Rheumatic manifestations of endocrine disease.

PURPOSE OF REVIEW: Musculoskeletal complaints are a feature of several endocrine diseases. This review will update clinicians on their association, presentation, and treatment. RECENT FINDINGS: To update clinicians on the recent literature as it is related to pathophysiology, genetic, and clinical findings on the association of these diseases and musculoskeletal complaints. SUMMARY: Rheumatologists in the clinic are faced with different presentations of various musculoskeletal complaints every day. Every new patient encounter requires the differential diagnosis of these complaints. The first task is usually to decide with what disease in internal medicine these complaints are associated. The endocrinopathies are a group of illnesses that either present initially or exhibit sometime during the course of the disease as a variety of musculoskeletal complaints. Rheumatic manifestations may often be the initial presentation of an endocrine disorder. Each endocrine disorder may also have its own arthritic complaints, which can present as a definitive rheumatic disease such as calcium pyrophosphate dihydrate deposition disease or as a rheumatic symptom such as diffuse arthralgia. The rheumatologist as well as the primary care physician should be knowledgeable about the ways in which muscles, tendons, ligaments, and joints are affected by diseases of the endocrine system.

Comparison of physician and patient global assessments over time in patients with rheumatoid arthritis: a retrospective analysis from the RADIUS cohort.

BACKGROUND: In rheumatoid arthritis (RA), there is discordance between patient and physician assessments of disease severity and treatment response. OBJECTIVE: This retrospective analysis of the RADIUS (RA Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) 1 cohort examined specific factors that influence differences in global assessments for therapeutic effectiveness of disease-modifying antirheumatic drugs made by physicians (physician global assessment [PhGA]) and patients (patient global assessment [PtGA]). METHODS: The RADIUS 1 cohort consisted of primarily community-based private practice patients with RA requiring either the addition of or a switch to a new biologic or nonbiologic disease-modifying antirheumatic drug and who were followed for up to 5 years by their rheumatologists. Periodic assessments included PhGA, PtGA, Health Assessment Questionnaire-Disability Index (HAQ-DI), 28-item tender/painful joint count (TJC28), swollen joint count (SJC28), pain Visual Analog Scale (VAS), and acute-phase reactants. RESULTS: Among 4359 patients (mean disease duration, 7.3 years), PhGA most highly correlated with TJC28 (0.6956; 95% confidence interval [CI], 0.6881-0.7030) and SJC28 (0.6757; 95% CI, 0.6678-0.6834). Moderate overall correlations were observed for PtGA with TJC28 (0.5000; 95% CI, 0.4890-0.5108) and less 50 with SJC28 (0.3754; 95% CI, 0.3628-0.3878). Patient global assessment most strongly correlated with pain VAS (0.8349; 95% CI, 0.8305-0.8392) and moderately correlated with HAQ-DI (0.5979; 95% CI, 0.5886-0.6071). Acute-phase reactants poorly correlated with PhGA and PtGA. CONCLUSIONS: Low correlations between PhGA and acute-phase reactants suggest that these measurements have a limited contribution compared with the physical examination when physicians make global assessments. These results also suggest that physicians should consider patients' assessments of their disease activity (HAQ, pain VAS, and PtGA) and put joint counts into proper context.

Rheumatic manifestations of endocrine diseases.

PURPOSE OF REVIEW: Musculoskeletal complaints accompanying or as a result of endocrine disorders are common and have been well described. This review re-examines these associations in light of newer information on biology and genetics. RECENT FINDINGS: In this article, we describe the recent studies on pathophysiology of the muscular skeletal complaints in endocrine disease. In addition we report on population as well as genetic studies, which address the relationship between endocrine and rheumatologic disease, both of which are autoimmune. SUMMARY: Very often, the presentation of rheumatic manifestations is the initial presentation of endocrine disease. Being aware of the presentation as well as the unique physiology of these complaints will help alert the clinician to an early diagnosis of endocrine disease. In addition understanding whether certain endocrine disease occurs more often in rheumatologic illness will enable the clinician to investigate their occurrence early, leading to earlier intervention and resulting in decreased morbidity from these concomitant illnesses.

Opioid-sparing Effects of SoluMatrix Indomethacin in a Phase 3 Study in Patients With Acute Postoperative Pain.

