Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).

BACKGROUND: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). METHODS: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. RESULTS: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. CONCLUSIONS: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).

Coping during COVID-19: how attitudinal, efficacy, and personality differences drive adherence to protective measures.

INTRODUCTION: COVID-19 has had a devastating impact on people's lives since its initial outbreak and global spread in 2020. While the U.S. government and public health officials have recommended best practices such as social distancing, wearing a mask, and avoiding large public gatherings, these orders have been met with varying levels of acceptance from the public. Given the disparate compliance, this study builds on Social Cognitive Theory (SCT) to explore individual differences and personal motivation factors in order to better understand what may influence one's likelihood to adhere to COVID-19 protective measures. METHODS: A U.S. national survey (N = 2,049) was conducted April-May 2020, roughly one month after stay-at-home orders were issued in some states. Participants were asked to report their likelihood of taking individual and community protective measures. Multivariate hierarchical linear regressions were run to analyze the extent to which participants' concerns about COVID-19's impact, individual and collective self-efficacy, coping behaviors, and personality traits influenced the dependent variables. RESULTS: Findings showed that COVID-19-related health concerns, collective efficacy, and proactive coping strategies were positively related to participants' likelihood of taking protective measures. Those with greater concerns about their general well-being and the economy, adverse coping strategies like denial and joking, as well as sensation-seeking personalities, were less likely to take protective measures. CONCLUSION: The discussion considers how individual differences fit into broader global efforts to stem COVID-19. Practical implications for public health messaging are that communication may focus on facilitating efficacy in order to boost compliance with protective measures.

A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome.

BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/µL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/µL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Enhanced toxicity to chemoradiation in a patient with Anti-Jo-1-antisynthetase syndrome.

Appropriate counseling of patients with autoimmune connective tissue disorders (ACTDs) is often challenging for radiation oncologists, especially regarding anticipated side-effects of radiation treatment. These patients can have highly variable and unpredictable sequelae from radiation therapy, and the uncertainty builds when radiation is convoluted by the addition of concurrent chemotherapy. While many patients may experience a mild intensification of toxicity above what is expected, some patients experience much more severe toxicity. These patients become critical learning cases, enabling a better understanding of the delicate and complex ways in which radiation response is altered in the context of ACTDs while allowing other patients with similar ACTD profiles to benefit from past experience. Our report makes an important contribution to this space by describing a particularly severe case of toxicity that manifested in such a patient and the ensuing clinical decision-making. Comprehensive genotyping of classic pharmacokinetic and pharmacodynamic pathway genes (including mutations in DPD and CDA) did not reveal any signatures that might explain her enhanced toxicity and we demonstrate that severe toxicity can still manifest in the era of modern conformal radiation treatments for rectal cancer. We urge caution in the treatment of patients with rare ACTDs, but also emphasize that curative treatment should not be withheld in such patients. We conclude by advocating for the development and maintenance of a prospective multiinstitutional database of patients with ACTDs to help inform and improve future practice.

KPI-121 1% for pain and inflammation in ocular surgery.

Pain and inflammation are common experiences following ocular surgery and, if uncontrolled, can compromise patients' vision, functioning and quality of life. Corticosteroid drugs are available to manage inflammation and discomfort but have limitations in penetrating the ocular mucus barrier to reach the target ocular tissues. KPI-121 1% (INVELTYS®) is a novel formulation of loteprednol etabonate that employs innovative proprietary technology to deliver nanoparticle-sized mucus-penetrating particles to the cornea. Results from clinical trials demonstrate that KPI-121 1% is effective and well tolerated. KPI-121 1% uses mucopenetrative technology for ophthalmic use and is the only US FDA-approved twice-daily ocular corticosteroid indicated for the treatment of inflammation and pain after ocular surgery.

Bilateral Effect of OC-01 (Varenicline Solution) Nasal Spray for Treatment of Signs and Symptoms in Individuals with Mild, Moderate, and Severe Dry Eye Disease.

