Endothelial Dysfunction in Systemic Sclerosis.

Systemic sclerosis, commonly known as scleroderma, is an autoimmune disorder characterized by vascular abnormalities, autoimmunity, and multiorgan fibrosis. The exact etiology is not known but believed to be triggered by environmental agents in a genetically susceptible host. Vascular symptoms such as the Raynaud phenomenon often precede other fibrotic manifestations such as skin thickening indicating that vascular dysfunction is the primary event. Endothelial damage and activation occur early, possibly triggered by various infectious agents and autoantibodies. Endothelial dysfunction, along with defects in endothelial progenitor cells, leads to defective angiogenesis and vasculogenesis. Endothelial to mesenchymal cell transformation is another seminal event during pathogenesis that progresses to tissue fibrosis. The goal of the review is to discuss the molecular aspect of the endothelial dysfunction that leads to the development of systemic sclerosis.

Safety of Recombinant Zoster Vaccine in Rheumatology Patients.

OBJECTIVES: Recombinant zoster vaccine (RZV) is Food and Drug Administration approved for the prevention of herpes zoster (shingles) in adults 50 years old and older. Immunocompromised subjects were excluded from the pivotal vaccine trials. We studied the safety of this vaccine in our university-affiliated rheumatology practice. METHODS: This was a single-center, retrospective study focusing on subjects who received RZV during 2018. We collected the demographic data, any self-reported adverse events after vaccination, C-reactive protein, Routine Assessment of Patient Index Data 3 (RAPID3) scores for subjects with rheumatoid arthritis, and available RAPID3 scores for all study subjects before and after the vaccination. RESULTS: Comparision of C-reactive protein (n = 40), RAPID3 scores for subjects with rheumatoid arthritis (n = 16), and available RAPID3 scores for all subjects (n = 21) using the paired t test, did not show significant differences before and after the administration of RZV. A total of 6.4% of patients reported adverse events after vaccination. The adverse events were mild and did not lead to hospitalization, end organ damage, or change in treatment plan. CONCLUSIONS: The RZV was safe and well tolerated among our study population.

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air.

Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.

Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators, Endothelial Gap Junctions and Beyond.

Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell disorders may be responsible. More recently, novel syndromes such as delayed reactions to red meat and hereditary alpha tryptasemia have been described. Anaphylaxis manifests as sudden onset urticaria, pruritus, flushing, erythema, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor (FcεRI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF). Of these, histamine, tryptase, cathepsin G, TNF-α, LTC4, PAF and VEGF can increase vascular permeability. Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions that can result in phenotypes resembling IgE-mediated anaphylaxis. Such classifications can lead the way to precision medicine approaches to the management of this complex disease.

Impact of ß-Lactam Allergies on Antimicrobial Selection in an Outpatient Setting.

OBJECTIVE: The primary objective of this study was to determine whether patients prescribed nonpreferred antibiotics received appropriate alternative antibiotics. METHODS: This was a retrospective observational analysis of military veteran patients with a ß-lactam allergy treated in an outpatient clinic or emergency department for an infection during a 5-year span. Antibiotic regimens were first stratified as preferred or nonpreferred based on infection-specific guidelines. The nonpreferred regimens were then evaluated for appropriateness based on allergy history and culture and sensitivity reports. RESULTS: Of 445 fills of antibiotics evaluated, 269 met inclusion criteria, comprising 253 unique infections in 80 patients. Patients received nonpreferred antibiotics for their infection type in 57% of cases. Of the nonpreferred antibiotics, 56% were inappropriate based on guideline-recommended alternatives, allergy history, and culture and sensitivity data. Of the 88 allergies, 97% were historical/self-reported and 48% were cutaneous. In addition, 39% of patients safely received ß-lactam antibiotics after documentation of their allergy. CONCLUSIONS: Patients with documented ß-lactam allergies are at high risk of receiving nonpreferred and inappropriate antibiotics, and many reactions likely do not reflect true allergies. These data emphasize the negative impact of the "ß-lactam allergy" label and the importance of reassessing allergies.

