Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort.

BACKGROUND: More than 80,000 postmenopausal breast cancer patients in the United States each year are estimated to begin a 5-year course of aromatase inhibitors (AIs) to prevent recurrence. AI-related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause. This study sought to describe 1-year arthralgia trajectories and baseline covariates among patients with AI and a postmenopausal comparison group. METHODS: Patients initiating AIs (n = 91) were surveyed at the time of AI initiation and at 6 repeated assessments over 1 year. A comparison group of postmenopausal women without breast cancer (n = 177) completed concomitantly timed surveys. Numeric rating scales (0-10) were used to measure pain in 8 joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes). Poisson regression models were used to analyze arthralgia trajectories and risk factors. RESULTS: By week 6, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means = 1.8, 95% confidence interval = 1.24-2.7, P = .002), adjusting for baseline characteristics. Arthralgia then worsened further over 1 year in the AI group. Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe arthralgia over time. CONCLUSIONS: Patients initiating AI should be told about the timing of arthralgia over the first year of therapy, and advised that it does not appear to resolve over the course of a year. Menopausal symptoms and joint-related comorbidity at AI initiation can help identify patients at risk for developing AI-related arthralgia.

The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*.

OBJECTIVES: Plasma tryptophan levels are associated with delirium in critically ill patients. Although tryptophan has been linked to the pathogenesis of other neurocognitive diseases through metabolism to neurotoxins via the kynurenine pathway, a role for kynurenine pathway activity in intensive care unit brain dysfunction (delirium and coma) remains unknown. This study examined the association between kynurenine pathway activity as determined by plasma kynurenine concentrations and kynurenine/tryptophan ratios and presence or absence of acute brain dysfunction (defined as delirium/coma-free days) in intensive care unit patients. DESIGN, SETTING, AND PATIENTS: This was a prospective cohort study that utilized patient data and blood samples from the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction trial, which compared sedation with dexmedetomidine vs. lorazepam in mechanically ventilated patients. MEASUREMENTS AND MAIN RESULTS: Baseline plasma kynurenine and tryptophan concentrations were measured using high-performance liquid chromatography with or without tandem mass spectrometry. Delirium was assessed daily using the Confusion Assessment Method for the Intensive Care Unit. Linear regression examined associations between kynurenine pathway activity and delirium/coma-free days after adjusting for sedative exposure, age, and severity of illness. Among 84 patients studied, median age was 60 yrs and Acute Physiology and Chronic Health Evaluation II score was 28.5. Elevated plasma kynurenine and kynurenine/tryptophan ratio were both independently associated with significantly fewer delirium/coma-free days (i.e., fewer days without acute brain dysfunction). Specifically, patients with plasma kynurenine or kynurenine/tryptophan ratios at the 75th percentile of our population had an average of 1.8 (95% confidence interval 0.6-3.1) and 2.1 (95% confidence interval 1.0-3.2) fewer delirium/coma-free days than those patients with values at the 25th percentile (p = .006 and p < .001, respectively). CONCLUSIONS: Increased kynurenine pathway activation, assessed by plasma kynurenine and kynurenine/tryptophan ratio, was associated with fewer days alive and without acute brain dysfunction in intensive care unit patients. Future studies are warranted to clarify this relationship and investigate potential therapeutic interventions.

TGFß signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment.

The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-ß (TGFß) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFß receptor 2 (TGFßR2) in lung epithelium were generated and crossed to cell fate reporter mice that express ß-galactosidase (ß-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFßR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFßR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/ß-gal(+)) fibroblasts. Attenuation of TGFß signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine.

A Blinded, Randomized, Placebo-Controlled Study to Investigate the Efficacy and Safety of Ferric Carboxymaltose in Iron-Deficient Patients with Fibromyalgia.