OBJECTIVES: To report the opioid-sparing effects of SoluMatrix indomethacin, developed using SoluMatrix Fine Particle Technology, in a phase 3 study in patients with acute pain following bunionectomy. METHODS: This phase 3, placebo-controlled study randomized 462 patients with moderate-to-severe pain following bunionectomy surgery to receive SoluMatrix indomethacin 40 mg 3 times daily, SoluMatrix indomethacin 40 mg twice daily, SoluMatrix indomethacin 20 mg 3 times daily, celecoxib 400-mg loading dose followed by 200 mg twice daily, or placebo. Patients were permitted to receive opioid-containing rescue medication throughout the study. The proportion of patients who used rescue medication and the amount of rescue medication used on the first (0 to 24 h) and second (>24 to 48 h) days following initial dose of study medication, as well as time to first rescue medication use, were assessed. RESULTS: Significantly fewer patients who received SoluMatrix indomethacin 40 or 20 mg 3 times daily used opioid-containing rescue medication on day 1 compared with those receiving placebo (P≤0.034), and fewer patients in all active treatment groups used rescue medication during the second day compared with those in the placebo group (P<0.001). All active treatment groups used significantly fewer rescue medication tablets on days 1 and 2 following randomization compared with placebo (P<0.001). The most common adverse events were nausea, postprocedural edema, and headache. DISCUSSION: SoluMatrix indomethacin was associated with opioid-sparing effects in patients with acute postoperative pain.

Dietary Recommendations for Adults With Psoriasis or Psoriatic Arthritis From the Medical Board of the National Psoriasis Foundation: A Systematic Review.

Importance: Psoriasis is a chronic, inflammatory skin disease and has significant associated morbidity and effect on quality of life. It is important to determine whether dietary interventions help reduce disease severity in patients with psoriatic diseases. Objective: To make evidence-based dietary recommendations for adults with psoriasis and/or psoriatic arthritis from the Medical Board of the National Psoriasis Foundation. Evidence Review: We used literature from prior systematic reviews as well as additional primary literature from the MEDLINE database from January 1, 2014, to August 31, 2017, that evaluated the impact of diet on psoriasis. We included observational and interventional studies of patients with psoriasis or psoriatic arthritis. The quality of included studies was assessed using the Newcastle-Ottawa scale for observational studies and the Cochrane Risk of Bias Tool for interventional studies. We made evidence-based dietary recommendations, which were voted on by the National Psoriasis Foundation Medical Board. Findings: We identified 55 studies meeting the inclusion criteria for this review. These studies represent 77 557 unique participants of which 4534 have psoriasis. Based on the literature, we strongly recommend dietary weight reduction with a hypocaloric diet in overweight and obese patients with psoriasis. We weakly recommend a gluten-free diet only in patients who test positive for serologic markers of gluten sensitivity. Based on low-quality data, select foods, nutrients, and dietary patterns may affect psoriasis. For patients with psoriatic arthritis, we weakly recommend vitamin D supplementation and dietary weight reduction with a hypocaloric diet in overweight and obese patients. Dietary interventions should always be used in conjunction with standard medical therapies for psoriasis and psoriatic arthritis. Conclusions and Relevance: Adults with psoriasis and/or psoriatic arthritis can supplement their standard medical therapies with dietary interventions to reduce disease severity. These dietary recommendations from the National Psoriasis Foundation Medical Board will help guide clinicians regarding the utility of dietary interventions in adults with psoriatic diseases.

Real-world utilization of DMARDs and biologics in rheumatoid arthritis: the RADIUS (Rheumatoid Arthritis Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) study.

OBJECTIVE: Rheumatoid Arthritis (RA) Disease-Modifying Anti-Rheumatic Drug (DMARD) Intervention and Utilization Study (RADIUS) is a unique, real-world, prospective, 5-year, observational study of over 10 000 patients with RA. RADIUS provides a snapshot of use patterns, effectiveness, and safety of DMARDs, biologics, and combination therapies used to manage RA in clinical practice. RESEARCH DESIGN AND METHODS: Patients with RA requiring a new DMARD or biologic (addition or switch) were eligible for the RADIUS study. Two separate patient cohorts were enrolled; RADIUS 1 patients initiated any new therapy at entry, and RADIUS 2 patients initiated etanercept at entry. Patient demographics and disease activity measures were collected at study entry, and baseline characteristics were summarized for various subgroups. Effectiveness, safety, and patterns of use will be tracked for therapies utilized during the 5-year study. RESULTS: RADIUS 1 enrolled 4959 patients, and RADIUS 2 enrolled 5102 patients, mostly at community private practices (88%). In RADIUS 1, most patients initiated methotrexate (MTX) monotherapy, followed by MTX in combination with a biologic (e.g. infliximab plus MTX) or other DMARD. In RADIUS 2, most patients initiated etanercept in combination with MTX, followed by etanercept monotherapy. When a new therapy was required, physicians tended to add another therapy versus switching therapies. Patients initiating a biologic had a longer duration of RA and more severe disease compared with patients initiating non-biologic therapy. CONCLUSIONS: These real-world data provide evidence of the prescribing practices of rheumatologists in 2001-2003. Future analyses will allow evidence-based comparisons of the long-term safety and effectiveness of DMARDs, biologics, and combination therapies to assist physicians in clinical decision-making.

