Long-term safety and efficacy of risankizumab for the treatment of moderate-to-severe plaque psoriasis: Interim analysis of the LIMMitless open-label extension trial up to 5 years of follow-up.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease often requiring long-term therapy. OBJECTIVE: To evaluate the long-term safety and efficacy of risankizumab in patients with psoriasis. METHODS: LIMMitless is an ongoing phase 3, open-label extension study evaluating the long-term safety and efficacy of continuous risankizumab 150 mg every 12 weeks for adults with moderate-to-severe plaque psoriasis following multiple phase 2/3 base studies. This interim analysis assessed safety (ie, monitored treatment-emergent adverse events [TEAEs]) through 304 weeks. Efficacy assessments included determining the proportion of patients who achieved ≥90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90/100), static Physician's Global Assessment of clear/almost clear (sPGA 0/1), and Dermatology Life Quality Index of no effect on patient's life (DLQI 0/1) through 256 weeks. RESULTS: Among 897 patients randomized to risankizumab in the base studies, 706 were still ongoing at data cutoff. Rates of TEAEs, TEAEs leading to discontinuation, and TEAEs of safety interest were low. At week 256, 85.1%/52.3% of patients achieved PASI 90/100, respectively, 85.8% achieved sPGA 0/1, and 76.4% achieved DLQI 0/1. LIMITATIONS: Open-label study with no placebo or active-comparator group. CONCLUSIONS: Long-term continuous risankizumab treatment for up to 5 years was well tolerated and demonstrated high and durable efficacy.

Comparative Effectiveness of Persistent Use of a Name-Brand Levothyroxine (Synthroid®) vs. Persistent Use of Generic Levothyroxine on TSH Goal Achievement: A Retrospective Study Among Patients with Hypothyroidism in a Managed Care Setting.

INTRODUCTION: Levothyroxine monotherapy (Synthroid® or multiple generic levothyroxine [GL] formulations) is standard treatment for hypothyroidism. Our objective was to compare effectiveness (as measured by achievement of thyroid-stimulating hormone [TSH] levels) and economic outcomes of Synthroid vs. any one of multiple GLs in patients with hypothyroidism. METHODS: Data for this retrospective cohort study were obtained from the HealthCore Integrated Research Database®. All study patients had ≥ 2 claims between 1 January 2006 and 31 December 2017 with ICD-9/10-CM diagnosis codes for hypothyroidism; were persistent users of Synthroid vs. any GL; and had ≥ 1 TSH laboratory result during 12-month follow-up. Patients were divided into one of two cohorts based on index medication and were 1:1 matched using propensity scores. The primary outcome was the proportion of patients with last TSH laboratory result during follow-up within the reference range (0.3-4.12 mIU/L). Secondary outcomes included all-cause and hypothyroidism-related healthcare resource utilization (HCRU) and costs. RESULTS: After propensity score matching, the Synthroid and GL cohorts each contained 18,382 patients. At follow-up, significantly more patients receiving Synthroid were in the TSH reference range vs. GL (78.5% vs. 77.2%, respectively, p = 0.002). HCRU and costs were broadly similar between the cohorts in terms of all-cause inpatient hospitalizations, emergency department visits, outpatient services, and pharmacy fills. Irrespective of index medication, patients with TSH within the reference range had significantly lower hypothyroidism-related medical and total costs compared to those outside the range. CONCLUSIONS: This real-world data study showed Synthroid was associated with better TSH target achievement vs. GL in a US managed care population. Achieving TSH goals may provide substantial economic value by reducing hypothyroidism-related HCRU and costs.

The direct and indirect economic burden of hypothyroidism in the United States: a retrospective claims database study.

