An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-gamma and type I IFN-alphabeta signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-alphabeta signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.

Interferon-γ release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

OBJECTIVE: To evaluate the performance of an interferon-γ release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti-tumor necrosis factor therapy in patients with autoimmune inflammatory diseases. METHODS: This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test. RESULTS: In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157-0.279; P=0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guérin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P=0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P=0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported. CONCLUSION: In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST.

Rheumatoid Arthritis: Early Diagnosis and Treatment.

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disorder that manifests as a symmetric polyarthritis of small and large joints that may lead to joint and periarticular structural damage and the consequences of systemic inflammation. This overview of early RA examines the unmet needs and challenges in RA, how to best diagnose RA, and pitfalls in early diagnosis and treatment. The rules for referral to a rheumatologist are reviewed. Primary care physicians are at the front line of early diagnosis and need to start disease-modifying therapy as soon as a diagnosis of RA is established.

Rheumatoid Arthritis: Early Diagnosis and Treatment.

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disorder that manifests as a symmetric polyarthritis of small and large joints that may lead to joint and periarticular structural damage and the consequences of systemic inflammation. This overview of early RA examines the unmet needs and challenges in RA, how to best diagnose RA, and pitfalls in early diagnosis and treatment. The rules for referral to a rheumatologist are reviewed. Primary care physicians are at the front line of early diagnosis and need to start disease-modifying therapy as soon as a diagnosis of RA is established.

Perceptions of Pregnancy and Lactation from the Pregnancy and Lactation Autoimmune Network Registry.

OBJECTIVE: The Pregnancy and Lactation Autoimmune Network (PLAN) registry was established to evaluate the concerns of women with autoimmune or inflammatory rheumatic diseases (AIRD) pertaining to pregnancy and lactation. METHODS: The registry was started as a survey of patients with AIRD at a single rheumatology specialty center in November 2016 and included questions regarding fertility, pregnancy, miscarriages, and lactation before and after diagnosis. RESULTS: The study included 154 subjects from the PLAN registry. More than half (52%) of respondents indicated that their diagnosis negatively changed their views on pregnancy and nearly a third (30%) decided not to have children after AIRD diagnosis. Most (66%) women were concerned that medication use during the childbearing process would affect the baby. One-third (34%) indicated their views on breastfeeding negatively changed as a result of their disease diagnosis. The rates and duration of breastfeeding did not differ significantly for babies born before or after the mothers' diagnosis (p = 0.50 and p = 0.21, respectively). Eighteen women in our study avoided breastfeeding or stopped breastfeeding earlier than planned to start a medication (including etanercept, adalimumab, hydroxychloroquine, and certolizumab) they believed to be contraindicated during lactation. The PLAN registry included 19 women who breastfed 22 babies while being exposed to a disease-modifying antirheumatic drug or biologic. None of these 19 women reported a delay in their children's developmental milestones or higher infection rates. CONCLUSION: This study highlights an unmet need in patients with AIRD of childbearing potential for data and education regarding pregnancy and lactation.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

Unresolved issues in identifying and overcoming inadequate response in rheumatoid arthritis: weighing the evidence.

Rheumatoid arthritis (RA) is a chronic, multisystem, inflammatory disorder of the joints that affects about 1% of the world population. The ultimate goals of therapy include remission of disease and prevention of joint damage. Reaching these goals has become a realistic outcome for an increasing number of patients as treatment options have expanded over the past 3 decades. In addition to older therapies, such as methotrexate (MTX), other disease modifying drugs (DMARD), and tumor necrosis factor (TNF) inhibitors, newer biologic treatments have become available. For the substantial number of patients who experience an inadequate response to standard medications, biologic response modifiers (BRM) provide an important therapeutic alternative. The availability of multiple treatment options in the absence of clear definitions or criteria for remission and inadequate response, however, makes clinical decisions about measuring outcomes, predicting response to treatment, and prescribing pharmacologic therapies challenging. In this program, distinguished rheumatologists weigh the evolving body of clinical evidence to draw sound conclusions and resolve key issues in managing inadequate response to treatment and in achieving optimal outcomes in RA.

Routine Use of Quantitative Disease Activity Measurements among US Rheumatologists: Implications for Treat-to-target Management Strategies in Rheumatoid Arthritis.

