Anaphylaxis: Mediators, Biomarkers, and Microenvironments.

The life-threatening nature of anaphylactic reactions has increased interest in discovering new biomarkers that could improve diagnosis and prevention. However, the diverse nature of the clinical features and the etiology and pathogenesis of anaphylaxis hinder the identification of valuable molecular indicators of disease. Most studies on anaphylaxis focus on the immune system. Anaphylactic reactions are characterized primarily by IgE-mediated activation of mast cells and basophils and release of mediators. Determination of serum tryptase levels is the main in vitro test used to confirm the reaction, although there are no biomarkers that can predict it. Nevertheless, recent research has postulated that alternative pathways, cell types, and systems are involved. Consequently, various molecular products have been explored and considered potential biomarkers, although none of them are yet used in clinical practice. The products that are altered in patients with anaphylaxis include vasoactive agents, proteases, proteoglycans, lipids, interleukins, cytokines, products of the complement-contact and coagulation systems, circulating proteins, extracellular vesicles, microRNAs, and metabolites. The recognition of biological processes and molecular pathways affecting the microenvironments involved in anaphylaxis will considerably improve clinical practice and the identification of better molecular markers. We offer a broad review of the various mediators described in anaphylaxis, consider their usefulness as potential biomarkers of this pathological event, and examine their role in the molecular basis of the reaction.

Serum P-glycoprotein level: a potential biomarker of DMARD failure in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥ 6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 < 3.2; and (2) patients without a response to DMARDs, with persistent DAS28 ≥ 3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression. RESULTS: Serum P-gp levels were significantly higher in RA patients (n = 151) than in the controls (n = 30) (158.70 ± 182.71 ng/mL vs. 14.12 ± 8.97 ng/mL, p < 0.001). The P-gp level was correlated with the DAS28 score (r = 0.39, p < 0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206 ± 21.47 ng/mL vs 120.60 ± 15.70 ng/mL; p = 0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54-7.27, p = 0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29-5.40, p = 0.01). CONCLUSION: Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.

Polymorphism rs2073618 of the TNFRSF11B (OPG) Gene and Bone Mineral Density in Mexican Women with Rheumatoid Arthritis.

Osteoporosis (OP) is highly prevalent in rheumatoid arthritis (RA) and is influenced by genetic factors. Single-nucleotide polymorphism (SNP) rs2073618 in the TNFRSF11B osteoprotegerin (OPG) gene has been related to postmenopausal OP although, to date, no information has been described concerning whether this polymorphism is implied in abnormalities of bone mineral density (BMD) in RA. We evaluated, in a case-control study performed in Mexican-Mestizo women with RA, whether SNP rs2073618 in the TNFRSF11B gene is associated with a decrease in BMD. RA patients were classified as follows: (1) low BMD and (2) normal BMD. All patients were genotyped for the rs2073618 polymorphism by PCR-RFLP. The frequency of low BMD was 74.4%. Higher age was observed in RA with low BMD versus normal BMD (62 and 54 years, resp.; p < 0.001). Worse functioning and lower BMI were observed in RA with low BMD (p = 0.003 and p = 0.002, resp.). We found similar genotype frequencies in RA with low BMD versus RA with normal BMD (GG genotype 71% versus 64.4%, GC 26% versus 33%, and CC 3% versus 2.2%, resp.; p = 0.6). We concluded that in Mexican-Mestizo female patients with RA, the rs2073618 polymorphism of the TNRFS11B gene is not associated with low BMD.

Association between -174G/C and -572G/C interleukin 6 gene polymorphisms and severe radiographic damage to the hands of Mexican patients with rheumatoid arthritis: a preliminary report.

Several interleukin 6 gene (IL6) polymorphisms are implicated in susceptibility to rheumatoid arthritis (RA). It has not yet been established with certainty if these polymorphisms are associated with the severe radiographic damage observed in some RA patients, particularly those with the development of joint bone ankylosis (JBA). The objective of the present study was to evaluate the association between severe radiographic damage in hands and the -174G/C and -572G/C IL6 polymorphisms in Mexican Mestizo people with RA. Mestizo adults with RA and long disease duration (>5 years) were classified into two groups according to the radiographic damage in their hands: a) severe radiographic damage (JBA and/or joint bone subluxations) and b) mild or moderate radiographic damage. We compared the differences in genotype and allele frequencies of -174G/C and -572G/C IL6 polymorphisms (genotyped using polymerase chain reaction-restriction fragment length polymorphism) between these two groups. Our findings indicated that the -174G/C polymorphism of IL6 is associated with severe joint radiographic damage [maximum likelihood odds ratios (MLE_OR): 8.03; 95%CI 1.22-187.06; P = 0.03], whereas the -572G/C polymorphism of IL6 exhibited no such association (MLE_OR: 1.5; 95%CI 0.52-4.5; P = 0.44). Higher anti-cyclic citrullinated peptide antibody levels were associated with more severe joint radiographic damage (P = 0.04). We conclude that there is a relevant association between the -174G/C IL6 polymorphism and severe radiographic damage. Future studies in other populations are required to confirm our findings.