Treatment of persistent pain associated with osteoarthritis with controlled-release oxycodone tablets in a randomized controlled clinical trial.

OBJECTIVE: This study, lasting up to 90 days, was undertaken in patients with osteoarthritis with persistent moderate to severe pain uncontrolled by standard therapy (nonsteroidal anti-inflammatory drugs, acetaminophen, and/or short-acting opioids) to evaluate functional outcomes, as well as efficacy and safety, of controlled-release oxycodone versus placebo. METHODS: One hundred seven patients received either controlled-release oxycodone or placebo every 12 hours in this double blind, randomized, placebo-controlled, parallel-group study. Stable previous regimens of acetaminophen or nonsteroidal anti-inflammatory agents were allowed to continue. Primary efficacy variables included Brief Pain Inventory average pain intensity scores at completion of initial titration, Western Ontario and McMaster Universities Osteoarthritis Index scores at days 30 and 60, and the percentage of patients discontinuing due to inadequate pain control. RESULTS: Controlled-release oxycodone was significantly superior to placebo in decreasing average pain intensity and in reducing pain-induced interference with general activity, walking ability (except at day 30), and normal work, as well as mood, sleep, relations with people (at days 60 and 90), and enjoyment in life. Daily functioning, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index, was also significantly improved in the controlled-release oxycodone group. In the placebo group, a significantly greater percentage of patients discontinued due to inadequate pain control. Adverse events were consistent with opioid adverse events, and no safety concerns were noted. DISCUSSION: Treatment with controlled-release oxycodone of patients with osteoarthritis with persistent moderate to severe pain uncontrolled by standard therapy resulted in significant pain control and improvements in physical functioning.

Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. OBJECTIVE: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. DESIGN: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: 20 centers in the United States and Canada. PATIENTS: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. INTERVENTION: Leflunomide or matching placebo added to existing methotrexate therapy. MEASUREMENTS: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. RESULTS: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. CONCLUSIONS: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Low-dose SoluMatrix diclofenac in the treatment of osteoarthritis: A 1-year, open-label, Phase III safety study.

INTRODUCTION: Diclofenac is used for the treatment of osteoarthritis (OA); however, like other nonsteroidal anti-inflammatory drugs (NSAIDs) it can be associated with serious dose-related adverse events (AEs). Low-dose SoluMatrix® diclofenac has been developed to provide efficacy at lower diclofenac doses. A recently published Phase III study evaluated the efficacy and safety of SoluMatrix diclofenac 35 mg twice daily (b.i.d.) and thrice daily (t.i.d.) in patients with OA pain treated for 12 weeks. METHODS: This Phase III multicenter, open-label study assessed the safety of SoluMatrix diclofenac in patients with OA dosed up to 52 weeks (ClinicalTrials.gov: NCT01510912). The study enrolled 602 chronic NSAID/acetaminophen users, aged ≥40 years with OA of the knee or hip. Patients received SoluMatrix diclofenac 35 mg b.i.d., which could be increased to t.i.d. and subsequently reduced to b.i.d. as needed. Safety assessments included AEs, vital signs, physical examination findings, 12-lead electrocardiogram, and clinical laboratory test results. Patient-reported outcomes were evaluated by the Short Form-36 (SF-36). RESULTS: A total of 601 patients received SoluMatrix diclofenac; 373 of 601 patients (62.1%) received treatment for ≥11 months. The most frequent AEs included upper respiratory tract infection, headache, urinary tract infection, diarrhea, nasopharyngitis, and nausea. Serious gastrointestinal, cardiovascular, renal, and hepatic AEs were uncommon. A small proportion (99 patients, 16.5%) of patients discontinued participation in the study due to AEs. Clinically meaningful improvements from baseline in Physical Component Summary Scores of the SF-36 were noted at week 12 and were sustained through week 52. Improvements in six of the eight individual physical and mental SF-36 domains were also noted. CONCLUSION: SoluMatrix diclofenac treatment for up to 1 year was generally well tolerated in patients with OA pain and associated with improvement in quality of life measures. TRIAL REGISTRATION: www.clinicaltrials.gov identifier: NCT01510912.

The demographics of chronic pain management.

Pain is the most common symptom for which patients seek care. The management of pain advanced considerably with the development of cyclooxygenase (COX)-2-specific inhibitors (coxibs). The clinical usefulness of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is often limited by the occurrence of adverse effects, such as gastric toxicity and bleeding complications, which have been attributed to the inhibition of COX-1. At the recommended dosage by targeting only COX-2, coxibs offer patients anti-inflammatory and analgesic relief with reduced gastrotoxicity compared with traditional NSAIDs. Individualization of therapy based on a careful assessment of risks versus benefits of different agents is an important consideration in pain management. This review summarizes clinical evidence of the comparable efficacy but improved tolerability of the coxibs compared with conventional NSAIDs. Important patient considerations and risk factors involved in the selection of appropriate analgesic/anti-inflammatory treatments are highlighted.