OBJECTIVE: The aim of our study was to examine why real-world practices and attitudes regarding quantitative measurements of rheumatoid arthritis (RA) have received limited attention. METHODS: An e-mail survey asked US rheumatologists to self-report on their use of quantitative measurements (metric). RESULTS: Among 439 respondents, metric rheumatologists (58%) were more likely to be in group practice and to use tumor necrosis factor inhibitors. The quantitative tools most commonly used were the Health Assessment Questionnaire (35.5%) and the Routine Assessment of Patient Index Data 3 (27.1%). Reasons for not measuring included time needed and electronic availability. Based on simulated case scenarios, providing more quantitative information increased the likelihood that a patient would change to a different disease-modifying antirheumatic drug or biologic. CONCLUSION: Routine use of quantitative measurement for patients in the United States with RA is increasing over time but remains low.

Pregnancy Outcomes After Exposure to Certolizumab Pegol: Updated Results From a Pharmacovigilance Safety Database.

OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) medications are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti-TNF agents are often discontinued early in gestation. Certolizumab pegol (CZP), a PEGylated, Fc-free anti-TNF agent approved for the treatment of rheumatic diseases and/or Crohn's disease, has minimal to no active placental transfer. This analysis was undertaken to evaluate pregnancy outcomes in women receiving CZP, especially those exposed during early pregnancy. METHODS: Prospective and retrospective data on maternal CZP exposure were extracted from the UCB Pharma safety database through March 6, 2017. Analysis was limited to prospective reports to avoid potential bias associated with retrospective submissions. The numbers of live births, miscarriages, elective abortions, stillbirths, and major congenital malformations were ascertained. RESULTS: Of 1,137 prospectively reported pregnancies with maternal exposure to CZP, 528 (including 10 twin pregnancies) had 538 known outcomes: 459 live births (85.3%), 47 miscarriages (8.7%), 27 elective abortions (5.0%), and 5 stillbirths (0.9%). There were 8 major congenital malformations (1.7%) among the 459 infants. First trimester exposure occurred in 367 (81.2%) of 452 pregnancies resulting in 459 live births. Exposure during all 3 trimesters occurred in 201 (44.5%) of 452 pregnancies. CONCLUSION: This analysis represents the largest cohort of pregnant women exposed to an anti-TNF agent for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP, compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with CZP.

Iatrogenic rheumatic syndromes in the elderly.

Rheumatic complaints are common in the geriatric population. However, uncommonly autoimmune or musculoskeletal complaints and disorders may arise as a consequence of pharmacotherapy. These rare events include stain myopathy, drug-induced lupus, arthralgias, vasculitis, or tight skin syndromes. This article discusses the possible iatrogenic causes of rheumatic conditions, potential inciting agents, and the various types of rheumatic manifestations seen in the elderly.

Early rheumatoid arthritis -- is there a window of opportunity?

The early diagnosis and treatment of nascent rheumatoid arthritis (RA) has become a prime objective for rheumatologists and clinicians who care for patients with arthritis. Population-based studies have consistently shown that patients with RA are at substantial risk for progressive joint damage, disability, and increased morbidity and mortality. These inevitable outcomes are closely linked to the consequences of rheumatoid inflammation, which begins early and is progressive in all. At issue is whether early diagnosis, coupled with aggressive therapy, might alter the natural history of this RA. If this "window of opportunity" exists, then outcomes should be substantially altered by delivering the right therapies at the right time. A growing body of evidence has emphasized the consistent clinical and radiographic benefits of early, aggressive treatment of RA. These studies confirm that all therapies - monotherapy, combination disease modifying antirheumatic drugs (DMARD), biologics - work better in early disease than in long-established RA. Earlier identification, referral, and an accurate diagnosis of RA can now be rewarded with highly effective DMARD or biologic therapies. Rheumatologists should rise to the challenge and educate clinicians about this window of opportunity, the potential for remission, and superior clinical responses when patients with early RA or undifferentiated arthritis are referred to and managed by experts in aggressive rheumatologic care.

Acute polyarthritis.

Arthritis is the most common cause of disability. Hence, prompt recognition and management of acute-onset polyarthritis are paramount to prevent progressive damage. When rheumatoid arthritis is considered as a prototypical example of polyarthritis, the stakes of early and accurate evaluation are evident. The challenge is in determining when undifferentiated polyarthritis ends and rheumatoid arthritis begins. This chapter reviews the evidence to help clinicians identify and manage patients who present with acute polyarticular inflammation.