The changing face of anaphylaxis in adults and adolescents.

BACKGROUND: Our institution has published serial studies of adults and adolescents with anaphylactic events. The first series was published in 1993 and the last was published in 2006. It was our perception that the nature of anaphylactic episodes had changed over the 2 decades since the last review. OBJECTIVE: To determine whether the etiologies and presentations of anaphylaxis have changed during the past decade in our population. METHODS: Patient charts were identified based on International Classification of Diseases, Ninth Revision codes for anaphylactic shock. Charts identified were analyzed for clinical symptoms reported, comorbidities, etiology, investigative testing, and subsequent treatment. These cases were categorized as definitive, probable, or idiopathic based on history and results from testing, similar to our prior reports. RESULTS: We identified 281 possible cases, of which 218 met criteria for anaphylaxis. Of these cases, median age was 42 years (range 9-78) and 64% were female. In the review of cases, 85 (39%) were determined to have a definitive etiology, 57 were determined to have a probable etiology (26%), and 76 (35%) were idiopathic. Interestingly, of those with a definitive cause, the most common etiology identified was galactose-α-1,3-galactose, accounting for 28 cases (33%). Foods were the second leading cause, accounting for 24 cases (28%). CONCLUSION: In this follow-up report on anaphylaxis etiology from a single center, the most common etiology was galactose-α-1,3-galactose. This differs greatly from prior reports from our center. Interestingly, the percentage of cases attributed to idiopathic anaphylaxis decreased from 59% in our previous report to 35% in the present report, which could largely be explained by the number of galactose-α-1,3-galactose cases.

Pediatric Angioedema.

PURPOSE OF REVIEW: The aims of this study are to update the clinician on current understanding of angioedema as it presents in the pediatric population and to review proper diagnostic techniques and treatment modalities for various types of angioedema. RECENT FINDINGS: Angioedema is still best classified by whether it is likely histaminergic or kinin-mediated. New guidelines have been published around the world to help diagnose and treat both forms (urticaria/angioedema and hereditary angioedema). The vast majority of the studies on treatment have been conducted in the adult population; however, there are data available in the pediatric population. In the realm of hereditary angioedema, there are multiple new therapies that have been studied in the pediatric population (down to 2 years in some studies) in recent years and offer the clinician options for treatment. Angioedema (whether occurring with or without urticaria) is common in the pediatric population. The majority of the recent studies has been conducted in hereditary angioedema, and now, the clinician should have various options to treat all forms of angioedema. Many treatment options, especially for hereditary angioedema, are further being examined specifically in the pediatric population.

Screening and Treatment of Latent Tuberculosis Among Patients Receiving Biologic Agents: A National and International Survey of Rheumatologists.

OBJECTIVE: We sought to understand the current practice patterns of both US and international members of the American College of Rheumatology (ACR) in this regard. METHODS: A set of questionnaires developed by a focus group of faculties and fellows of the Rheumatology Division of University of Tennessee Health Science Center, Memphis, TN, was sent electronically using an online survey tool to 4433 rheumatologists who are ACR members in the United States and internationally. RESULTS: Seven hundred sixty-eight physicians out of 4433 ACR members responded to the electronic survey, with a response rate of 17.32%. The preferred screening method by most of the respondents was either tuberculin skin test (19%) or interferon γ release assay (32%) or both. For treatment of latent tuberculosis infection (LTBI) overall, 49% of the respondents would refer management to infectious disease specialist or the health department, 37% would initiate isoniazid for 9 or 12 months, and 14% would use isoniazid for 6 months. Approximately 60% of respondents would initiate anti-tumor necrosis factor therapy after being on LTBI treatment for 1 month. The other respondents were almost equally divided among the 3 responses: 2, 3, 6, or 9 months. CONCLUSIONS: There is a large disagreement regarding the method used and how often to screen for LTBI after initiating biologic therapy and how soon biologic treatment would be started after initiating LTBI therapy. Another disagreement exists regarding the duration of LTBI therapy. The information obtained from the survey can be taken into account when ACR or other international member organizations formulate future recommendations regarding screening and treatment of LTBI.

