Combined oral contraceptive use in rheumatoid arthritis for the purpose of pregnancy prevention and additional benefits: A narrative review.

Combined oral contraceptives are a common method of contraception and many females prefer them regardless of their medical history. The use in patients with rheumatoid and autoimmune disorders has not been extensively studied with previous reviews focusing on the safety component. This review seeks to address the effectiveness and benefits of utilizing combined oral contraceptives in females with rheumatoid arthritis (RA). Current literature regarding combined oral contraceptives was surveyed for its use in RA and two PubMed searches were conducted, yielding 202 and 142 results, respectively. Results were screened and analyzed for relevance to this review topic. Eighteen results, consisting of clinical trials, observational studies, patient cases, and meta-analyses were used in this narrative review. Historically, it was thought that females with an autoimmune disorder such as RA need to be on contraception due to the teratogenicity potential with disease-modifying therapy but no evidence exists about which type of contraception is the most effective and least interacting. Current evidence available shows no preference for types of contraception in this population, but it has been demonstrated that combination oral contraceptives may provide contraceptive benefits and have a potential for other benefits such as less disability and the prevention of disease progression. Although current evidence provides reasoning to believe combination oral contraceptives are safe and efficacious in patients with RA and may even offer additional benefits, further studies and clinical trials are needed to completely understand the role combination oral contraceptives play in this patient population.

Stinging Nettle (Urtica dioica): An Unusual Case of Galactorrhea.

BACKGROUND The increasing popularity and availability of herbal supplements among patients necessitates a better understanding of their mechanism of action and the effects they have on the body, both intended and unintended. Stinging nettle (Urtica dioica) is an herbaceous shrub found throughout the world that has been used for medicinal purposes for centuries. CASE REPORT A 30-year-old woman with obesity and GERD presented to a primary care clinic with new-onset galactorrhea. A urine pregnancy test was negative. Prolactin, thyroid-stimulating hormone (TSH), and a metabolic panel were all within normal limits. A mammogram demonstrated scattered areas of fibroglandular density and benign-appearing calcifications in the left breast. The breast ultrasound showed no suspicious findings. Her medications included intermittent Echinacea, etonogestrel implant 68 mg subdermal, and the supplement stinging nettle 500 mg, which she had been taking over the past month for environmental allergies. After consultation with a clinical pharmacist, the stinging nettle was discontinued. No additional changes to her medications or supplements were made. One week after discontinuation, she returned to the clinic with complete resolution of the galactorrhea. CONCLUSIONS Stinging nettle (Urtica dioica) is a common supplement and has effects on (1) sex hormone-binding globulin, (2) histamine-induced prolactin release, and (3) serotonin-induced release of thyrotropin-releasing hormone. The local estrogen bioactivity in breast tissue may subsequently lead to gynecomastia and/or galactorrhea. Supplements are an often overlooked but a critical component of medication reconciliation and potential clinical adverse effects.

Rate of broad-spectrum antibiotic overuse in patients receiving outpatient parenteral antibiotic therapy (OPAT).

Broad-spectrum antibiotics with once-daily dosing are often chosen for outpatient parenteral antibiotic therapy (OPAT) due to convenience even when narrower-spectrum antibiotics are appropriate. At our institution, up to 50% of select broad-spectrum OPAT regimens had potential to be narrowed, highlighting the need to re-evaluate regimens for de-escalation prior to discharge.

Characterization of a universal screening approach for congenital CMV infection based on a highly-sensitive, quantitative, multiplex real-time PCR assay.

The majority of congenital cytomegalovirus (cCMV) infections are asymptomatic at birth and therefore not diagnosed. Approximately 10-15% of these infants develop late-onset hearing loss and other developmental disorders. Implementation of a universal screening approach at birth may allow early initiation of symptomatic interventions due to a closer follow-up of infants at risk and offers the opportunity to consider treatment of late-onset disease. Real-time PCR assays for the detection of CMV DNA in buccal swab samples demonstrated feasibility and good clinical sensitivity in comparison to a rapid culture screening assay. Because most cCMV infections remain asymptomatic, a universal screening assay that stratifies CMV infected infants according to low and high risk of late-onset cCMV disease could limit the parental anxiety and reduce follow-up costs. We therefore developed and characterized a screening algorithm based on a highly-sensitive quantitative real-time PCR assay that is compatible with centralized testing of samples from universal screening and allows to determine CMV DNA load of saliva samples either as International Units (IU)/ml saliva or IU/105 cell equivalents. 18 of 34 saliva samples of newborns that tested positively by the screening algorithm were confirmed by detection of CMV DNA in blood and/or urine samples obtained during the first weeks of life. All screening samples that could not be confirmed had viral loads of <2.3x105 IU/ml saliva (median: 6.8x103) or 1.3x105 IU/105 cell equivalents (median: 4.0x102). The viral load of screening samples with confirmed cCMV infection ranged from 7.5x102 to 8.2x109 IU/ml saliva (median: 9.3x107) or 1.5x102 to 5.6x1010 IU/105 cell equivalents (median: 3.5x106). Clinical follow-up of these newborns with confirmed cCMV infection should reveal whether the risk of late-onset cCMV disease correlates with CMV DNA load in early life saliva samples and whether a cut-off can be defined identifying cCMV infected infants with or without risk for late-onset cCMV disease.