INTRODUCTION: This study sought to compare efficacy and safety of ferric carboxymaltose vs. placebo in iron-deficient patients with fibromyalgia. METHODS: This blinded, placebo-controlled, phase 2 study randomized adults with fibromyalgia and Revised Fibromyalgia Impact Questionnaire (FIQR) scores ≥ 60, ferritin levels < 0.05 µg/ml, and transferrin saturation < 20% (1:1) to receive ferric carboxymaltose [15 mg/kg (up to 750 mg)], or placebo (15 cc normal saline) intravenously on study days 0 and 5. Patients visited the clinic on days 14, 28, and 42 for efficacy and safety assessments. The primary efficacy endpoint was proportion of patients with a ≥ 13-point improvement from baseline to day 42 in FIQR scale score. Secondary endpoints included changes from baseline in FIQR scale, Brief Pain Inventory (BPI) total score, Medical Outcomes Study (MOS) Sleep scale, Fatigue Visual Numeric Scale (VNS), iron indices (transferrin saturation and ferritin), and safety. RESULTS: The efficacy analysis group comprised 80 patients, and the safety analysis group comprised 81. More ferric carboxymaltose patients (77%) vs. placebo patients (67%) achieved the primary endpoint, but the difference was not significant. Greater improvements from baseline to day 42 were observed for ferric carboxymaltose vs. placebo in FIQR total score, BPI total score, Fatigue VNS score, and iron indices. Mean changes in MOS Sleep scale scores were similar between groups. Ferric carboxymaltose was safe and well tolerated. CONCLUSIONS: Compared with placebo, ferric carboxymaltose improved measures of fibromyalgia severity and was well tolerated. The current results suggest that ferric carboxymaltose shows benefit in iron-deficient patients with concurrent fibromyalgia. FUNDING: Luitpold Pharmaceuticals, Inc. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02409459.

Fibromyalgia: the prototypical central sensitivity syndrome.

Fibromyalgia syndrome (FM), the most common central sensitivity syndrome (CSS) affecting over 5% of the population, is a disorder of chronic widespread pain accompanied by numerous other symptoms that causes significant functional impairment. The core FM symptom domains can be recalled using the FIBRO mnemonic and include Fatigue and Fog (cognitive dysfunction), Insomnia (difficulties with all aspects of sleep including initiation, maintenance and restorative), Blues (depression and anxiety), Rigidity (stiffness in muscles and joints) and Ow! (widespread pain and tenderness). While typically presenting in middle-aged women, FM can affect both sexes at any age. FM is a syndrome of abnormal central pain processing and increased central sensitivity caused by neurobiological changes that cause dysregulation of mechanisms that normally regulate pain sensation. There are currently three different methods for diagnosing FM; the 1990, 2010 and modified 2010 American College of Rheumatology (ACR) criteria. While disabling, FM symptoms can be managed with a regimen of pharmacologic and nonpharmacologic treatments. Medication types with benefit in treating FM include anticonvulsants, antidepressants, anti-inflammatories, muscle relaxers, tramadol, and stimulants. Beneficial nonpharmacologic therapies include aerobic and resistance exercise, stretching, cognitive behavioral therapy, and education. Effective management requires formulation of an individualized regimen since patients differ widely in symptoms and treatments they find beneficial. Such an individualized regimen should be based on a systematic assessment of problematic symptoms conducted at baseline and each follow-up with treatments modified over time. While challenging, FM symptoms can be effectively managed and patients can lead full, productive lives.

A comprehensive evaluation of standardized assessment tools in the diagnosis of fibromyalgia and in the assessment of fibromyalgia severity.

Standard assessments for fibromyalgia (FM) diagnosis and core FM symptom domains are needed for biomarker development and treatment trials. Diagnostic and symptom assessments are reviewed and recommendations are made for standards. Recommendations for existing assessments include the American College of Rheumatology FM classification criteria using the manual tender point Survey for diagnosis, the brief pain inventory average pain visual analogue scale for pain intensity, the function subscale of the revised fibromyalgia impact questionnaire (FIQR) for physical function, the patient global impression of change and FIQR for overall/global improvement, the hospital anxiety and depression scale depression subscale for depression, the multiple ability self-report questionnaire for cognitive dysfunction, the fatigue severity scale for fatigue, the FIQR for multidimensional function/health-related quality of life, the jenkins sleep scale for sleep disturbance, and the fibromyalgia intensity score for tenderness. Forthcoming assessments including the FIQR for diagnosis, NIH PROMIS, and FIBRO Change scales are discussed.

The cost-effectiveness of pregabalin in the treatment of fibromyalgia: US perspective.