PURPOSE: This study compares outcomes of therapy with OC-01 (varenicline solution) for dry eye disease in study eyes and nonstudy fellow eyes of participants in 2 pivotal clinical trials. METHODS: All 891 patients randomized to receive OC-01 (varenicline solution) 0.03 mg, OC-01 (varenicline solution) 0.06 mg, or vehicle control (VC) in each nostril twice daily for 28 days in the Phase IIb ONSET-1 (Evaluation of the Efficacy of OC-01 Nasal Spray on Signs and Symptoms of Dry Eye Disease) and Phase III ONSET-2 trials were included in this post hoc analysis. One eye was designated as the study eye. The mean change from baseline in anesthetized Schirmer test score (STS) and the percentage of eyes achieving a ≥10-mm STS improvement were compared between treatments in study and fellow eyes overall and by baseline Eye Dryness Score. FINDINGS: In the study eyes, the mean STS improvement from baseline to day 28 was 10.4 mm, 10.5 mm, and 4.9 mm in the 0.03 mg, 0.06 mg, and VC groups, respectively; comparable values in nonstudy fellow eyes were 8.7 mm, 8.8 mm, and 2.7 mm, respectively. The percentages of study eyes achieving a ≥10-mm STS improvement were 48.1%, 48.4%, and 25.9%, respectively, whereas the comparable values in nonstudy eyes were 42.9%, 43.9%, and 19.7%, respectively. No significant treatment-subgroup interactions were observed in study or fellow eye STS outcomes by baseline Eye Dryness Scores <40 and ≥40 (p > 0.05 for all). IMPLICATIONS: OC-01 (varenicline solution) nasal spray had significant tear film production improvements compared with VC in both study and fellow eyes. These findings suggest efficacy across a broad spectrum of presenting disease severity.

Presbyopia - A Review of Current Treatment Options and Emerging Therapies.

Presbyopia is a common age-related vision disorder characterized by a progressive inability to focus on near objects. If uncorrected or under-corrected, presbyopia can significantly impact patients' quality of life. Presbyopia represents an area of considerable unmet need due to its rising prevalence worldwide as the population ages, the high proportion of under-treated individuals in some parts of the world, and the limitations of currently available corrective methods. Progressive or bifocal spectacles are associated with peripheral blur, a restricted visual field and impaired depth perception, which have been linked to an increased risk of falls in the elderly. Contact lens options can be difficult to maintain due to the development of age-related dry eye symptoms and reduced manual dexterity. Other corrective methods involve surgical interventions that modify the optics of the cornea, replace the crystalline lens, or attempt to restore active accommodation. While patients undergoing surgery report satisfactory outcomes post-operatively, many of them eventually require reading glasses. Non-invasive therapies with novel mechanisms of action are currently being investigated; these include miotic agents and UNR844, a lipoic acid choline ester. In this narrative review, available evidence on presbyopia prevalence, quality of life impact and risk factors are described, with a focus on observational studies in non-clinical settings. The diagnosis pathway and patient journey in presbyopia are outlined, and various treatment options are analyzed. The data reviewed herein reveals significant gaps in the provision of vision correction for this common condition, with a paucity of effective, non-invasive treatment options broadly accessible to presbyopic individuals.

Multifocal calcific periarthritis with distinctive clinical and radiological features in patients with CD73 deficiency.

OBJECTIVES: Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the ecto-5'-nucleotidase gene. Periarticular calcification has been reported but the clinical characterization of arthritis as well as the microstructure and chemical composition of periarticular calcifications and SF crystals has not been systematically investigated. METHODS: Eight ACDC patients underwent extensive rheumatological and radiological evaluation over a period of 11 years. Periarticular and synovial biopsies were obtained from four patients. Characterization of crystal composition was evaluated by compensated polarized light microscopy, Alizarin Red staining for synovial fluid along with X-ray diffraction and X-ray micro tomosynthesis scanner for periarticular calcification. RESULTS: Arthritis in ACDC patients has a clinical presentation of mixed erosive-degenerative joint changes with a median onset of articular symptoms at 17 years of age and progresses over time to the development of fixed deformities and functional limitations of small peripheral joints with, eventually, larger joint and distinct axial involvement later in life. We have identified calcium pyrophosphate and calcium hydroxyapatite (CHA) crystals in SF specimens and determined that CHA crystals are the principal component of periarticular calcifications. CONCLUSION: This is the largest study in ACDC patients to describe erosive peripheral arthropathy and axial enthesopathic calcifications over a period of 11 years and the first to identify the composition of periarticular calcifications and SF crystals. ACDC should be considered among the genetic causes of early-onset OA, as musculoskeletal disease signs may often precede vascular symptoms.