OBJECTIVE: To examine direct and indirect economic burden associated with hypothyroidism in the United States. METHODS: Medical costs attributable to hypothyroidism were estimated for patients with hypothyroidism. Non-hypothyroid (euthyroid) controls were matched to patients with hypothyroidism based upon patient characteristics and availability of productivity data. Multivariable analyses examined resource utilization, annual medical costs, comorbidities, and productivity costs. RESULTS: Estimates of hypothyroidism-related total medical costs ranged from $460 to $2,555 per patient per year. Compared to euthyroid controls, patients with hypothyroidism had significantly higher all-cause medical costs and medical resource utilization. For the subset of patients with available productivity data, hypothyroidism was associated with significantly higher absenteeism and long- and short-term disability costs but significantly lower worker's compensation costs. CONCLUSIONS: Hypothyroidism is associated with significant direct and indirect economic burden among employed, commercially insured patients in the US. Clinical Significance: Despite the availability of relatively inexpensive generic therapies for hypothyroidism, this study found significant direct and indirect costs associated with the condition. The large number of patients diagnosed with hypothyroidism combined with increased costs associated with hypothyroidism result in a significant burden for patients, payers, and employers.

The Association Between Switching from Synthroid® and Clinical Outcomes: US Evidence from a Retrospective Database Analysis.

INTRODUCTION: Clinical guidelines recommend levothyroxine as the standard of care for hypothyroidism and that patients should be treated with a consistent preparation of synthetic levothyroxine without switching among formulations. This study examines the likelihoods of negative clinical outcomes between continuous users of Synthroid® (AbbVie, Inc.) and patients who switch from Synthroid® to an alternative formulation of levothyroxine. METHODS: This retrospective cohort analysis utilized data from Optum Clinformatics™ DataMart covering May 1, 2000 to March 30, 2016. After 6 months of consistent use of Synthroid®, patients were categorized as continuous users or as switchers (by filling a prescription for an alternative formulation). Key outcomes included the likelihood of a thyroid-stimulating hormone (TSH) laboratory value out of a guideline recommended range and/or an adverse clinical composite endpoint identified by ICD codes in the patient's claims data over the following 2 years for any of the following: chronic kidney disease, depression, fatigue, heart failure, hyperlipidemia, hypertension, or obesity. Individual components of the composite endpoint were also examined. Outcomes were analyzed using multivariable logistic models on propensity score matched cohorts. Analyses controlled for patient characteristics using SAS 9.4 software. Chi-square and t tests were employed and P < 0.05 was pre-specified as statistically significant. RESULTS: Propensity score matching resulted in a sample of 9925 continuous users and 9925 switchers. Switchers were significantly more likely than continuers to have a TSH laboratory value out-of-range in the post-period [odds ratio (OR) 1.15; 95% confidence interval (CI) (1.08-1.23)]. Switchers were also more likely to have the composite clinical endpoint [OR 1.23; CI (1.12-1.37)] and to have individual diagnoses of chronic kidney disease, depression, fatigue, hypertension, or obesity in the post-period. CONCLUSIONS: Results of this large retrospective study over an extended time horizon support clinical guideline recommendations that switching among alternative formulations of synthetic levothyroxine should generally be avoided. Continuous use of Synthroid® was associated with a significantly higher likelihood of maintaining the TSH laboratory value within a guideline recommended range and a significantly lower likelihood of being diagnosed with adverse clinical outcomes.

Hypothyroidism Treatment Among Older Adults: Evidence from a Claims Database.