OBJECTIVE: To evaluate the cost-effectiveness of pregabalin in the treatment of fibromyalgia in a US patient population. METHODS: A decision-analytic model was developed comparing pregabalin 150 mg twice a day (BID) and pregabalin 225 mg BID to placebo, duloxetine, gabapentin, tramadol, milnacipran, and amitriptyline in patients with severe fibromyalgia (Fibromyalgia Impact Questionnaire score >59; pain score >6.5). The model estimated response rates for all treatments at 12 weeks based on three randomized trials with pregabalin and a systematic review of published randomized controlled trials. Response was categorized as ≥30% improvement in baseline pain score plus global impression of change rating of much improved or very much improved. After 12 weeks of treatment, responders to treatment entered a treatment Markov model in which response was maintained, lost, or treatment discontinued. The cost-effectiveness end-points were cost per responder at 12 weeks and 1 year. Resource use was estimated from published studies and costs were estimated from the societal perspective. RESULTS: Over 12 weeks, total cost per patient was $229 higher with pregabalin 150 mg BID than placebo, whereas pregabalin 225 mg BID was $866 less costly than placebo. At 1 year, pregabalin was cost saving and more effective than placebo, duloxetine, tramadol, milnacipran, and gabapentin. Compared with amitriptyline, pregabalin was not cost-effective at both dosages, although when excluding old and methodologically weak studies of clinical effectiveness of amitriptyline, pregabalin 225 mg BID became cost saving and pregabalin 150 mg BID was cost-effective. LIMITATIONS: Comparisons between pregabalin and other active agents are based on indirect comparisons, not head-to-head trials, and so should be interpreted with caution. Limitations for comparators include an inability to access sub-group data, inconsistency of response definitions, inclusion of older trials, and absence of long-term studies. CONCLUSIONS: This model found pregabalin to be cost-effective in treating patients with severe fibromyalgia.

Portability of an algorithm to identify rheumatoid arthritis in electronic health records.

OBJECTIVES: Electronic health records (EHR) can allow for the generation of large cohorts of individuals with given diseases for clinical and genomic research. A rate-limiting step is the development of electronic phenotype selection algorithms to find such cohorts. This study evaluated the portability of a published phenotype algorithm to identify rheumatoid arthritis (RA) patients from EHR records at three institutions with different EHR systems. MATERIALS AND METHODS: Physicians reviewed charts from three institutions to identify patients with RA. Each institution compiled attributes from various sources in the EHR, including codified data and clinical narratives, which were searched using one of two natural language processing (NLP) systems. The performance of the published model was compared with locally retrained models. RESULTS: Applying the previously published model from Partners Healthcare to datasets from Northwestern and Vanderbilt Universities, the area under the receiver operating characteristic curve was found to be 92% for Northwestern and 95% for Vanderbilt, compared with 97% at Partners. Retraining the model improved the average sensitivity at a specificity of 97% to 72% from the original 65%. Both the original logistic regression models and locally retrained models were superior to simple billing code count thresholds. DISCUSSION: These results show that a previously published algorithm for RA is portable to two external hospitals using different EHR systems, different NLP systems, and different target NLP vocabularies. Retraining the algorithm primarily increased the sensitivity at each site. CONCLUSION: Electronic phenotype algorithms allow rapid identification of case populations in multiple sites with little retraining.

Simplifying Fibromyalgia Assessment: The VASFIQ Brief Symptom Scale.

OBJECTIVES: We tested the ability of the VASFIQ, a seven-item scale composed of Fibromyalgia Impact Questionnaire (FIQ) visual analog scales (VASs), to quantify fibromyalgia global disease severity and identify fibromyalgia patients with significant symptoms of fatigue, poor sleep, depression or anxiety. METHODS: Spearman rank correlations were used to compare global VASFIQ, FIQ and Patient Global Impression of Change (PGIC) scores and individual FIQ VAS scores with full-length, validated questionnaire scores for fatigue (Multidimensional Assessment of Fatigue-Global Fatigue Index [MAF-GFI]), poor sleep (Medical Outcomes Study Sleep Problems Index [SPI]) and depression and anxiety (Hospital Anxiety and Depression Scale [HADS]). Patient scores used in the analyses were derived from 2229 patients enrolled in three pregabalin fibromyalgia trials. Receiver operating characteristic analyses determined VASFIQ cutoff scores identifying patients with clinically significant symptom levels using full-length, validated symptom questionnaires to define cases. RESULTS: Global VASFIQ and FIQ scores correlated highly at baseline and study endpoints (ρ = 0.94 and 0.97, respectively; both p<0.0001). Change in global VASFIQ and FIQ scores correlated similarly to PGIC scores at study endpoints (ρ = 0.58 and 0.61, respectively; both p<0.0001). Individual FIQ VAS scores correlated with corresponding full-length symptom questionnaire scores at baseline and study endpoints (VASfatigue with MAF-GFI, ρ = 0.64 and 0.76; VASsleep with SPI, ρ = 0.50 and 0.67; VASdepression with HADS-D, ρ = 0.43 and 0.62; VASanxiety with HADS-A, ρ = 0.47 and 0.67, respectively; p <0.0001 for all). Patients with significant symptoms of fatigue were identified by VASfatigue >7.5, poor sleep by VASsleep >7.9, depression by VASdepression >5.8 and anxiety by VASanxiety >6.0. VASFIQ global scores ≥31.4 and ≥45.0 identified patients with moderate and severe global fibromyalgia symptoms, respectively. CONCLUSIONS: The VASFIQ scale accurately quantifies global fibromyalgia severity and identifies patients with significant symptoms of fatigue, poor sleep, depression or anxiety with brevity, enabling rapid patient assessment and informing treatment decisions in busy clinics.