Nonallergic rhinitis.

Rhinitis is normally defined by the symptoms of nasal congestion, postnasal drainage, rhinorrhea, and sneezing. It has been associated with various pathologic changes, but can occur in the absence of any inflammation. Thus, the diagnosis is based on the clinical presentation. There are no clear-cut criteria to distinguish when rhinitis becomes chronic, but in its chronic form, it can be complex. Chronic forms of rhinitis that occur in the absence of any detectable specific IgE against relevant aeroallergens in its broadest sense can be called chronic nonallergic rhinitis. This review will concentrate on chronic nonallergic rhinitis in its various forms, discussing the epidemiology, underlying mechanisms, and its therapy.

Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps.

OBJECTIVE: To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. METHODS: We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty's syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects. RESULTS: Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients. CONCLUSION: Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.

Relapse and Outcome of Lupus Nephritis After Renal Transplantation in the Modern Immunosuppressive Era.

Background Recurrence of lupus nephritis in the graft is a concern in lupus patients with end-stage renal disease undergoing renal transplantation. The recurrence of lupus nephritis has been variable among different studies depending on the patient characteristics, immunosuppressive regimen, and indications of renal biopsy. Therefore, we investigated the recurrence of lupus nephritis among our patients to see if the new post-transplant regimen has impacted the recurrence. Methods We collected data on all recipients with end-stage renal disease secondary to lupus nephritis, who received renal transplants between 2006-2017 in our center. Patient demographics, transplant, and dialysis-related information have been recorded including kidney biopsy, graft loss, and survival were recorded. An association between recurrent lupus nephritis with survival and/or graft loss was examined using survival models. Results The overall mean±SD age at baseline was 42±13 years; 89% were female; 89% were African American; the previous time on dialysis was a median of 4 years (IQR: 2-8 years), 81% received hemodialysis and 31% received living donor transplantation in the cohort. Our patients received the standard immunosuppressive regimen consisting of prednisone, tacrolimus, and mycophenolate mofetil. Four (10.5%) of the 38 patients had biopsy-proven lupus nephritis recurrence. A total of 10 patients (26%) had graft loss or died during the median follow-up time of 1,230 days (IQR: 460-2,227 days). Recurrence of lupus nephritis showed a trend for increased risk of graft loss or patient death (Hazard Ratio: 3.14, 95%Confidence Interval: 0.65-15.24) compared to the recipient without recurrence in our unadjusted proportional Cox regression model. Conclusion The recurrence rate of lupus nephritis in our patient population is much lower compared to past studies from different immunosuppressive eras. Patients with recurrent lupus nephritis showed an increased risk of graft loss or death.

Impact of Beta-Lactam Allergies on Selection of Antimicrobials in an Inpatient Setting Among Veteran Population.