Angiotensin Receptor Blockers Effect on Serum Uric Acid-A Class Effect?

PURPOSE: To provide a comprehensive review to determine whether there is a class effect among angiotensin receptor blockers (ARBs) in relation to serum uric acid. SUMMARY: A literature search was conducted and 8 articles were identified for inclusion in this review. In the studies reviewed, candesartan and valsartan were shown to have either a neutral or negative effect on serum uric acid. Azilsartan was shown to have a negative impact on serum uric acid while eprosartan appeared to have no impact on serum uric acid levels. Irbesartan demonstrated either a neutral or positive effect on serum uric acid while losartan exhibited a positive effect. CONCLUSION: The available data indicate that the reduction of serum uric acid is not a class effect of ARBs. Of the available agents, only losartan has clear evidence of its ability to lower serum uric acid. For patients with high blood pressure and elevated serum uric acid, losartan should be considered as a first-line agent with irbesartan as an alternative when appropriate.

A community-wide quality improvement initiative to improve hypertension control and reduce disparities.

Initiatives to improve hypertension control within academic medical centers and closed health systems have been extensively studied, but large community-wide quality improvement (QI) initiatives have been both less common and less successful in the United States. The authors examined a community-wide QI initiative across 226 843 patients from 198 practices in nine counties across upstate New York to improve hypertension control and reduce disparities. The QI initiative focused on (a) providing population and practice-level comparative data, (b) community engagement, especially in underserved communities, and (c) practice-level quality improvement assistance, but was not designed to examine causality of specific components. Across the nine counties, hypertension control rates improved from 61.9% in 2011 to 69.5% in 2016. Improvements were greatest among whites (73.7%-81.5%) and more modest among black patients (58.8%-64.7%). The authors noted a considerable improvement in BP within the group of patients with the highest risk (defined as a BP ≥ 160/100) and a decrease in disparities within this group. The quality collaborative identified five key lessons to help guide future community initiatives: (a) anticipate a plateauing of response; (b) distinguish the needs of disparate populations and create subpopulation-specific strategies to address and reduce disparities; (c) recognize the variation across low SES practices; (d) remain open to the refinement of outcome measures; and (e) continually seek best practices and barriers to success. Overall, a large community-wide QI initiative, involving multiple different stakeholders, was associated with improvements in BP control and modest reductions in some targeted disparities.

Patient Experience With Care and Its Association With Adherence to Hypertension Medications.

BACKGROUND: Medication adherence is crucial to effective chronic disease management, yet little is known about the influence of the patient-provider interaction on medication adherence to hypertensive regimens. We aimed to examine the association between the patient's experience with care and medication adherence. METHODS: We collected 2,128 surveys over 4 years from a convenience sample of hypertensive patients seeking care at three urban safety-net practices in upstate New York. The survey collected adherence measures using the Morisky Medication Adherence Scale (MMAS-8) and patient experience measures. We used regression models to adjust for age, gender, race/ethnicity, self-reported health status, and clustering by patients. The primary outcome was reporting of medium-to-high adherence (MMAS ≥ 6) vs. low adherence. RESULTS: A total of 62.5% of respondents reported medium-to-high medication adherence. The concern the provider demonstrated for patient questions or worries (adjusted odds ratio [AOR] 1.4; 95% confidence interval [CI] 1.1-1.7), provider efforts to include the patient in decisions (AOR 1.5; 95% CI 1.8-1.9), information given (AOR 1.3; 95% CI 1.0-1.6), and the overall rating of care received (AOR 1.4; 95% CI 1.1-1.8) were associated with higher medication adherence. The amount of time the provider spent was not associated with medication adherence (AOR 1.2; 95% CI 0.9-1.4). Medium-to-high medication adherence was in turn associated with increased hypertension control rates. CONCLUSIONS: Overall, better experiences with care were associated with higher adherence to hypertension regimens. However, the amount of time the provider spent with the patient was not statistically associated with medication adherence, suggesting that the quality of communication may be more important than the absolute quantity of time.