Duloxetine in the management of diabetic peripheral neuropathic pain.

Diabetic neuropathy affects up to 70% of diabetics, and diabetic peripheral neuropathic pain (DPNP) is the most common and debilitating of the diabetic neuropathies. DPNP significantly reduces quality of life and increases management costs in affected patients. Despite the impact of DPNP, management is poor with one-quarter of patients receiving no treatment and many treated with medications having little or no efficacy in managing DPNP. Duloxetine is one of two drugs approved by the United States Food and Drug Administration for DPNP management. Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) proven safe, effective, and cost-saving in reducing DPNP symptoms at a dose of 60 mg/day. Duloxetine doses greater than 60 mg/day for DPNP management are not recommended since they are no more efficacious and associated with more side effects; addition of pregabalin or gabapentin for these patients may be beneficial. Side effects of duloxetine are generally mild and typical for the SNRI class including nausea, dizziness, somnolence, fatigue, sweating, dry mouth, constipation, and diarrhea. Given its other indications, duloxetine is a particularly good choice for DPNP treatment in patients with coexisting depression, anxiety, fibromyalgia, or chronic musculoskeletal pain. Duloxetine treatment had no clinically significant effect on glycemic control and did not increase the risk of cardiovascular events in diabetes patients. However, duloxetine use should be avoided in patients with hepatic disease or severe renal impairment. Given its safety, efficacy, and tolerability, duloxetine is an excellent choice for DPNP treatment in many patients.

The FIBRO System: A Rapid Strategy for Assessment and Management of Fibromyalgia Syndrome.

Fibromyalgia syndrome (FMS) is a complex disorder of widespread pain and tenderness associated with numerous other symptoms including fatigue, cognitive dysfunction, nonrestorative sleep, depression, anxiety, and stiffness. While new diagnostic criteria and previous management guidelines require quantitation of the severity of associated FMS symptoms experienced by individual patients, no system for rapid patient assessment has been made available to provide a basis for diagnosis, treatment selection and follow-up for clinicians in busy practices who have limited time. This review presents the FIBRO System, an easily remembered system for FMS symptom quantitation using the FIBRO mnemonic along with verbal questions on simple 0-10 scales to assess symptom severity (the FIBRO Problem Scale) and response to treatment (the FIBRO Change Scale) along with recommendations for pharmacologic and nonpharmacologic therapies to address individual FIBRO symptoms. This symptom-based approach can improve the care of FMS patients by providing a comprehensive, focused assessment in limited time.

Pregabalin for the management of fibromyalgia syndrome.

This last article in a three-part series on approved medications for managing fibromyalgia syndrome (FMS) reviews pregabalin (Lyrica(®)). Pregabalin was the first drug approved for FMS management and, as an anticonvulsant, differs from the other approved agents that are antidepressants. Pregabalin inhibits presynaptic excitatory neurotransmitter release by blocking α(2)δ calcium channels. Five randomized, placebo-controlled trials have demonstrated pregabalin reduces pain and improves sleep and health-related quality of life in FMS patients. While indicated dosing is 300-450 mg divided twice daily, initial dosing of 25-50 mg at night is recommended owing to side effects including somnolence, dizziness, and cognitive dysfunction. Since side effects such as weight gain and peripheral edema are dose-related, uptitration in weekly increments based on tolerability and therapeutic response is recommended. Due to its lack of protein binding and negligible hepatic metabolism, pregabalin can be safely combined with other medications and used in patients with renal failure when the dose is appropriate. Pregabalin may worsen sedation when combined with central nervous system depressants. Pregabalin should be discontinued gradually. Pregabalin-treated patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior. Pregabalin in combination with the other approved medications may be synergistic in treating FMS.

