against sepsis induced by cecal ligation and puncture. Regulation of proinflammatory response and IgM anti-LPS antibody production as associated mechanisms.

OBJECTIVE: To explore the efficacy of prophylactic oral lipopolysaccharide (LPS) in sepsis induced by cecal ligation and puncture (CLP). MATERIAL: Male Balb/c mice. LPS serotype O55: B5 TREATMENT: Mice were treated every 4 days for a total of 5 times with 50 mug of LPS by intraperitoneal (IP) or oral (O) routes. Treatment was stopped one week prior to CLP. Control (C) groups received the vehicle orally, and sham (S) groups were used as reference. METHODS: Histopathology was performed to determine inflammation in liver and lung. Serum cytokines were measured by ELISA, and TNFalpha tissue expression by RTPCR. Antibodies against LPS were measured by ELISA. RESULTS: Administration of LPS by the oral route significantly increased survival (p<0.05) of mice in association with a reduction of Kupffer cells in liver, pulmonary edema in lung, shorter or delayed TNFalpha expression in target organs, a trend to decreased IFN gamma and increased IL-10 serum levels, and a notable increase in the production of specific IgM anti-LPS antibodies. CONCLUSIONS: LPS by oral route protected against CLP. The underlying mechanisms could be the modulation of the proinflammatory response and an increased production of IgM anti-LPS antibodies.

Leontiasis ossea: a paleopathologic case report.

We describe the archeological and imaging findings of a unique specimen (skull and mandible) with leontiasis ossea (LO) that is on display in the National Museum of Anthropology and History in Mexico City. The specimen shows diffuse and irregular periosteal bone proliferation, which produces a grossly nodular appearance involving the neurocranium and the facial skeleton. Plain radiography and helical computed tomography revealed generalized hyperostosis obliterating the maxillary and sphenoidal sinuses and 2 exuberant bony masses arising from the maxilla with encroachment of the anterior nasal aperture.Currently, LO is a purely descriptive term applied to a variety of osseous conditions that have in common hyperostosis of craniofacial bones leading to a leonine appearance. Clinicians who see such lionlike facies should consider the main causes of LO, which include renal osteodystrophy, Paget disease and, as most likely in this specimen, fibrous dysplasia.