PURPOSE: Beta-lactam antibiotics are among the most common and widely used antibiotics. However, reported allergy to this class of antibiotics is also common, leading to the use of alternative broad-spectrum antibiotics by healthcare providers. This has led to the emergence of various negative health outcomes. The purpose of the study is to investigate the impact of using alternative antibiotics secondary to a beta-lactam allergy among U.S. veterans who have otherwise multiple comorbidities. METHODS: This retrospective observational analysis was conducted over a 5-year period (January 1, 2011 to December 31, 2016) at the Memphis Veterans Affairs Medical Center (VAMC). Admitted patients with a documented beta-lactam allergy were categorized to preferred or non-preferred status based on initial antibiotic therapy antibiotic, allergy history, published guidelines, and local antibiogram. Preferred therapy was defined as the optimal antibiotic treatment for a given indication based on patient allergy history, published Infectious Disease Society of America guidelines, and local antibiogram of Memphis VAMC. The therapy was classified as "non-preferred" if it did not satisfy the preferred therapy criteria. Non-preferred treatments were further assessed for appropriateness based on indication and patient-specific factors. Chi-square and Fisher's exact tests were conducted to find a difference in rates of negative sequelae among patients receiving preferred vs. non-preferred treatments and appropriate vs. inappropriate treatments. FINDINGS: Of the 1806 admissions identified, data were collected on 95 unique patients with 147 different antibiotic regimens. There were 68 (52%) preferred treatment regimens and 64 (48%) non-preferred treatment regimens. Of the 64 non-preferred treatments, 43 (67%) were inappropriate. There was a statistically significant decrease in the number of adverse drug events and in the combined negative sequelae outcome among patients receiving preferred therapy vs. non-preferred therapy (2 vs. 12; P < .01 and 11 vs. 23; P < .01, respectively). IMPLICATIONS: The receipt of non-preferred antibiotic therapy among veterans with a recorded beta-lactam allergy may be associated with an increased risk of developing negative outcomes. Among military personnel, removing unnecessary beta-lactam allergies would improve readiness with optimal antibiotic choices and avoidance of unnecessary risks, expediting return to full duty.

Eosinophilic Granulomatosis Polyangiitis (EGPA) Masquerading as a Mycotic Aneurysm of the Abdominal Aorta: Case Report and Review of Literature.

INTRODUCTION: Aortic involvement leading to aortitis in eosinophilic granulomatosis polyangiitis (EGPA) is infrequent, and only 2 cases have been reported so far in the literature. Even more so, aortic aneurysm, secondary to EGPA, has never been reported and remains a diagnostic and therapeutic challenge. Case Presentation. We present a 63-year-old Caucasian male patient with a prior diagnosis of EGPA presenting with abdominal pain, nausea, and loose stools to the emergency department. Physical examination showed periumbilical tenderness. He had no peripheral eosinophilia but had high C-reactive protein and procalcitonin levels. CT abdomen revealed a mycotic aneurysm involving the infrarenal abdominal aorta. The patient declined surgical repair initially and was treated with IV antibiotics only. Unfortunately, 24 hours later, the aneurysm ruptured, leading to emergent axillofemoral bypass surgery. Surgical biopsy showed aortitis, periaortitis, and active necrotizing vasculitis. CONCLUSION: Abdominal aneurysms should be considered a complication of EGPA, and earlier immunosuppressive therapy should be considered to prevent further complications.

Common variable immunodeficiency (CVID) with granulomatous interstitial lung disease (GLILD) and SARS COVID-19 infection: case report and review of literature.

BACKGROUND: We present a case of CVID complicated by granulomatous interstitial lung disease (GLILD). This patient clinical course was further complicated by COVID-19 infection. This is only the 2nd known case report of COVID 19 in CVID with GLILD. The clinical course and outcome of COVID 19 infection with common variable immunodeficiency (CVID) and GLILD is not well known. CASE PRESENTATION: Our patient met the clinical features of CVID secondary to low IgG/IgA, recurrent infections, and failure to respond to pneumococcal vaccination. He was treated with monthly maintenance IVIG therapy. Our patient also was diagnosed with co-existing GLILD that despite IVIG treatment was progressing. The patient needed to be started on Rituxan and Mycophenolate mofetil to achieve control but unfortunately became infected with COVID19 delaying his treatment for GLILD. Our patient only suffered from mild COVID 19 infection and was able to make antibodies to this. We believe severe infection was avoided as his CVID was well controlled with IVIG therapy despite progression of his granulomatous interstitial lung disease. CONCLUSION: In conclusion, our patient with CVID with co-existing biopsy proven granulomatous interstitial lung disease despite being very high risk for severe COVID 19 infections only had mild infection. This was believed to be due to well controlled CVID with IVIG therapy.

Infusion-related angioedema associated with infliximab-abda: Case report.