Milnacipran for the management of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a widespread pain condition associated with fatigue, cognitive dysfunction, sleep disturbance, depression, anxiety, and stiffness. Milnacipran is one of three medications currently approved by the Food and Drug Administration in the United States for the management of adult FMS patients. This review is the second in a three-part series reviewing each of the approved FMS drugs and serves as a primer on the use of milnacipran in FMS treatment including information on pharmacology, pharmacokinetics, safety and tolerability. Milnacipran is a mixed serotonin and norepinephrine reuptake inhibitor thought to improve FMS symptoms by increasing neurotransmitter levels in descending central nervous system inhibitory pathways. Milnacipran has proven efficacy in managing global FMS symptoms and pain as well as improving symptoms of fatigue and cognitive dysfunction without affecting sleep. Due to its antidepressant activity, milnacipran can also be beneficial to FMS patients with coexisting depression. However, side effects can limit milnacipran tolerability in FMS patients due to its association with headache, nausea, tachycardia, hyper- and hypotension, and increased risk for bleeding and suicidality in at-risk patients. Tolerability can be maximized by starting at low dose and slowly up-titrating if needed. As with all medications used in FMS management, milnacipran works best when used as part of an individualized treatment regimen that includes resistance and aerobic exercise, patient education and behavioral therapies.

Effective rheumatoid arthritis treatment requires comprehensive management strategies.

Work by Lee and colleagues has shown that decreased sleep quality and increased psychiatric distress increase pain sensitivity at both articular and nonarticular sites in rheumatoid arthritis (RA) patients. This work is consistent with prior studies showing that factors independent of RA disease activity can influence RA outcome measures. Owing to increasing pressure on rheumatologists to use outcome measures to inform treatment decisions, the work by Lee and colleagues highlights the need for comprehensive RA management strategies to understand and address the human factors that influence outcomes measures. Such strategies will ensure appropriate use of increasingly expensive therapies while maximizing patient satisfaction and reimbursement.

A symptom-based approach to pharmacologic management of fibromyalgia.

Fibromyalgia is a prevalent disorder that is characterized by widespread pain along with numerous other symptoms, including fatigue, poor sleep, mood disorders, and stiffness. Previous guidelines for the management of fibromyalgia recommended an approach that integrates pharmacologic and nonpharmacologic therapies selected according to the symptoms experienced by individual patients. However, they offered no recommendations for a system of patient assessment that would provide a basis for individualized treatment selection. We present a simple, rapid and easily remembered system for symptom quantitation and pharmacologic management of fibromyalgia that combines visual analogue scale symptom scores from a modified form of the disease-neutral Fibromyalgia Impact Questionnaire, with a review of medications that can be used to treat the individual symptoms. This symptom-based approach is amenable to caring for patients with fibromyalgia in a busy clinical practice.

Duloxetine for the management of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a widespread pain condition associated with a wide range of additional symptoms including fatigue, insomnia, depression, anxiety and stiffness. Duloxetine is one of three medications currently FDA approved for use in FMS management. Duloxetine is a mixed serotonin and norepinephrine reuptake inhibitor (SNRI) that functions by increasing central nervous system levels of serotonin and norepinephrine. This review is a primer on use of duloxetine in FMS management and includes information on pharmacology and pharmacokinetics, a review of the three duloxetine FMS treatment trials currently in publication, a discussion of the safety and tolerability of duloxetine, and patient-focused perspectives on duloxetine use in FMS management. Duloxetine has proven efficacy in managing pain and mood symptoms in adult FMS patients with and without major depressive disorder. However, due to side effects, duloxetine must be used with caution in patients with fatigue, insomnia, gastrointestinal complaints, headache, cardiovascular disease, bleeding-risk, and in those 24 years of age and younger due to risk of suicidality. Duloxetine use should be avoided in patients with liver disease or alcoholics. As with all medications, duloxetine is best used as part of an individualized regimen that includes nonpharmacologic modalities of exercise, education and behavioral therapies.