SGLT-2 Inhibitors: Is There a Role in Type 1 Diabetes Mellitus Management?

OBJECTIVE: The purpose of this review is to identify and evaluate disease management of patients with type 1 diabetes mellitus (T1DM) who were treated with a sodium-glucose cotransporter 2 (SGLT-2) inhibitor as an adjunct to insulin therapy. DATA SOURCES: A PubMed (1969 to March 2017) and Ovid (1946 to March 2017) search was performed for articles published utilizing the following MESH terms: canagliflozin, empagliflozin, dapagliflozin, type 1 diabetes mellitus, insulin dependent diabetes, insulin, sodium-glucose transporter 2. There were no limitations placed on publication type. STUDY SELECTION AND DATA EXTRACTION: All English-language articles were evaluated for association of SGLT-2 inhibitors and type 1 diabetes. Further studies were identified by review of pertinent manuscript bibliographies. DATA SYNTHESIS: All 3 SGLT-2 inhibitors, when combined with insulin, resulted in an overall reduction of hemoglobin A1C (up to 0.49%), lower total daily insulin doses, and a reduction in weight (up to 2.7 kg). The combination therapy of insulin and SGLT-2 inhibitors also resulted in a lower incidence of hypoglycemia. Study duration varied from 2 to 18 weeks. CONCLUSION: A review of the identified literature indicated that there is a potential role for the combination of SGLT-2 inhibitors with insulin in T1DM for improving glycemic control without increasing the risk of hypoglycemia. The short duration and small sample sizes limit the ability to fully evaluate the incidences of diabetic ketoacidosis and urogenital infections. The risks associated with this combination of medications require further evaluation.

Dipeptidyl Peptidase-4 Inhibitor-Associated Pancreatic Carcinoma: A Review of the FAERS Database.

BACKGROUND: To date, there is limited literature regarding the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and pancreatic carcinoma. OBJECTIVE: To describe the comparative incidence of DPP-4 inhibitors and pancreatic carcinoma as reportedly available in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. The goal was to provide health care practitioners a general understanding of the drug-disease occurrence. METHODS: This is a case/noncase study utilizing Empirica Signal software to query FAERS from November 1968 to December 31, 2013. The software was used to calculate a disproportionality statistic--namely, the empirical Bayesian geometric mean (EBGM)--for reports of DPP-4 inhibitors-associated pancreatic carcinoma. The FDA considers an EBGM significant if the fifth percentile of the distribution is at least 2, defined as an EB05 ≥ 2. With use of a disproportionality analysis, DPP-4 inhibitors were compared with all agents listed in FAERS. RESULTS: A total of 156 patients experienced pancreatic carcinoma while receiving DPP-4 inhibitor therapy. An EB05 of 10.3 was determined for sitagliptin, 7.1 for saxagliptin, 4.9 for linagliptin, and 1.4 for alogliptin, compared with all other agents included in FAERS. Although an EB05 > 2 was achieved in 2 other antihyperglycemic agents, the findings were not consistent within their medication classes. CONCLUSION: There appears to be a statistical association between DPP-4 inhibitor use and pancreatic carcinoma. Causality cannot be inferred from the data provided. Additional clinical studies are needed to further explore this statistical association.

Effectiveness of a multidisciplinary intervention to improve hypertension control in an urban underserved practice.

Patient-centered, multidisciplinary interventions offer one of the most promising strategies to improve blood pressure (BP) control, yet effectiveness trials in underserved real-world settings are limited. We used a multidisciplinary strategy to improve hypertension control in an underserved urban practice. We collected 1007 surveys to monitor medication adherence and used weighted generalized estimating equations to examine trends in BP control. We examined 13,404 visits from patients with hypertension between August 2010 and February 2014. Overall, BP control rates increased from 51.0% to 67.4% (adjusted odds ratio, 1.58; 95% confidence interval, 1.44-1.74) by the end of the intervention phase and were maintained during the postintervention phase (adjusted odds ratio, 1.60; 95% confidence interval, 1.41-1.82). Medication adherence scores increased across the intervention (5.9-6.6; P < .001), but were not sustained at the conclusion of the study (5.9-6.2; P = .16). A multidisciplinary team approach involving registered nurses, pharmacists, and physicians resulted in substantial improvements in hypertension control in a real-world underserved setting.