Remodeling a rheumatology practice to facilitate early referral.

In the next 12 months, 7500 Canadians and 75,000 Americans will be afflicted with the onset of rheumatoid arthritis. Little is known about the health care use of patients with early RA. Nonetheless, rheumatologists and outcomes researchers strongly endorse the need for early diagnosis and treatment of this population. This article reviews trends and impediments to early referral of new-onset arthritis patients. The slow growth of early arthritis clinics is summarized in a survey that characterizes 23 early arthritis programs in North America. Also, several screening tools and models to capture these early-onset arthritis patients are presented.

Iatrogenic rheumatic syndromes in the elderly.

Rheumatic complaints are common in the geriatric population. However, uncommonly autoimmune or musculoskeletal complaints and disorders may arise as a consequence of pharmacotherapy. These rare events include statin myopathy, drug-induced lupus, arthralgias, vasculitis, or tight skin syndromes. This article will discuss the possible iatrogenic causes of rheumatic conditions, potential inciting agents, and the various types of rheumatic manifestations seen in the elderly.

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.

Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol.

OBJECTIVE: To provide information on pregnancy outcomes in women receiving certolizumab pegol (CZP). METHODS: The UCB Pharma safety database was searched for pregnancies through to September 1, 2014. Reports for maternal and paternal CZP exposure were included and outcomes examined, and data on CZP exposure, pregnancy, comorbidities, and infant events were extracted by 2 independent reviewers. Concomitant medications and disease activity were reviewed for clinical trial patients. RESULTS: Of 625 reported pregnancies, 372 (59.5%) had known outcomes. Paternal exposure pregnancies (n = 33) reported 27 live births, 4 miscarriages, 1 induced abortion, and 1 stillbirth. Maternal exposure pregnancies (n = 339) reported 254 live births, 52 miscarriages, 32 induced abortions, and 1 stillbirth. Almost all reported pregnancies had exposure to CZP in the first trimester, when organogenesis takes place, and a third of them continued the drug into the second and/or third trimesters. The most frequent indications for maternal CZP use were Crohn disease (192/339) and rheumatic diseases (118/339). Twelve cases of congenital malformation and a single neonatal death were reported. CONCLUSION: Analysis of pregnancy outcomes after exposure to CZP supports previous reports, suggesting a lack of harmful effect of maternal CZP exposure on pregnancy outcomes. However, additional data from a larger number of outcomes after exposure and studies including an unexposed comparison group are required to fully evaluate CZP safety and tolerability in pregnancy.

Safety overview of new disease-modifying antirheumatic drugs.

Beginning in 1998, a surge of new agents has expanded treatment options for rheumatoid arthritis (RA) patients. Although the disease modifying potential of these agents is encouraging, their use must be weighed against an evolving array of new safety concerns. Because of the popularity of these agents with patients and rheumatologists alike, clinicians must be prepared to discuss the potential risks associated with novel disease-modifying antirheumatic drugs and biologic therapies as they begin to appear with greater frequency in practice. This article discusses the safety issues arising from clinical trial and postmarketing experience with several new and commonly used agents, with specific emphasis on adalimumab, etanercept, infliximab, anakinra, and leflunomide.

Autoinflammatory syndromes.

Autoinflammatory syndromes comprise a diagnostically challenging group of systemic inflammatory disorders uniquely related by (1) dysregulation of innate immunity, (2) inflammasome activation, (3) dramatic clinical features (high fevers, neutrophilic rashes, and bone or synovial involvement), (4) impressive acute phase responses, and (5) effective treatment with cytokine inhibitors. This review details some of the more common autoinflammatory disorders, their distinguishing features and dermatologic manifestations, and how an accurate diagnosis can be established in patients presenting with periodic or intermittent febrile disorders.

Comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab, a human anti-tumor necrosis factor antibody, in Phase III clinical trials.

OBJECTIVE: Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti-tumor necrosis factor (anti-TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab. METHODS: Data from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy. RESULTS: No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times the upper limit of normal). CONCLUSION: Comprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB-endemic regions. Treatment for latent TB infection appeared effective, since no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti-TB medication was generally well tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF inhibitors, since prompt diagnosis and treatment can improve outcomes.