A case of VEXAS syndrome presenting with unusual bone marrow granulomas: a diagnostic dilemma.

BACKGROUND: VEXAS is a recently described inflammatory disease caused by mutations in the UBA1 gene. Symptoms are diverse and include fevers, cartilaginous inflammation, lung inflammation, vasculitis, neutrophilic dermatoses, and macrocytic anemia. Cytoplasmic inclusions in myeloid and erythroid progenitors in the bone marrow are a hallmark feature. Here we report the first case of VEXAS with non-caseating granulomas in the bone marrow. CASE PRESENTATION: A 62-year-old Asian male presented with fevers, erythema nodosum, inflammatory arthritis, and periorbital inflammation. Labs were significant for persistently elevated inflammatory markers and macrocytic anemia. Over the years his symptoms and inflammatory markers only improved with glucocorticoids and recurred when prednisone dose was lowered below 15-20 mg daily. He underwent bone marrow biopsy showing non-caseating granulomas and PET scan showing hilar/mediastinal lymphadenopathy. He was initially diagnosed with IgG4-related disease (treated with rituximab) and later sarcoidosis (treated with infliximab). After failing these agents, the possibility of VEXAS was considered and later confirmed by molecular testing. CONCLUSIONS: To the best of our knowledge, this is the first observation of non-caseating granulomas in VEXAS, a cautionary reminder of its non-specificity since misinterpretation can lead to diagnostic delay. VEXAS should be in the differential in patients with symptoms of chronic inflammation responding positively to steroids (but not to B-cell depletion or TNF inhibition), which is in line with previous literature.

Rare complication of a commonly used antihypertensive agent: A case of hydralazine-induced ANCA-associated vasculitis presenting as rapidly progressive glomerulonephritis.

Hydralazine-induced ANCA-associated vasculitis is a rare clinical entity, with complications including rapidly progressive glomerulonephritis, pulmonary hemorrhage, and pulmonary-renal syndrome. We present this case to highlight the clinical features that support this challenging diagnosis and to emphasize the importance of prompt recognition and aggressive intervention given its significant morbidity and mortality.

A 39 year-old woman with milk-alkali syndrome complicated by posterior reversible encephalopathy syndrome.

Milk-alkali syndrome (MAS) is characterized by the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury. Once thought to be a rare condition, there has been a resurgence of cases due to the consumption of calcium-containing supplements for osteoporosis prevention and dyspepsia in the general population. We describe the case of a female who presented with acute encephalopathy, hypercalcemia, and new-onset seizure. An extensive hypercalcemia workup and ruling out of other causes led to the diagnosis of MAS from excessive intake of calcium carbonate. Brain magnetic resonance imaging revealed signal abnormalities in the occipital and posterior parietal lobes that were indicative of posterior reversible encephalopathy syndrome. The patient's encephalopathy resolved after treatment of her hypercalcemia with fluid resuscitation and cessation of her calcium supplements. We present our case to highlight this unusual presentation of MAS, challenges in diagnosis, and briefly discuss the pathophysiology underlying hypercalcemia-induced encephalopathy.

Intracerebral tuberculomas: A rare cause of seizure in an immunocompetent young male.

Central nervous system (CNS) involvement occurs in about 1% of all tuberculosis (TB) cases, classically presenting as a meningitis. Intracerebral tuberculomas are a much rarer manifestation. We describe the case of a young black male who presented with new-onset seizure. Cerebral computerized tomography from an outside hospital reportedly showed findings concerning for septic emboli. Brain magnetic resonance imaging at our institution confirmed the presence of multiple, peripherally enhancing lesions in the right frontal and temporal lobes, cerebellum, and pons. Thoracentesis was performed for a concomitant pleural effusion, which contained elevated levels of adenosine deaminase and ultimately grew Mycobacterium tuberculosis. After ruling out other causes, we reached a diagnosis of CNS TB manifesting as cerebral tuberculomas. The patient was initiated on a course of rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by rifampin and isoniazid to complete at least twelve months of antimicrobial therapy. We present this case to highlight this unusual manifestation of CNS TB and review the challenges in diagnosis.