Real-World Experience with Lifitegrast Ophthalmic Solution (Xiidra®) in the US and Canada: Retrospective Study of Patient Characteristics, Treatment Patterns, and Clinical Effectiveness in 600 Patients with Dry Eye Disease.

PURPOSE: This study evaluated real-world treatment of dry eye disease (DED) with lifitegrast. PATIENTS AND METHODS: Ophthalmologists and optometrists treating patients with DED were invited to participate through a healthcare provider (HCP)-based panel. HCPs completed a provider survey and contributed data toward a chart review for up to five qualifying patients with DED who initiated lifitegrast ophthalmic solution (index date) between 01/01/2017 (US) or 01/01/2018 (Canada) and 06/30/2019. Patient demographics, treatments, clinical characteristics, and outcomes (ie, severity, signs, symptoms) were collected for the 6-month pre-index period and up to 12-months post-index. RESULTS: For this study, 517 HCPs contributed 600 patient charts. Among 554 and 281 patients with follow-up at 6 and 12-months post-index, 512 (92.4%) and 238 (84.7%) patients had ongoing lifitegrast treatment, respectively. Other DED-related treatments were less frequently used post-index with lifitegrast vs pre-index: over-the-counter artificial tear use (45.2% vs 75.5%), topical corticosteroids (3.8% vs 18.8%), any cyclosporine (3.0% vs 20.5%). At 3-months (n=571) and 12-months (n=320) post-index vs pre-index, fewer patients had eye dryness (47 [8.2%] and 16 [5.0%] vs 525 [87.5%]), blurred vision (28 [4.9%] and 11 [3.4%] vs 346 [57.7%]), ocular burning/stinging (25 [4.4%] and 8 [2.5%] vs 336 [56.0%]), depression (8 [1.4%] and 9 [2.8%] vs 55 [9.2%]), fatigue (4 [0.7%] and 1 [0.3%] vs 82 [13.7%]), and headache (1 [0.2%] and 0 vs 19 [3.2%]). At 3 and 12-months post-index vs pre-index, average corneal staining score was numerically lower (2.7 and 2.0 vs 6.5), and average Schirmer score (10.6 and 10 vs 6.3) and tear film break-up time (7.3 and 8.0 vs 4.8) higher. CONCLUSION: The majority of patients had ongoing lifitegrast treatment 6-months post-index with reduction in overall treatment burden. Improvement in DED signs and symptoms, including QoL impacts, was evident at 3 months and up to 12 months after lifitegrast initiation.

Risk Factors for COVID-19 and Rheumatic Disease Flare in a US Cohort of Latino Patients.

OBJECTIVE: Latino patients are overrepresented among cases of coronavirus disease 2019 (COVID-19) and are at an increased risk of severe disease. Prevalence of COVID-19 in Latinos with rheumatic diseases is poorly reported. This study was undertaken to characterize COVID-19 clinical features and outcomes in Latino patients with rheumatic diseases. METHODS: We conducted a retrospective study of Latino patients with rheumatic diseases from an existing observational cohort in the Washington, DC area. Patients seen between April 1, 2020 and October 15, 2020 were analyzed in this study. We reviewed demographic characteristics, body mass index (BMI), comorbidities, and use of immunomodulatory therapies. An exploratory classification and regression tree (CART) analysis along with logistic regression analyses were performed to identify risk factors for COVID-19 and rheumatic disease flare. RESULTS: Of 178 Latino patients with rheumatic diseases, 32 (18%) were identified as having COVID-19, and the incidence rate of infection was found to be 3-fold higher than in the general Latino population. No patients required intensive care unit-level care. A CART analysis and multivariable logistic regression analysis identified a BMI of >30.35 as a risk factor for COVID-19 (odds ratio [OR] 3.37 [95% confidence interval (95% CI) 1.5-7.7]; P = 0.004). COVID-19 positivity was a risk factor for rheumatic disease flare (OR 4.57 [95% CI 1.2-17.4]; P = 0.02). CONCLUSION: Our findings indicate that Latino patients with rheumatic diseases have a higher rate of COVID-19 compared with the general Latino population. Obesity is a risk factor for COVID-19, and COVID-19 is a risk factor for rheumatic disease flare. Latino patients with risk factors should be closely followed up, especially post-COVID-19 in anticipation of disease flare.