Association between bone turnover markers, clinical variables, spinal syndesmophytes and bone mineral density in Mexican patients with ankylosing spondylitis.

OBJECTIVES: To compare bone turnover marker (BTM) levels and bone mineral density (BMD) between patients with ankylosing spondylitis (AS) and healthy controls (HC) and to evaluate, in AS, the association between BTM levels and clinical variables, spinal syndesmophytes, and BMD using multivariate analysis. METHOD: Seventy-eight AS patients were compared with 58 HC matched by gender. Spinal syndesmophytes in AS and other characteristics were assessed. C-terminal telopeptide fragments of type I collagen (CTX), bone-specific alkaline phosphatase (BAP), osteocalcin (OC) serum levels, and BMD of the lumbar spine, femoral neck, and forearm were evaluated. RESULTS: AS males and females had lower BAP levels than their respective HC (p < 0.001 and p = 0.001). AS patients with bridging syndesmophytes had higher OC levels than AS patients either with non-bridging syndesmophytes (p = 0.001) or without spinal syndesmophytes (p < 0.001). OC and CTX levels correlated significantly with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). In the multivariate linear regression adjusted by age, gender, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BMD in the lumbar spine, and C-reactive protein (CRP), we observed an association between BAP levels and anti-tumour necrosis factor (anti-TNF) use (p = 0.05) whereas OC levels were associated with mSASSS (p < 0.001) and anti-TNF use (p = 0.05), and CTX levels were exclusively associated with mSASSS (p = 0.03). In the logistic regression analysis, only OC levels were associated with the presence of syndesmophytes in AS [odds ratio (OR) 2.42, 95% confidence interval (CI) 1.19-5.75]. CONCLUSIONS: We observed an increase in OC levels in AS patients with syndesmophytes. BTM levels were associated with the severity of spinal damage. Future longitudinal studies should evaluate whether these BTMs should be included as tools to determine the prognosis and progression of spinal damage.

Stability after laser in situ keratomileusis in moderately and extremely myopic eyes.

OBJECTIVE: To evaluate the stability, mechanism, and degree of regression following laser in situ keratomileusis (LASIK) in cases with moderate to extreme myopia after 2 years of follow-up. SETTING: Single-center clinical trial. METHODS: Fifty-two eyes of 38 patients were enrolled in the study. One year follow-up was available for 47 eyes of 35 patients and 2 year follow-up for 39 eyes of 27 patients. Eyes were divided into 2 groups based on the level of preoperative myopia: Group 1, moderate to high myopia > or =15.0 diopters (D) (range -7.0 to -15.0 D, n = 24); Group 2, extreme myopia >15.0 D (range -15.3 to -25.8 D, n = 15). Laser in situ keratomileusis was performed using the Chiron Automated Corneal Shaper(R) microkeratome and the Summit OmniMed excimer laser. Manifest spherical equivalent, mean central keratometry, and central corneal thickness (CCT) were measured preoperatively and 12 and 24 months postoperatively. RESULTS: Group 1 exhibited a mild myopic shift (mean -0.07 +/- 0.28 D; P >.2) and a mild increase in keratometry (mean 0.05 +/- 0.46 D; P >.6), with an accompanying increase in CCT (mean 7.5 +/- 12.2 microm; (P =.006) at 24 months. Group 2 displayed a significant myopic shift (mean -0.7 +/- 0.7 D; P =.001) and a significant increase in keratometry (mean 0.4 +/- 0.5 D; P =.01), with a mild increase in CCT (mean 2.4 +/- 9.7 microm; P =.35) at 24 months. Corneal ectasia was evident in 1 eye in the extreme myopia group. CONCLUSION: The refractive effect of myopic LASIK up to -15.0 D remained reasonably stable during the second postoperative year. Significant regression of the refractive effect occurred in eyes with higher levels of myopia (>15.0 D), with the risk of progressive ectasia. Extreme caution is recommended when myopic LASIK is performed in eyes with higher levels of myopia.

Bitoric laser in situ keratomileusis for the correction of simple myopic and mixed astigmatism.