Conditional, Genetically Encoded, Small Molecule-Regulated Inhibition of NFκB Signaling in RPE Cells.

Purpose: Nuclear factor κB (NFκB) is a ubiquitously expressed, proinflammatory transcription factor that controls the expression of genes involved in cell survival, angiogenesis, complement activation, and inflammation. Studies have implicated NFκB-dependent cytokines or complement-related factors as being detrimentally involved in retinal diseases, thus making inhibition of NFκB signaling a potential therapeutic target. We sought to develop a conditional and reversible method that could regulate pathogenic NFκB signaling by the addition of a small molecule. Methods: We developed a genetically based, trimethoprim (TMP)-regulated approach that conditionally inhibits NFκB signaling by fusing a destabilized dihydrofolate reductase (DHFR) domain to an inhibitor of NFκB, IκBα, in ARPE-19 cells. We then challenged ARPE-19 cells with a number of stimuli that have been demonstrated to trigger NFκB signaling, including LPS, TNFα, IL-1α, and A2E. Western blotting, electrophoretic mobility shift assay, quantitative PCR, ELISA, and NFκB reporter assays were used to evaluate the effectiveness of this DHFR-IκBα approach. Results: This destabilized domain approach, coupled with doxycycline-inducibility, allowed for accurate control over the abundance of DHFR-IκBα. Stabilization of DHFR-IκBα with TMP prevented IL-1α-, A2E-, LPS-, and TNFα-induced NFκB-mediated upregulation and release of the proinflammatory cytokines IL-1ß and IL-6 from ARPE-19 cells (by as much as 93%). This strategy is dosable, completely reversible, and can be cycled "on" or "off" within the same cell population repeatedly to confer protection at desired time points. Conclusions: These studies lay the groundwork for the use of destabilized domains in retinal pigment epithelium (RPE) cells in vivo and in this context, demonstrate their utility for preventing inflammatory signaling.

An inducible form of Nrf2 confers enhanced protection against acute oxidative stresses in RPE cells.

Increasing evidence suggests that overt oxidative stress within the retina plays an important role in the progression of age-related retinal decline, and in particular, in the disease age-related macular degeneration (AMD). Nuclear factor erythroid 2-like 2 (Nrf2) is a master transcription factor that upregulates numerous of antioxidant/detoxification genes. Nrf2-/- mice develop progressive retinal degeneration that includes the formation of drusen-like deposits, lipofuscin, and sub-retinal pigment epithelium (RPE) deposition of inflammatory proteins. Furthermore, strategies that promote Nrf2 activation have shown promise for the treatment of cone/rod dystrophies and other forms of retinal degeneration. Herein we explored whether utilizing a small molecule-inducible version of Nrf2 confers additional protection against oxidative stresses when compared to a constitutively expressed version of Nrf2. Stable populations of human ARPE-19 cells were generated that express either constitutive FLAG-tagged (FT) Nrf2 (FT cNrf2) or doxycycline (dox)-inducible FT Nrf2 (FT iNrf2) at low levels (∼4.5 fold vs. endogenous). Expression of either FT cNRF2 or FT iNrf2 upregulated canonical antioxidant genes (e.g., NQO1, GCLC). Both FT cNrf2 and FT iNrf2 ARPE-19 cells were protected from cigarette smoke extract-induced nitric oxide generation to similar extents. However, only FT iNrf2 cells demonstrated enhanced resistance to doxorubicin and cumene hydroperoxide-mediated increases in mitochondrial superoxide and lipid peroxidation, respectively, and did so in a dox-dependent manner. These results suggest that therapeutic approaches which conditionally control Nrf2 activity may provide additional protection against acute oxidative stresses when compared to constitutively expressed Nrf2 strategies.