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.

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.

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 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.

RNA recognition by human TLR8 can lead to autoimmune inflammation.

Studies on the role of the RNA receptor TLR8 in inflammation have been limited by its different function in human versus rodents. We have generated multiple lines of transgenic mice expressing different levels of human TLR8. The high copy number chimeras were unable to pass germline; developed severe inflammation targeting the pancreas, salivary glands, and joints; and the severity of the specific phenotypes closely correlated with the huTLR8 expression levels. Mice with relatively low expression levels survived and bred successfully but had increased susceptibility to collagen-induced arthritis, and the levels of huTLR8 correlated with proinflammatory cytokines in the joints of the animals. At the cellular level, huTLR8 signaling exerted a DC-intrinsic effect leading to up-regulation of co-stimulatory molecules and subsequent T cell activation. A pathogenic role for TLR8 in human diseases was suggested by its increased expression in patients with systemic arthritis and the correlation of TLR8 expression with the elevation of IL-1ß levels and disease status. We found that the consequence of self-recognition via TLR8 results in a constellation of diseases, strikingly distinct from those related to TLR7 signaling, and points to specific inflammatory diseases that may benefit from inhibition of TLR8 in humans.

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.

Proceedings of the 2013 Rheumatology Winter Clinical Symposia.

Advances in rheumatology occur at a rapid pace and staying abreast of important changes is a challenge for all. Both novel drug development and enhanced understanding of conventional or historic therapies have molded current day rheumatologic practice. Rheumatology has led the way in the use of outcome measures and imaging modalities in common disorders like rheumatoid arthritis, osteoarthritis, and gout. The expertise of the rheumatologist has widened such that knowledge of economics, legal issues, related disorders and extraarticular disease is essential. In February 2013, the 6th annual Rheumatology Winter Clinical Symposium was held. At this meeting, faculty and participants held discussions and exchanged knowledge about new scientific data and how it may impact the care of rheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clinical Symposium 2013 are included in this review. These and other presentations can be viewed in their entirety at http://www.r-w-c-s.com.

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.

Nonserious infections: should there be cause for serious concerns?

Nonserious infections (NSIE) as colds, flu syndromes, and urinary tract infection, are the most common infections seen in patients with immune mediated inflammatory diseases. Yet, little is known about the impact of immunosuppression, particularly with tumor necrosis factor inhibitors (TNFi), on these infections. A systemic review of large, randomized controlled trials was conducted to identify incidence, types, and outcomes of NSIE associated with the most commonly prescribed TNFi: adalimumab, etanercept, and infliximab.

Malignancy risks with biologic therapies.

The management of rheumatoid arthritis (RA) dramatically changed in 1998 with the introduction of etanercept and infliximab for the treatment of RA and Crohn colitis. Nine biologic agents are currently in use for treating RA. However, speculation has grown that the long-term use of these biopharmaceuticals may alter normal immunosurveillance, thereby contributing to an individual's cancer risk. Whether malignancy is a consequence of rheumatoid inflammation or the therapies used to treat RA has been unclear until recently. This article addresses the growing data on the short- and long-term cancer risks associated with biologic use in RA.

Refining drug safety in rheumatology.

This issue explores several important safety concerns that currently plague the rheumatologist and health care providers who care for patients with rheumatic diseases. Weighing safety against efficacy can be a complex task that is best alleviated by understanding the issues, nature, and breadth of problems associated with drug use. Therapeutic decision-making must be evidence-based, judicious, and appropriate for the patient and situation. Understanding drug safety is paramount to ensuring both success of therapy and benefit to the patient. Similarly, it is important not to underestimate the impact of uncontrolled disease activity in decision-making. Drug safety must be weighed against the severity and risks of the disease under treatment. Clearly the benefit/risk ratio has improved for many of the therapies discussed in this book. The use of both conventional and novel therapies mandates an understanding of the mechanisms of action, unique toxicities, screening and monitoring measures, and rules for drug avoidance.

Proceedings of the 2012 Rheumatology Winter Clinical Symposia.

Recent years have witnessed important developments in rheumatology. Novel diagnostic methods, stratification approaches, and treatment paradigms have been brought into the clinic for a number of rheumatologic and autoimmune diseases. In addition, there have been developments in related medical disciplines that are relevant to the care of patients with rheumatic diseases. Keeping pace with these many developments is a challenge, and clinical rheumatologists have used various methods to educate themselves about these advances. In January 2012, the 5th annual Rheumatology Winter Clinical Symposium was held. At this meeting, faculty and participants held discussions and exchanged knowledge about new scientific data and how it may impact the care of rheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clinical Symposium 2012 are included in this review. These and other presentations can be viewed in their entirety at http://www.r-w-c-s.com.

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.