INTRODUCTION: Hypothyroidism is a common but often unrecognized condition associated with significant morbidity in the older adult population. This study characterizes a large population of older adults diagnosed with hypothyroidism and examines concordance of their treatment with recommendations from expert bodies, e.g., the American Thyroid Association and American Association of Clinical Endocrinologists. METHODS: Individuals seen in general and/or specialty practices who were age ≥ 65 years and diagnosed with hypothyroidism were included in this observational, retrospective cohort study using a large US claims database. Analyses describe the population and examine the prevalence of hypothyroidism, treatment with levothyroxine and, among those treated, whether TSH laboratory values are within a guideline-recommended target range. RESULTS: Prevalence of hypothyroidism in this older adult population increased from 5.62% to 8.24% over the 2007-2015 period. Among older adults diagnosed with hypothyroidism (N = 4025), a substantial proportion (28.0%) did not receive levothyroxine therapy, and, of those who were receiving such therapy (N = 2899), 32.9% did not have evidence of being monitored to determine whether the dosage was appropriate. Moreover, the laboratory results of those who were treated suggest that a significant proportion (17.4%) had a TSH level above the recommended target range, while TSH levels for a smaller proportion (3.7%) were below target. CONCLUSIONS: Many older adults diagnosed with hypothyroidism may not have received medical care complying with clinical practice guidelines. Results of this study reveal a number of areas to target to potentially improve the treatment of older adults with hypothyroidism.

Levothyroxine Treatment of Pregnant Women with Hypothyroidism: Retrospective Analysis of a US Claims Database.

BACKGROUND: Approximately 2-4% of women of reproductive age have hypothyroidism. This study characterizes pregnant women with hypothyroidism and examines adherence to guidelines during pregnancy. METHODS: Women age 18 to 49 who were pregnant in 2014 and identified with hypothyroidism (N = 3448) were included in the retrospective study. The analyses examined differences in characteristics and comorbidities between pregnant women treated with levothyroxine and untreated women and adherence to guidelines by measuring thyroid-stimulating hormone (TSH) target achievement for women treated with levothyroxine. RESULTS: The average age was 32.76 years, and the median TSH value was 1.97 mIU/l. Compared with untreated pregnant women, pregnant women treated with levothyroxine were significantly younger, had a lower Charlson Comorbidity Index score and had lower rates of comorbid type 2 diabetes and migraines. Among women treated with levothyroxine, 52.61% had a last recorded TSH value consistent with American Thyroid Association (ATA) guidelines, 23.85% were undertreated, 1.03% were overtreated, and 22.52% did not have TSH monitored during their pregnancy. CONCLUSIONS: A large percentage of pregnant women, including many treated with levothyroxine, was not treated in a manner consistent with clinical guidelines. Additionally, there were significant differences in general health and comorbidities between pregnant women treated with levothyroxine and those untreated.

The association between adherence to levothyroxine and economic and clinical outcomes in patients with hypothyroidism in the US.

OBJECTIVE: To evaluate outcomes associated with adherence to levothyroxine (LT4) in the US adult hypothyroidism population. METHODS: We used data from Truven's MarketScan databases from 1 July 2011 through 31 December 2015. Patients aged 18 or older were diagnosed with hypothyroidism (confirmed at least twice) and prescribed LT4. Patients were excluded if they did not have continuous insurance coverage or if they received a diagnosis of thyroid cancer or pregnancy during the study period. Multivariable analyses on a matched cohort of adherent and nonadherent patients examined the relationships among patient outcomes and adherence, defined as the proportion of days covered ≥80%. Outcomes included all-cause and hypothyroidism-related medical costs and resource utilization and comorbid diagnoses measured over the 1 year post-period following the first prescription for LT4. The analyses controlled for patient age, sex, region of residence, type of insurance coverage, diagnosing physician and pre-period general health status as proxied by the Charlson Comorbidity Index. RESULTS: Prior to matching, there were 168,457 patients identified as adherent and 198,443 patients identified as nonadherent. The matched cohort consisted of 318,628 individuals, with equal numbers of adherent and nonadherent patients (n = 159,314). Patients who were adherent used significantly fewer resources and had significantly lower all-cause ($14,136 vs. $14,926; p < .0001) and hypothyroidism-related ($1672 vs. $1709; p < .0001) total costs, although the costs of drugs were higher in the adherent group. Furthermore, adherent patients, compared to nonadherent patients, were significantly less likely to be diagnosed with comorbid Addison's disease, bipolar disorder, chronic kidney disease, depression, migraine, obesity, type 1 diabetes or type 2 diabetes during the follow-up period. CONCLUSIONS: Compared to nonadherence, adherence to LT4 among patients with hypothyroidism was associated with a significant reduction in all-cause and hypothyroidism-related costs and resource utilization as well as significantly lower rates of many comorbid diagnoses.

Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy.

OBJECTIVE: Hypothyroidism is relatively common, occurring in approximately 5% of the general US population aged ≥12 years. Levothyroxine (LT4) monotherapy is the standard of care. Approximately, 5%-10% of patients who normalise thyroid-stimulating hormone levels with LT4 monotherapy may have persistent symptoms that patients and clinicians may attribute to hypothyroidism. A long-standing debate in the literature is whether addition of levotriiodothyronine (LT3) to LT4 will ameliorate lingering symptoms. Here, we explore the evidence for and against LT4/LT3 combination therapy as the optimal approach to treat euthyroid patients with persistent complaints. METHODS: Recent literature indexed on PubMed was searched in March 2017 using the terms "hypothyroid" or "hypothyroidism" and "triiodothyronine combination" or "T3 combination." Relevant non-review articles published in English during the past 10 years were included and supplemented with articles already known to the authors. FINDINGS: Current clinical evidence is not sufficiently strong to support LT4/LT3 combination therapy in patients with hypothyroidism. Polymorphisms in deiodinase genes that encode the enzymes that convert T4 to T3 in the periphery may provide potential mechanisms underlying unsatisfactory treatment results with LT4 monotherapy. However, results of studies on the effect of LT4/LT3 therapy on clinical symptoms and thyroid-responsive genes have thus far not been conclusive. CONCLUSIONS: Persistent symptoms in patients who are biochemically euthyroid with LT4 monotherapy may be caused by several other conditions unrelated to thyroid function, and their cause should be aggressively investigated by the clinician.

Evaluation of Lipid Profile and Residual Cardiovascular Risk in Patients Prior to Initiation of Niaspan Therapy.

Background: Despite significant impact of statins, there are a number of patients with residual risk of cardio vascular disease who have optimally controlled low-density lipoprotein cholesterol (LDL-C). Niaspan (extended-release nicotinic acid or niacin-ER) is indicated for its use as monotherapy for the treatment of very high triglyceride (TG) levels and for the raising of high-density lipoprotein cholesterol (HDL-C) representing those residual risk populations. The patient characteristics and lipid profile, prior to initiation of therapy, in the real-world clinical setting has not been well documented. Objectives: This study evaluated lipid levels among patients initiating Niaspan in real-world clinical practice. Methods: Patients with a first prescription of Niaspan were identified using electronic medical record data from GE. Lipid values were categorized into optimal and nonoptimal TG or HDL-C levels. Results: There were 89 091 new users. Most patients had nonoptimal TG, HDL-C, TG/HDL-C ratio, LDL-C, and non-HDL-C levels. Among those with nonoptimal TG and HDL, the ratio of TG to HDL-C was higher among younger age groups (mean ratio 12.0 in males; 10.58 in females aged 18 to <40 years). TG was significantly correlated with non-HDL-C (0.41, P < .001) but not with LDL-C. Among those with LDL-C <100 mg/dL, 64.3% had nonoptimal TG/HDL-C ratio and approximately 70% had non-HDL-C ≥130 mg/dL. More than a third of the patients had diagnosis of coronary heart disease or coronary heart disease risk equivalent. Conclusion: Majority of Niaspan users had nonoptimal TG and/or HDL-C. The correlation of nonoptimal TG levels with non-HDL-C levels further support that Niaspan was targeted to population with residual risk for cardiovascular disease.

Gluten and Aluminum Content in Synthroid® (Levothyroxine Sodium Tablets).