Characterization of autoantibodies, immunophenotype and autoimmune disease in a prospective cohort of patients with idiopathic CD4 lymphocytopenia.

OBJECTIVE: Characterize autoantibodies and autoimmune diseases in a prospective cohort of patients with Idiopathic CD4 Lymphocytopenia (ICL) a rare immunodeficiency characterized by an absolute CD4+ T count of <300 cells/µl in the absence of HIV or HTLV infection. METHODS: Single-Center prospective study of 67 patients conducted over an 11-year period. Rheumatologic evaluation and measurement of autoantibodies were systematically conducted, and flow cytometry of immune cell subsets was performed in a subset of patients. RESULTS: 54% of referred patients had clinical evidence of autoimmunity, with 34% having at least one autoimmune disease, most commonly autoimmune thyroid disease. 19%, had autoantibodies or incomplete features of autoimmune disease. Patients with autoimmune disease had more elevated serum immunoglobulins, and more effector memory T cells than those without autoimmunity. CONCLUSIONS: Evidence of autoimmunity, including autoimmune diseases, is more prevalent in ICL than the general population, and should be considered part of this syndrome.

Neutrophil-mediated carbamylation promotes articular damage in rheumatoid arthritis.

Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamylated proteins and that RA subjects develop autoantibodies against carbamylated NET (cNET) antigens that, in turn, correlate with levels of anti-CarP. Transgenic mice expressing the human RA shared epitope (HLADRB1* 04:01) immunized with cNETs develop antibodies to citrullinated and carbamylated proteins. Furthermore, anti-carbamylated histone antibodies correlate with radiographic bone erosion in RA subjects. Moreover, anti-carbamylated histone-immunoglobulin G immune complexes promote osteoclast differentiation and potentiate osteoclast-mediated matrix resorption. These results demonstrate that carbamylated proteins present in NETs enhance pathogenic immune responses and bone destruction, which may explain the association between anti-CarP and erosive arthritis in RA.

Immune checkpoint inhibitor-induced inflammatory arthritis: identification and management.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have proved to be groundbreaking in the field of oncology. However, immune system overactivation from ICIs has introduced a novel medical entity known as immune-related adverse events (irAEs), that can affect any organ or tissue. ICI-induced inflammatory arthritis (ICI-IIA) is the most common musculoskeletal irAE and can lead to significant morbidity and limitation in anti-cancer therapy. AREAS COVERED: In this review, the authors focus on ICI-IIA. Relevant articles were identified through PubMed searches, spanning 2010 to the present. The authors detail the current understanding of its pathogenesis, diagnostic evaluation, and management strategies. EXPERT OPINION: ICI-IIA is a complex irAE that we are just beginning to understand mechanistically and pathologically. It often presents later in the disease course than other irAEs and, due to various reasons, is under-recognized. In some patients, ICI-IIA may become a chronic disease, which distinguishes it from most irAEs that resolve after ICI discontinuation. Multiple important questions still demand further research including which patients may develop ICI-IIA? What are possible diagnostic and prognostic markers? Do anti-arthritis therapies interfere with the anti-tumor response? and when should steroid-sparing agents be initiated? Close collaboration and shared decision-making between oncologists, rheumatologists, and the patient are essential when managing this particular irAE.

Safety of Janus Kinase Inhibitors in Older Patients: A Focus on the Thromboembolic Risk.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a membrane-to-nucleus signaling cascade that effects activation of gene transcription. JAK inhibitors have demonstrated effectiveness in autoimmune diseases such as rheumatoid arthritis. An increased risk of infection, mainly varicella-zoster reactivation, with these new agents is of concern. Comorbid conditions, along with pharmacokinetic variations in drug metabolism in the older population, further increase the risk of adverse outcomes. Newly raised concerns for potential adverse effects such as deep vein thrombosis and pulmonary embolism are essential considerations for clinicians. Older patients are at increased risk because of multiple comorbid conditions and pharmacokinetic changes related to drug metabolism and excretion. Both the US FDA and the European Medicines Agency have issued warnings regarding this risk. These warnings highlight individuals aged > 50 years with concomitant cardiovascular risk factors. Furthermore, the FDA released a black box warning for increased thromboembolic risk associated with JAK inhibitors. As the use of these drugs increases, a solid understanding of adverse effects and risks is critical to those treating older adults.

PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study.

BACKGROUND: Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success. METHODS: The novel PET tracer [11C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [11C]PS13. RESULTS: COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BPND) of [11C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [11C]PS13, was observed. The day after the second LPS injection, a brain lesion (~ 0.5 cm in diameter) with high COX-2 density and high BPND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [11C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [11C]MC1 successfully imaged upregulated COX-2 in the arthritic hand and shoulder and apparently in the brain. Uptake was blocked by celecoxib, a COX-2 preferential inhibitor. CONCLUSIONS: Taken together, these results indicate that [11C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03912428. Registered April 11, 2019.

A Panoply of Rheumatological Manifestations in Patients with GATA2 Deficiency.

PURPOSE: To characterize rheumatological manifestations of GATA2 deficiency. METHODS: Single-center, retrospective review of 157 patients with GATA2 deficiency. Disease course, laboratory results, and imaging findings were extracted. In-person rheumatological assessments were performed on selected, available patients. A literature search of four databases was conducted to identify additional cases. RESULTS: Rheumatological findings were identified in 28 patients, out of 157 cases reviewed (17.8%). Twenty-two of those patients (78.6%) reported symptom onset prior to or in conjunction with the molecular diagnosis of GATA2 deficiency. Notable rheumatological manifestations included: piezogenic pedal papules (PPP), joint hyperextensibility, early onset osteoarthritis, ankylosing spondylitis, and seronegative erosive rheumatoid arthritis. In peripheral blood of patients with rheumatological manifestations and GATA2 deficiency, CD4+ CD3+ helper T cells and naïve CD3+ CD4+ CD62L+ CD45RA+ helper T cell subpopulation fractions were significantly lower, while CD8+ cytotoxic T cell fractions were significantly higher, compared to those without rheumatological manifestations and with GATA2 deficiency. No changes in CD19, CD3, or NK populations were observed. CONCLUSION: GATA2 deficiency is associated with a broad spectrum of rheumatological disease manifestations. Low total helper T lymphocyte proportions and low naïve helper T cell proportions are associated with those most at risk of overt rheumatological manifestations. Further, PPP and joint hyperextensibility may explain some of the nonimmunologically-mediated joint problems encountered in patients with GATA2 deficiency. This catalogue suggests that rheumatological manifestations and immune dysregulation are relatively common in GATA2 deficiency.

Loteprednol Etabonate for the Treatment of Dry Eye Disease.

Dry eye disease (DED) is a common ocular condition that can impair vision and may adversely impact quality of life. Due to the inflammatory nature of this disorder, topical corticosteroids are an effective treatment option, particularly for moderate-to-severe DED when first-line treatments, such as ocular lubricants, are insufficient. Loteprednol etabonate (LE) is a retrometabolically designed corticosteroid with a low propensity to cause corticosteroid-related adverse effects, such as elevated intraocular pressure (IOP). This review was conducted to provide an assessment of published studies on the use of LE for treatment of inflammation associated with DED. Twelve prospective and 2 retrospective studies evaluating LE ophthalmic suspension 0.5% and 2 prospective studies evaluating LE ophthalmic gel 0.5% were identified. LE given as monotherapy or with artificial tears (AT) improved signs of DED, especially among patients with a more pronounced inflammatory component, and also improved DED symptoms compared to baseline and/or control. Treatment with LE before cyclosporine A (CsA) therapy reduced stinging upon CsA initiation and provided more rapid relief of DED signs and symptoms than CsA plus AT alone. In patients with meibomian gland dysfunction, LE alone, or in addition to eyelid scrubs/warm compresses, reduced clinical signs and symptoms, and tear proinflammatory cytokine levels. Overall, LE was safe and well tolerated, with minimal effects on IOP. While larger and longer-term studies are warranted, these data support the use of LE as a safe and effective treatment option for DED.