PURPOSE: A case of infusion-related angioedema associated with the use of an infliximab biosimilar (infliximab-abda) is reported in order to bring awareness that this adverse effect is still highly possible in biosimilars, similar to the reference infliximab biologic. SUMMARY: A 37-year-old white male with a past medical history significant for ileocolonic fistulizing Crohn's disease, depression, and gastroesophageal reflux disease (GERD) presented to an emergency department with shortness of breath, urticaria, and tongue swelling that had developed shortly after initiation of an infusion of infliximab-abda. The patient had no documented allergies at the time of presentation. The patient was taking oral budesonide 9 mg daily and oral azathioprine 50 mg daily for treatment of Crohn's disease. Other medications included oral omeprazole 40 mg every morning for GERD and oral sertraline 100 mg daily for depression. The patient's tongue swelling worsened, and he was intubated for airway protection. The patient received supportive care treatment for angioedema with intravenous (IV) dexamethasone 8 mg every 8 hours, IV diphenhydramine 50 mg every 8 hours, and IV famotidine 20 mg every 12 hours. He was extubated approximately 43 hours later and observed overnight in a medical intensive care unit. He was transferred to a general medicine unit the next day for further care. The total hospital length of stay was 4 days. CONCLUSION: A 37-year-old man developed infusion-related angioedema with use of infliximab-abda. Discontinuation of the biosimilar product along with supportive care brought about resolution of angioedema. There are no prior published reports of infusion-related angioedema reactions secondary to infliximab-abda use.

Implementation and Impact of a ß-Lactam Allergy Assessment Protocol in a Veteran Population.

BACKGROUND: Approximately 10% of the US population reports having a ß-lactam allergy, although nearly 90% do not have a true immunoglobulin E (IgE)-mediated reaction. This misconception results in using nonpreferred antibiotics, leading to antimicrobial resistance and treatment failure. To evaluate, clarify, and clear ß-lactam allergies, we implemented a pharmacist-driven ß-lactam allergy assessment (BLAA) protocol and penicillin allergy clinic (PAC). The purpose of this study was to illustrate the BLAA process, including the pharmacist-run PAC, and assess the impact on allergy clearance. METHODS: Clinical pharmacy specialists (CPS) evaluated hospitalized veterans with ß-lactam allergies, using the BLAA protocol. Eligible patients could later be seen in PAC. This was a retrospective observational review of the BLAA protocol to assess recommendations for ß-lactam antibiotic use and PAC outcomes. RESULTS: Between November 2017 and February 2020, 278 patients were evaluated, and 32 were seen in the clinic. The most common allergen was penicillin, and the most reported reaction was a rash (27%) or pruritus and urticaria (18%). Through PAC and the BLAA protocol, 86 patients (31%) were cleared for allergy removal, and 188 (68%) were cleared for alternative ß-lactams. The evaluation revealed that 274 patients (99%) were eligible to receive a ß-lactam antibiotic, and only 4 patients (1%) were recommended for avoidance of all ß-lactams. CONCLUSIONS: These findings highlight the utility of the pharmacist-driven BLAA protocol. We illustrated that most patients with documented ß-lactam allergies were eligible for alternative ß-lactams. The implementation of the BLAA protocol and pharmacist-run PAC facilitated allergy clearance and has the potential to promote alternative ß-lactam use.

Vasomotor rhinitis.

Vasomotor rhinitis is a common disorder that is seen routinely in allergy practice. It affects millions of Americans and results in significant morbidity. The pathophysiology of this complex heterogeneous disorder is unknown, but we are making advances in this regard. Symptoms and signs can closely resemble those of allergic rhinitis and can be difficult to differentiate from those resulting from allergy. A careful history, physical examination, and diagnostic testing help clinicians arrive at a definitive diagnosis, but treatment can be challenging. Therapy should be based on the presenting symptoms of vasomotor rhinitis. Combination therapy with topical corticosteroids and azelastine is useful. However, in patients whose predominant symptom is rhinorrhea, use of atopical anticholinergic agents can be quite useful. Up-to-date pathogenesis, epidemiology, diagnosis, and treatment approaches are discussed in this review.