A Review of Current Evidence of Olmesartan Medoxomil Mimicking Symptoms of Celiac Disease.

Objective:To review the evidence of an association between olmesartan medoxomil and symptoms mimicking celiac disease.Data Sources:Literature was searched in PubMed (1965-November 2013) using the key words or MeSH terms olmesartan, enteropathy, celiac disease, sprue, and diarrhea. References from the Food and Drug Administration (FDA) and Dipiro's Pharmacotherapy eighth edition textbook were also reviewed.Data Synthesis:There have been recent implications of olmesartan medoxomil being linked to symptoms mimicking celiac disease. Investigators first identified the association in 22 patients who presented with presumed refractory celiac disease. Upon further evaluation, it was discovered that these symptoms improved when olmesartan was discontinued. In response to this report, additional case studies have been published. DeGaetani et al also further analyzed patients with seronegative villous atrophy from the Celiac Disease Center and found that olmesartan accounted for 22% of previously unclassified sprue cases. Conversely, the authors of the ROADMAP trial, which compared olmesartan to placebo, found no significant differences in the incidence of gastrointestinal adverse effects.Conclusions:There is growing evidence supporting the association between olmesartan and sprue-like symptoms; however, further research is warranted. These symptoms can be life threatening and clinicians should be aware of the potential association.

CD3-positive B cells: a storage-dependent phenomenon.

The majority of clinical studies requires extensive management of human specimen including e.g. overnight shipping of blood samples in order to convey the samples in a central laboratory or to simultaneously analyze large numbers of patients. Storage of blood samples for periods of time before in vitro/ex vivo testing is known to influence the antigen expression on the surface of lymphocytes. In this context, the present results show for the first time that the T cell antigen CD3 can be substantially detected on the surface of human B cells after ex vivo storage and that the degree of this phenomenon critically depends on temperature and duration after blood withdrawal. The appearance of CD3 on the B cell surface seems to be a result of contact-dependent antigen exchange between T and B lymphocytes and is not attributed to endogenous production by B cells. Since cellular subsets are often classified by phenotypic analyses, our results indicate that ex vivo cellular classification in peripheral blood might result in misleading interpretations. Therefore, in order to obtain results reflecting the in vivo situation, it is suggested to minimize times of ex vivo blood storage after isolation of PBMC. Moreover, to enable reproducibility of results between different research groups and multicenter studies, we would emphasize the necessity to specify and standardize the storage conditions, which might be the basis of particular findings.

Clinical activity of pemphigus vulgaris relates to IgE autoantibodies against desmoglein 3.

Pemphigus vulgaris (PV) is a severe autoimmune bullous skin disease and is primarily associated with IgG against desmoglein 3 (dsg3), a desmosomal adhesion protein. In light of the recent association of autoreactive T helper (Th) 2 cells with active PV, the present study sought to relate the occurrence of Th2-regulated dsg3-specific autoantibody subtypes, i.e. IgE and IgG4, in 93 well-characterized PV patients. Patients with acute onset PV (n=37) showed the highest concentrations of serum IgE and IgG4 autoantibodies, which were significantly lower in PV patients in remission (n=14). Furthermore, there was a strong correlation between dsg3-reactive IgE and IgG4 in acute onset, but not in chronic active (n=42) or remittent patients. Additionally, intercellular IgE deposits were detected in the epidermis of acute onset PV. Thus, dsg3-specific IgE and IgG4 autoantibodies are related to acute onset disease which provides additional support to the concept that PV is a Th2-driven autoimmune disorder.

Rituximab mediates a strong elevation of B-cell-activating factor associated with increased pathogen-specific IgG but not autoantibodies in pemphigus vulgaris.