INTRODUCTION: Inquiries from healthcare providers and patients about the gluten and aluminum content of Synthroid® (levothyroxine sodium tablets) have increased. The objective of this study was to measure and evaluate the gluten content of the raw materials used in the manufacturing of Synthroid. Additionally, this study determined the aluminum content in different strengths of Synthroid tablets by estimating the amount of aluminum in the raw materials used in the manufacturing of Synthroid. METHODS: Gluten levels of three lots of the active pharmaceutical ingredient (API) and one lot of each excipient from different vendors were examined. The ingredients in all current Synthroid formulations (strengths) were evaluated for their quantity of aluminum. RESULTS: Gluten concentrations were below the lowest limit of detection (<3.0 ppm) for all tested lots of the API and excipients of Synthroid tablets. Aluminum content varied across tablet strengths (range 19-137 µg/tablet). Gluten levels of the API and excipients were found to be below the lowest level of detection and are considered gluten-free based on the US Food and Drug Administration (FDA) definition for food products. Across the various tablet strengths of Synthroid, the maximum aluminum levels were well below the FDA-determined minimal risk level for chronic oral aluminum exposure (1 mg/kg/day). CONCLUSION: These data demonstrate that Synthroid tablets are not a source for dietary gluten and are a minimal source of aluminum. FUNDING: AbbVie Inc.

Diagnosis and Management of Subclinical Hypothyroidism in Elderly Adults: A Review of the Literature.

The estimated prevalence of subclinical hypothyroidism (SCH) in the general population is 3% to 8%. As the average age of the population in the United States and other countries continues to increase, the overall prevalence of SCH may also be expected to increase. Although age-related changes in thyroid function are well described, normal thyroid-stimulating hormone (TSH) reference limits, derived for age-specific populations, are not routinely used to identify thyroid dysfunction in elderly adults. Therefore, currently accepted values for the upper limit of normal of TSH may be inappropriate for diagnosing SCH in individuals aged 65 and older, resulting in potential overestimation of the prevalence of SCH in this population. This review discusses the current evidence of the effects of SCH on cardiovascular health and neuropsychiatric function in older adults. Although the results of some studies are conflicting, the overall evidence suggests that the consequences of SCH may be different for elderly adults than for younger populations. Treatment of SCH in older individuals requires special consideration with regard to thyroid hormone replacement therapy and expected clinical outcomes. Although careful identification of individuals with persistent SCH who could benefit from levothyroxine treatment is necessary, current evidence suggests that individuals with TSH levels greater than 10 mIU/L who test positive for antithyroid antibodies or are symptomatic may benefit from levothyroxine treatment to reduce the risk of progression to overt hypothyroidism, decrease the risk of adverse cardiovascular events, and improve their quality of life. After treatment is initiated, careful monitoring is essential.

Clinical perspectives on the rationale for potassium supplementation.

Hypokalemia is a common electrolyte disturbance, observed in > 20% of hospitalized patients. Hypokalemia, although not formally defined, is generally considered to be when serum potassium levels fall below the normal value of 3.6 mmol/L. In contrast to other electrolytes, potassium is primarily an intracellular ion: only 2% of all potassium in the body is present in the extracellular fluid, so a small decrease in serum potassium may represent a significant decrease in intracellular potassium. Individuals with mildly decreased potassium levels (3.0-3.5 mmol/L) may be asymptomatic, but patients with more pronounced decreases may report symptoms including muscle weakness, fatigue, and constipation. Very low serum potassium levels (≤ 2.5 mmol/L) can lead to muscle necrosis, paralysis, cardiac arrhythmias, and impaired respiration, which can be life-threatening. Absent comprehensive and robust treatment guidelines, strategies for the prevention or treatment of hypokalemia, such as how to diagnose hypokalemia, when to treat patients, what dosage regimen of potassium supplementation to use and for how long, are often based on the experience of the physician and empirical evidence. However, proper evaluation and treatment of hypokalemia in patients is essential because of associated morbidities. Because small potassium deficits in serum represent large body losses, potassium repletion requires substantial and prolonged supplementation. For patients with known risk factors for hypokalemia (e.g. hypertension, heart failure, or diabetes), careful monitoring is crucial to avoid the adverse sequelae associated with potassium deficits and to ensure that adequate and timely preventive measures can be taken. In this review, we provide practical insights into the etiology, differential diagnosis, and treatment of hypokalemia, including treatment strategies for patients with known risk factors.