OBJECTIVE: To evaluate the safety and efficacy of bitoric laser in situ keratomileusis (LASIK) for the correction of simple myopic and mixed astigmatism. DESIGN: Retrospective, single-center, and noncomparative case series. PARTICIPANTS: Eighty-six eyes of 56 patients were analyzed for this study. Six-month and 1-year follow-up data were available on 86 eyes and 72 eyes, respectively. Eyes were divided in two groups according to the type of astigmatism: myopic astigmatism with low sphere (< -2 diopters) and mixed astigmatism. The range of astigmatism was 1.25 to 7.5 diopters. INTERVENTION: LASIK was performed using the Automated Corneal Shaper (ACS) microkeratome (Bausch & Lomb, Claremont, CA) to create a cornea flap using the 130- or 160-micron thickness plate. A bitoric mid-stromal ablation was performed using the Nidek EC-5000 excimer laser (Nidek Company, Gamagori, Japan). MAIN OUTCOME MEASURES: Uncorrected visual acuity, manifest refraction, and best spectacle-corrected visual acuity were the parameters measured preoperatively and at months 1, 3, 6, and 12. RESULTS: At the last visit, an uncorrected visual acuity of 20/20 or better was achieved in 77% and 68% of the myopic and mixed astigmatism groups, respectively. Ninety-two percent of all eyes had a mean spherical equivalent within +/- 0.50 diopter of emmetropia. A mean decrease in the vectorial magnitude of the astigmatism of 94% and 91% was achieved for those eyes with myopic and mixed astigmatism, respectively. There was no loss of best spectacle-corrected visual acuity. In two eyes, the axis of the positive cylinder was misaligned. CONCLUSION: Bitoric LASIK is an effective procedure to correct myopic and mixed astigmatism. Eighty-five percent of the eyes achieved an uncorrected visual acuity of 20/25 or better and had a final cylinder of 0.5 diopter or less. It is a safe operation, because no eyes lost any lines of best spectacle-corrected visual acuity. Longer follow-up may be needed to assess these results.

Laser in situ keratomileusis for myopia of -1.50 to -6.00 diopters.

PURPOSE: To evaluate the results of laser in situ keratomileusis (LASIK) for the correction of low and moderate myopia and astigmatism using the Nidek EC-5000 excimer laser with a modified algorithm. METHODS: Three hundred and ninety-six eyes of 257 patients with myopia ranging from -1.50 to -6.00 D and astigmatism of no more than 4.00 D were included. Manifest spherical equivalent refraction, uncorrected and spectacle-corrected visual acuity were assessed at 1 month (357 eyes, 90%), 3 months (220 eyes, 56%), and 6 months (168 eyes, 42%) after LASIK. RESULTS: Mean preoperative spherical equivalent refraction was -3.60 +/- 1.27 D and mean cylinder was -1.01 +/- 1.08 D. Mean postoperative spherical equivalent refraction was -0.12 +/- 0.31 D and mean cylinder was -0.19 +/- 0.33 D. At 6 months follow-up, 158 eyes (94%) had a mean postoperative spherical equivalent refraction within +/- 0.50 D of emmetropia; 168 eyes (100%) were within +/- 1.00 D. Uncorrected visual acuity was 20/20 or better in 81% (136 eyes) and 20/40 or better in 100%. Two eyes (1.2%) lost 1 line of spectacle-corrected visual acuity due to a decentered ablation. No eye lost 2 or more lines of spectacle-corrected visual acuity. CONCLUSION: Our modified LASIK algorithm with the Nidek EC-5000 excimer laser resulted in safe and predictable outcomes for treatment of low and moderate amounts of myopia and astigmatism.

Laser in situ keratomileusis for simple myopic, mixed, and simple hyperopic astigmatism.

PURPOSE: To summarize initial results of astigmatic laser in situ keratomileusis (LASIK) for 41 eyes of 26 patients using the EC-5000 Nidek system and assess its safety, efficacy and predictability. METHODS: The EC-5000 Nidek excimer laser was used to correct simple myopic, mixed, and simple hyperopic astigmatism with manifest cylinder from 2.00 to 6.50 D. Ablation zone diameters were 6.5 mm (steep meridian ablation) to 7.5 mm (flat meridian ablation) with a repetition rate of 40-41 Hz. In eyes with simple myopic and mixed astigmatism, ablation was performed in both meridians; in eyes with simple hyperopic astigmatism, ablation was performed in the flat meridian alone. Follow-up was 3 months in all eyes. RESULTS: Uncorrected visual acuity was 20/40 or better in 85% of the eyes. Uncorrected visual acuity was equal to the preoperative spectacle-corrected visual acuity in 63% of the eyes. Intended cylinder correction was within 1.00 D in 95% of eyes. No eyes lost lines of spectacle-corrected visual acuity. CONCLUSION: LASIK using the EC-5000 excimer laser appears to effective in the treatment of simple myopic, mixed, and simple hyperopic astigmatism, with favorable results as compared to those previously described for astigmatic keratotomy.