Pemphigus vulgaris (PV) is a severe autoimmune disease affecting the skin and mucous membranes, characterized by autoantibodies mainly against desmoglein 3 (dsg3). This study investigated the effects of different treatment options on two B-cell mediators, B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), in 19 PV patients on immunosuppressive drugs alone or in combination with immunoadsorption and anti-CD20 antibody, respectively. Serum BAFF and APRIL levels, circulating desmoglein-reactive autoantibodies, and serum IgG specific for varicella-zoster virus (VZV) and Epstein-Barr virus (EBV) were determined by ELISA before and at different time points after initiation of the respective therapy. In contrast to immunosuppressive therapy alone and in combination with adjuvant immunoadsorption, respectively, rituximab treatment led to a strong and significant elevation of BAFF, but not of APRIL levels, which normalized upon recovery of peripheral CD19(+) B cells. Moreover, rituximab treatment led to a statistically significant increase of anti-VZV-IgG and anti-EBV-IgG titers, whereas anti-dsg1 and -3 specific autoantibody titers decreased significantly. Our results suggest that elevated BAFF levels might exert a differential effect on the induction of autoreactive versus pathogen-specific IgG antibody production in PV patients, possibly due to promotion of antibody release of pathogen-specific long-lived plasma cells.

B-cell-directed therapy for inflammatory skin diseases.

The basic understanding of inflammatory dermatoses and autoimmune-mediated skin disorders has greatly advanced and broadened our understanding of underlying immune mechanisms that shape the complex network of chronic inflammation and autoimmunity. The new treatment options for psoriasis exemplify how new insights into (auto)immune responses, especially the role and function of various immune cells and proinflammatory cytokines, may lead to new therapeutic strategies. The concept of targeting B cells in autoimmune-mediated disorders is closely related to the discovery of autoantibodies and their cellular origin. However, the appreciation of B cells in autoimmunity has significantly changed and is not limited to their role as progenitors of autoantibody secreting plasma cells. Recent investigations of various inflammatory skin diseases, that is, autoimmune blistering disorders, collagen vascular diseases, and atopic dermatitis, actually support the concept that B cells might be as important as T cells in the etiopathogenesis of these disorders. The striking clinical improvement seen in patients with rheumatoid arthritis following B-cell depletion with the anti-CD20 mAb rituximab has tremendously catalyzed the interest in B-cell-targeted therapies in different autoimmune diseases. Future translational and clinical investigations are mandatory to precisely define the role and the contribution of impaired B-cell function in (auto)immune-mediated skin diseases.

Rituximab exerts a dual effect in pemphigus vulgaris.

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting the skin and mucous membranes. Autoreactive CD4(+) T helper (Th) lymphocytes are crucial for the autoantibody response against the desmosomal adhesion molecules, desmoglein (dsg)-3 and dsg1. Eleven patients with extensive PV were treated with the anti-CD20 antibody, rituximab (375 mg per m(2) body surface area once weekly for 4 weeks). Frequencies of autoreactive CD4(+) Th cells in the peripheral blood of the PV patients were determined 0, 1, 3, 6, and 12 months after rituximab treatment. Additionally, the clinical response was evaluated and serum autoantibody titers were quantified by ELISA. Rituximab induced peripheral B-cell depletion for 6-12 months, leading to a dramatic decline of serum autoantibodies and significant clinical improvement in all PV patients. The frequencies of dsg3-specific CD4(+) Th1 and Th2 cells decreased significantly for 6 and 12 months, respectively, while the overall count of CD3(+)CD4(+) T lymphocytes and the frequency of tetanus toxoid-reactive CD4(+) Th cells remained unaffected. Our findings indicate that the response to rituximab in PV involves two mechanisms: (1) the depletion of autoreactive B cells and (2) the herein demonstrated, presumably specific downregulation of dsg3-specific CD4(+) Th cells.

Type I regulatory T cells in autoimmunity and inflammatory diseases.

Regulatory T cells exert a critical role in controlling autoimmunity and maintaining peripheral tolerance. The best described regulatory T cells are the naturally occurring CD4+CD25+ regulatory T cells, which have been shown to be continuously produced within the thymus. Other T-cell subsets bearing suppressive capacity have been reported, including T-helper-3 cells (Th3) and type 1 regulatory T (Tr1) cells. Tr1 cells have been shown to be induced upon antigen exposure under certain tolerogenic conditions and are characterized by the production of the immunosuppressive cytokines IL-10 and TGF-beta, while Th3 cells preferentially produce TGF-beta upon induction by intestinal tolerance. Recent progress has been made in the characterization of Tr1 cells in terms of isolation and induction, respectively. The present review provides an overview of the presence of Tr1 cells in inflammation, infection and neoplastic disorders. Moreover, the relationship between different regulatory T cell subsets and their transcriptional control is discussed. The recent development of methods allowing the ex vivo expansion of regulatory T cells may be the first step towards a cellular therapy with regulatory T cells to control T-cell-mediated pathology in inflammatory disorders.