Reversible morbidity markers in subclinical hypothyroidism.

IMPORTANCE: Subclinical hypothyroidism (SCH) is a common clinical entity with a putative role in a wide range of disorders. The impact of SCH on mortality and markers of morbidity has been demonstrated, but studies have shown inconsistent results. Evidence regarding the effect of levothyroxine treatment on reversing morbidity markers is emerging, but the value of treatment is still unclear. OBJECTIVE: The objectives of this review were to assess recent, high-quality studies evaluating the role of SCH in cardiovascular health, cognition, mood, pregnancy, anemia, and renal disease; to examine the effects of levothyroxine on reducing mortality or reversing markers of morbidity in these conditions; and to consider how new research insights may help guide clinical practice. EVIDENCE REVIEW: A PubMed search was conducted (using 'subclinical hypothyroidism' [Title/Abstract] AND morbidity [MeSH Subheading] as search criteria) and was restricted to human studies published in the English language between 1990 and 2013. Subsequent searches of retrieved articles yielded further studies, which were included based on quality. Emphasis was given to large observational studies, well-conducted meta-analyses, and randomized controlled trials. FINDINGS: The difficulty of diagnosing SCH, particularly in the elderly, may underlie many of the conflicting results seen in the literature. Increased understanding of the at-risk patient population will result in better selection of study subjects and, likely, unequivocal results. Regardless of the current confusion, emerging evidence suggests that certain markers of morbidity are reversed by levothyroxine therapy across the disorders examined here. CONCLUSION AND RELEVANCE: Future large, well-controlled studies will not only clarify the role of SCH but also help identify patients for whom levothyroxine treatment will provide the most benefit.

Laryngeal electromyography.

Laryngeal electromyography (LEMG) evaluates the integrity of the neuromuscular system in the larynx by recording action potentials generated in the laryngeal muscles during voluntary and involuntary contraction. LEMG is particularly useful for helping to differentiate between disorders involving upper motor neurons, lower motor neurons, peripheral nerves, the neuromuscular junction, muscle fibers, and the laryngeal cartilages and joints. LEMG should be considered to be an extension of the physical examination, not an isolated laboratory procedure. A careful history and laryngeal evaluation determine the indication for LEMG and which muscles or muscle groups, in particular, are to be studied. Abnormalities detected by LEMG are always interpreted within the context of the clinical picture.

Thoracic paraparesis following an embolic vascular event during lumbar spinal surgery.

OBJECTIVE: A case report illustrating the rare occurrence of thoracic paraparesis following the presumed occurrence of an embolic vascular event during lumbar spinal surgery is presented. The goal is to investigate the potential causes of acute postoperative paraparesis following lumbar spine surgery. A discussion of the symptoms, diagnosis, differential diagnosis, and management of spinal cord ischemia and postembolic infarction is presented. This manuscript is intended to heighten the awareness of the potential for this rare complication to improve the speed and accuracy of diagnosis, allowing the timely institution of appropriate treatment. METHODS: Data analyzed include the patient history, preoperative and postoperative physical examination, clinical course, imaging studies, and input of various consulting services. A review of the English literature on spinal cord ischemia and postembolic infarction was performed. RESULTS: The most likely etiology for the patient's acute postoperative paraparesis appears to be related to an embolic spinal cord infarction. CONCLUSIONS: Management of a spinal cord ischemic event should focus on the following key issues: a prompt diagnosis with timely perioperative imaging studies (magnetic resonance imaging), the attainment of a normotensive state, the institution of systemic anticoagulation if clinically warranted, and maximization of physical function through early rehabilitation.