Rheumatoid arthritis disease-modifying antirheumatic drug intervention and utilization study: safety and etanercept utilization analyses from the RADIUS 1 and RADIUS 2 registries.

OBJECTIVE: to report the rates of serious adverse events (SAE), serious infectious events (SIE), and events of medical interest (EMI) in patients receiving etanercept; to identify the risk factors for SAE, SIE, and EMI; and to report time to switching from etanercept therapy, reasons for switching, and time to restarting treatment with etanercept in patients with rheumatoid arthritis (RA) in US clinical practice. METHODS: adults ≥ 18 years of age who fulfilled the 1987 American Rheumatism Association criteria for RA were eligible for enrollment in 2 prospective, 5-year, multicenter, observational registries. RADIUS 1 (Rheumatoid Arthritis DMARD Intervention and Utilization Study) enrolled patients with RA who required a change in treatment [either an addition or a switch of a biologic or nonbiologic disease-modifying antirheumatic drug (DMARD)]. In RADIUS 2, patients with RA were required to start etanercept therapy at entry. Patients were seen at a frequency determined by their rheumatologist. RADIUS 1 and RADIUS 2 were registered under the US National Institutes of Health ClinicalTrials.gov identifiers NCT00116714 and NCT00116727, respectively. RESULTS: in these patients, SAE, SIE, and EMI occurred at rates comparable to those seen in clinical trials. No unexpected safety signals were observed. Rates for SAE, SIE, and EMI in etanercept-treated patients were comparable to rates observed in patients receiving methotrexate monotherapy and did not increase with greater exposure to etanercept therapy. CONCLUSION: the RADIUS registries provide a better understanding of the safety of etanercept in patients with RA in the US practice setting.

Persistence with anti-tumor necrosis factor therapies in patients with rheumatoid arthritis: observations from the RADIUS registry.

OBJECTIVE: To evaluate persistence with anti-tumor necrosis factor (TNF) therapy and predictors of discontinuation in patients with rheumatoid arthritis (RA). METHODS: This retrospective analysis used data from RADIUS 1, a 5-year observational registry of patients with RA, to determine time to first- and second-course discontinuation of etanercept, infliximab, and adalimumab. First-course therapy was defined as first exposure to anti-TNF therapy, and second-course therapy was defined as exposure to anti-TNF therapy after the first discontinuation. Kaplan-Meier survival analysis was used to assess persistence, log-rank tests were used to compare therapies, and Cox proportional hazards models were used to assess potential predictors of treatment discontinuation. RESULTS: This analysis included 2418 patients. Mean persistence rates were similar among treatments [first-course: etanercept, 51%; infliximab, 48%; adalimumab, 48% (followup was 54 weeks for etanercept and infliximab and 42 weeks for adalimumab); second-course: 56%, 50%, 46%, respectively (followup was 36 weeks for etanercept and infliximab and 30 weeks for adalimumab)]. Discontinuations of first-course therapy due to ineffectiveness were similar among treatments (etanercept, 19%; infliximab, 19%; adalimumab, 20%) and discontinuations due to adverse events were significantly (p = 0.0006) lower for etanercept than for infliximab (etanercept, 14%; infliximab, 22%; adalimumab, 17%). Predictors from univariable analysis of first- or second-course therapy discontinuation included increased comorbidities (etanercept), female sex (infliximab), Clinical Disease Activity Index > 22 (infliximab), and a Stanford Health Assessment Questionnaire score > 0.5 (adalimumab). CONCLUSION: In this population, first- and second-course persistence was similar among anti-TNF therapies. First-course discontinuation due to adverse events was lower with etanercept compared with infliximab.

Role of biological agents in immune-mediated inflammatory diseases.

A new era in the treatment of immune-mediated inflammatory disorders has begun with the clinical availability of anticytokine therapy. Biological agents that are currently available include 3 agents that decrease the activity of tumor necrosis factor-alpha (infliximab, adalimumab, etanercept) and an interleukin-1 receptor antagonist (anakinra), with many more in development. Those extraordinarily effective medications are an important addition to our therapeutic armamentarium, and, although originally developed for rheumatoid arthritis and Crohn disease, have been found to be efficacious in the treatment of seronegative spondyloarthropathies (psoriatic arthritis, ankylosing spondylitis) and juvenile rheumatoid arthritis. Their role is currently being defined in other autoimmune disorders such as uveitis, sarcoidosis, interstitial lung disease, vasculitis, inflammatory myopathies, graft-versus-host disease, and Sjögren syndrome.